Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 29

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 32

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::load() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 161

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 138

Strict Standards: Non-static method JRequest::clean() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 33

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 462

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 463

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 464

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 465

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 466

Strict Standards: Non-static method JRequest::_cleanArray() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/environment/request.php on line 467

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 35

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 38

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 39

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::load() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 161

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 138

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 46

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 47

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 50

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 53

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::import() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 54

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/loader.php on line 71

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 57

Strict Standards: Non-static method JLoader::register() should not be called statically in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php on line 58

Warning: session_start(): Cannot send session cookie - headers already sent by (output started at /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php:29) in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/session/session.php on line 413

Warning: session_start(): Cannot send session cache limiter - headers already sent (output started at /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php:29) in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/session/session.php on line 413

Warning: Cannot modify header information - headers already sent by (output started at /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/import.php:29) in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/session/session.php on line 416

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

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Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

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Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

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Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

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Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

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Warning: mktime(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 83

Warning: date(): It is not safe to rely on the system's timezone settings. You are *required* to use the date.timezone setting or the date_default_timezone_set() function. In case you used any of those methods and you are still getting this warning, you most likely misspelled the timezone identifier. We selected the timezone 'UTC' for now, but please set date.timezone to select your timezone. in /hermes/bosnacweb08/bosnacweb08az/b29/ipw.wellbeyo/public_html/libraries/joomla/utilities/date.php on line 186

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Hugh's Views--postings about this and that. /index.php?option=com_content&view=section&id=5&layout=blog&Itemid=55 2024-04-29T20:26:13Z Joomla! 1.5 - Open Source Content Management 2010-05-16T23:24:38Z 2010-05-16T23:24:38Z /index.php?option=com_content&view=article&id=4135:pfizer-nysepfe-will-it-rise-again&catid=39:biotechnology-companies&Itemid=64

<p>Pfizer is a major pharmaceutical company headquartered in New York. Founded in 1849, Pfizer evolved into the pharmaceutical behemoth it is today through internal innovation and, more recently, acquisition. Based on revenues, Pfizer is today the second largest pharmaceutical company in the world. Only Johnson & Johnson is larger.<br /><br />Pfizer has languished in the past few years: hit by imminent patent expirations and a lack luster development pipeline, the stock hasn’t performed well. Is there hope for this former bellwether of the pharmaceutical industry? Even though Lipitor is expiring, it's beginning to look as if things are improving for Pfizer.</p><p>Pfizer is one of the more widely held companies among individual investors.  A member of the Dow Jones Industrial Average since April of 2004, Pfizer has a long history of innovation and growth.  For almost seventy years, Pfizer distinguished itself in having a steadily increasing dividend: this trend stopped abruptly when the company merged with Wyeth and the dividend was summarily cut in half.</p><p>The current drug portfolio of Pfizer illustrates both its recent acquisitions and the range of its internal research capabilities: a range that is currently being reined in.  Its major blockbuster drug, Lipitor a $12 billion blockbuster, was introduced into the Pfizer portfolio through the merger with Warner Lambert, which was announced in 1999.  Other leading drugs include Caduet in the cardiovascular market, Celebrex a leading drug in the osteoarthritis market, Chantix to suppress the desire to smoke, Detrol in the bladder control market, Enbrel for in the rheumatoid arthritis market, Lyrica in the pain market, Norvasc in the hypertension market, Spiriva for breathing concerns, Viagra, the drug which made Pfizer a household name in 1998, in the erectile dysfunction market, Zeldox in the CNS market and Zyvox in the antibacterial market.  The fact that many of these branded drugs are household names is testament to the marketing budget, in fact the size, of this company.</p><p>While Pfizer has a strong discovery arm, the company is first and foremost a successful marketing company.  It often enjoys pride of place in many therapy classes thanks in no small measure to its acumen in direct-to-consumer (DTC) marketing.  Part of this skill involves recognizing opportunities.  For many years, Pfizer was a company that grew organically; this situation changed in the 1990s through successive mergers with other companies, each of which had a leading drug that was added to the Pfizer franchise.  The first major merger occurred in 2000 with Warner Lambert, followed a few years later with Pharmacia.  The most recent merger, which closed recently, was with Wyeth.  While Pfizer has been successful in its efforts with major companies, it also has development or marketing deals with scores of emerging pharmaceutical companies.  When I recently ran through a database of major deals involving Pfizer, well over one hundred programs in the clinic passed the screen.</p><p>The Wyeth merger is interesting in that it’s unlikely to return all the benefits discussed when the deal was first announced.  In the late 90s the Economist magazine ran an interesting analysis of pharmaceutical company mergers which illustrated that they essentially destroyed shareholder value.  Of course, the big imponderable is what would have occurred had the merger never happened.  Nonetheless, the analysis belied the promises of management about the synergistic benefits to shareholders of such combinations.  In Pfizer’s case, it can be argued that the merger with WL increased shareholder value: PFE had a much more ambitious marketing program for Lipitor than did the innovator of the drug.  The deal increased Pfizer’s revenues by a cumulative value in excess of $60 billion.  The Pharmacia deal probably bought less value, but at least shareholders ended up with Monsanto, which outperformed pharma companies for many of the past few years. </p><p>Wyeth does a number of things for Pfizer.  The cynic in me says that a merger buys management more time: whatever happens to the stock price, blame the merger and refer to experts that assure you that mergers take two to three years to work—true, but not that gratifying.  It shores up company financials; something that Pfizer needs with the pending loss of Lipitor.  It also introduces Pfizer into macromolecules, an area where Wyeth is experienced.  The merger complements the current offerings of Pfizer and introduces the company into markets such as vaccines where it had little if any presence.  Pfizer may also have some small wins.  Wyeth enjoyed a philosophy of outsourcing the bulk of its manufacturing needs; Pfizer has excess capacity.  It may be possible for Pfizer to bring material in-house giving better capacity utilization, thus avoiding having to either shutter or sell more capacity in a market where there’s a glut of such offerings.</p><p>The first quarter results recently reported by the company were important as they highlighted the fact that the company was on track to make its 2010 numbers.  I have looked at the likely revenue growth of the combined companies, together with the profit margin.  Pfizer should hit $2.17 in earnings this year and would be closer to $2.25 in 2011: it’s a paltry 3.6% increase but keep in mind it includes the loss of a major, $12 b franchise, Lipitor.  Based on its historic PE behavior and its projected earnings growth, I believe that Pfizer should see improved fortunes, with the stock trading in the $19 to $25 range.  On Friday, the stock closed at $16.20: hitting the median projected price of $22 in 2011 represents an increase of 36%; $19 is a more modest but still impressive 17%.  I am continuing to add Pfizer when its stock dips below $16: it’s a long-term investment.  I think in the next two or three years as Pfizer realizes the benefits of the recent merger, the company should start to turn around.</p><p>The bottom line is that Pfizer looks like a buy right now for those with a long-term investing horizon.  The company should return 17% in the next twelve to eighteen months.  Dividends should give that return an extra four to six percentage points over the same period.</p>

<p>Pfizer is a major pharmaceutical company headquartered in New York. Founded in 1849, Pfizer evolved into the pharmaceutical behemoth it is today through internal innovation and, more recently, acquisition. Based on revenues, Pfizer is today the second largest pharmaceutical company in the world. Only Johnson & Johnson is larger.<br /><br />Pfizer has languished in the past few years: hit by imminent patent expirations and a lack luster development pipeline, the stock hasn’t performed well. Is there hope for this former bellwether of the pharmaceutical industry? Even though Lipitor is expiring, it's beginning to look as if things are improving for Pfizer.</p><p>Pfizer is one of the more widely held companies among individual investors.  A member of the Dow Jones Industrial Average since April of 2004, Pfizer has a long history of innovation and growth.  For almost seventy years, Pfizer distinguished itself in having a steadily increasing dividend: this trend stopped abruptly when the company merged with Wyeth and the dividend was summarily cut in half.</p><p>The current drug portfolio of Pfizer illustrates both its recent acquisitions and the range of its internal research capabilities: a range that is currently being reined in.  Its major blockbuster drug, Lipitor a $12 billion blockbuster, was introduced into the Pfizer portfolio through the merger with Warner Lambert, which was announced in 1999.  Other leading drugs include Caduet in the cardiovascular market, Celebrex a leading drug in the osteoarthritis market, Chantix to suppress the desire to smoke, Detrol in the bladder control market, Enbrel for in the rheumatoid arthritis market, Lyrica in the pain market, Norvasc in the hypertension market, Spiriva for breathing concerns, Viagra, the drug which made Pfizer a household name in 1998, in the erectile dysfunction market, Zeldox in the CNS market and Zyvox in the antibacterial market.  The fact that many of these branded drugs are household names is testament to the marketing budget, in fact the size, of this company.</p><p>While Pfizer has a strong discovery arm, the company is first and foremost a successful marketing company.  It often enjoys pride of place in many therapy classes thanks in no small measure to its acumen in direct-to-consumer (DTC) marketing.  Part of this skill involves recognizing opportunities.  For many years, Pfizer was a company that grew organically; this situation changed in the 1990s through successive mergers with other companies, each of which had a leading drug that was added to the Pfizer franchise.  The first major merger occurred in 2000 with Warner Lambert, followed a few years later with Pharmacia.  The most recent merger, which closed recently, was with Wyeth.  While Pfizer has been successful in its efforts with major companies, it also has development or marketing deals with scores of emerging pharmaceutical companies.  When I recently ran through a database of major deals involving Pfizer, well over one hundred programs in the clinic passed the screen.</p><p>The Wyeth merger is interesting in that it’s unlikely to return all the benefits discussed when the deal was first announced.  In the late 90s the Economist magazine ran an interesting analysis of pharmaceutical company mergers which illustrated that they essentially destroyed shareholder value.  Of course, the big imponderable is what would have occurred had the merger never happened.  Nonetheless, the analysis belied the promises of management about the synergistic benefits to shareholders of such combinations.  In Pfizer’s case, it can be argued that the merger with WL increased shareholder value: PFE had a much more ambitious marketing program for Lipitor than did the innovator of the drug.  The deal increased Pfizer’s revenues by a cumulative value in excess of $60 billion.  The Pharmacia deal probably bought less value, but at least shareholders ended up with Monsanto, which outperformed pharma companies for many of the past few years. </p><p>Wyeth does a number of things for Pfizer.  The cynic in me says that a merger buys management more time: whatever happens to the stock price, blame the merger and refer to experts that assure you that mergers take two to three years to work—true, but not that gratifying.  It shores up company financials; something that Pfizer needs with the pending loss of Lipitor.  It also introduces Pfizer into macromolecules, an area where Wyeth is experienced.  The merger complements the current offerings of Pfizer and introduces the company into markets such as vaccines where it had little if any presence.  Pfizer may also have some small wins.  Wyeth enjoyed a philosophy of outsourcing the bulk of its manufacturing needs; Pfizer has excess capacity.  It may be possible for Pfizer to bring material in-house giving better capacity utilization, thus avoiding having to either shutter or sell more capacity in a market where there’s a glut of such offerings.</p><p>The first quarter results recently reported by the company were important as they highlighted the fact that the company was on track to make its 2010 numbers.  I have looked at the likely revenue growth of the combined companies, together with the profit margin.  Pfizer should hit $2.17 in earnings this year and would be closer to $2.25 in 2011: it’s a paltry 3.6% increase but keep in mind it includes the loss of a major, $12 b franchise, Lipitor.  Based on its historic PE behavior and its projected earnings growth, I believe that Pfizer should see improved fortunes, with the stock trading in the $19 to $25 range.  On Friday, the stock closed at $16.20: hitting the median projected price of $22 in 2011 represents an increase of 36%; $19 is a more modest but still impressive 17%.  I am continuing to add Pfizer when its stock dips below $16: it’s a long-term investment.  I think in the next two or three years as Pfizer realizes the benefits of the recent merger, the company should start to turn around.</p><p>The bottom line is that Pfizer looks like a buy right now for those with a long-term investing horizon.  The company should return 17% in the next twelve to eighteen months.  Dividends should give that return an extra four to six percentage points over the same period.</p> 2010-05-16T22:13:28Z 2010-05-16T22:13:28Z /index.php?option=com_content&amp;view=article&amp;id=4136:keryx-nasdaqkerx-does-it-have-a-magic-bullet&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Keryx is an emerging pharmaceutical company headquartered in New York.  It’s not an innovator company, instead Keryx acquires pharmaceutical products, then develops and commercializes them.  The company has had a rocky few years, but recently, the news has improved for Keryx.</p><p>Keryx is an emerging pharmaceutical company based in New York City.  The company is virtual in that it appears to have minimal internal capabilities outsourcing its activities to third party CROs and CMOs instead.  The company has two clinical programs, discussed in a moment, Zerenex (ferric citrate) for patients in end-stage renal disease and perifosine (KRX-0401) undergoing two phase III trials, one for multiple myeloma and another for colorectal cancer.  Additionally, perifosine is in some other phase II trials for various cancers.</p><p>The company enjoyed revenues of $25 million in 2009 with net income of over $10 million.  No revenues were reported in either of the last two quarters.  The company has a relatively healthy balance sheet with assets of $40 million and little long-term debt.  The company had negative cash flow of over $3.5 million in the most recent quarter.</p><h3>Zerenex</h3><p>Zerenex is an oral compound, ferric citrate, that binds phosphate.  As kidney failure progresses, various toxins amass in the blood stream; there are various ways to fight this problem.  A tablet which allows the absorption of ferric citrate into the bloodstream is a simple solution.  The company is currently engaged in a phase III clinical trial under a Special Protocol Assessment (see the glossary) with the FDA on January 5, 2010.  The implication of this agreement being that if safety and efficacy are demonstrated as well as a positive risk/benefit assessment, then the clinical trial is sufficient to realize marketing approval for the drug.  Interestingly, I haven’t been able to find mention of this NDA on the FDA website, which isn’t a concern.  The company announced a registration program for the trial on May 6.  Here’s the link to that trial:</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01074125?term=keryx&rank=11">http://www.clinicaltrials.gov/ct2/show/NCT01074125?term=keryx&rank=11</a></p><h3>Perifosine</h3><p>Perifosine (octadecyl-(N,N-dimethylpiperidino-4-yl)phosphate) is a small molecule drug active, it appears, against different cancers.  The molecule appears to characteristics of a cellular membrane causing inhibition of cell growth.  There are currently seven, ongoing clinical trials with this API.  The mechanism of action of this drug is such that it could play a role in a great many different cancers.</p><p>The company reported that in its extensive clinical trials the drug doesn’t seem to induce the side effects seen in many competing therapies.  The company has an ongoing phase III trial in refractory multiple myeloma.  The FDA has given both Orphan Drug and Fast Track status for this indication.  Last April, registration started on a phase III trial for colorectal cancer.  Additionally, there is a phase I/II trial for recurrent or progressive malignant glioma; a phase II trial in small lymphocytic lymphoma; a phase I trial in various forms of leukemia; and two phase I trials in the area of solid tumors.</p><p>For Keryx, renal failure is a good market, but it’s not going to drive the company to the next level; Keryx must be successful in the cancer market.  To date, indications are very positive for KRX-0401, but the true test of any drug is the phase III trial.  It’s impossible to predict the outcome.  Many promising drugs have crashed and burned in the clinic.</p><p>While its challenging enough trying to decipher the science, one also has to divine human behavior and determine what the masses are going to do with Keryx.  It looks to me as if Zerenex could get approved.  If it doesn’t, I don’t see it as being a good, but not great drug.  In fact, approval could be an anticlimax; it could be even better for the average investor if the FDA turns the drug down.  We have to wait first for the results of the ongoing trial, then the verdict of the FDA.  If the trial results are good, then I think there’s a ninety percent chance that the FDA will approve the drug.  The next thing to watch will be the clinical trial results, then the FDA filing for KRX-0401.</p><p>At the current level, based on the financials alone, KERX seems overpriced to me.  I am inclined to wait, hoping that the stock might retrench to the $3 range before splurging on this company.  Every drug that I have ever seen has some sort of glitch or hiccup in the approval process.  It’s very rare to see a drug go through all the steps unscathed.  I’d expect Keryx to enjoy a similar experience.  The investigational drugs that this company has, particularly those targeting cancer, look good; if they continue towards approval, they have the potential to generate at least $300 to $500 million each.</p><p>For now, I am putting Keryx on my watch list.  If the stock price retreats, I will move in; I need more news.</p>

<p>Keryx is an emerging pharmaceutical company headquartered in New York.  It’s not an innovator company, instead Keryx acquires pharmaceutical products, then develops and commercializes them.  The company has had a rocky few years, but recently, the news has improved for Keryx.</p><p>Keryx is an emerging pharmaceutical company based in New York City.  The company is virtual in that it appears to have minimal internal capabilities outsourcing its activities to third party CROs and CMOs instead.  The company has two clinical programs, discussed in a moment, Zerenex (ferric citrate) for patients in end-stage renal disease and perifosine (KRX-0401) undergoing two phase III trials, one for multiple myeloma and another for colorectal cancer.  Additionally, perifosine is in some other phase II trials for various cancers.</p><p>The company enjoyed revenues of $25 million in 2009 with net income of over $10 million.  No revenues were reported in either of the last two quarters.  The company has a relatively healthy balance sheet with assets of $40 million and little long-term debt.  The company had negative cash flow of over $3.5 million in the most recent quarter.</p><h3>Zerenex</h3><p>Zerenex is an oral compound, ferric citrate, that binds phosphate.  As kidney failure progresses, various toxins amass in the blood stream; there are various ways to fight this problem.  A tablet which allows the absorption of ferric citrate into the bloodstream is a simple solution.  The company is currently engaged in a phase III clinical trial under a Special Protocol Assessment (see the glossary) with the FDA on January 5, 2010.  The implication of this agreement being that if safety and efficacy are demonstrated as well as a positive risk/benefit assessment, then the clinical trial is sufficient to realize marketing approval for the drug.  Interestingly, I haven’t been able to find mention of this NDA on the FDA website, which isn’t a concern.  The company announced a registration program for the trial on May 6.  Here’s the link to that trial:</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01074125?term=keryx&rank=11">http://www.clinicaltrials.gov/ct2/show/NCT01074125?term=keryx&rank=11</a></p><h3>Perifosine</h3><p>Perifosine (octadecyl-(N,N-dimethylpiperidino-4-yl)phosphate) is a small molecule drug active, it appears, against different cancers.  The molecule appears to characteristics of a cellular membrane causing inhibition of cell growth.  There are currently seven, ongoing clinical trials with this API.  The mechanism of action of this drug is such that it could play a role in a great many different cancers.</p><p>The company reported that in its extensive clinical trials the drug doesn’t seem to induce the side effects seen in many competing therapies.  The company has an ongoing phase III trial in refractory multiple myeloma.  The FDA has given both Orphan Drug and Fast Track status for this indication.  Last April, registration started on a phase III trial for colorectal cancer.  Additionally, there is a phase I/II trial for recurrent or progressive malignant glioma; a phase II trial in small lymphocytic lymphoma; a phase I trial in various forms of leukemia; and two phase I trials in the area of solid tumors.</p><p>For Keryx, renal failure is a good market, but it’s not going to drive the company to the next level; Keryx must be successful in the cancer market.  To date, indications are very positive for KRX-0401, but the true test of any drug is the phase III trial.  It’s impossible to predict the outcome.  Many promising drugs have crashed and burned in the clinic.</p><p>While its challenging enough trying to decipher the science, one also has to divine human behavior and determine what the masses are going to do with Keryx.  It looks to me as if Zerenex could get approved.  If it doesn’t, I don’t see it as being a good, but not great drug.  In fact, approval could be an anticlimax; it could be even better for the average investor if the FDA turns the drug down.  We have to wait first for the results of the ongoing trial, then the verdict of the FDA.  If the trial results are good, then I think there’s a ninety percent chance that the FDA will approve the drug.  The next thing to watch will be the clinical trial results, then the FDA filing for KRX-0401.</p><p>At the current level, based on the financials alone, KERX seems overpriced to me.  I am inclined to wait, hoping that the stock might retrench to the $3 range before splurging on this company.  Every drug that I have ever seen has some sort of glitch or hiccup in the approval process.  It’s very rare to see a drug go through all the steps unscathed.  I’d expect Keryx to enjoy a similar experience.  The investigational drugs that this company has, particularly those targeting cancer, look good; if they continue towards approval, they have the potential to generate at least $300 to $500 million each.</p><p>For now, I am putting Keryx on my watch list.  If the stock price retreats, I will move in; I need more news.</p> 2010-05-15T22:07:45Z 2010-05-15T22:07:45Z /index.php?option=com_content&amp;view=article&amp;id=4133:poniard-nasdaqpard-is-at-a-turning-point&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>I have been following Poniard Pharmaceuticals for a few years; this company appears to be at a turning point. The webcast last Monday was interesting; it’s clear that the company is at a crossroads.</p><p>Like many biotech companies in the Bay Area, Poniard has had a storied history; you might remember the company as NeoRX.  The company has been around longer than many of its peers: it’s over twenty years old—ancient by biotech standards and a little sad too.  Companies that old have either succeeded wildly or been absorbed into a larger, more successful entity; most have died.  A few, like Poniard, linger on hoping for that great break in the clinic.</p><p>Platinum has had a long history as an agent to fight cancer.  Picoplatin is an organic complex of this metal designed to act as a chemotherapeutic agent against cancer, particularly in solid tumors where platinum resistance is observed.  Most recently, Poniard used the material in an unsuccessful trial to fight small cell lung cancer: the company failed to meet the endpoint.  Management has expressed the likely legitimate concern that the way cancer is treated in Europe versus the US essentially messed up the results.  The company believes that treatment with the drug showed a trend towards a survival advantage; the post treatment chemotherapy in Europe favored patients that received the standard or care, the control group, over those on Picoplatin.  Incidentally, Pharmacyclics had a similar issue after its failed phase III trial.  For the case of Pharmacyclics, the company claimed that analyzing a subset of data clearly demonstrated the efficacy of the drug in the phase III trial.  The FDA doesn’t permit this sort of retrospective analysis.  Poniard is caught in a similar trap—at least that’s the sense of the argument provided by management.  The company has one more last shot: a phase III trial on colorectal cancer—quite a big market.</p><p>Poniard presented results for its phase II colorectal cancer trial this summer; the data were pretty impressive.  The company is now working with the FDA towards staging the required Phase III trials, which, if successful, would help secure approval for the drug.</p><p>The company is short of cash, but it has had some moderate good news in the past few months.  Just over $6 million were raised through the sale of shares of common stock to a value fund.  The company received a composition of matter patent, which covers the use of picoplatin in any cancer.  The patent covers the drug through early 2016 and the potential exists for an additional five year extension under the Waxman Hatch Act.  The company is also seeking marketing partners for picoplatin.</p><p>While the clinical results are ambiguous, the drug is certainly not dead.  A better designed protocol may help address concerns about picoplatin for small cell lung cancer; the upcoming phase III trial for colorectal cancer is critical.  Licensing the drug for a specific therapy could be a way to generate the cash this company needs to survive.</p><p>Poniard is a high risk investment—maybe one should wait for another clinical result before investigating this company further.  If the company manages to secure a partnership, with some of the risk mitigated, PARD would be in inviting investment opportunity.</p>

<p>I have been following Poniard Pharmaceuticals for a few years; this company appears to be at a turning point. The webcast last Monday was interesting; it’s clear that the company is at a crossroads.</p><p>Like many biotech companies in the Bay Area, Poniard has had a storied history; you might remember the company as NeoRX.  The company has been around longer than many of its peers: it’s over twenty years old—ancient by biotech standards and a little sad too.  Companies that old have either succeeded wildly or been absorbed into a larger, more successful entity; most have died.  A few, like Poniard, linger on hoping for that great break in the clinic.</p><p>Platinum has had a long history as an agent to fight cancer.  Picoplatin is an organic complex of this metal designed to act as a chemotherapeutic agent against cancer, particularly in solid tumors where platinum resistance is observed.  Most recently, Poniard used the material in an unsuccessful trial to fight small cell lung cancer: the company failed to meet the endpoint.  Management has expressed the likely legitimate concern that the way cancer is treated in Europe versus the US essentially messed up the results.  The company believes that treatment with the drug showed a trend towards a survival advantage; the post treatment chemotherapy in Europe favored patients that received the standard or care, the control group, over those on Picoplatin.  Incidentally, Pharmacyclics had a similar issue after its failed phase III trial.  For the case of Pharmacyclics, the company claimed that analyzing a subset of data clearly demonstrated the efficacy of the drug in the phase III trial.  The FDA doesn’t permit this sort of retrospective analysis.  Poniard is caught in a similar trap—at least that’s the sense of the argument provided by management.  The company has one more last shot: a phase III trial on colorectal cancer—quite a big market.</p><p>Poniard presented results for its phase II colorectal cancer trial this summer; the data were pretty impressive.  The company is now working with the FDA towards staging the required Phase III trials, which, if successful, would help secure approval for the drug.</p><p>The company is short of cash, but it has had some moderate good news in the past few months.  Just over $6 million were raised through the sale of shares of common stock to a value fund.  The company received a composition of matter patent, which covers the use of picoplatin in any cancer.  The patent covers the drug through early 2016 and the potential exists for an additional five year extension under the Waxman Hatch Act.  The company is also seeking marketing partners for picoplatin.</p><p>While the clinical results are ambiguous, the drug is certainly not dead.  A better designed protocol may help address concerns about picoplatin for small cell lung cancer; the upcoming phase III trial for colorectal cancer is critical.  Licensing the drug for a specific therapy could be a way to generate the cash this company needs to survive.</p><p>Poniard is a high risk investment—maybe one should wait for another clinical result before investigating this company further.  If the company manages to secure a partnership, with some of the risk mitigated, PARD would be in inviting investment opportunity.</p> 2010-05-15T19:54:29Z 2010-05-15T19:54:29Z /index.php?option=com_content&amp;view=article&amp;id=4134:pharmacyclics-nasdaqpcyc-so-close-and-yet-so-far&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Pharmacyclics is an emerging, small molecule pharmaceutical company located in the environs of Silicon Valley in California. The company had been public for almost fifteen years and has enjoyed both good and bad times. It’s currently recovering from a failed attempt to have a potentially potent anti-cancer drug approved by the FDA.</p><p>Pharmacyclics has been around for many years.  It’s had a difficult time with its lead drug, Motexafin gadolinium (MGd) which it tried to get approved by the FDA: no dice.  The drug itself has a novel and interesting mode of action against cancer cells—specifically brain cancer.  MGd differentially accumulates in the cells and enhances the effects of ionizing radiation on the cells causing apoptosis or cell death.  Clinical trial showed an extension of life of many months for patients suffering from this fatal disease.  The drug is back in the clinic undergoing two Phase II trials sponsored by the NCI (National Cancer Institute).<br /> <br />Pharmacyclics filed an NDA for Motexafin gadolinium, trade name Xcytrin, on December 22, 06 for the treatment of non-small cell lung cancer patients with brain metastases.  If you’re a chemist by trading, check out Motexafin gadolinium on Wikipedia and imagine the synthetic route to that beast.  The company received a refusal-to-file letter (see glossary) on February 21, 2007.  The FDA refused to file citing failure to demonstrate statistically significant differences between treatment arms in the primary endpoint of the pivotal study to support approval.  The company refiled on April 23 using a mechanism called “over protest,” which means that it disagreed with the initial screening and requested that the entire NDA be judged on its merits—a very risky approach!  In the meantime, the company continued to announce other successful phase 2 trials for Xcytrin.<br /> <br />On December 21, 2007, a year after it filed the NDA, Pharmacyclics received its non-approvable letter from the FDA.  What was interesting if you follow these things is that the stock didn’t drop dramatically when Pharmacyclics tried to essentially overrule the FDA the first time, it cratered after December 21.  April 23 was a good time to be purchase PUTs or sell short—a very good time.<br /> <br />On September 11, 2008, good news: there was a major shakeup on the board and the CEO resigned.  The CEO had been engaged in public criticism of the FDA; it was time for him to go.  The stock hovered around $1.<br /> <br />Under normal circumstances with its lead drug in critical care and running short of cash, the company would fold; however, Pharmacyclics in-licensed some novel, small molecules, which it is currently developing.  The stock has done well too, increasing form a low of $1 to a respectable $7 today.<br /> <br />The company is in relatively good shape: it has three active programs; it’s not flush with cash, but it has sufficient to ride out the next six months—with a stock price on the rise, it could go back and raise more funds.  In fact, it needs more funds: it secured financing when the stock was at a low; trading at $7 today, the company could raise more cash without serious dilution.<br /> <br />There is still risk, much risk associated with this company; however, its lead programs, PCI-32765 is in phase I for oncology; PCI-27483 targets tumor growth and metastases.  All is not lost for Motexafin gadolinium.  I have been following this molecule since 1997: it is a drug; it just needs a successful trial.<br /> <br />I have Pharmacyclics in my wait-and-see pile.  I believe it will go out and raise more cash in the short term.  I also believe it will publish at least one successful clinical trial result.  I want to wait until the stock moves back into the $3 to $5 range.  I am hoping all this happens before news on MGd takes off.  If I can purchase this company in the $3 to $4 range, I expect it to move into the high teens ($15 to $17) when MGd successfully completes its current phase II trials and moves into two phase III trials.  I have a twelve to eighteen month time horizon on his company.</p>

<p>Pharmacyclics is an emerging, small molecule pharmaceutical company located in the environs of Silicon Valley in California. The company had been public for almost fifteen years and has enjoyed both good and bad times. It’s currently recovering from a failed attempt to have a potentially potent anti-cancer drug approved by the FDA.</p><p>Pharmacyclics has been around for many years.  It’s had a difficult time with its lead drug, Motexafin gadolinium (MGd) which it tried to get approved by the FDA: no dice.  The drug itself has a novel and interesting mode of action against cancer cells—specifically brain cancer.  MGd differentially accumulates in the cells and enhances the effects of ionizing radiation on the cells causing apoptosis or cell death.  Clinical trial showed an extension of life of many months for patients suffering from this fatal disease.  The drug is back in the clinic undergoing two Phase II trials sponsored by the NCI (National Cancer Institute).<br /> <br />Pharmacyclics filed an NDA for Motexafin gadolinium, trade name Xcytrin, on December 22, 06 for the treatment of non-small cell lung cancer patients with brain metastases.  If you’re a chemist by trading, check out Motexafin gadolinium on Wikipedia and imagine the synthetic route to that beast.  The company received a refusal-to-file letter (see glossary) on February 21, 2007.  The FDA refused to file citing failure to demonstrate statistically significant differences between treatment arms in the primary endpoint of the pivotal study to support approval.  The company refiled on April 23 using a mechanism called “over protest,” which means that it disagreed with the initial screening and requested that the entire NDA be judged on its merits—a very risky approach!  In the meantime, the company continued to announce other successful phase 2 trials for Xcytrin.<br /> <br />On December 21, 2007, a year after it filed the NDA, Pharmacyclics received its non-approvable letter from the FDA.  What was interesting if you follow these things is that the stock didn’t drop dramatically when Pharmacyclics tried to essentially overrule the FDA the first time, it cratered after December 21.  April 23 was a good time to be purchase PUTs or sell short—a very good time.<br /> <br />On September 11, 2008, good news: there was a major shakeup on the board and the CEO resigned.  The CEO had been engaged in public criticism of the FDA; it was time for him to go.  The stock hovered around $1.<br /> <br />Under normal circumstances with its lead drug in critical care and running short of cash, the company would fold; however, Pharmacyclics in-licensed some novel, small molecules, which it is currently developing.  The stock has done well too, increasing form a low of $1 to a respectable $7 today.<br /> <br />The company is in relatively good shape: it has three active programs; it’s not flush with cash, but it has sufficient to ride out the next six months—with a stock price on the rise, it could go back and raise more funds.  In fact, it needs more funds: it secured financing when the stock was at a low; trading at $7 today, the company could raise more cash without serious dilution.<br /> <br />There is still risk, much risk associated with this company; however, its lead programs, PCI-32765 is in phase I for oncology; PCI-27483 targets tumor growth and metastases.  All is not lost for Motexafin gadolinium.  I have been following this molecule since 1997: it is a drug; it just needs a successful trial.<br /> <br />I have Pharmacyclics in my wait-and-see pile.  I believe it will go out and raise more cash in the short term.  I also believe it will publish at least one successful clinical trial result.  I want to wait until the stock moves back into the $3 to $5 range.  I am hoping all this happens before news on MGd takes off.  If I can purchase this company in the $3 to $4 range, I expect it to move into the high teens ($15 to $17) when MGd successfully completes its current phase II trials and moves into two phase III trials.  I have a twelve to eighteen month time horizon on his company.</p> 2010-05-13T20:06:44Z 2010-05-13T20:06:44Z /index.php?option=com_content&amp;view=article&amp;id=4132:naproxcinod-gets-thumbs-down-from-fda-review-panel&amp;catid=39:biotechnology-companies&amp;Itemid=64

The review panel published its opinion of naproxcinod yesterday and gave the drug a thumbs down. The stock dropped over fifty percent in response settling with a loss for the day of 40%.<br /><br />The FDA published a background document for the panel on Monday. As I said on Monday, the analysis wasn't very flattering for the drug: it doesn't work better than the current standard of care; it didn't function as a antihypertensive agent.<br /><br />The FDA is still free to approve the drug, but with a 16-1 vote against the therapy by the review panel, I'd deem it unlikely that this drug will receive marketing approval.<br /><br />The PDUFA date for this drug is July 24.

The review panel published its opinion of naproxcinod yesterday and gave the drug a thumbs down. The stock dropped over fifty percent in response settling with a loss for the day of 40%.<br /><br />The FDA published a background document for the panel on Monday. As I said on Monday, the analysis wasn't very flattering for the drug: it doesn't work better than the current standard of care; it didn't function as a antihypertensive agent.<br /><br />The FDA is still free to approve the drug, but with a 16-1 vote against the therapy by the review panel, I'd deem it unlikely that this drug will receive marketing approval.<br /><br />The PDUFA date for this drug is July 24. 2010-05-13T10:59:39Z 2010-05-13T10:59:39Z /index.php?option=com_content&amp;view=article&amp;id=4131:jazz-pharma-nasdaqjazz-drug-may-face-a-review-panel&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>It's very possible that the fibromyalgia drug, JZP-6, from Jazz Pharmaceuticals may face an FDA review panel. The drug has a PDUFA date of October 11, so it could face a review between mid-July to mid-August at the latest.</p><p>Jazz Pharmaceuticals is an emerging company in the Bay Area of California.  It recently announced a public offering of 7 million shares of common stock to be priced at $8.35 a share.  The stock has preformed well over the last twelve months, rising from below a dollar (about eighty cents) to a recent high of almost $14.  The company closed on Wednesday at $8.65.</p><p>The company has two marketed products and four active clinical programs.  JZP-6 for fibromyalgia is furthest along.  On February 28, 2010, the company reported that the FDA had accepted its NDA which was reported as submitted on December 15, 2009 and that it had a PDUFA date of October 11.  It echoed previous reports that two successful phase III trials were completed on JZP-6.  Looking at the schedule of upcoming meetings, I think it's likely that the drug could face a review panel in mid-July.</p><p>A positive outcome could give the drug a boost; if the committee concurs that both phase III trials gave meaningful results and there are no safety or potential abuse issues with the drug, it could likely be approved in October.  The stock could move to between $12 and $16 a share.</p>

<p>It's very possible that the fibromyalgia drug, JZP-6, from Jazz Pharmaceuticals may face an FDA review panel. The drug has a PDUFA date of October 11, so it could face a review between mid-July to mid-August at the latest.</p><p>Jazz Pharmaceuticals is an emerging company in the Bay Area of California.  It recently announced a public offering of 7 million shares of common stock to be priced at $8.35 a share.  The stock has preformed well over the last twelve months, rising from below a dollar (about eighty cents) to a recent high of almost $14.  The company closed on Wednesday at $8.65.</p><p>The company has two marketed products and four active clinical programs.  JZP-6 for fibromyalgia is furthest along.  On February 28, 2010, the company reported that the FDA had accepted its NDA which was reported as submitted on December 15, 2009 and that it had a PDUFA date of October 11.  It echoed previous reports that two successful phase III trials were completed on JZP-6.  Looking at the schedule of upcoming meetings, I think it's likely that the drug could face a review panel in mid-July.</p><p>A positive outcome could give the drug a boost; if the committee concurs that both phase III trials gave meaningful results and there are no safety or potential abuse issues with the drug, it could likely be approved in October.  The stock could move to between $12 and $16 a share.</p> 2010-05-13T10:35:47Z 2010-05-13T10:35:47Z /index.php?option=com_content&amp;view=article&amp;id=4130:achillion-nasdaqachn-gets-a-nice-pop-on-hep-c-results&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Shares of Achillion Pharmaceuticals, an emerging pharmaceutical company based in New Haven, CT, took a nice jump today base on an early clinical success with its hepatitis C drug. If the company successfully develop and marketed an approved drug, the stock would be worth over $70 a share: a nice jump from $2.70, where it closed today. The company has a long way to go before it can celebrate.</p><p>Hepatitis C is an infectious viral disease which affects the liver.  The virus is spread in a manner similar to HIV.  While reports claim it is slightly less infectious, the incidence of hepatitis C infection is much higher.  There are estimates that as many as twenty million people in the US carry this virus.</p><p>Most infected people exhibit few if any symptoms for many years.  In fact, it can take over twenty to thirty years before major symptoms start to appear.  Fibrosis (scarring) of the liver usually occurs first, followed in many cases by the cirrhosis and the onset of liver disease, which may lead to liver cancer or complete liver failure.  Currently the standard of care is peginterferon alfa-2a or -2b and the pro-drug Reterol (Schering Plough) which is also sold as Copegus by Roche.</p><p>Over three hundred drugs are in development for the hepatitis C market.  About 150 companies have developmental or clinical programs for this indication.</p><p>The report from Achillion was from preliminary data in a Phase 1 clinical trial on ACH-1625 a protease inhibitor.  Pharmacokinetic studies show rapid partitioning to the liver; the drug has been demonstrated as potent at low (nanomolar) concentrations to the hepatitis C virus (HCV); the company also reports that the drug has no serious toxicity issues.</p><p>The clinical trial is taking place in Europe, so no information is available on <a href="http://www.clinicaltrials.gov/">www.clinicaltrials.gov</a>.  The company has given periodic reports on the progress of the drug.  The trial is designated as Phase 1b—safety with efficacy data.  The dosing ranges from 50 to 2000 mg: typical doses for antiviral drugs are really high: 2000 mg is two grams—approximately the same mass as to M&M's.  The results reported on Wednesday showed that the group dosed with either 200 mg or 600 mg of the drug showed a measurable drop in viral load.</p><p>These results are good, but the company has a long way to go.  It will have to work on a number of successful phase II clinical studies, long-term toxicity studies and at least two successful phase III trials.  If the news continues to get better, the stock will rise; however, as a result of the HCV data, I don't expect any major surge in the stock in the near term.  We're at least three to five years away from knowing if this company has a drug.  Things are looking good, but fundamental questions remain to be answered.</p>

<p>Shares of Achillion Pharmaceuticals, an emerging pharmaceutical company based in New Haven, CT, took a nice jump today base on an early clinical success with its hepatitis C drug. If the company successfully develop and marketed an approved drug, the stock would be worth over $70 a share: a nice jump from $2.70, where it closed today. The company has a long way to go before it can celebrate.</p><p>Hepatitis C is an infectious viral disease which affects the liver.  The virus is spread in a manner similar to HIV.  While reports claim it is slightly less infectious, the incidence of hepatitis C infection is much higher.  There are estimates that as many as twenty million people in the US carry this virus.</p><p>Most infected people exhibit few if any symptoms for many years.  In fact, it can take over twenty to thirty years before major symptoms start to appear.  Fibrosis (scarring) of the liver usually occurs first, followed in many cases by the cirrhosis and the onset of liver disease, which may lead to liver cancer or complete liver failure.  Currently the standard of care is peginterferon alfa-2a or -2b and the pro-drug Reterol (Schering Plough) which is also sold as Copegus by Roche.</p><p>Over three hundred drugs are in development for the hepatitis C market.  About 150 companies have developmental or clinical programs for this indication.</p><p>The report from Achillion was from preliminary data in a Phase 1 clinical trial on ACH-1625 a protease inhibitor.  Pharmacokinetic studies show rapid partitioning to the liver; the drug has been demonstrated as potent at low (nanomolar) concentrations to the hepatitis C virus (HCV); the company also reports that the drug has no serious toxicity issues.</p><p>The clinical trial is taking place in Europe, so no information is available on <a href="http://www.clinicaltrials.gov/">www.clinicaltrials.gov</a>.  The company has given periodic reports on the progress of the drug.  The trial is designated as Phase 1b—safety with efficacy data.  The dosing ranges from 50 to 2000 mg: typical doses for antiviral drugs are really high: 2000 mg is two grams—approximately the same mass as to M&M's.  The results reported on Wednesday showed that the group dosed with either 200 mg or 600 mg of the drug showed a measurable drop in viral load.</p><p>These results are good, but the company has a long way to go.  It will have to work on a number of successful phase II clinical studies, long-term toxicity studies and at least two successful phase III trials.  If the news continues to get better, the stock will rise; however, as a result of the HCV data, I don't expect any major surge in the stock in the near term.  We're at least three to five years away from knowing if this company has a drug.  Things are looking good, but fundamental questions remain to be answered.</p> 2010-05-11T20:15:27Z 2010-05-11T20:15:27Z /index.php?option=com_content&amp;view=article&amp;id=4128:cell-therapeutics-nasdaqctic-things-are-getting-worse&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Cell Therapeutics is going to hold a board meeting this Friday, May 14. It's the second attempt to hold a meeting. On April 9, the shareholder meeting collapsed for lack of a quorum.</p><p>Cell Therapeutics is an emerging pharmaceutical company based in Seattle, Washington.  The company was once a high flyer, with its share price surging into the stratosphere.  Today the company is fighting for its survival.</p><p>The meeting on Friday will be a request by the board to amend the articles of incorporation and allow them company to further dilute its shares, increasing the number authorized by 50%.  With these extra four hundred million shares, the company hopes to raise cash to survive.  At the current share price, accounting of the dilutive effect, etc., the company would be lucky to raise $20 to $30 million: it's a tough market out there, even for excellent companies; CTIC is going to find it really, really, tough.  It generated a loss of around $44 million in the most recent quarter.</p><p>The problems started on April 9, when the FDA turned down its NDA application requesting an additional clinical trial.  It's a problem, but if the company can put together another convincing trial, it may be able to scrape through the approval process.  For now, I think CTIC is to be avoided.  If the company behaves like wounded biotechs in a similar situation, there will be ample opportunities to buy the stock at depressed prices in the coming months.  If it can pull off a successful Phase III trial and successful refile, CTIC could be a buying opportunity some time in the future.  I'll keep watching the company.</p>

<p>Cell Therapeutics is going to hold a board meeting this Friday, May 14. It's the second attempt to hold a meeting. On April 9, the shareholder meeting collapsed for lack of a quorum.</p><p>Cell Therapeutics is an emerging pharmaceutical company based in Seattle, Washington.  The company was once a high flyer, with its share price surging into the stratosphere.  Today the company is fighting for its survival.</p><p>The meeting on Friday will be a request by the board to amend the articles of incorporation and allow them company to further dilute its shares, increasing the number authorized by 50%.  With these extra four hundred million shares, the company hopes to raise cash to survive.  At the current share price, accounting of the dilutive effect, etc., the company would be lucky to raise $20 to $30 million: it's a tough market out there, even for excellent companies; CTIC is going to find it really, really, tough.  It generated a loss of around $44 million in the most recent quarter.</p><p>The problems started on April 9, when the FDA turned down its NDA application requesting an additional clinical trial.  It's a problem, but if the company can put together another convincing trial, it may be able to scrape through the approval process.  For now, I think CTIC is to be avoided.  If the company behaves like wounded biotechs in a similar situation, there will be ample opportunities to buy the stock at depressed prices in the coming months.  If it can pull off a successful Phase III trial and successful refile, CTIC could be a buying opportunity some time in the future.  I'll keep watching the company.</p> 2010-05-11T01:52:27Z 2010-05-11T01:52:27Z /index.php?option=com_content&amp;view=article&amp;id=4129:nymox-nasdaqnymx-reports-safety-data-for-nx-1207&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Nymox reported good safety data for its lead drug, NX-1207, which is about to enter Phase III.</p><p>The lead drug, NX-1207, targets benign prostatic hyperplasia—an enlarged prostate—a common ailment in older males.  The company has successfully completed trials in phase I and II; today, it reported, that on safety data as preparations are underway for the investigational drug to enter phase III clinical trials.  The company reported no significant safety concerns for the program.  Patient recruitment for two trials continues.</p><p>The first trial is designated as NX02-0017</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00918983?term=nymox&rank=1">www.clinicaltrials.gov/ct2/show/NCT00918983?term=nymox&rank=1</a></p><p>The first trial has a tentative end date of August 2011.  The control group will take a placebo administered intravenously.  The experimental group will take a single intraprostatic injection of 2.5 mg NX-1207.  The company hopes to recruit 500 patients. </p><p>The second trial is designated as NX02-0018</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00945490?term=nymox&rank=2">www.clinicaltrials.gov/ct2/show/NCT00945490?term=nymox&rank=2</a></p><p>where recruiting started about six weeks later from the first appears to be a duplicate effort.  The FDA requires two, successful (that is, meets the endpoint) clinical trials before approving a drug.</p><p>Nymox is thinly traded, but may be worth considering as an investment closer to the conclusion of the current phase III trials.</p>

<p>Nymox reported good safety data for its lead drug, NX-1207, which is about to enter Phase III.</p><p>The lead drug, NX-1207, targets benign prostatic hyperplasia—an enlarged prostate—a common ailment in older males.  The company has successfully completed trials in phase I and II; today, it reported, that on safety data as preparations are underway for the investigational drug to enter phase III clinical trials.  The company reported no significant safety concerns for the program.  Patient recruitment for two trials continues.</p><p>The first trial is designated as NX02-0017</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00918983?term=nymox&rank=1">www.clinicaltrials.gov/ct2/show/NCT00918983?term=nymox&rank=1</a></p><p>The first trial has a tentative end date of August 2011.  The control group will take a placebo administered intravenously.  The experimental group will take a single intraprostatic injection of 2.5 mg NX-1207.  The company hopes to recruit 500 patients. </p><p>The second trial is designated as NX02-0018</p><p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00945490?term=nymox&rank=2">www.clinicaltrials.gov/ct2/show/NCT00945490?term=nymox&rank=2</a></p><p>where recruiting started about six weeks later from the first appears to be a duplicate effort.  The FDA requires two, successful (that is, meets the endpoint) clinical trials before approving a drug.</p><p>Nymox is thinly traded, but may be worth considering as an investment closer to the conclusion of the current phase III trials.</p> 2010-05-11T01:47:22Z 2010-05-11T01:47:22Z /index.php?option=com_content&amp;view=article&amp;id=4127:fda-advisory-committee-meeting-schedule&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>The posts that follow provide a tenative schedule of meetings of the various FDA advisory committees. A definition of an advisory committee, which is sometimes referred to as a panel, is provided in the glossary.</p><h3>May 2010 Advisory Committee Meetings</h3><p>May 11 - Dental Products Panel <br />May 12 - Joint Meeting of the Arthritis Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committees <br />May 13-14 - Neurological Devies Panel <br />May 17 - Science Board to the Food and Drug Administration <br />May 19 - Ear, Nose, and Throat Devices Panel <br />May 20-21 - General and Plastic Surgery Devices Panel <br />May 27 - Endocrinologic and Metabolic Drugs Advisory Committee <br />May 27 - Circulatory System Devices Panel</p><h3>June 2010 Advisory Committee Meetings</h3><p>June 2 - Antiviral Drugs Advisory Committee <br />June 8-9 - Tobacco Constituents Subcommittee of the Tobacco Products Scientific Advisory Committee <br />June 9-10 - Orthopaedic and Rehabilitation Devices Panel <br />June 10 - Peripheral and Central Nervous System Drugs Advisory Committee <br />June 16-17 - Clinical Chemistry and Clinical Toxicology Devices Panel <br />June 17 - Advisory Committee for Reproductive Health Drugs <br />June 17-18 - Gastroenterology-Urology Devices Panel <br />June 18 - Advisory Committee for Reproductive Health Drugs <br />June 21-22 - Pediatric Advisory Committee <br />June 23 - Anesthesiology and Respiratory Therapy Devices Panel <br />June 24-25 - Ophthalmic Devices Panel <br />June 28 - Dermatologic and Ophthalmic Drugs Advisory Committee</p><h3>July 2010 Advisory Committee Meetings</h3><p>July 8-9 - Hematology and Pathology Devices Panel <br />July 8-9 - Neurological Devices Panel <br />July 13 - Dental Products Panel <br />July 13-14 - Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committees <br />July 15 - Endocrinologic and Metabolic Drugs Advisory Committee <br />July 15-16 - Obstetrics and Gynecology Devices Panel <br />July 20 - Oncologic Drugs Advisory Committee <br />July 21 - Radiological Devices Panel <br />July 22 - Device Good Manufacturing Practice Advisory Committee <br />July 22-23 - Joint Meeting of the Anesthetic and Life Support Drugs and Drug Safety & Risk Management Advisory Committees <br />July 26-27 - Blood Products Advisory Committee <br />July 28 - Cardiovascular and Renal Drugs Advisory Committee <br />July 28-29 - General Hospital and Personal Use Devices Panel <br />July 29 - Cardiovascular and Renal Drugs Advisory Committee <br />July dates to be announced - Tobacco Products Scientific Advisory Committee</p><h3>August 2010 Advisory Committee Meetings</h3><p>August 12-13 - General and Plastic Surgery Devices Panel <br />August 16 - Science Board to the Food and Drug Administration <br />August 19 - Anesthetic and Life Support Drugs Advisory Committee <br />August 19-20 - Risk Communication Advisory Committee <br />August 25 - Ear, Nose, and Throat Devices Panel <br />August 25-26 - Antiviral Drugs Advisory Committee</p><h3>September 2010 Advisory Committee Meetings</h3><p>September 1 - Oncologic Drugs Advisory Committee <br />September 2 - Oncologic Drugs Advisory Committee <br />September 7 - Anti-Infective Drugs Advisory Committee <br />September 9-10 - Gastroenterology-Urology Devices Panel <br />September 14 - Dental Products Panel <br />September 14 - Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Nonprescription Drugs Advisory Committee <br />September 15 - Radiological Devices Panel <br />September 15 - Anesthesiology and Respiratory Therapy Devices Panel <br />September 15 - Immunology Devices Panel <br />September 15-16 - Endocrinologic and Metabolic Drugs Advisory Committee <br />September 15-16 - Cellular, Tissue and Gene Therapies Advisory Committee <br />September 15-16 - Vaccines and Related Biological Products Advisory Committee <br />September 16 - Device Good Manufacturing Practice Advisory Committee <br />September 17 - Cardiovascular and Renal Drugs Advisory Committee <br />September 20-21 - Pediatric Advisory Committee <br />September 23 - Circulatory System Devices Panel <br />September 23 - Microbiology Devices Panel</p><h3>October 2010 Advisory Committee Meetings</h3><p>October 5-6 - Molecular and Clinical Genetics Panel <br />October 7-8 - Neurological Devices Panel <br />October 13-14 - Orthopaedic and Rehabilitation Devices Panel <br />October 20-21 - Clinical Chemistry and Clinical Toxicology Devices Panel <br />October 21-22 - Hematology and Pathology Devices Panel <br />October 21-22 - Obstetrics and Gynecology Devices Panel <br />October 26 - Allergenic Products Advisory Committee <br />October 28-29 - Transmissible Spongiform Encephalopathies Advisory Committee <br />October 28-29 - Ophthalmic Devices Panel <br />October dates to be announced - Anti-Infective Drugs Advisory Committee</p><h3>November 2010 Advisory Committee Meetings</h3><p>November 3-4 - Ear, Nose, and Throat Devices Panel <br />November 4-5 - General and Plastic Surgery Devices Panel <br />November 8-9 - Risk Communication Advisory Committee <br />November 10 - Anesthesiology and Respiratory Therapy Devices Panel <br />November 15 - Science Board to the Food and Drug Administration Advisory Committee <br />November 17 - Radiological Devices Panel <br />November 17-18 - Science Advisory Board to the National Center for Toxicological Research <br />November 17-18 - Vaccines and Related Biological Products Advisory Committee <br />November 17-18 - General Hospital and Personal Use Devices Panel <br />November 18-19 - Blood Products Advisory Committee <br />November 18-19 - Cellular, Tissue and Gene Therapies Advisory Committee <br />November 18-19 - Ophthalmic Devices Panel <br />November dates to be announced - Tobacco Products Scientific Advisory Committee <br />November dates to be announced - Gastrointestinal Drugs Advisory Committee</p><h3>December 2010 Advisory Committee Meetings</h3><p>December 1 - Oncologic Drugs Advisory Committee <br />December 1-2 - Orthopaedic and Rehabilitation Devices Panel <br />December 2 - Oncologic Drugs Advisory Committee <br />December 2-3 - Gastroenterology-Urology Devices Panel <br />December 6 - Immunology Devices Panel <br />December 6-7 - Pediatric Advisory Committee <br />December 8 - Cardiovascular and Renal Drugs Advisory Committee <br />December 8-9 - Circulatory System Devices Panel <br />December 9-10 - Neurological Devices Panel <br />December 16-17 - Obstetrics and Gynecology Devices Panel</p>

<p>The posts that follow provide a tenative schedule of meetings of the various FDA advisory committees. A definition of an advisory committee, which is sometimes referred to as a panel, is provided in the glossary.</p><h3>May 2010 Advisory Committee Meetings</h3><p>May 11 - Dental Products Panel <br />May 12 - Joint Meeting of the Arthritis Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committees <br />May 13-14 - Neurological Devies Panel <br />May 17 - Science Board to the Food and Drug Administration <br />May 19 - Ear, Nose, and Throat Devices Panel <br />May 20-21 - General and Plastic Surgery Devices Panel <br />May 27 - Endocrinologic and Metabolic Drugs Advisory Committee <br />May 27 - Circulatory System Devices Panel</p><h3>June 2010 Advisory Committee Meetings</h3><p>June 2 - Antiviral Drugs Advisory Committee <br />June 8-9 - Tobacco Constituents Subcommittee of the Tobacco Products Scientific Advisory Committee <br />June 9-10 - Orthopaedic and Rehabilitation Devices Panel <br />June 10 - Peripheral and Central Nervous System Drugs Advisory Committee <br />June 16-17 - Clinical Chemistry and Clinical Toxicology Devices Panel <br />June 17 - Advisory Committee for Reproductive Health Drugs <br />June 17-18 - Gastroenterology-Urology Devices Panel <br />June 18 - Advisory Committee for Reproductive Health Drugs <br />June 21-22 - Pediatric Advisory Committee <br />June 23 - Anesthesiology and Respiratory Therapy Devices Panel <br />June 24-25 - Ophthalmic Devices Panel <br />June 28 - Dermatologic and Ophthalmic Drugs Advisory Committee</p><h3>July 2010 Advisory Committee Meetings</h3><p>July 8-9 - Hematology and Pathology Devices Panel <br />July 8-9 - Neurological Devices Panel <br />July 13 - Dental Products Panel <br />July 13-14 - Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committees <br />July 15 - Endocrinologic and Metabolic Drugs Advisory Committee <br />July 15-16 - Obstetrics and Gynecology Devices Panel <br />July 20 - Oncologic Drugs Advisory Committee <br />July 21 - Radiological Devices Panel <br />July 22 - Device Good Manufacturing Practice Advisory Committee <br />July 22-23 - Joint Meeting of the Anesthetic and Life Support Drugs and Drug Safety & Risk Management Advisory Committees <br />July 26-27 - Blood Products Advisory Committee <br />July 28 - Cardiovascular and Renal Drugs Advisory Committee <br />July 28-29 - General Hospital and Personal Use Devices Panel <br />July 29 - Cardiovascular and Renal Drugs Advisory Committee <br />July dates to be announced - Tobacco Products Scientific Advisory Committee</p><h3>August 2010 Advisory Committee Meetings</h3><p>August 12-13 - General and Plastic Surgery Devices Panel <br />August 16 - Science Board to the Food and Drug Administration <br />August 19 - Anesthetic and Life Support Drugs Advisory Committee <br />August 19-20 - Risk Communication Advisory Committee <br />August 25 - Ear, Nose, and Throat Devices Panel <br />August 25-26 - Antiviral Drugs Advisory Committee</p><h3>September 2010 Advisory Committee Meetings</h3><p>September 1 - Oncologic Drugs Advisory Committee <br />September 2 - Oncologic Drugs Advisory Committee <br />September 7 - Anti-Infective Drugs Advisory Committee <br />September 9-10 - Gastroenterology-Urology Devices Panel <br />September 14 - Dental Products Panel <br />September 14 - Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Nonprescription Drugs Advisory Committee <br />September 15 - Radiological Devices Panel <br />September 15 - Anesthesiology and Respiratory Therapy Devices Panel <br />September 15 - Immunology Devices Panel <br />September 15-16 - Endocrinologic and Metabolic Drugs Advisory Committee <br />September 15-16 - Cellular, Tissue and Gene Therapies Advisory Committee <br />September 15-16 - Vaccines and Related Biological Products Advisory Committee <br />September 16 - Device Good Manufacturing Practice Advisory Committee <br />September 17 - Cardiovascular and Renal Drugs Advisory Committee <br />September 20-21 - Pediatric Advisory Committee <br />September 23 - Circulatory System Devices Panel <br />September 23 - Microbiology Devices Panel</p><h3>October 2010 Advisory Committee Meetings</h3><p>October 5-6 - Molecular and Clinical Genetics Panel <br />October 7-8 - Neurological Devices Panel <br />October 13-14 - Orthopaedic and Rehabilitation Devices Panel <br />October 20-21 - Clinical Chemistry and Clinical Toxicology Devices Panel <br />October 21-22 - Hematology and Pathology Devices Panel <br />October 21-22 - Obstetrics and Gynecology Devices Panel <br />October 26 - Allergenic Products Advisory Committee <br />October 28-29 - Transmissible Spongiform Encephalopathies Advisory Committee <br />October 28-29 - Ophthalmic Devices Panel <br />October dates to be announced - Anti-Infective Drugs Advisory Committee</p><h3>November 2010 Advisory Committee Meetings</h3><p>November 3-4 - Ear, Nose, and Throat Devices Panel <br />November 4-5 - General and Plastic Surgery Devices Panel <br />November 8-9 - Risk Communication Advisory Committee <br />November 10 - Anesthesiology and Respiratory Therapy Devices Panel <br />November 15 - Science Board to the Food and Drug Administration Advisory Committee <br />November 17 - Radiological Devices Panel <br />November 17-18 - Science Advisory Board to the National Center for Toxicological Research <br />November 17-18 - Vaccines and Related Biological Products Advisory Committee <br />November 17-18 - General Hospital and Personal Use Devices Panel <br />November 18-19 - Blood Products Advisory Committee <br />November 18-19 - Cellular, Tissue and Gene Therapies Advisory Committee <br />November 18-19 - Ophthalmic Devices Panel <br />November dates to be announced - Tobacco Products Scientific Advisory Committee <br />November dates to be announced - Gastrointestinal Drugs Advisory Committee</p><h3>December 2010 Advisory Committee Meetings</h3><p>December 1 - Oncologic Drugs Advisory Committee <br />December 1-2 - Orthopaedic and Rehabilitation Devices Panel <br />December 2 - Oncologic Drugs Advisory Committee <br />December 2-3 - Gastroenterology-Urology Devices Panel <br />December 6 - Immunology Devices Panel <br />December 6-7 - Pediatric Advisory Committee <br />December 8 - Cardiovascular and Renal Drugs Advisory Committee <br />December 8-9 - Circulatory System Devices Panel <br />December 9-10 - Neurological Devices Panel <br />December 16-17 - Obstetrics and Gynecology Devices Panel</p> 2010-05-11T01:15:02Z 2010-05-11T01:15:02Z /index.php?option=com_content&amp;view=article&amp;id=4126:naproxinod-background-package-published-it-doesnt-look-good-for-the-drug&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>The FDA issued the Review Committee background package for naproxcinod earlier today; here's the link.<br /><br /><a href="http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM211466.pdf">www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM211466.pdf</a></p><p>Naproxcinod is a drug developed by the French company NicOx.<br /><br />Based on what I read, I'd say that competing therapies don't appear to have anything to worry about. The reviewer concluded that from the analysis of the data, claims that naproxcinod performed better than a competing therapy were not supported. The drug was effective in reducing the symptoms of osteoarthritis and the safety profile is similar to other NSAID drugs. The data also didn't support the idea that the drug is an antihypertensive agent.<br /><br />Based on what I read in the review, there is nothing special about this drug. The agency asked the committee to analyze very specific topics, so they may not commment on whether it should be approved; but based on my reading of the data, it doesn't seem to me that this drug would introduce anything new to the market were it to be approved. Based on what has been made public thus far, I would not be surprised to see the FDA decline to give marketing approval for this drug.</p>

<p>The FDA issued the Review Committee background package for naproxcinod earlier today; here's the link.<br /><br /><a href="http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM211466.pdf">www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM211466.pdf</a></p><p>Naproxcinod is a drug developed by the French company NicOx.<br /><br />Based on what I read, I'd say that competing therapies don't appear to have anything to worry about. The reviewer concluded that from the analysis of the data, claims that naproxcinod performed better than a competing therapy were not supported. The drug was effective in reducing the symptoms of osteoarthritis and the safety profile is similar to other NSAID drugs. The data also didn't support the idea that the drug is an antihypertensive agent.<br /><br />Based on what I read in the review, there is nothing special about this drug. The agency asked the committee to analyze very specific topics, so they may not commment on whether it should be approved; but based on my reading of the data, it doesn't seem to me that this drug would introduce anything new to the market were it to be approved. Based on what has been made public thus far, I would not be surprised to see the FDA decline to give marketing approval for this drug.</p> 2010-05-10T09:54:18Z 2010-05-10T09:54:18Z /index.php?option=com_content&amp;view=article&amp;id=4125:glossary-of-terms-useful-to-investors-in-pharma-and-biotech&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>This thread consists of a glossary of terms used in many of the articles found in the group Pharmaceuticals and Biotech. These are terms that investors in such companies will encounter on websites, published reports, financial filings, etc. If you find a term that isn’t included here, let me know, and I will write up a definition.<br /><br />I found this exercise useful as it forced me to think through the drug development, filing and marketing processes and to think back on all the major terms that I have seen in 10-K/Q, 8-K and related filings, press releases and analyst reports. The glossary is in no way complete, so I will update it periodically.<br /><br />I’ve tended to use the expression that I have seen most often in financial-relevant publications. It may be a shorthand expression and not technically totally accurate, but since it’s commonly found, I used it as the main definition. The more precise definition is also included and they're cross referenced.<br /><br />Ideally, I’d like to be able to use a different color for words or terms available elsewhere in this glossary; unfortunately, that option isn’t open to me!</p><h3>Pharmaceutical Terms 0 to 9</h3><p>120 Safety Update<br />The safety update is an amendment to the original NDA filed with the FDA by the company which contains additional safety and/or efficacy data for the drug under review.  This submission is likely to have been previously discussed with the agency, so the submission is expected and likely necessary to complete the review by the PDUFA date.</p><p>74-Day Letter<br />When the FDA receives an NDA from a pharmaceutical company, it does a high level review of the document to ensure that it is in the correct format and that the main points required for a complete review are addressed.  This analysis is done within 60 calendar days of receiving the submission.  If the NDA is acceptable, it is filed for a complete review.  If there are problems, the agency issues a “Refusal to File” letter to the submitting party.  This letter lists the defects in the filing that need to be corrected before the NDA can be accepted.  These problems are communicated to the party within 74-days, hence the term 74-Day Letter.  It’s more correctly called a “Filing Review Notification.”  These steps are part of PDUFA, described elsewhere, which is a series of actions by Congress to speed up the approval process.  The party will also be notified if the drug will undergo standard review (ideally 10 months from NDA filing) or accelerated review (6 months from initial filing).</p><p>482 (Form 482)<br />Form 482 is presented by an FDA inspector upon arrival at a manufacturing or formulation site; it details a notice of inspection.  The FDA has the regulatory authority to inspect a site involved in the pharmaceutical industry at any time without warning.  The FDA also inspects manufacturing and formulation sites outside the USA; however, in this case, the FDA gives two week’s notice to the manufacturing site of the planned inspection.  This notice does not occur in plants based in the US.</p><p>483 (Form 483)<br />Form 483 is a Notice of Inspectional Observations provided by an FDA inspector to the compliance officer or other designated party at a manufacturing or formulation plant.  The form contains observations by the inspector that show points of concern or significant non-compliance with the SOPs in the cGMP system or deviations from generally accepted industry practices that impacts the manufacturing or production process.  Form 483 is reviewed at the FDA office and forwarded as an official communication to the company, when it becomes the position of the agency.  Failure to respond to items listed on a 483 could result in the issuance of a Warning Letter or regulatory action by the FDA.</p><h3>Pharmaceutical Terms A</h3><p>Accelerated Review<br />In certain situations after the NDA is reviewed for completeness, the agency may inform the submitting party that the NDA will receive an accelerated review.  In this case, the PDUFA date is normally six months after the initial filing of the NDA rather than the standard ten.</p><p>Active Pharmaceutical Ingredient (API)<br />The active pharmaceutical ingredient, API or drug substance, is the molecule, the chemical entity, that does the work in slowing or arresting a biological process.  In a typical tablet, the active ingredient is often under one percent by weight of the total mass of the drug.  The API is the item that is usually patented by the drug company.  It must be manufactured under cGMP (discussed elsewhere) and adhere to rigorous quality, safety and purity standards.  Active ingredients typically cost hundreds to thousands of dollars per kilogram and are often the most expensive component in a drug.</p><p>ADME<br />ADME stands for absorption, distribution, metabolism and excretion.  It represents a series of experiments carried out on all active ingredients in animal systems to determine how the drug gets into the body, where it is found in the body, how the body metabolizes or chemically destroys the drug and how it is expelled from the body.  To be useful, a drug has to have a certain concentration in the bloodstream to reach the target cell where it does the work of interrupting the progression of a disease: too low and it is ineffective; too high and it could be toxic.  The route of administration of a drug influences the ADME properties of a drug.  ADME studies show if the ideal concentration, the therapeutic window, can be reached.  ADME studies are part of the determination of the pharmacokinetics of the drug.</p><p>Adverse Event<br />An adverse event or AE is the term used instead of “side effect.”  Adverse events are most often discussed in the context of a clinical trial and are classified in various ways.  The most serious adverse event is, of course, the death of the subject.  Fatalities are carefully examined and often an independent panel adjudicates to the cause to determine if the drug was involved.  Other AEs include things like headaches, nausea, rashes, etc.  Monitoring and reporting of AEs fall under Good Clinical Practices.  If it’s clear that AEs are associated with a drug, they may be included in the drug label.</p><p>Advisory Committee<br />An advisory committee is a panel of experts—often practicing physicians, scientists, clinicians, consultants, etc.—experience in a given field and assembled by the FDA to give input on important issues.  The most common use of these Advisory Committees or Panels is in giving input on the efficacy and safety of new drugs; the committee meeting is often used to discuss what the reviewer might see as deficiencies in the filing.  The FDA has around 50 such committees in different areas.  About 20 to 25% of NDAs are referred to a committee or committees for review.  The committee gives its opinion—usually at least 55 days before the PDUFA date for the drug.  The FDA is not obliged to follow the recommendations of the committee.  It sometimes declines to approve a drug that the committee recommends.  More rarely, the FDA grants marketing approval to a drug that the committee turns down.</p><p>Amendments<br />An amendment is a submission by a pharmaceutical company following either a request for information from the FDA to its NDA or to supplement the original submission.  Most amendments focus on clinical issues, followed by updates to the CMC section.  </p><p>Antisense<br />Biotechnology drugs, macromolecules, are proteins, monoclonal antibodies (another type of protein), anti-sense drugs and gene therapy.  DNA consists of two strands: one is the complement of the other.  RNA (there are different types of RNA) is a single strand of DNA-like components.  RNA carries information from DNA to another apart of the cell where a protein is made.  An anti-sense drug consists of components that complement those in RNA.  So the concept is to introduce a complementary strand which would “stick” to the RNA and prevent it for continuing in a biochemical process.  Anti-sense drugs are a different way to trying to interrupt the progress of a disease.  Anti-sense drugs are still in the development phase.</p><p>API (see Active Pharmaceutical Ingredient)</p><p>Approval Letter<br />An approval letter is a communication form the FDA confirming that the company filing an NDA has marketing approval for the drug.</p><h3>Pharmaceutical Terms B - C</h3><p>Biotech Company<br />Wall Street defines a biotech company very broadly to include small molecule discovery companies, large molecule discovery companies, tools and information companies.  Often, if a company was founded after, say, 1980 and is focused on the development or on supporting the development of novel or generic drugs, it’s referred to as a biotech company.  It’s a frustratingly imprecise definition, but the problem is that Wall Street tends to be very sloppy what it includes as a biotech company.  Biotechnology itself is more a collection of enabling technologies targeted on living processes at the molecular level rather than a defined discipline such as chemistry or physics.</p><p>Brand Name<br />A brand name drug is a drug that is marketed under a trademarked name.  The active ingredient may be patented, but the drug itself is trademarked.  For example, Lipitor is the brand name or trade name for Atorvastatin.  </p><p>CBER<br />CBER, the Center for Biologics Evaluation and Research is one of the six centers in the Food and Drug Administration.  The acronym CEBR is produced as SEE bear.  The center focuses on biological drugs, though the center has evaluated small molecule drugs too.  CBER has responsibility for vaccines, gene therapy, and blood transfusion.  CBER reviews many biological drugs.</p><p>CDER<br />CDER (pronounced like the tree, cedar) is one of the six centers in the US Food and Drug Administration.  CDER stands for Center for Drug Evaluation and Research.  CDER has oversight over most drugs; most small molecule drugs are submitted to CDER for marketing approval.  Large molecule drugs are submitted to CBER.  </p><p>cGMP<br />cGMP stands for current good manufacturing practices, a framework to ensure manufacturing consistency and quality outlined in summary form in the US Code of Federal Regulations.  GMP, as its often called, is now found worldwide for the manufacture of drugs, food and nutritional products.  GMP is a ‘moving target”: in many respects, the FDA doesn’t set the bar for what constitutes good manufacturing practices: it expects the manufacturers and formulators of drugs to be current with the best practices in the industry and to have a written cGMP system to which it rigorously adheres.  Deviations from the quality system employed by the company or practices which fall short of what’s standard in the industry can result in the FDA taking action against a company.  The FDA regularly inspects manufacturing and formulation sites.</p><p>Clinical Trial<br />A clinical trial is a highly controlled scientific experiment where a drug is administered to a group of human volunteers who freely agree to participate in the activity in an effort to yield safety and efficacy information on the API.  Clinical trials are used to discover things like the requisite doses of the drug; to compare and experimental drug to an existing standard of care; or to determine the effect of a combination of drugs used together.  These trials are carried out under Good Clinical Practices.  The FDA requires two, phase III trials that meet the primary endpoint before a drug is given marketing approval.  Trials are carried out in a controlled setting, such as hospitals, by trained experts, often physicians.  The trials are controlled (one group chosen at random receives the drug, the other receives a placebo or current standard of care); double-blind (neither patient nor doctors know who receives the drug in question), and multi-centered: carried out in different parts of the country.  Worldwide, there are about twelve million people currently enrolled in different clinical trials.</p><p>CMC section (Chemistry, Manufacturing and Controls)<br />The CMC section is included in a regulatory filing to support an IND or NDA filing with a regulatory authority.  The CMC section includes information on how and where the drug substance is manufactured, produced and related items.</p><p>Contract Manufacturing Organization<br />A contract manufacturing organization, a CMO, is a company that manufactures the API for a pharmaceutical company.  CMOs often work on the development of the synthetic route to the drug too and provide material to support the clinical trials for the drug.  CMOs can work on biological or small molecule drugs.  CMOs are one of the fastest growing parts of the pharmaceutical industry.</p><p>Contract Research Organization<br />A contract research organization, a CRO, is a company that supports the preclinical development of a drug; analytical work for a drug; clinical trial activity for a drug or other analytical and preparatory work for a regulatory filing such as an IND or NDA.  A CRO is distinguished from a CMO in that it doesn’t develop the process for or the manufacturing of a new chemical or biological entity.  A CRO often provides support for all other activities.</p><h3>Pharmaceutical Terms D - E</h3><p>Dosage Form<br />The dosage form is the method through which the drug is delivered: a tablet, capsule, aerosol, a patch, in an injectable form, etc.  The dosage form is produced under cGMP conditions and is highly regulated by the FDA and other national agencies.</p><p>Drug Development<br />Drug development refers to how the small molecule or biologic is developed from a simple laboratory process to a stable and reproducible manufacturing process.  It may also refer to the development, scale-up and commercial-scale manufacture of the final dosage form.</p><p>Drug Product<br />Drug Product is an older expression that is used to distinguish the final dosage form (see dosage form) from the drug substance (the API or active pharmaceutical ingredient).</p><p>Drug Recall<br />A drug recall is a voluntary or regulatory effort to pull a prescription or generic drug from the market.  Drug recalls are extremely expensive and can be triggered by defects in the manufacturing process or the appearance of adverse events.  The FDA has the statutory authority to recall drugs, though in most cases it is done in agreement with the drug company.</p><p>Drug Substance (see Active Pharmaceutical Ingredient)</p><p>Endpoint (see Primary Endpoint)</p><p>EMA<br />The EMA is the European Medicines Agency and is, in some respects, the European counterpart of the FDA.  The EMA works closely and coordinates the separate national agencies of EU member states.  For certain drugs, the EMA can grant marketing approval for drugs in the EU.</p><p>Emerging Pharmaceutical Company<br />An emerging pharmaceutical company is generally viewed as a discovery and development company in the pharmaceutical space that has get to generate sustainable earnings.  Gilead, Biogen, Genzyme, Genentech and Amgen once in this group and are now fiscally stable companies.  Emerging companies usually depend on partnership agreements, secondary offerings from public markets, or infusions of cash from venture capitalists to sustain the company.</p><p>End of Phase 2 Meeting<br />This is one of the two major meetings that most drug companies have with the FDA.  This meeting occurs after the Phase 2 studies are completed and before the plans for a Phase 3 study are finalized.  At this meeting, the company discusses its plans with the FDA, detailing the phase 3 studies it intends to carry out; the FDA works with the company on an “endpoint”: if the clinical trials meet this endpoint, they are deemed successful.  A discussion also takes place on any scientific, manufacturing or safety issues surrounding the drug.  This meeting is extremely important because the FDA essentially relays to the company what it needs to accomplish to get its drug approved.</p><p>Excipient<br />Drugs consist of active and inactive pharmaceutical ingredients.  The active is often called the drug substance; the inactive ingredients are called excipients.  In tablet form, excepients include coatings, binders, colorants, flavors, preservatives, etc.  Most of a tablet consists of excipients; they’re chosen so that the tablet will break apart at the correct point in the digestive track.  They can also help the active ingredient permeate the digestive track to get to the bloodstream where the active ingredient does its work.  The combination of the active ingredient and the excipients is called the drug formulation.  The formulation is usually a trade secret.  In older drugs, the active ingredient could weigh a large fraction of a gram (say 100 to 500 milligrams); in modern drugs, the active is on the order of 10 milligrams.  As a point of reference, an M&M weighs approximately a gram.  The active ingredient in Lipitor is often 1% of a gram; the other 99% are excipients.</p><h3>Pharmaceutical Terms F - G</h3><p>Fast Track Development Program<br />When a drug is deemed to be superior, has other exceptional characteristics or where there is a clear and imminent need for the therapy, the FDA may include the development of the drug in the fast track program.  In this program, the FDA works with the pharmaceutical company on the development and clinical plans to ensure that the work is carried out as quickly and safely as possible.  Inclusion in this program is requested by the pharmaceutical company and granted by the FDA.</p><p>Final Dosage Form (see Dosage Form)</p><p>First-in-Man Study (FIM)<br />A first-in-man study is a clinical trial where the investigational new drug is first given to human subjects; it is almost always a Phase I clinical trial.</p><p>FDA<br />FDA, the US Food and Drug Administration, is an administration under the Department of Health and Human Services with regulatory oversight over food, drugs and cosmetics.  The FDA was founded in 1906.  It oversees drug approval and marketing.</p><p>Filing Review Notification (see 74-day letter)</p><p>First in Class<br />First in class refers to a drug that focuses on a new biological mechanism to treat a disease.  First in class often means that the innovating company has discovered a new biological target, which may give it a few years lead before another innovator can work on a competing therapy.</p><p>Gene Therapy<br />Gene therapy is an umbrella term used to develop therapies to treat genetic based illnesses by changing the chemical makeup of a gene in a living cell.</p><p>Generic<br />Broadly speaking, a drug becomes generic when the patent on the active ingredient expires.  Patents are usually filed when the drug is in development, before the drug enters the clinic.  While patents last twenty years, companies usually have eight to twelve years of marketing exclusivity before generic equivalents are given marketing approval by a regulatory agency such as the FDA.</p><p>GMP (see cGMP)</p><p>Good Clinical Practices<br />Good clinical practice (GCP) is a global standard for the conduct of clinical trials where a drug is administered to humans.  GCP is guided by the ICH, the international committee on harmonization, which also provides standards for stability studies and, increasingly, cGMP for manufacturing.</p><p>Good Manufacturing Practices (see cGMP)</p><h3>Pharmaceutical Terms H - L</h3><p>Information Request<br />An information request is a communication from the FDA made to a company submitted an NDA for supplemental data or clarification.  The request is made during the review process.  The request may be made to address shortcomings in the regulatory filing, the NDA.  Delays in responding to the FDA could result in the PDUFA date being pushed forward.</p><p>In silico<br />In silico is a term used for a computer simulation.  Some chemical and biological processes are modeled on computer systems and these are used to complement animal and clinical studies.</p><p>In vitro<br />In vitro experiments are those that are conducted in the laboratory or glassware.  Work in vitro is normally carried out in the preclinical phase of drug discovery or to support chemical development work.</p><p>In vivo<br />In vivo work is carried out in living entities, cell lines or animals.  The experiments are designed to mimic systems in the human body.</p><p>Inactive Pharmaceutical Ingredient (see Excipient)</p><p>Indication<br />An indication, as opposed to a contraindication, is the reason that a drug is applied.  Drugs are approved for specific indications.</p><p>Investigational New Drug (IND)<br />An IND is a regulatory filing with the FDA that requests permission to administer the drug to humans in a clinical trial.  The application contains details of the preclinical work carried out by the company, the target indication, how the drug is to be administered and the clinical trial conducted.  The IND must be approved by the FDA prior to administering the drug to humans.</p><p>Labeling<br />A drug label is a document approved by the FDA that provides all printed detailed information on the drug, its usage and any warnings or other issues with the drug.</p><p>Large Molecule (see Macromolecule)</p><h3>Pharmaceutical Terms M - N</h3><p>Macromolecule<br />The world of drugs, broadly speaking, is divided into traditional small molecules and macromolecules.  A macromolecule is a protein, antibody, antisense molecule, peptide or a hormone.  Macromolecules are produced in biological processes.  Small molecules may be synthesized in a traditional chemical processes; they can also be produced through fermentation.  Macromolecules are normally the province of traditional biotechnology companies.</p><p>Marketing Status<br />The marketing status refers to how the drug is sold: prescription or non-prescription (over-the-counter).  Tentatively approved means that the drug is awaiting patent expiry of the innovator.</p><p>Metabolism<br />Metabolism refers to biochemistry in living systems.  </p><p>Mechanism of Action<br />The mechanism of action (sometimes incorrectly referred to as the Mode of Action) is the specific biochemical process or processes through which a drug produces the desired effect in the body.  The FDA needs an adequate description and understanding of the mechanism of action before approval is given to administer the drug in humans; laboratory and animal studies help provide this information.</p><p>Monoclonal Antibody (mAb)<br />Monoclonal antibodies. mAbs, are identical copies of an protein produced by an immune cell that is cloned.  Monoclonal antibodies are increasingly used as drugs in various applications.  Once it enters the clinical, a mAb has about three times the chances of approval of a traditional small molecule drug.</p><p>New Chemical Entity (NCE)<br />A new chemical entity is a novel molecule never before used as an API.</p><p>New Drug Application or NDA<br />An NDA is a regulatory filing with the FDA to gain marketing approval for a drug in the United States.  An NDA contains complete details on the preclinical and clinical development of the drug, including manufacturing, formulation, and packaging.  The NDA is reviewed by the FDA, which can respond within as few as six to ten months.  The goal of the review is to determine if the drug is safe and effective and is produced in a control fashion.</p><p>New Molecular Entity (NME)<br />A new molecular entity is an umbrella term for new chemical or new biological entities.</p><h3>Pharmaceutical Terms O - P</h3><p>Orphan Drug Status<br />An orphan drug is a designation for a therapy to treat a small patient population.  In the US orphan drug status, granted by the FDA, is for patient populations of under 200,000.  Companies that market orphan drug get certain tax and exclusivity status from the government.</p><p>Over the Counter<br />Over-the-counter drugs (OTC) are those that may be sold without a prescription: Aspirin for example.  Like prescription drugs, OTC drugs must undergo the same approval steps to receive marketing approval by the FDA.</p><p>Parenteral Drug<br />A parenteral drug is one where the delivery mechanism by a route other than oral; parenteral usually refers to intravenous administration of a drug.  Other routes of administration include transdermal, aerosol, sublingual, etc.  Because the route of administration in non-oral drugs often by-passes the digestive system and potentially delivers the dosage more directly to the bloodstream, higher manufacturing standards are required.  Parenteral drugs often have much lower doses than those delivered orally.  If a drug has different formulations, each must have its own clinical trial or trials to support the different label claims.</p><p>PDUFA Date<br />The PDUFA date has its origins in the Prescription Drug User Fee Act of 1993.  With this act, innovators pay fees—over one million dollars—for the review process.  Upon acceptance of the NDA, the FDA gives the company a PDUFA date, normally either six (accelerated) or ten (normal) months after submission of the NDA.  If the agency is going to refer the drug to an Advisory Committee, the company is informed at least fifty-five days prior to the PDUFA date.</p><p>Pharmacokinetics<br />Pharmacokinetics, of which ADME is part, is a branch of pharmacology that studies the biological processes involved in the fate of an API in a biological system.</p><p>Phase I (clinical trial)<br />A phase I clinical trial is a controlled experiment where a drug is administered to human volunteer subjects to study safety and pharmacokinetics.  Phase I trials are normally conducted on 20 to 50 healthy volunteers.</p><p>Phase II (clinical trial)<br />A phase II trial is a controlled experiment where a drug is administered to human volunteer subjects to study dosage in the therapeutic window and efficacy.  Phase II trials are conducted on 50 to 200 subjects with the indication of interest and few other complications.</p><p>Phase III (clinical trial)<br />A Phase III trial is a large controlled experiment on human volunteer subjects in a randomized, double-blind, multi-center study against a placebo or the current standard of care.  The drug must demonstrate statistically significant efficacy to reach its endpoint.  The FDA normally requires two, successful phase III clinical trials to grant marketing approval.</p><p>Post-marketing surveillance<br />This term is also called post-marketing study or study commitments; it is also referred to as Phase IV commitments and involves ongoing studies of the safety and effectiveness of the drug post-approval.  This surveillance is required for drugs in various situations, including those that receive accelerated approval.</p><p>Pre-Approval Inspection (PAI)<br />A pre-approval inspection or PAI is an investigation by the FDA of either the manufacturing site of the active ingredient or the formulation site of the drug product.  A PAI takes place after an NDA is accepted by the FDA; successful completion of the inspection is necessary is marketing approval is to be granted.</p><p>Pre-clinical<br />Pre-clinical is the sum total of all activities carried out on a drug before it is administered to humans.  Clinical studies are carried out on humans; pre-clinical studies are carried out in silico, in vitro and on model systems.</p><p>Pre-NDA meeting<br />A pre-NDA meeting is carried out between the innovative company and the FDA after the final phase III clinical trial but before an NDA is submitted.  At this meeting, regulatory filing issues are discussed as well as data analysis and how the data will be presented.  This meeting is normally the last interaction with the FDA before the NDA is submitted.</p><p>Pre-submission meetings<br />The two main pre-submission meetings are End of Phase II meeting and the Pre-NDA Meeting that takes place between a drug company and the FDA.</p><p>Protein<br />A protein is a macromolecule constructed from hundreds to tens of thousands amino acids.  Proteins fold and unfold in specific ways; the way a protein folds on itself is critical to the biological processes that it governs.  Proteins are ubiquitous in nature and are responsible for biological processes at the cellular level.  A protein is often the biological target for a small molecule or peptide drug.</p><p>Primary Endpoint<br />A primary endpoint is a measurable factor established prior to the start of a clinical trial that governs if the trial is deemed successful.  For a fatal disease, a primary endpoint may mean survival.  If there is a statistically meaningful differen</p><h3>Pharmaceutical Terms Q - S</h3><p>Reference Listed Drug<br />The Reference Listed Drug is usually the novel drug to which generic formulations are compared to show bioequivalence.  A company that wishes to market a generic form of the drug must compare favorably to the original therapy before it may be sold in the US.</p><p>Refusal to File Letter<br />A Refusal to File Letter is issued by the FDA following submission of an NDA if the regulatory filing is incomplete or deficient in some fashion.  Review of the filing is discontinued until the filing is complete.  The decision is made sixty days after submission and the information is communicated to the drug company via the “74-day letter.”  Generally, companies may address the concerns in the letter and resubmit the filing.</p><p>Route of Administration<br />The route of administration is the pathway through which the drug enters the body.  Most drugs are administered in oral form as a tablet, syrup or other mixture that is consumed like food through the digestive process.  Other routes of administration include injection, topical, patch, sublingual, etc.  There are cultural sensitivities surrounding the route of administration.  For example suppositories are not view favorably in North America and northern Europe; this route of administration finds greater acceptance in countries such as France.</p><p>Side Effect (see Adverse Event)</p><p>Small Molecule<br />A small molecule is a chemical entity that is produced in a traditional chemical manufacturing plant.  Small molecules average thirty to one hundred atoms.</p><p>SPA (Special Protocol Assessment)<br />The SPA is a way in which the FDA gives evaluation and guidance on the protocols that form the basis of an NDA.  Final marketing approval for the drug still depends on the safety and efficacy of the drug as determined in the phase III clinical trial and the overall risk/benefit determined by the FDA.  The link below takes you to the official guidance document issued by the FDA in May, 2002.</p><p><a href="http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080571.pdf">http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080571.pdf</a></p><p><br />Standard of Care<br />The standard of care of the standard therapy is the appropriate course of action to treat a given disease.  In life threatening diseases, a phase III clinical trial often uses a group receiving the standard of care or “gold standard” as the control.</p><h3>Pharmaceutical Terms T- Z</h3><p>Target<br />A target is a biological molecule or process that a research hopes to destroy or disrupt in an effort to eliminate or reduce the rate of development of a disease state.</p><p>Tentative Approval<br />Tentative approval is granted to the producer of a generic drug before the patent has expired.  The communication from the FDA details the conditions under which the drug may be sold.  Marketing is only permitted after all issues of exclusivity have been resolved.</p><p>Therapy<br />A therapy is an attempt at remediation of medical condition.  Therapy often includes the administration of drugs.</p><p>Toxicity<br />Toxicity refers to usually unwanted biochemical processes which damage a biological system.</p><p>Trade Name (see Brand Name)</p><p>Warning Letter<br />A warning letter is a document issued by the FDA to a drug manufacturer or formulator drawing attention to major or repeated and non-addressed findings by the agency at a production site.  To assure that a warning letter gets the appropriate attention, they are addressed to the chief executive officer or general manager of a company.  Failure to acknowledge and address the issues raised in a warning letter can lead to enforcement action, often severe, which could prevent a company from supply material to the industry for months or years.  The FDA maintains a searchable database of companies that have received warning letters from the agency.</p>

<p>This thread consists of a glossary of terms used in many of the articles found in the group Pharmaceuticals and Biotech. These are terms that investors in such companies will encounter on websites, published reports, financial filings, etc. If you find a term that isn’t included here, let me know, and I will write up a definition.<br /><br />I found this exercise useful as it forced me to think through the drug development, filing and marketing processes and to think back on all the major terms that I have seen in 10-K/Q, 8-K and related filings, press releases and analyst reports. The glossary is in no way complete, so I will update it periodically.<br /><br />I’ve tended to use the expression that I have seen most often in financial-relevant publications. It may be a shorthand expression and not technically totally accurate, but since it’s commonly found, I used it as the main definition. The more precise definition is also included and they're cross referenced.<br /><br />Ideally, I’d like to be able to use a different color for words or terms available elsewhere in this glossary; unfortunately, that option isn’t open to me!</p><h3>Pharmaceutical Terms 0 to 9</h3><p>120 Safety Update<br />The safety update is an amendment to the original NDA filed with the FDA by the company which contains additional safety and/or efficacy data for the drug under review.  This submission is likely to have been previously discussed with the agency, so the submission is expected and likely necessary to complete the review by the PDUFA date.</p><p>74-Day Letter<br />When the FDA receives an NDA from a pharmaceutical company, it does a high level review of the document to ensure that it is in the correct format and that the main points required for a complete review are addressed.  This analysis is done within 60 calendar days of receiving the submission.  If the NDA is acceptable, it is filed for a complete review.  If there are problems, the agency issues a “Refusal to File” letter to the submitting party.  This letter lists the defects in the filing that need to be corrected before the NDA can be accepted.  These problems are communicated to the party within 74-days, hence the term 74-Day Letter.  It’s more correctly called a “Filing Review Notification.”  These steps are part of PDUFA, described elsewhere, which is a series of actions by Congress to speed up the approval process.  The party will also be notified if the drug will undergo standard review (ideally 10 months from NDA filing) or accelerated review (6 months from initial filing).</p><p>482 (Form 482)<br />Form 482 is presented by an FDA inspector upon arrival at a manufacturing or formulation site; it details a notice of inspection.  The FDA has the regulatory authority to inspect a site involved in the pharmaceutical industry at any time without warning.  The FDA also inspects manufacturing and formulation sites outside the USA; however, in this case, the FDA gives two week’s notice to the manufacturing site of the planned inspection.  This notice does not occur in plants based in the US.</p><p>483 (Form 483)<br />Form 483 is a Notice of Inspectional Observations provided by an FDA inspector to the compliance officer or other designated party at a manufacturing or formulation plant.  The form contains observations by the inspector that show points of concern or significant non-compliance with the SOPs in the cGMP system or deviations from generally accepted industry practices that impacts the manufacturing or production process.  Form 483 is reviewed at the FDA office and forwarded as an official communication to the company, when it becomes the position of the agency.  Failure to respond to items listed on a 483 could result in the issuance of a Warning Letter or regulatory action by the FDA.</p><h3>Pharmaceutical Terms A</h3><p>Accelerated Review<br />In certain situations after the NDA is reviewed for completeness, the agency may inform the submitting party that the NDA will receive an accelerated review.  In this case, the PDUFA date is normally six months after the initial filing of the NDA rather than the standard ten.</p><p>Active Pharmaceutical Ingredient (API)<br />The active pharmaceutical ingredient, API or drug substance, is the molecule, the chemical entity, that does the work in slowing or arresting a biological process.  In a typical tablet, the active ingredient is often under one percent by weight of the total mass of the drug.  The API is the item that is usually patented by the drug company.  It must be manufactured under cGMP (discussed elsewhere) and adhere to rigorous quality, safety and purity standards.  Active ingredients typically cost hundreds to thousands of dollars per kilogram and are often the most expensive component in a drug.</p><p>ADME<br />ADME stands for absorption, distribution, metabolism and excretion.  It represents a series of experiments carried out on all active ingredients in animal systems to determine how the drug gets into the body, where it is found in the body, how the body metabolizes or chemically destroys the drug and how it is expelled from the body.  To be useful, a drug has to have a certain concentration in the bloodstream to reach the target cell where it does the work of interrupting the progression of a disease: too low and it is ineffective; too high and it could be toxic.  The route of administration of a drug influences the ADME properties of a drug.  ADME studies show if the ideal concentration, the therapeutic window, can be reached.  ADME studies are part of the determination of the pharmacokinetics of the drug.</p><p>Adverse Event<br />An adverse event or AE is the term used instead of “side effect.”  Adverse events are most often discussed in the context of a clinical trial and are classified in various ways.  The most serious adverse event is, of course, the death of the subject.  Fatalities are carefully examined and often an independent panel adjudicates to the cause to determine if the drug was involved.  Other AEs include things like headaches, nausea, rashes, etc.  Monitoring and reporting of AEs fall under Good Clinical Practices.  If it’s clear that AEs are associated with a drug, they may be included in the drug label.</p><p>Advisory Committee<br />An advisory committee is a panel of experts—often practicing physicians, scientists, clinicians, consultants, etc.—experience in a given field and assembled by the FDA to give input on important issues.  The most common use of these Advisory Committees or Panels is in giving input on the efficacy and safety of new drugs; the committee meeting is often used to discuss what the reviewer might see as deficiencies in the filing.  The FDA has around 50 such committees in different areas.  About 20 to 25% of NDAs are referred to a committee or committees for review.  The committee gives its opinion—usually at least 55 days before the PDUFA date for the drug.  The FDA is not obliged to follow the recommendations of the committee.  It sometimes declines to approve a drug that the committee recommends.  More rarely, the FDA grants marketing approval to a drug that the committee turns down.</p><p>Amendments<br />An amendment is a submission by a pharmaceutical company following either a request for information from the FDA to its NDA or to supplement the original submission.  Most amendments focus on clinical issues, followed by updates to the CMC section.  </p><p>Antisense<br />Biotechnology drugs, macromolecules, are proteins, monoclonal antibodies (another type of protein), anti-sense drugs and gene therapy.  DNA consists of two strands: one is the complement of the other.  RNA (there are different types of RNA) is a single strand of DNA-like components.  RNA carries information from DNA to another apart of the cell where a protein is made.  An anti-sense drug consists of components that complement those in RNA.  So the concept is to introduce a complementary strand which would “stick” to the RNA and prevent it for continuing in a biochemical process.  Anti-sense drugs are a different way to trying to interrupt the progress of a disease.  Anti-sense drugs are still in the development phase.</p><p>API (see Active Pharmaceutical Ingredient)</p><p>Approval Letter<br />An approval letter is a communication form the FDA confirming that the company filing an NDA has marketing approval for the drug.</p><h3>Pharmaceutical Terms B - C</h3><p>Biotech Company<br />Wall Street defines a biotech company very broadly to include small molecule discovery companies, large molecule discovery companies, tools and information companies.  Often, if a company was founded after, say, 1980 and is focused on the development or on supporting the development of novel or generic drugs, it’s referred to as a biotech company.  It’s a frustratingly imprecise definition, but the problem is that Wall Street tends to be very sloppy what it includes as a biotech company.  Biotechnology itself is more a collection of enabling technologies targeted on living processes at the molecular level rather than a defined discipline such as chemistry or physics.</p><p>Brand Name<br />A brand name drug is a drug that is marketed under a trademarked name.  The active ingredient may be patented, but the drug itself is trademarked.  For example, Lipitor is the brand name or trade name for Atorvastatin.  </p><p>CBER<br />CBER, the Center for Biologics Evaluation and Research is one of the six centers in the Food and Drug Administration.  The acronym CEBR is produced as SEE bear.  The center focuses on biological drugs, though the center has evaluated small molecule drugs too.  CBER has responsibility for vaccines, gene therapy, and blood transfusion.  CBER reviews many biological drugs.</p><p>CDER<br />CDER (pronounced like the tree, cedar) is one of the six centers in the US Food and Drug Administration.  CDER stands for Center for Drug Evaluation and Research.  CDER has oversight over most drugs; most small molecule drugs are submitted to CDER for marketing approval.  Large molecule drugs are submitted to CBER.  </p><p>cGMP<br />cGMP stands for current good manufacturing practices, a framework to ensure manufacturing consistency and quality outlined in summary form in the US Code of Federal Regulations.  GMP, as its often called, is now found worldwide for the manufacture of drugs, food and nutritional products.  GMP is a ‘moving target”: in many respects, the FDA doesn’t set the bar for what constitutes good manufacturing practices: it expects the manufacturers and formulators of drugs to be current with the best practices in the industry and to have a written cGMP system to which it rigorously adheres.  Deviations from the quality system employed by the company or practices which fall short of what’s standard in the industry can result in the FDA taking action against a company.  The FDA regularly inspects manufacturing and formulation sites.</p><p>Clinical Trial<br />A clinical trial is a highly controlled scientific experiment where a drug is administered to a group of human volunteers who freely agree to participate in the activity in an effort to yield safety and efficacy information on the API.  Clinical trials are used to discover things like the requisite doses of the drug; to compare and experimental drug to an existing standard of care; or to determine the effect of a combination of drugs used together.  These trials are carried out under Good Clinical Practices.  The FDA requires two, phase III trials that meet the primary endpoint before a drug is given marketing approval.  Trials are carried out in a controlled setting, such as hospitals, by trained experts, often physicians.  The trials are controlled (one group chosen at random receives the drug, the other receives a placebo or current standard of care); double-blind (neither patient nor doctors know who receives the drug in question), and multi-centered: carried out in different parts of the country.  Worldwide, there are about twelve million people currently enrolled in different clinical trials.</p><p>CMC section (Chemistry, Manufacturing and Controls)<br />The CMC section is included in a regulatory filing to support an IND or NDA filing with a regulatory authority.  The CMC section includes information on how and where the drug substance is manufactured, produced and related items.</p><p>Contract Manufacturing Organization<br />A contract manufacturing organization, a CMO, is a company that manufactures the API for a pharmaceutical company.  CMOs often work on the development of the synthetic route to the drug too and provide material to support the clinical trials for the drug.  CMOs can work on biological or small molecule drugs.  CMOs are one of the fastest growing parts of the pharmaceutical industry.</p><p>Contract Research Organization<br />A contract research organization, a CRO, is a company that supports the preclinical development of a drug; analytical work for a drug; clinical trial activity for a drug or other analytical and preparatory work for a regulatory filing such as an IND or NDA.  A CRO is distinguished from a CMO in that it doesn’t develop the process for or the manufacturing of a new chemical or biological entity.  A CRO often provides support for all other activities.</p><h3>Pharmaceutical Terms D - E</h3><p>Dosage Form<br />The dosage form is the method through which the drug is delivered: a tablet, capsule, aerosol, a patch, in an injectable form, etc.  The dosage form is produced under cGMP conditions and is highly regulated by the FDA and other national agencies.</p><p>Drug Development<br />Drug development refers to how the small molecule or biologic is developed from a simple laboratory process to a stable and reproducible manufacturing process.  It may also refer to the development, scale-up and commercial-scale manufacture of the final dosage form.</p><p>Drug Product<br />Drug Product is an older expression that is used to distinguish the final dosage form (see dosage form) from the drug substance (the API or active pharmaceutical ingredient).</p><p>Drug Recall<br />A drug recall is a voluntary or regulatory effort to pull a prescription or generic drug from the market.  Drug recalls are extremely expensive and can be triggered by defects in the manufacturing process or the appearance of adverse events.  The FDA has the statutory authority to recall drugs, though in most cases it is done in agreement with the drug company.</p><p>Drug Substance (see Active Pharmaceutical Ingredient)</p><p>Endpoint (see Primary Endpoint)</p><p>EMA<br />The EMA is the European Medicines Agency and is, in some respects, the European counterpart of the FDA.  The EMA works closely and coordinates the separate national agencies of EU member states.  For certain drugs, the EMA can grant marketing approval for drugs in the EU.</p><p>Emerging Pharmaceutical Company<br />An emerging pharmaceutical company is generally viewed as a discovery and development company in the pharmaceutical space that has get to generate sustainable earnings.  Gilead, Biogen, Genzyme, Genentech and Amgen once in this group and are now fiscally stable companies.  Emerging companies usually depend on partnership agreements, secondary offerings from public markets, or infusions of cash from venture capitalists to sustain the company.</p><p>End of Phase 2 Meeting<br />This is one of the two major meetings that most drug companies have with the FDA.  This meeting occurs after the Phase 2 studies are completed and before the plans for a Phase 3 study are finalized.  At this meeting, the company discusses its plans with the FDA, detailing the phase 3 studies it intends to carry out; the FDA works with the company on an “endpoint”: if the clinical trials meet this endpoint, they are deemed successful.  A discussion also takes place on any scientific, manufacturing or safety issues surrounding the drug.  This meeting is extremely important because the FDA essentially relays to the company what it needs to accomplish to get its drug approved.</p><p>Excipient<br />Drugs consist of active and inactive pharmaceutical ingredients.  The active is often called the drug substance; the inactive ingredients are called excipients.  In tablet form, excepients include coatings, binders, colorants, flavors, preservatives, etc.  Most of a tablet consists of excipients; they’re chosen so that the tablet will break apart at the correct point in the digestive track.  They can also help the active ingredient permeate the digestive track to get to the bloodstream where the active ingredient does its work.  The combination of the active ingredient and the excipients is called the drug formulation.  The formulation is usually a trade secret.  In older drugs, the active ingredient could weigh a large fraction of a gram (say 100 to 500 milligrams); in modern drugs, the active is on the order of 10 milligrams.  As a point of reference, an M&M weighs approximately a gram.  The active ingredient in Lipitor is often 1% of a gram; the other 99% are excipients.</p><h3>Pharmaceutical Terms F - G</h3><p>Fast Track Development Program<br />When a drug is deemed to be superior, has other exceptional characteristics or where there is a clear and imminent need for the therapy, the FDA may include the development of the drug in the fast track program.  In this program, the FDA works with the pharmaceutical company on the development and clinical plans to ensure that the work is carried out as quickly and safely as possible.  Inclusion in this program is requested by the pharmaceutical company and granted by the FDA.</p><p>Final Dosage Form (see Dosage Form)</p><p>First-in-Man Study (FIM)<br />A first-in-man study is a clinical trial where the investigational new drug is first given to human subjects; it is almost always a Phase I clinical trial.</p><p>FDA<br />FDA, the US Food and Drug Administration, is an administration under the Department of Health and Human Services with regulatory oversight over food, drugs and cosmetics.  The FDA was founded in 1906.  It oversees drug approval and marketing.</p><p>Filing Review Notification (see 74-day letter)</p><p>First in Class<br />First in class refers to a drug that focuses on a new biological mechanism to treat a disease.  First in class often means that the innovating company has discovered a new biological target, which may give it a few years lead before another innovator can work on a competing therapy.</p><p>Gene Therapy<br />Gene therapy is an umbrella term used to develop therapies to treat genetic based illnesses by changing the chemical makeup of a gene in a living cell.</p><p>Generic<br />Broadly speaking, a drug becomes generic when the patent on the active ingredient expires.  Patents are usually filed when the drug is in development, before the drug enters the clinic.  While patents last twenty years, companies usually have eight to twelve years of marketing exclusivity before generic equivalents are given marketing approval by a regulatory agency such as the FDA.</p><p>GMP (see cGMP)</p><p>Good Clinical Practices<br />Good clinical practice (GCP) is a global standard for the conduct of clinical trials where a drug is administered to humans.  GCP is guided by the ICH, the international committee on harmonization, which also provides standards for stability studies and, increasingly, cGMP for manufacturing.</p><p>Good Manufacturing Practices (see cGMP)</p><h3>Pharmaceutical Terms H - L</h3><p>Information Request<br />An information request is a communication from the FDA made to a company submitted an NDA for supplemental data or clarification.  The request is made during the review process.  The request may be made to address shortcomings in the regulatory filing, the NDA.  Delays in responding to the FDA could result in the PDUFA date being pushed forward.</p><p>In silico<br />In silico is a term used for a computer simulation.  Some chemical and biological processes are modeled on computer systems and these are used to complement animal and clinical studies.</p><p>In vitro<br />In vitro experiments are those that are conducted in the laboratory or glassware.  Work in vitro is normally carried out in the preclinical phase of drug discovery or to support chemical development work.</p><p>In vivo<br />In vivo work is carried out in living entities, cell lines or animals.  The experiments are designed to mimic systems in the human body.</p><p>Inactive Pharmaceutical Ingredient (see Excipient)</p><p>Indication<br />An indication, as opposed to a contraindication, is the reason that a drug is applied.  Drugs are approved for specific indications.</p><p>Investigational New Drug (IND)<br />An IND is a regulatory filing with the FDA that requests permission to administer the drug to humans in a clinical trial.  The application contains details of the preclinical work carried out by the company, the target indication, how the drug is to be administered and the clinical trial conducted.  The IND must be approved by the FDA prior to administering the drug to humans.</p><p>Labeling<br />A drug label is a document approved by the FDA that provides all printed detailed information on the drug, its usage and any warnings or other issues with the drug.</p><p>Large Molecule (see Macromolecule)</p><h3>Pharmaceutical Terms M - N</h3><p>Macromolecule<br />The world of drugs, broadly speaking, is divided into traditional small molecules and macromolecules.  A macromolecule is a protein, antibody, antisense molecule, peptide or a hormone.  Macromolecules are produced in biological processes.  Small molecules may be synthesized in a traditional chemical processes; they can also be produced through fermentation.  Macromolecules are normally the province of traditional biotechnology companies.</p><p>Marketing Status<br />The marketing status refers to how the drug is sold: prescription or non-prescription (over-the-counter).  Tentatively approved means that the drug is awaiting patent expiry of the innovator.</p><p>Metabolism<br />Metabolism refers to biochemistry in living systems.  </p><p>Mechanism of Action<br />The mechanism of action (sometimes incorrectly referred to as the Mode of Action) is the specific biochemical process or processes through which a drug produces the desired effect in the body.  The FDA needs an adequate description and understanding of the mechanism of action before approval is given to administer the drug in humans; laboratory and animal studies help provide this information.</p><p>Monoclonal Antibody (mAb)<br />Monoclonal antibodies. mAbs, are identical copies of an protein produced by an immune cell that is cloned.  Monoclonal antibodies are increasingly used as drugs in various applications.  Once it enters the clinical, a mAb has about three times the chances of approval of a traditional small molecule drug.</p><p>New Chemical Entity (NCE)<br />A new chemical entity is a novel molecule never before used as an API.</p><p>New Drug Application or NDA<br />An NDA is a regulatory filing with the FDA to gain marketing approval for a drug in the United States.  An NDA contains complete details on the preclinical and clinical development of the drug, including manufacturing, formulation, and packaging.  The NDA is reviewed by the FDA, which can respond within as few as six to ten months.  The goal of the review is to determine if the drug is safe and effective and is produced in a control fashion.</p><p>New Molecular Entity (NME)<br />A new molecular entity is an umbrella term for new chemical or new biological entities.</p><h3>Pharmaceutical Terms O - P</h3><p>Orphan Drug Status<br />An orphan drug is a designation for a therapy to treat a small patient population.  In the US orphan drug status, granted by the FDA, is for patient populations of under 200,000.  Companies that market orphan drug get certain tax and exclusivity status from the government.</p><p>Over the Counter<br />Over-the-counter drugs (OTC) are those that may be sold without a prescription: Aspirin for example.  Like prescription drugs, OTC drugs must undergo the same approval steps to receive marketing approval by the FDA.</p><p>Parenteral Drug<br />A parenteral drug is one where the delivery mechanism by a route other than oral; parenteral usually refers to intravenous administration of a drug.  Other routes of administration include transdermal, aerosol, sublingual, etc.  Because the route of administration in non-oral drugs often by-passes the digestive system and potentially delivers the dosage more directly to the bloodstream, higher manufacturing standards are required.  Parenteral drugs often have much lower doses than those delivered orally.  If a drug has different formulations, each must have its own clinical trial or trials to support the different label claims.</p><p>PDUFA Date<br />The PDUFA date has its origins in the Prescription Drug User Fee Act of 1993.  With this act, innovators pay fees—over one million dollars—for the review process.  Upon acceptance of the NDA, the FDA gives the company a PDUFA date, normally either six (accelerated) or ten (normal) months after submission of the NDA.  If the agency is going to refer the drug to an Advisory Committee, the company is informed at least fifty-five days prior to the PDUFA date.</p><p>Pharmacokinetics<br />Pharmacokinetics, of which ADME is part, is a branch of pharmacology that studies the biological processes involved in the fate of an API in a biological system.</p><p>Phase I (clinical trial)<br />A phase I clinical trial is a controlled experiment where a drug is administered to human volunteer subjects to study safety and pharmacokinetics.  Phase I trials are normally conducted on 20 to 50 healthy volunteers.</p><p>Phase II (clinical trial)<br />A phase II trial is a controlled experiment where a drug is administered to human volunteer subjects to study dosage in the therapeutic window and efficacy.  Phase II trials are conducted on 50 to 200 subjects with the indication of interest and few other complications.</p><p>Phase III (clinical trial)<br />A Phase III trial is a large controlled experiment on human volunteer subjects in a randomized, double-blind, multi-center study against a placebo or the current standard of care.  The drug must demonstrate statistically significant efficacy to reach its endpoint.  The FDA normally requires two, successful phase III clinical trials to grant marketing approval.</p><p>Post-marketing surveillance<br />This term is also called post-marketing study or study commitments; it is also referred to as Phase IV commitments and involves ongoing studies of the safety and effectiveness of the drug post-approval.  This surveillance is required for drugs in various situations, including those that receive accelerated approval.</p><p>Pre-Approval Inspection (PAI)<br />A pre-approval inspection or PAI is an investigation by the FDA of either the manufacturing site of the active ingredient or the formulation site of the drug product.  A PAI takes place after an NDA is accepted by the FDA; successful completion of the inspection is necessary is marketing approval is to be granted.</p><p>Pre-clinical<br />Pre-clinical is the sum total of all activities carried out on a drug before it is administered to humans.  Clinical studies are carried out on humans; pre-clinical studies are carried out in silico, in vitro and on model systems.</p><p>Pre-NDA meeting<br />A pre-NDA meeting is carried out between the innovative company and the FDA after the final phase III clinical trial but before an NDA is submitted.  At this meeting, regulatory filing issues are discussed as well as data analysis and how the data will be presented.  This meeting is normally the last interaction with the FDA before the NDA is submitted.</p><p>Pre-submission meetings<br />The two main pre-submission meetings are End of Phase II meeting and the Pre-NDA Meeting that takes place between a drug company and the FDA.</p><p>Protein<br />A protein is a macromolecule constructed from hundreds to tens of thousands amino acids.  Proteins fold and unfold in specific ways; the way a protein folds on itself is critical to the biological processes that it governs.  Proteins are ubiquitous in nature and are responsible for biological processes at the cellular level.  A protein is often the biological target for a small molecule or peptide drug.</p><p>Primary Endpoint<br />A primary endpoint is a measurable factor established prior to the start of a clinical trial that governs if the trial is deemed successful.  For a fatal disease, a primary endpoint may mean survival.  If there is a statistically meaningful differen</p><h3>Pharmaceutical Terms Q - S</h3><p>Reference Listed Drug<br />The Reference Listed Drug is usually the novel drug to which generic formulations are compared to show bioequivalence.  A company that wishes to market a generic form of the drug must compare favorably to the original therapy before it may be sold in the US.</p><p>Refusal to File Letter<br />A Refusal to File Letter is issued by the FDA following submission of an NDA if the regulatory filing is incomplete or deficient in some fashion.  Review of the filing is discontinued until the filing is complete.  The decision is made sixty days after submission and the information is communicated to the drug company via the “74-day letter.”  Generally, companies may address the concerns in the letter and resubmit the filing.</p><p>Route of Administration<br />The route of administration is the pathway through which the drug enters the body.  Most drugs are administered in oral form as a tablet, syrup or other mixture that is consumed like food through the digestive process.  Other routes of administration include injection, topical, patch, sublingual, etc.  There are cultural sensitivities surrounding the route of administration.  For example suppositories are not view favorably in North America and northern Europe; this route of administration finds greater acceptance in countries such as France.</p><p>Side Effect (see Adverse Event)</p><p>Small Molecule<br />A small molecule is a chemical entity that is produced in a traditional chemical manufacturing plant.  Small molecules average thirty to one hundred atoms.</p><p>SPA (Special Protocol Assessment)<br />The SPA is a way in which the FDA gives evaluation and guidance on the protocols that form the basis of an NDA.  Final marketing approval for the drug still depends on the safety and efficacy of the drug as determined in the phase III clinical trial and the overall risk/benefit determined by the FDA.  The link below takes you to the official guidance document issued by the FDA in May, 2002.</p><p><a href="http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080571.pdf">http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080571.pdf</a></p><p><br />Standard of Care<br />The standard of care of the standard therapy is the appropriate course of action to treat a given disease.  In life threatening diseases, a phase III clinical trial often uses a group receiving the standard of care or “gold standard” as the control.</p><h3>Pharmaceutical Terms T- Z</h3><p>Target<br />A target is a biological molecule or process that a research hopes to destroy or disrupt in an effort to eliminate or reduce the rate of development of a disease state.</p><p>Tentative Approval<br />Tentative approval is granted to the producer of a generic drug before the patent has expired.  The communication from the FDA details the conditions under which the drug may be sold.  Marketing is only permitted after all issues of exclusivity have been resolved.</p><p>Therapy<br />A therapy is an attempt at remediation of medical condition.  Therapy often includes the administration of drugs.</p><p>Toxicity<br />Toxicity refers to usually unwanted biochemical processes which damage a biological system.</p><p>Trade Name (see Brand Name)</p><p>Warning Letter<br />A warning letter is a document issued by the FDA to a drug manufacturer or formulator drawing attention to major or repeated and non-addressed findings by the agency at a production site.  To assure that a warning letter gets the appropriate attention, they are addressed to the chief executive officer or general manager of a company.  Failure to acknowledge and address the issues raised in a warning letter can lead to enforcement action, often severe, which could prevent a company from supply material to the industry for months or years.  The FDA maintains a searchable database of companies that have received warning letters from the agency.</p> 2010-05-09T22:26:01Z 2010-05-09T22:26:01Z /index.php?option=com_content&amp;view=article&amp;id=4124:nicox-frcox-awaits-advisory-committee-comments&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>NicOx is a French-based emerging pharmaceutical company with offices in the US. The lead drug for the company, naproxcinod, will be reviewed by FDA Advisory Committees on May 12.</p><p>NicOx is a emerging pharmaceutical company headquartered in France and with offices in the US. In September 2009, it submitted an NDA to the FDA for naproxcinod for relief of symptoms associated with osteoarthritis. The FDA accepted the filing and scheduled a PDUFA date of July 24, 2010.<br /><br />On March 8, the company announced that the FDA would refer the filing to the Arthritis Drugs Advisory and the Drug Safety and Risk Management committees for review. The meeting is scheduled for May 12; however, it is likely that the FDA will post background material on the FDA website tomorrow morning, May 10.</p>

<p>NicOx is a French-based emerging pharmaceutical company with offices in the US. The lead drug for the company, naproxcinod, will be reviewed by FDA Advisory Committees on May 12.</p><p>NicOx is a emerging pharmaceutical company headquartered in France and with offices in the US. In September 2009, it submitted an NDA to the FDA for naproxcinod for relief of symptoms associated with osteoarthritis. The FDA accepted the filing and scheduled a PDUFA date of July 24, 2010.<br /><br />On March 8, the company announced that the FDA would refer the filing to the Arthritis Drugs Advisory and the Drug Safety and Risk Management committees for review. The meeting is scheduled for May 12; however, it is likely that the FDA will post background material on the FDA website tomorrow morning, May 10.</p> 2010-05-09T20:35:30Z 2010-05-09T20:35:30Z /index.php?option=com_content&amp;view=article&amp;id=4122:vivus-nasdaqvvus-drug-qnexa-heads-for-panel-review&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>VIVUS, an emerging pharmaceutical company in the Bay Area of California announced that the FDA Endocrinologic and Metabolic Drugs Advisory Committee will review its NDA filing for its lead drug, Qnexa. The review is scheduled for July 15, 2010. The Advisory Committee Briefing Document shoudl appear on the FDA website around July 13, 2010.</p><h3>VIVUS drug Qnexa to get Panel Review</h3><p>VIVUS announced in late March that the FDA had scheduled Qnexa for review at a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee on July 15.</p><p>The FDA refers about 20 to 25% of NDA submissions for new chemical entities for committee or panel review.  The panel consists of experts in the area of the indication itself or general field around this indication; these experts scrutinize a synopsis of the submitted and related data and render an opinion on the safety and efficacy of the drug.  The FDA does not often follow the advice of this panel.  It sometimes, though infrequently, accepts a drug that the panel rejects; there are more examples of the agency rejecting a drug that the committee votes for approval.</p><p>There are currently three drugs submitted for marketing approval.  Qnexa is the only one thus far that has been submitted to a review panel.  The NDA was filed on December 28, 2009 and accepted for review on March 1.  Three weeks later on March 26, the drug was referred to the review committee.  On or about July 13, the FDA should publish an advisory committee briefing document on the website.  Sometimes the reviewer includes his or her opinion about whether the drug should be approved.  It’s likely that the drug was referred to the panel for an assessment on safety rather than efficacy.  VIVUS continues to carry out work to support the safety claims of the drug.  Last Monday, May 5, VIVUS posted a press release about a presentation at the European Congress Focused on Cardiovascular Prevention and Rehabilitation where the a lead investigator, Dr Kishore Gadde of the obesity clinical trials at Duke University presented data supporting the safety of the drug.</p><p>VIVUS is in a head-to-head race with Arena Pharmaceuticals, which also submitted an NDA for a weight reduction drug, lorcaserin.  Lorcaserin was issued a PDUFA date of October 22, 2010; so far, the drug has not been referred to an independent panel for review.  Qnexa has a PDUFA date a week later on October 28.  VIVUS showed greater weight reduction with Qnexa, but questions remain about the long-term safety of the drug; the Arena drug, lorcaserin, showed a slightly lower weight loss; however, there are fewer concerns about the safety of this therapy.</p><p>The next date to watch is the publication of the Advisory Committee Briefing Document for Qnexa which should appear on the FDA website around July 13.</p>

<p>VIVUS, an emerging pharmaceutical company in the Bay Area of California announced that the FDA Endocrinologic and Metabolic Drugs Advisory Committee will review its NDA filing for its lead drug, Qnexa. The review is scheduled for July 15, 2010. The Advisory Committee Briefing Document shoudl appear on the FDA website around July 13, 2010.</p><h3>VIVUS drug Qnexa to get Panel Review</h3><p>VIVUS announced in late March that the FDA had scheduled Qnexa for review at a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee on July 15.</p><p>The FDA refers about 20 to 25% of NDA submissions for new chemical entities for committee or panel review.  The panel consists of experts in the area of the indication itself or general field around this indication; these experts scrutinize a synopsis of the submitted and related data and render an opinion on the safety and efficacy of the drug.  The FDA does not often follow the advice of this panel.  It sometimes, though infrequently, accepts a drug that the panel rejects; there are more examples of the agency rejecting a drug that the committee votes for approval.</p><p>There are currently three drugs submitted for marketing approval.  Qnexa is the only one thus far that has been submitted to a review panel.  The NDA was filed on December 28, 2009 and accepted for review on March 1.  Three weeks later on March 26, the drug was referred to the review committee.  On or about July 13, the FDA should publish an advisory committee briefing document on the website.  Sometimes the reviewer includes his or her opinion about whether the drug should be approved.  It’s likely that the drug was referred to the panel for an assessment on safety rather than efficacy.  VIVUS continues to carry out work to support the safety claims of the drug.  Last Monday, May 5, VIVUS posted a press release about a presentation at the European Congress Focused on Cardiovascular Prevention and Rehabilitation where the a lead investigator, Dr Kishore Gadde of the obesity clinical trials at Duke University presented data supporting the safety of the drug.</p><p>VIVUS is in a head-to-head race with Arena Pharmaceuticals, which also submitted an NDA for a weight reduction drug, lorcaserin.  Lorcaserin was issued a PDUFA date of October 22, 2010; so far, the drug has not been referred to an independent panel for review.  Qnexa has a PDUFA date a week later on October 28.  VIVUS showed greater weight reduction with Qnexa, but questions remain about the long-term safety of the drug; the Arena drug, lorcaserin, showed a slightly lower weight loss; however, there are fewer concerns about the safety of this therapy.</p><p>The next date to watch is the publication of the Advisory Committee Briefing Document for Qnexa which should appear on the FDA website around July 13.</p> 2010-05-09T10:02:53Z 2010-05-09T10:02:53Z /index.php?option=com_content&amp;view=article&amp;id=4123:somaxon-nasdaqsomx-did-something-go-wrong&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Somaxon is a specialty pharmaceutical company located in San Diego, CA.  A specialty company is one that often doesn’t engage in research itself but licenses in drugs discovered by others, develops them, then either partners with other companies or markets the drug itself.  Such drugs tend not to be as profitable as novel therapies, new chemical entities described in the glossary, as the market is often smaller.  The market is smaller because the more profitable indications for the active ingredient has been exploited by other companies.</p><p>Somaxon developed a drug that it called Silenor to be used for those suffering from insomnia.  There are other existing therapies for insomnia, so since Silenor isn’t a first-in-class therapy, it is unlikely to be a blockbuster drug.  Nevertheless, some specialty companies are able to develop a specialty pharmaceutical drug into a few hundred million dollars in revenue: both respectable and profitable.</p><p>The active ingredient in Silenor is doxepin, an active ingredient discovered by Boehringer, which is now part of Roche; the drug was approved for various psychiatric conditions about forty years ago.  It has been off-patent for some time.</p><p>Somaxon has had an interesting history in its efforts to secure marketing approval for Silenor.  I’ll run through some of the significant events.  The company filed its New Drug Application almost 28 months ago on January 31, 2008.  The filing contained results on four phase III clinical trials for the drug.  On April 15, 2008, the FDA announced that it had accepted the filing and that the NDA was now under review.  The FDA reported that it would issue an action letter by December 1, 2008: the PDUFA date for Silenor: so far, so good.</p><p>On May 22, the company announced that it had secured $65 in financing: a $15 million loan and $50 million in newly issued equity.  This latter event would have a dilutive effect on existing shareholders.  On November 24, 2008, the company reported that the FDA would not complete the review of the NDA filing by the PDUFA date; the agency would need up to an additional three months to complete the process.  The FDA misses the PDUFA date in about 1 in 5 cases.  The company stated that the FDA did not request any additional information or raise any issues about the submission.</p><p>On February 26, 2009, Somaxon received a response letter from the FDA: the news was not good.  The FDA determined that based on the NDA, Silenor could not be approved.  The release indicated that the agency had reviewed the efficacy data and questioned the results.  Not surprisingly for a drug with a forty year history, no safety issues were raised.  On March 26, with the stock price down to forty cents or so, the company received notice from the NASDAQ about non-compliance with listing requirements.  On April 7, Somaxon reported on its meeting with the FDA to discuss the letter issued by the agency in February.  Somaxon announced that it would reanalyze the data obtained in the clinical trials and resubmit the results to the FDA.  This resubmission with the additional statistical analyses was announced on June 4.  On July 7, the company announced that the FDA accepted the resubmission; the company also announced it had raised an additional $6 million through the issuance of 5.1 million new shares of stock.</p><p>On December 7, 2009, almost a year after its original PDUFA date, the company received a complete response letter from the FDA.  Once again the news wasn’t good; the company reported that the NDA could not be accepted in its present form.  The company announced, once again, that it would meet with the FDA.  On January 21, 2010, the company reported a successful meeting with the FDA; the release indicated that all open issues had been addressed and that the FDA would accept a resubmission.  At this point, the stock traded at around $2.25 a share; the January 21 release contained very good news.</p><p>On March 18, 2010, Somaxon received marketing approval for Silenor and shares in the company jumped from around $4 to $10.  The real news actually occurred on January 21, when the company, essentially, reported that it had cleared up all open issues with the FDA.  It wasn’t exactly clear how it addressed the concerns raised about sleep maintenance efficacy in non-elderly adults with primary insomnia, but it was clear that the agency seemed happy with what the company proposed.</p><p>Specialty companies don’t always get a nice bounce in the value of its shares when an approval is announced.  Their drugs often don’t hold as much value as those from an innovator.  However, in this case, Somaxon had a number of false starts, which probably created uncertainty about the approval of Silenor.  The January 21 release contained very good news, but it wasn’t really reflected in the stock price.</p><p>It’s often difficult to decide if one should sell when there’s a run up after a drug approval.  In this case, however, Somaxon helped with the decision: four days after approval on March 22, the company announced that it was offering to sell an additional 4 million shares of stock.  At that point shares in the company were trading at around $9; however, in this situation, I think it was time to sell.  Often the share price of specialty companies slide after approval; this dilutive effect was going to almost guarantee that the stock couldn't remain at $10 a share, particularly since Silenor wasn't going to be anything close to a blockbuster drug.</p><p>Going forward, this company will be measured to an increasing extent on its ability to generate revenues and earnings.  The days of selling investors on future prospects are drawing to a close.</p>

<p>Somaxon is a specialty pharmaceutical company located in San Diego, CA.  A specialty company is one that often doesn’t engage in research itself but licenses in drugs discovered by others, develops them, then either partners with other companies or markets the drug itself.  Such drugs tend not to be as profitable as novel therapies, new chemical entities described in the glossary, as the market is often smaller.  The market is smaller because the more profitable indications for the active ingredient has been exploited by other companies.</p><p>Somaxon developed a drug that it called Silenor to be used for those suffering from insomnia.  There are other existing therapies for insomnia, so since Silenor isn’t a first-in-class therapy, it is unlikely to be a blockbuster drug.  Nevertheless, some specialty companies are able to develop a specialty pharmaceutical drug into a few hundred million dollars in revenue: both respectable and profitable.</p><p>The active ingredient in Silenor is doxepin, an active ingredient discovered by Boehringer, which is now part of Roche; the drug was approved for various psychiatric conditions about forty years ago.  It has been off-patent for some time.</p><p>Somaxon has had an interesting history in its efforts to secure marketing approval for Silenor.  I’ll run through some of the significant events.  The company filed its New Drug Application almost 28 months ago on January 31, 2008.  The filing contained results on four phase III clinical trials for the drug.  On April 15, 2008, the FDA announced that it had accepted the filing and that the NDA was now under review.  The FDA reported that it would issue an action letter by December 1, 2008: the PDUFA date for Silenor: so far, so good.</p><p>On May 22, the company announced that it had secured $65 in financing: a $15 million loan and $50 million in newly issued equity.  This latter event would have a dilutive effect on existing shareholders.  On November 24, 2008, the company reported that the FDA would not complete the review of the NDA filing by the PDUFA date; the agency would need up to an additional three months to complete the process.  The FDA misses the PDUFA date in about 1 in 5 cases.  The company stated that the FDA did not request any additional information or raise any issues about the submission.</p><p>On February 26, 2009, Somaxon received a response letter from the FDA: the news was not good.  The FDA determined that based on the NDA, Silenor could not be approved.  The release indicated that the agency had reviewed the efficacy data and questioned the results.  Not surprisingly for a drug with a forty year history, no safety issues were raised.  On March 26, with the stock price down to forty cents or so, the company received notice from the NASDAQ about non-compliance with listing requirements.  On April 7, Somaxon reported on its meeting with the FDA to discuss the letter issued by the agency in February.  Somaxon announced that it would reanalyze the data obtained in the clinical trials and resubmit the results to the FDA.  This resubmission with the additional statistical analyses was announced on June 4.  On July 7, the company announced that the FDA accepted the resubmission; the company also announced it had raised an additional $6 million through the issuance of 5.1 million new shares of stock.</p><p>On December 7, 2009, almost a year after its original PDUFA date, the company received a complete response letter from the FDA.  Once again the news wasn’t good; the company reported that the NDA could not be accepted in its present form.  The company announced, once again, that it would meet with the FDA.  On January 21, 2010, the company reported a successful meeting with the FDA; the release indicated that all open issues had been addressed and that the FDA would accept a resubmission.  At this point, the stock traded at around $2.25 a share; the January 21 release contained very good news.</p><p>On March 18, 2010, Somaxon received marketing approval for Silenor and shares in the company jumped from around $4 to $10.  The real news actually occurred on January 21, when the company, essentially, reported that it had cleared up all open issues with the FDA.  It wasn’t exactly clear how it addressed the concerns raised about sleep maintenance efficacy in non-elderly adults with primary insomnia, but it was clear that the agency seemed happy with what the company proposed.</p><p>Specialty companies don’t always get a nice bounce in the value of its shares when an approval is announced.  Their drugs often don’t hold as much value as those from an innovator.  However, in this case, Somaxon had a number of false starts, which probably created uncertainty about the approval of Silenor.  The January 21 release contained very good news, but it wasn’t really reflected in the stock price.</p><p>It’s often difficult to decide if one should sell when there’s a run up after a drug approval.  In this case, however, Somaxon helped with the decision: four days after approval on March 22, the company announced that it was offering to sell an additional 4 million shares of stock.  At that point shares in the company were trading at around $9; however, in this situation, I think it was time to sell.  Often the share price of specialty companies slide after approval; this dilutive effect was going to almost guarantee that the stock couldn't remain at $10 a share, particularly since Silenor wasn't going to be anything close to a blockbuster drug.</p><p>Going forward, this company will be measured to an increasing extent on its ability to generate revenues and earnings.  The days of selling investors on future prospects are drawing to a close.</p> 2010-05-09T00:18:14Z 2010-05-09T00:18:14Z /index.php?option=com_content&amp;view=article&amp;id=4121:questcor-nasdaqqcor-gets-thumbs-up-from-panel&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>As I expected, the Peripheral and Central Nervous System Drugs Advisory Committee, an FDA advisory committee, recommended approval for Questcor's H. P. Acthar Gel on Thursday.  The panel voted 22 - 1 in favor of the efficacy of the drug, a drug which was first approved in 1952.  The same panel voted in favor of the safety of the drug by a margin of 20 - 1: there were two abstentions.  Trading of Questcor [NASDAQ:QCOR] halted all day on Thursday in anticipation of the news.</p><p>The drug is already used in an off label application for Infantile Spasms [IS].  Questcor's review and re-examination of available data developed a dosing regimen for the drug for IS.</p><p>In a release on December 24, 2009, Questcor indicated that the PDUFA date for the drug will be June 11, 2010: there is no chance in this date.</p><p>Given that there are some adverse events with this drug and that it is already in the market and prescribed for the target indication, the best that Questcor can hope for is marketing approval but with the requirement that more safety studies be carried out.  If the drug progresses successful, I would expect the stock for QCOR to run up as high as $12 to $14 prior to the June 11 PDUFA date.</p>

<p>As I expected, the Peripheral and Central Nervous System Drugs Advisory Committee, an FDA advisory committee, recommended approval for Questcor's H. P. Acthar Gel on Thursday.  The panel voted 22 - 1 in favor of the efficacy of the drug, a drug which was first approved in 1952.  The same panel voted in favor of the safety of the drug by a margin of 20 - 1: there were two abstentions.  Trading of Questcor [NASDAQ:QCOR] halted all day on Thursday in anticipation of the news.</p><p>The drug is already used in an off label application for Infantile Spasms [IS].  Questcor's review and re-examination of available data developed a dosing regimen for the drug for IS.</p><p>In a release on December 24, 2009, Questcor indicated that the PDUFA date for the drug will be June 11, 2010: there is no chance in this date.</p><p>Given that there are some adverse events with this drug and that it is already in the market and prescribed for the target indication, the best that Questcor can hope for is marketing approval but with the requirement that more safety studies be carried out.  If the drug progresses successful, I would expect the stock for QCOR to run up as high as $12 to $14 prior to the June 11 PDUFA date.</p> 2010-05-08T21:34:02Z 2010-05-08T21:34:02Z /index.php?option=com_content&amp;view=article&amp;id=4120:how-to-get-a-drug-to-market-the-approval-process&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>In this article I am going to detail in broad strokes the necessary steps to getting marketing approval to sell a drug in the US. It's a complex process, but the various steps are easy to follow. It's also critical to understand this process if you wish to profit from investing in biotech and pharma.</p><p>To sell a drug in the United States, a company must get permission from the Food and Drug Administration, an entity which is part of the Department of Health and Human Services.  The FDA enjoys authority over a large part of the economy, but exercises it most clearly when it comes to the marketing and sale of medications and medical devices.</p><p>Contrary to what is written in many investing publications, the FDA is actually a very easy entity to navigate.  I am not saying that it’s an agency without problems.  It has a clear process for drug approval and, if these are met, a company should expect permission to sell its product in the United States.</p><p>In Europe there are similar entities, but on the national and EU level: Europe is moving towards a centralized system of drug approval.  In fact, the EMA, formerly called the EMEA, can grant approval for marketing in all EU member states under certain conditions; otherwise, the EMA seems to function more as a coordinating body.  It has similar characteristics to the FDA.  Japan has its own approval process and is, in many important respects, similar to the US.</p><p>The FDA focuses on two things during the approval process: is the drug safe and is it effective.  Companies spend hundreds of millions of dollars trying to answer these questions before they receive marketing approval.  In most cases, companies do not get permission to sell their drug; if they do, there’s only a 30% chance that they will recoup their development expenses.  For those that follow biotech companies, most companies fail because most development candidates fail.  The chance of success is dependent on a number of factors, but speaking very generally, for ten to fifteen drugs that enter a phase 1 clinical trial, only 1 makes it to the market.  Remember, that drug has only a 30% chance of recouping its development costs.</p><p>Later today, I will add a number of posts that detail the approval process in the US.  This process is mirrored pretty closely in other countries.</p><p>I am going to skip over the early discovery efforts as they’re not really germane to the conversation and focus instead on the necessary steps to entering the clinic.  Entering the clinic means administering an investigational drug to humans—you’re essentially using humans as test subjects.</p><p>As said previously, the FDA wants to see that a drug is both safe and effective.  The company tests the drug in many biological and model systems to demonstrate efficacy.  Often animals, mammals, but usually mice or rats, are specifically bred with a condition: a type of cancer or other disease.  The drug is tested against these animals and if the experiment works, the drug is pushed along towards the clinic.  These animals or other model systems are administered escalating doses of the drug and the response is monitored.  A therapeutic range is determined: how many milligrams of the drug is required per kilogram of body mass of the test subject.</p><p>In parallel companies carry out experiments on other animals to determine if the drugs are safe.  The animals are given escalating doses of the drug and their main organs and systems are examined for signs of toxicity.  The dose that most interests investigators is in the vicinity of the therapeutic range and higher.  How the drug is absorbed, distributes itself around the body, is metabolized (consumed by various biological processes) and is disposed of is also examine.  Animals are “sacrificed.”  It’s a part of science that makes many uncomfortable and scores of companies are investigation different ways of accomplishing he same results without the need for animal sacrifice; however, to date, no satisfactory alternative has been found.</p><p>The reason animals are used is that their DNA and, consequently, their biological systems resemble those of humans.  Yeast has 50% of our genes; higher primates are closer to 97 or more percent.</p><p>If the drug is found to be effective in some model systems and safe in lower life forms, the safety is tested in other animals: the experiment moves up the food chain.  Work carried out in rats and mice continues into dogs and, eventually, into primates.  There are chimpanzees who have “worked” in the pharmaceutical industry for thirty to forty years.  Primates aren’t sacrificed in the discovery/development process, but other animals are.  Typically, animals are administered </p><p>Once the company believes that the drug works effectively and that asks the FDA for permission to administer the drug in humans by submitting an IND or Investigational New Drug application.  The company shows that the results in animal and model systems and gives a proposal for how this drug will be administered in humans.  The goal is to demonstrated to the agency that the company knows what it is doing; it has developed meaningful scientific data in its preclinical studies and that it will administer this novel drug in humans in a responsible way under the guidance of professionals, ensuring that any problems with toxicity (side effects) are found quickly.</p><p>If the agency is happy with the IND and approval is granted, the company can begin a Phase 1 clinical trial.</p><p>The clinical trial process begins with successful submission of an NDA.  The company then conducts what are called clinical trials: experiments where the drug is administered to humans.  There are three main types of trials: a phase I where safety is evaluated; a larger phase II trial where the first determination of efficacy is made and a much, much larger phase III trial where efficacy is determined in a group that mirrors the target population.  Once the trials are completed, a New Drug Application, NDA, is submitted to the FDA.  If the FDA sees problems, it can send a “refusal to file” notice within two months; otherwise, it issues a PDUFA date, the date on which is will make its decision.  About 55 days or more before the PDUFA date, the FDA can announce an advisory panel.  This panel gives its recommendation which the FDA can decide to follow, though sometimes it doesn’t.  If the FDA is happy with the submission, it can grant marketing approval to the company, after which the company is free to sell the drug.</p><p>The next few posts will provide more details about this process.</p><h3>Phase I clinical trials</h3><p>Once the company receives approval from the FDA for its Investigational New Drug application, the company is free to administer the drug to humans using the protocols it proposed to the agency.  A pure phase I clinical trial is used to determine the safety of the drug—it doesn’t look at efficacy.  The goal is to ensure that the drug is safe to administer to humans in the proposed therapeutic window for the active ingredient: the molecule that does the work.  The therapeutic window is the concentration of the drug that’s anticipated to measure its effectiveness.</p><p>There are different types of Phase I trials.  However, the main goal is to determine safety in the therapeutic window.  The subjects selected for the trial are almost always healthy volunteers without the target indication.  Often escalating doses are administered to a small group of patients, around 20 to 50 people, and the response measured.  The trial usually occurs in a hospital setting and major systems and organs are monitored until the drug is safely expelled from the body.  How the body absorbs the drug, distributes it around the various organs, metabolizes it (destroys it through metabolic processes in the body) and gets rid of it are monitored carefully.  The dose may then be slowly escalated in other groups of subjects up to and above the effective level.  In no cases is the dose escalated to the level where it was found to be toxic in any animal studies.</p><p>For small organic molecules, about thirty percent or so of programs fail because of toxicity issues; the take home lesson here is that, while in many cases animal studies show the drug to be safe, it’s only in an actual human trial that this statement can be verified.  Suffice it to say that if investigators could find a better option than animal models, they would use it.  The success rate for large molecules, proteins (which includes monoclonal antibodies, etc.) is higher.  Over ninety percent of such drugs are successful in a phase 1 trial.</p><p>In rare instances a Phase I trial is carried out with subjects who have a serious condition.  This option is sometimes deemed appropriate for patients with, say, a fatal cancer were few if any other therapeutic options exist.</p><p>While healthy volunteers are used in the study, the company could conduct two or three clinical trials to ensure the safety of the drug at different doses and when administered under different conditions.  A complete phase I trial set can last from six months to, in some cases, two years.</p><p>The company presents its results to the FDA and if the drug is deemed safe, the company can then proceed to a phase II trial.</p><h3>Phase II Clinical Trials</h3><p>The combined efforts of preclinical and Phase I clinical activities convince the researchers that the drug candidate is safe: a determination is now made if the drug is effective.  A phase II clinical trial begins.</p><p>A Phase II trial typically consists of about 50 to 200 patients with the target indication, the disease or ailment, and few if any other problems.  The goal is to answer questions about the indication in question.  Some clinical trials can be larger; in a few instances they can be smaller.  A Phase II trial is larger than a Phase I with an emphasis on efficacy, but there is also an overriding emphasis on safety.</p><p>Nowadays, you’ll almost always hear of a company having “a Phase II trial” and a “Phase IIb trial.”  There are differences between the two.  A IIb is sometimes called a pivotal study.  Since the subjects in a Phase II trial are stricken with the indication of interest, dosing experiments are carried out to confirm or determine the therapeutic window: basically, now much drug to give a patient.  Typically a Phase II trial is the first time that a patient with the indication is administered the drug.</p><p>A Phase IIb trial is the one to watch, because here the efficacy of the drug is assessed.  The gold standard for such a trial, and one that the FDA requires for approval, is a double-blind, randomized study.  In this study, the patient group is divided in two, though not necessarily half; one group is administered the investigational drug, the other group is administered a placebo.  A placebo is a tablet or other drug form that has no therapeutic value but that, in its make-up, is indistinguishable from the real investigational drug.  Neither the medical practitioners administering the drug nor the patients receiving it know which group they are in.  The drugs, patients and practitioners are coded by the investigators who, at the end of the study, “unblind” the results and analyze the data.  Once analyzed, the company publishes the results at conventions or in referred journals and communicates the news to the FDA.  Successful completion of a Phase IIb clinical trial is necessary if the drug is to progress further.</p><p>It should be noted that in many instances a traditional placebo is not used.  When there are ethical implications—for example, if the indication is life threatening—the new therapy is compared against the current standard of care in a controlled environment.  It makes the statistical analysis of the results potentially more challenging, as the company must show that the new therapy is at the very least as good as what is currently offered in the market place.</p><p>The stock price of a public company general moves up after successful completion of a Phase IIb trial.  It is a major milestone for the company and greatly reduces, but doesn’t eliminate, the risk of failure of the company.</p><p>Small molecules have a higher rate of failure in Phase II than do large molecules such as proteins and related compounds.  Approximately of third of small molecule drugs are successful in a Phase II study; around two-thirds of large molecule drugs move from Phase II to III.  Phase II clinical trials can last for 6 months, in exceptional circumstances, to three years.</p><p>Once the trial is over, the company usually meets with the FDA to decide on next steps.</p><p>In some circumstances, the FDA can order the trial to halt if there are safety concerns.  If a death occurs, the company itself acts quickly and stops the trial, but there have been examples where the drug appears to be so effective that the FDA orders the study to be unblinded.  If it’s clear that the drug works as well as or better than expected, the agency usually tells the company to proceed immediately into Phase III.</p><p>A discussion on Phase III follows next.</p><h3>Phase III Clinical Trials</h3><p>A phase III clinical trial is where the proverbial rubber meets the road.  Without at least two successful phase III trials, a drug is unlikely to be approved by the FDA in the United States or the EMA (or national agencies) in Europe.  A phase III trial can, in rare instances, consist of as few as 300 enrollees to as many as 3,000.  Typical trials contain about 1,000 people.  The goal of the trial is to show that the treatment works in a typical cross section of the population that would take the medicine.  A phase II trial is much more controlled in that the patient population usually has the condition of interest and nothing else.  In a phase III trial, the goal is to mimic a typical user, so patients may be taking other mediations; they may have strange diet habits; they could have other ailments, etc.  One of the key challenges in constructing any clinical trial is compliance: that patients will continue to take the medication as prescribed.  If many patients fail to complete the course of therapy, it can affect the outcome of the results.  Therefore, companies usually enroll many more patients in the trial than are strictly required, since they’re aware that many will simply not complete the treatment.</p><p>A phase III clinical trial consists of a group of patients with the target ailment; the study is randomized: patients are divided into different groups for reasons discussed later; these selections are carried out randomly.  The study is double-blind: that is neither the clinician involved in the study nor the patients know which medicine, if any, they are receiving.  Finally, the investigational new drug is compared against a current therapy in a control group—often the “gold standard” or best therapy for the indication.  If the drug is demonstrated to be safe and more effective than the current, best therapy then it is almost certainly assured of receiving marketing approval from the FDA.</p><p>Trials are also usually conducted at multiple sites—five or more is not uncommon—so you’ll often hear of a “multicenter trial.”  The site is normally a hospital where a physician who is a leading practitioner in area heads the study.  To get approval, a company generally needs at least two successful, phase III, multicenter, double blind trials.  The trials must meet their endpoints.  The endpoint is a result that either (a) the FDA has as a standard or (b) that the company and the FDA have agreed together prior to the start of the trial.</p><p>The study is conducted in the hospital center.  Patients are carefully monitored for what are termed “adverse events” (AEs): side effects or signs of toxicity.  The worst of all AEs is the death of a patient: unless the trial is being carried out for an indication where the mortality rate is high, such an AE can have a serious impact on the ability of the company to continue the trial.  If an autopsy suggests that the medication in the trial was in any way responsible for the death of the subject, it is likely that the trial would be suspended or even ended.</p><p>In some cases where an AE occurs, if the reason isn’t clear, the result can be sent to an independent third-party panel for adjudication.  If the panel determines that there are no concerns, the trial could continue.</p><p>Pharmaceutical companies are all about label claims.  A good rule of thumb is that a company needs at least one phase III clinical trial for each label claim that is made.  When reading a medication, you’ll see often many claims made by the company.  For example, Lipitor says things like “LIPITOR, along with diet, is clinically proven to reduce the risk of heart attack, stroke, certain kinds of heart surgeries, and chest pain in patients with heart disease or several common risk factors for heart disease. Common risk factors include family history of early heart disease, high blood pressure, age, low HDL ("good") cholesterol, and smoking.”  Each of these claims must be demonstrated by a clinical trial for the FDA to grant permission to use the assertion.</p><p>Once the trial is completed, the results are unblinded and statisticians examine and analyze the results.  A comparison is made between the group or groups receiving the medication and those in the control group.  The goal is to demonstrate that the difference, if one exists, couldn’t occur randomly.  The assumption then becomes that the drug has beneficial effects.  If both clinical trials demonstrate efficacy, then it is in a good position to be approved by the FDA.</p><p>The success rate for small molecules in a phase III clinical trial is 60%, higher than in either phase I or II; for a large molecule (a macromolecule such as a protein), the success rate is closer to 45%.</p><p>The results are compiled into a submission called a “New Drug Application” (an NDA) and submitted to the FDA for review.  That process is described next.</p><h3>Requesting Marketing Approval from the FDA</h3><p>Once all the clinical trials are completed, the drug company combines all its preclinical and clinical results and combines them into a document known as a New Drug Application or NDA.  The form and format of the NDA is determined by the Food and Drug Administration.  While in the past, a paper submission could consists of tens of thousands of documents occupying millions of pages—enough to fill a semi—today, the FDA favors electronic submission and almost three-quarters of submissions are in electronic form.</p><p>The FDA reviews the submission to determine if the drug is safe and effective; if the manufacturing process for the drug is in control and if the labeling proposed by the company is accurate and appropriate.</p><p>It’s important to realize that the FDA does not conduct any clinical trials on the drug itself; they analyze those presented by the company.  The FDA may also take the raw data submitted by the company and subject it to an independent or different statistical analysis to determine efficacy.  The FDA may also visit both the manufacturer of the drug itself and the producer of the final medication (the tablet, patch, injectable form, etc.) to ensure that production is in control.</p><p>The submitting company is required to present a detail, unvarnished history of the development of the drug from its earliest stages in discover through its most recent clinical trial.  The company is not allowed to omit information that it believes is detrimental to the successful approval of the drug.  The review process has become pretty predictable following the enactment of the Prescription Drug User Fee Act of 1992, (PDUFA).  With this law, companies can pay fees which cover the costs that the FDA incurs in hiring, training and using its employees to review submissions.  Some believe that these PDUFA fees, which can total $1 million to $2 million per drug make the agency too close to the drug companies; other argue that a better analogy might be a toll collector and a driver.  The PDFUA act and changes made a few years later have really increased the speed at which drugs are reviewed.</p><p>Once the submission is received, the FDA makes an evaluation of the package within 60 days and issues a response within 74 days.  A reviewer will examine the package and the agency will issue either an acceptance letter or a “Refusal to File” letter.  This refusal letter is public and the agency will state why: the submission may not be in the correct form or the agency may have found a problem with some of the results.  If the application is accepted the agency will inform the company if it will receive standard (10 month) or accelerated (6 month) review.  A PDUFA date—the date on which a decision will be made—is most likely given.</p><p>A refusal to file letter is not a death sentence.  If the reason is trivial, the company can quickly correct the problem and submit amendments to the application.  Overreaction to such a response in the market could present a buying opportunity for an astute investor.</p><p>The FDA can continue to make more requests for information or clarification during the review process.  Unless these requests are deemed substantive by the company, it’s unlikely that any public disclosure will be made.</p><p>At least fifty-five days before the PDFUA date, the FDA can inform the company that the application will be referred to an advisory committee, often called a panel.  The FDA has forty to fifty standard committees made up of experts in different fields of medicine, biology, etc.  The committee reviews an abbreviated document of around 200 pages that describes the drug, its development, clinical trials, other therapies, etc.  The committee, which can consist of a few dozen experts, will vote on efficacy and safety.  The FDA has no obligation to follow the advice of the committee.  About 20 to 30% of applications are referred to advisory committees.  FDA guidance documents are published two days before the committee meets and provide good insight into the process.  Involvement of an advisory committee or panel doesn’t appear to have any impact on the ultimate success of the drug in the approval process.</p><p>The final step is a decision on marketing approval by the FDA.  In about 1 in 5 cases, the FDA has failed to meet its PDUFA date obligation and has delayed a decision by up to six months.  The FDA will publish its decision called an approval letter if the result is positive.  If the FDA declines marketing approval, it will state the reason or reasons in a non-approval letter.  The agency will communicate to the comapny any actions it needs to take to correct defects in the original submission.</p><h3>Other Things that Happen during the Approval Process</h3><p>The approval process starts when a company files its NDA with the FDA.  At that point a clock starts ticking leading to drug approval ideally twelve months after the NDA is received by the FDA.  During that time a number of things might happen.</p><h3>Inspection of Manufacturing Sites</h3><p>Prior to receiving marketing approval, the FDA has the right to inspect the manufacturing site where the active ingredient is made (the molecule that does the work) and where the drug is formulated and packaged (where the active ingredient is formulated into a tablet or other end product).  These inspections are called Pre-Approval Inspections or PAIs.  In some cases, where the FDA has a good relationship with the manufacturing or formulation site, the agency might waive this inspection.</p><p>Companies manufacture and formulate according to a quality philosophy called current Good Manufacturing Practices or cGMP.  It is a philosophy as the FDA insists that each manufacturing site keep abreast of standards of excellence within the industry and to incorporate them into the manufacturing processes for a particular site.  Each manufacturing site develops its own cGMP system run by standard operating procedures (SOPs).  An FDA inspector will examine these guiding documents to ensure they meet current standards.  SOPs drive things like Master Batch Records, MBRs, the “recipe” by which a chemical is produced.  The FDA will look at executed MBRs, which are documents which chemical operators have followed in carrying out a chemical step in making the active ingredient.  The executed MBR will contain appropriate details of what the operator did and when he or she did it.  If problems occurred, these will be noted and addressed following the appropriate SOP in the GMP system.  Chemicals will be tested as required following steps outlined in the appropriate document.  It’s a complex document-driven system that details, step-by-step, what must be done.  It is designed to ensure the highest quality of the end product and complete repeatability in the manufacturing process.  The process for formulating the API into a tablet or other deliverable uses a similar, cGMP system; an FDA inspector reviews a final dosage form manufacturing site in a similar fashion.</p><p>If an FDA inspector notes problems in the process, he or she can issue an observation on form 483, detailing what was observed and what corrective actions are necessary.  If the problems are serious, the matter can be escalated to the point of shutting the plant down.  If the manufacturing site does not pass the PAI, the NDA will be rejected or, more likely, delayed.  Problems in the manufacturing process, problems in carrying out a long-term stability study, or problems in the formulation or packaging are sufficient to delay marketing approval for a drug.</p><p>Large pharmaceutical companies often carry out chemical manufacturing, formulation and packaging in their own facilities.  However, almost all emerging pharmaceutical companies outsource these activities to one of scores of Contract Manufacturing Organizations (CMOs) located in the US, Europe and Asia.</p>

<p>In this article I am going to detail in broad strokes the necessary steps to getting marketing approval to sell a drug in the US. It's a complex process, but the various steps are easy to follow. It's also critical to understand this process if you wish to profit from investing in biotech and pharma.</p><p>To sell a drug in the United States, a company must get permission from the Food and Drug Administration, an entity which is part of the Department of Health and Human Services.  The FDA enjoys authority over a large part of the economy, but exercises it most clearly when it comes to the marketing and sale of medications and medical devices.</p><p>Contrary to what is written in many investing publications, the FDA is actually a very easy entity to navigate.  I am not saying that it’s an agency without problems.  It has a clear process for drug approval and, if these are met, a company should expect permission to sell its product in the United States.</p><p>In Europe there are similar entities, but on the national and EU level: Europe is moving towards a centralized system of drug approval.  In fact, the EMA, formerly called the EMEA, can grant approval for marketing in all EU member states under certain conditions; otherwise, the EMA seems to function more as a coordinating body.  It has similar characteristics to the FDA.  Japan has its own approval process and is, in many important respects, similar to the US.</p><p>The FDA focuses on two things during the approval process: is the drug safe and is it effective.  Companies spend hundreds of millions of dollars trying to answer these questions before they receive marketing approval.  In most cases, companies do not get permission to sell their drug; if they do, there’s only a 30% chance that they will recoup their development expenses.  For those that follow biotech companies, most companies fail because most development candidates fail.  The chance of success is dependent on a number of factors, but speaking very generally, for ten to fifteen drugs that enter a phase 1 clinical trial, only 1 makes it to the market.  Remember, that drug has only a 30% chance of recouping its development costs.</p><p>Later today, I will add a number of posts that detail the approval process in the US.  This process is mirrored pretty closely in other countries.</p><p>I am going to skip over the early discovery efforts as they’re not really germane to the conversation and focus instead on the necessary steps to entering the clinic.  Entering the clinic means administering an investigational drug to humans—you’re essentially using humans as test subjects.</p><p>As said previously, the FDA wants to see that a drug is both safe and effective.  The company tests the drug in many biological and model systems to demonstrate efficacy.  Often animals, mammals, but usually mice or rats, are specifically bred with a condition: a type of cancer or other disease.  The drug is tested against these animals and if the experiment works, the drug is pushed along towards the clinic.  These animals or other model systems are administered escalating doses of the drug and the response is monitored.  A therapeutic range is determined: how many milligrams of the drug is required per kilogram of body mass of the test subject.</p><p>In parallel companies carry out experiments on other animals to determine if the drugs are safe.  The animals are given escalating doses of the drug and their main organs and systems are examined for signs of toxicity.  The dose that most interests investigators is in the vicinity of the therapeutic range and higher.  How the drug is absorbed, distributes itself around the body, is metabolized (consumed by various biological processes) and is disposed of is also examine.  Animals are “sacrificed.”  It’s a part of science that makes many uncomfortable and scores of companies are investigation different ways of accomplishing he same results without the need for animal sacrifice; however, to date, no satisfactory alternative has been found.</p><p>The reason animals are used is that their DNA and, consequently, their biological systems resemble those of humans.  Yeast has 50% of our genes; higher primates are closer to 97 or more percent.</p><p>If the drug is found to be effective in some model systems and safe in lower life forms, the safety is tested in other animals: the experiment moves up the food chain.  Work carried out in rats and mice continues into dogs and, eventually, into primates.  There are chimpanzees who have “worked” in the pharmaceutical industry for thirty to forty years.  Primates aren’t sacrificed in the discovery/development process, but other animals are.  Typically, animals are administered </p><p>Once the company believes that the drug works effectively and that asks the FDA for permission to administer the drug in humans by submitting an IND or Investigational New Drug application.  The company shows that the results in animal and model systems and gives a proposal for how this drug will be administered in humans.  The goal is to demonstrated to the agency that the company knows what it is doing; it has developed meaningful scientific data in its preclinical studies and that it will administer this novel drug in humans in a responsible way under the guidance of professionals, ensuring that any problems with toxicity (side effects) are found quickly.</p><p>If the agency is happy with the IND and approval is granted, the company can begin a Phase 1 clinical trial.</p><p>The clinical trial process begins with successful submission of an NDA.  The company then conducts what are called clinical trials: experiments where the drug is administered to humans.  There are three main types of trials: a phase I where safety is evaluated; a larger phase II trial where the first determination of efficacy is made and a much, much larger phase III trial where efficacy is determined in a group that mirrors the target population.  Once the trials are completed, a New Drug Application, NDA, is submitted to the FDA.  If the FDA sees problems, it can send a “refusal to file” notice within two months; otherwise, it issues a PDUFA date, the date on which is will make its decision.  About 55 days or more before the PDUFA date, the FDA can announce an advisory panel.  This panel gives its recommendation which the FDA can decide to follow, though sometimes it doesn’t.  If the FDA is happy with the submission, it can grant marketing approval to the company, after which the company is free to sell the drug.</p><p>The next few posts will provide more details about this process.</p><h3>Phase I clinical trials</h3><p>Once the company receives approval from the FDA for its Investigational New Drug application, the company is free to administer the drug to humans using the protocols it proposed to the agency.  A pure phase I clinical trial is used to determine the safety of the drug—it doesn’t look at efficacy.  The goal is to ensure that the drug is safe to administer to humans in the proposed therapeutic window for the active ingredient: the molecule that does the work.  The therapeutic window is the concentration of the drug that’s anticipated to measure its effectiveness.</p><p>There are different types of Phase I trials.  However, the main goal is to determine safety in the therapeutic window.  The subjects selected for the trial are almost always healthy volunteers without the target indication.  Often escalating doses are administered to a small group of patients, around 20 to 50 people, and the response measured.  The trial usually occurs in a hospital setting and major systems and organs are monitored until the drug is safely expelled from the body.  How the body absorbs the drug, distributes it around the various organs, metabolizes it (destroys it through metabolic processes in the body) and gets rid of it are monitored carefully.  The dose may then be slowly escalated in other groups of subjects up to and above the effective level.  In no cases is the dose escalated to the level where it was found to be toxic in any animal studies.</p><p>For small organic molecules, about thirty percent or so of programs fail because of toxicity issues; the take home lesson here is that, while in many cases animal studies show the drug to be safe, it’s only in an actual human trial that this statement can be verified.  Suffice it to say that if investigators could find a better option than animal models, they would use it.  The success rate for large molecules, proteins (which includes monoclonal antibodies, etc.) is higher.  Over ninety percent of such drugs are successful in a phase 1 trial.</p><p>In rare instances a Phase I trial is carried out with subjects who have a serious condition.  This option is sometimes deemed appropriate for patients with, say, a fatal cancer were few if any other therapeutic options exist.</p><p>While healthy volunteers are used in the study, the company could conduct two or three clinical trials to ensure the safety of the drug at different doses and when administered under different conditions.  A complete phase I trial set can last from six months to, in some cases, two years.</p><p>The company presents its results to the FDA and if the drug is deemed safe, the company can then proceed to a phase II trial.</p><h3>Phase II Clinical Trials</h3><p>The combined efforts of preclinical and Phase I clinical activities convince the researchers that the drug candidate is safe: a determination is now made if the drug is effective.  A phase II clinical trial begins.</p><p>A Phase II trial typically consists of about 50 to 200 patients with the target indication, the disease or ailment, and few if any other problems.  The goal is to answer questions about the indication in question.  Some clinical trials can be larger; in a few instances they can be smaller.  A Phase II trial is larger than a Phase I with an emphasis on efficacy, but there is also an overriding emphasis on safety.</p><p>Nowadays, you’ll almost always hear of a company having “a Phase II trial” and a “Phase IIb trial.”  There are differences between the two.  A IIb is sometimes called a pivotal study.  Since the subjects in a Phase II trial are stricken with the indication of interest, dosing experiments are carried out to confirm or determine the therapeutic window: basically, now much drug to give a patient.  Typically a Phase II trial is the first time that a patient with the indication is administered the drug.</p><p>A Phase IIb trial is the one to watch, because here the efficacy of the drug is assessed.  The gold standard for such a trial, and one that the FDA requires for approval, is a double-blind, randomized study.  In this study, the patient group is divided in two, though not necessarily half; one group is administered the investigational drug, the other group is administered a placebo.  A placebo is a tablet or other drug form that has no therapeutic value but that, in its make-up, is indistinguishable from the real investigational drug.  Neither the medical practitioners administering the drug nor the patients receiving it know which group they are in.  The drugs, patients and practitioners are coded by the investigators who, at the end of the study, “unblind” the results and analyze the data.  Once analyzed, the company publishes the results at conventions or in referred journals and communicates the news to the FDA.  Successful completion of a Phase IIb clinical trial is necessary if the drug is to progress further.</p><p>It should be noted that in many instances a traditional placebo is not used.  When there are ethical implications—for example, if the indication is life threatening—the new therapy is compared against the current standard of care in a controlled environment.  It makes the statistical analysis of the results potentially more challenging, as the company must show that the new therapy is at the very least as good as what is currently offered in the market place.</p><p>The stock price of a public company general moves up after successful completion of a Phase IIb trial.  It is a major milestone for the company and greatly reduces, but doesn’t eliminate, the risk of failure of the company.</p><p>Small molecules have a higher rate of failure in Phase II than do large molecules such as proteins and related compounds.  Approximately of third of small molecule drugs are successful in a Phase II study; around two-thirds of large molecule drugs move from Phase II to III.  Phase II clinical trials can last for 6 months, in exceptional circumstances, to three years.</p><p>Once the trial is over, the company usually meets with the FDA to decide on next steps.</p><p>In some circumstances, the FDA can order the trial to halt if there are safety concerns.  If a death occurs, the company itself acts quickly and stops the trial, but there have been examples where the drug appears to be so effective that the FDA orders the study to be unblinded.  If it’s clear that the drug works as well as or better than expected, the agency usually tells the company to proceed immediately into Phase III.</p><p>A discussion on Phase III follows next.</p><h3>Phase III Clinical Trials</h3><p>A phase III clinical trial is where the proverbial rubber meets the road.  Without at least two successful phase III trials, a drug is unlikely to be approved by the FDA in the United States or the EMA (or national agencies) in Europe.  A phase III trial can, in rare instances, consist of as few as 300 enrollees to as many as 3,000.  Typical trials contain about 1,000 people.  The goal of the trial is to show that the treatment works in a typical cross section of the population that would take the medicine.  A phase II trial is much more controlled in that the patient population usually has the condition of interest and nothing else.  In a phase III trial, the goal is to mimic a typical user, so patients may be taking other mediations; they may have strange diet habits; they could have other ailments, etc.  One of the key challenges in constructing any clinical trial is compliance: that patients will continue to take the medication as prescribed.  If many patients fail to complete the course of therapy, it can affect the outcome of the results.  Therefore, companies usually enroll many more patients in the trial than are strictly required, since they’re aware that many will simply not complete the treatment.</p><p>A phase III clinical trial consists of a group of patients with the target ailment; the study is randomized: patients are divided into different groups for reasons discussed later; these selections are carried out randomly.  The study is double-blind: that is neither the clinician involved in the study nor the patients know which medicine, if any, they are receiving.  Finally, the investigational new drug is compared against a current therapy in a control group—often the “gold standard” or best therapy for the indication.  If the drug is demonstrated to be safe and more effective than the current, best therapy then it is almost certainly assured of receiving marketing approval from the FDA.</p><p>Trials are also usually conducted at multiple sites—five or more is not uncommon—so you’ll often hear of a “multicenter trial.”  The site is normally a hospital where a physician who is a leading practitioner in area heads the study.  To get approval, a company generally needs at least two successful, phase III, multicenter, double blind trials.  The trials must meet their endpoints.  The endpoint is a result that either (a) the FDA has as a standard or (b) that the company and the FDA have agreed together prior to the start of the trial.</p><p>The study is conducted in the hospital center.  Patients are carefully monitored for what are termed “adverse events” (AEs): side effects or signs of toxicity.  The worst of all AEs is the death of a patient: unless the trial is being carried out for an indication where the mortality rate is high, such an AE can have a serious impact on the ability of the company to continue the trial.  If an autopsy suggests that the medication in the trial was in any way responsible for the death of the subject, it is likely that the trial would be suspended or even ended.</p><p>In some cases where an AE occurs, if the reason isn’t clear, the result can be sent to an independent third-party panel for adjudication.  If the panel determines that there are no concerns, the trial could continue.</p><p>Pharmaceutical companies are all about label claims.  A good rule of thumb is that a company needs at least one phase III clinical trial for each label claim that is made.  When reading a medication, you’ll see often many claims made by the company.  For example, Lipitor says things like “LIPITOR, along with diet, is clinically proven to reduce the risk of heart attack, stroke, certain kinds of heart surgeries, and chest pain in patients with heart disease or several common risk factors for heart disease. Common risk factors include family history of early heart disease, high blood pressure, age, low HDL ("good") cholesterol, and smoking.”  Each of these claims must be demonstrated by a clinical trial for the FDA to grant permission to use the assertion.</p><p>Once the trial is completed, the results are unblinded and statisticians examine and analyze the results.  A comparison is made between the group or groups receiving the medication and those in the control group.  The goal is to demonstrate that the difference, if one exists, couldn’t occur randomly.  The assumption then becomes that the drug has beneficial effects.  If both clinical trials demonstrate efficacy, then it is in a good position to be approved by the FDA.</p><p>The success rate for small molecules in a phase III clinical trial is 60%, higher than in either phase I or II; for a large molecule (a macromolecule such as a protein), the success rate is closer to 45%.</p><p>The results are compiled into a submission called a “New Drug Application” (an NDA) and submitted to the FDA for review.  That process is described next.</p><h3>Requesting Marketing Approval from the FDA</h3><p>Once all the clinical trials are completed, the drug company combines all its preclinical and clinical results and combines them into a document known as a New Drug Application or NDA.  The form and format of the NDA is determined by the Food and Drug Administration.  While in the past, a paper submission could consists of tens of thousands of documents occupying millions of pages—enough to fill a semi—today, the FDA favors electronic submission and almost three-quarters of submissions are in electronic form.</p><p>The FDA reviews the submission to determine if the drug is safe and effective; if the manufacturing process for the drug is in control and if the labeling proposed by the company is accurate and appropriate.</p><p>It’s important to realize that the FDA does not conduct any clinical trials on the drug itself; they analyze those presented by the company.  The FDA may also take the raw data submitted by the company and subject it to an independent or different statistical analysis to determine efficacy.  The FDA may also visit both the manufacturer of the drug itself and the producer of the final medication (the tablet, patch, injectable form, etc.) to ensure that production is in control.</p><p>The submitting company is required to present a detail, unvarnished history of the development of the drug from its earliest stages in discover through its most recent clinical trial.  The company is not allowed to omit information that it believes is detrimental to the successful approval of the drug.  The review process has become pretty predictable following the enactment of the Prescription Drug User Fee Act of 1992, (PDUFA).  With this law, companies can pay fees which cover the costs that the FDA incurs in hiring, training and using its employees to review submissions.  Some believe that these PDUFA fees, which can total $1 million to $2 million per drug make the agency too close to the drug companies; other argue that a better analogy might be a toll collector and a driver.  The PDFUA act and changes made a few years later have really increased the speed at which drugs are reviewed.</p><p>Once the submission is received, the FDA makes an evaluation of the package within 60 days and issues a response within 74 days.  A reviewer will examine the package and the agency will issue either an acceptance letter or a “Refusal to File” letter.  This refusal letter is public and the agency will state why: the submission may not be in the correct form or the agency may have found a problem with some of the results.  If the application is accepted the agency will inform the company if it will receive standard (10 month) or accelerated (6 month) review.  A PDUFA date—the date on which a decision will be made—is most likely given.</p><p>A refusal to file letter is not a death sentence.  If the reason is trivial, the company can quickly correct the problem and submit amendments to the application.  Overreaction to such a response in the market could present a buying opportunity for an astute investor.</p><p>The FDA can continue to make more requests for information or clarification during the review process.  Unless these requests are deemed substantive by the company, it’s unlikely that any public disclosure will be made.</p><p>At least fifty-five days before the PDFUA date, the FDA can inform the company that the application will be referred to an advisory committee, often called a panel.  The FDA has forty to fifty standard committees made up of experts in different fields of medicine, biology, etc.  The committee reviews an abbreviated document of around 200 pages that describes the drug, its development, clinical trials, other therapies, etc.  The committee, which can consist of a few dozen experts, will vote on efficacy and safety.  The FDA has no obligation to follow the advice of the committee.  About 20 to 30% of applications are referred to advisory committees.  FDA guidance documents are published two days before the committee meets and provide good insight into the process.  Involvement of an advisory committee or panel doesn’t appear to have any impact on the ultimate success of the drug in the approval process.</p><p>The final step is a decision on marketing approval by the FDA.  In about 1 in 5 cases, the FDA has failed to meet its PDUFA date obligation and has delayed a decision by up to six months.  The FDA will publish its decision called an approval letter if the result is positive.  If the FDA declines marketing approval, it will state the reason or reasons in a non-approval letter.  The agency will communicate to the comapny any actions it needs to take to correct defects in the original submission.</p><h3>Other Things that Happen during the Approval Process</h3><p>The approval process starts when a company files its NDA with the FDA.  At that point a clock starts ticking leading to drug approval ideally twelve months after the NDA is received by the FDA.  During that time a number of things might happen.</p><h3>Inspection of Manufacturing Sites</h3><p>Prior to receiving marketing approval, the FDA has the right to inspect the manufacturing site where the active ingredient is made (the molecule that does the work) and where the drug is formulated and packaged (where the active ingredient is formulated into a tablet or other end product).  These inspections are called Pre-Approval Inspections or PAIs.  In some cases, where the FDA has a good relationship with the manufacturing or formulation site, the agency might waive this inspection.</p><p>Companies manufacture and formulate according to a quality philosophy called current Good Manufacturing Practices or cGMP.  It is a philosophy as the FDA insists that each manufacturing site keep abreast of standards of excellence within the industry and to incorporate them into the manufacturing processes for a particular site.  Each manufacturing site develops its own cGMP system run by standard operating procedures (SOPs).  An FDA inspector will examine these guiding documents to ensure they meet current standards.  SOPs drive things like Master Batch Records, MBRs, the “recipe” by which a chemical is produced.  The FDA will look at executed MBRs, which are documents which chemical operators have followed in carrying out a chemical step in making the active ingredient.  The executed MBR will contain appropriate details of what the operator did and when he or she did it.  If problems occurred, these will be noted and addressed following the appropriate SOP in the GMP system.  Chemicals will be tested as required following steps outlined in the appropriate document.  It’s a complex document-driven system that details, step-by-step, what must be done.  It is designed to ensure the highest quality of the end product and complete repeatability in the manufacturing process.  The process for formulating the API into a tablet or other deliverable uses a similar, cGMP system; an FDA inspector reviews a final dosage form manufacturing site in a similar fashion.</p><p>If an FDA inspector notes problems in the process, he or she can issue an observation on form 483, detailing what was observed and what corrective actions are necessary.  If the problems are serious, the matter can be escalated to the point of shutting the plant down.  If the manufacturing site does not pass the PAI, the NDA will be rejected or, more likely, delayed.  Problems in the manufacturing process, problems in carrying out a long-term stability study, or problems in the formulation or packaging are sufficient to delay marketing approval for a drug.</p><p>Large pharmaceutical companies often carry out chemical manufacturing, formulation and packaging in their own facilities.  However, almost all emerging pharmaceutical companies outsource these activities to one of scores of Contract Manufacturing Organizations (CMOs) located in the US, Europe and Asia.</p> 2010-05-08T21:00:01Z 2010-05-08T21:00:01Z /index.php?option=com_content&amp;view=article&amp;id=4119:whither-intermune-nasdaqitmn&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>InterMune suffered a major setback recently when the FDA rejected marketing approval for pirfenidone, a novel treatment for idiopathic pulmonary fibrosis. All is not lost: the agency asked for one more phase III clinical study. The big question is “Whither InterMune?” What's next for this company? Are there lessons to be learned?</p><h3>Introduction</h3><p>InterMune is an emerging pharmaceutical company based on Brisbane, CA—a short drive from San Francisco. InterMune suffered a major setback this week when the FDA rejected marketing approval for pirfenidone, a treatment for idiopathic pulmonary fibrosis. InterMune submitted two phase III clinical trials in its NDA: one study met the endpoint; the second did not. Traditionally, the FDA asks for at least two phase III studies, so it wasn’t surprising that a request was made for a second trial. Many people hoped that given the approval of the drug in Japan with successfully trials for that effort; the fact that there is no other treatment for this fatal complaint and that the second, unsuccessful trial was a “near miss,” the agency might give marketing approval under strict conditions, insisting on a third phase III trial to broaden the use of the drug. It wasn’t to happen: the agency followed the process used for decades and rejected the drug, requesting a second phase III trial. By the way, pirfenidone would have been marketed as Esbriet had it received approval.<br /><br />So, what happens next and what lessons can be learned?</p><h3>The CEO and some people in senior management need to go.</h3><p>InterMune messed up in a few areas, but the response to the agency earlier this week was, well, strange.<br /><br />"After the positive FDA Advisory Committee meeting of March 9 at which the Committee recommended the approval of the pirfenidone NDA by a 9-3 margin, we are disappointed by this outcome," said Dan Welch, Chairman, Chief Executive Officer and President of InterMune. "We will meet with the FDA as soon as possible to understand their points of view and to determine the most appropriate path forward to expeditiously make Esbriet available to the approximately 100,000 patients with IPF and their families who suffer from this terrible disease and for whom no FDA-approved medicines exist." <br /><br />This last comment wasn’t necessary. Embedded in its mission, the FDA has concerns for the 100,000 patients with IPF and their families. It was a poorly measured comment unworthy of a CEO of a pharmaceutical company. To those of us in the pharmaceutical industry, it raises questions about the corporate culture within InterMune: what was the CEO thinking? It’s by no means the worst of his sins, but it is symptomatic of something untoward in the corner office of InterMune.</p><h3>Why didn’t InterMune file another shelf registration last month?</h3><p>The company did well by raising closing $100 million in January, but why didn’t it go back to the trough? It’s a perplexing lack of ambition. The share price of emerging companies spends its early days in one of two places: intensive care or fantasy world. InterMune enjoyed a six week visit to fantasy world, it should have grabbed everything it could while good judgment deferred to greed. The share price on January 20 peaked at $14.82; it recently peaked in the mid to high 40s. With close to a quarter billion dollars in debt, a plausible argument could have been made for yet another offering to raise $250 million to pay down debt. Last week, when the company had a market cap of $2.5 billion, such an offering would have had minimal dilutive impact. In the optimism that surrounded the company, the shares would have been snapped up. There was no downside to raising more money: if the drug were approved, the company would have more R&D funds—important to keep the party going. If the FDA said no, which it did, the company would have funds to finish another trial. Management should have been prepared for the possibility of a run up months ago and filed an additional shelf registration; they didn’t, so it makes one wonder if they know how the world of biotech financing operates.</p><h3>Why did InterMune file an incomplete NDA?</h3><p>I outlined the reasons earlier why many hoped the agency would grant approval—even restricted marketing approval—to pirfenidone. However, there are scores of competent consultants in the industry, including many dozen FDA veterans that likely would have cautioned InterMune on their strategy. InterMune didn’t appear to hire the correct consultants: a fault of management. I can’t think of an example where the FDA has granted marketing approval to a drug without two complete, phase III trials. Why did InterMune management think that their company would be treated differently?</p><h3>Where is Plan B?</h3><p>Why didn’t InterMune have another, phase III trial running after the NDA submission? Why was there no plan B? Understanding how the agency works, one would think a company would have another phase III trial running as a backup. It does run the risk for forcing the hand of the reviewers: the FDA might just wait until the trial is completed. However, it does speak to a lack of understanding of how the FDA, a very conservative agency, works.</p><h3>What’s next for InterMune?</h3><p>Expect a downsizing. The company has negative cash flow and earnings; its balance sheet is reasonable for an emerging pharma company, but problematic for a company in its position. Without a fresh infusion, it doesn’t have sufficient cash to run a phase III clinical trial without inject sizeable risk into the long-term viability of the company. InterMune will have to downsize considerably—perhaps losing at least half of its employees.</p><h3>Get new management</h3><p>The company needs fresh management; for the reasons I annunciated earlier, I don’t have confidence in the management of InterMune and a major shake-up is necessary. There’s no guarantee that a new management team will be able to pull the company out of its current problems, but I would hold out little hope for the future of InterMune if the current team is left in place.</p><h3>InterMune might lose pirfenidone</h3><p>There’s a chance that InterMune will sell its assets. InterMune may not be able to pay for a new trial, but other companies could help. In return, ITMN would have to surrender substantial upside: bad for current investors. One way for the company to move forward would be for InterMune to license pirfenidone to another party. It would surprise me if this effort isn’t currently underway. This option shouldn’t be alien to InterMune as it bought the rights from Marnac, Inc. in 2007. In fact, it’s not clear to me that InterMune currently owns all the rights to pirfenidone. The agreement with Marnac: since the drug is not approved, they many actually owe Marnac $14.5 million. On a bright side, failure to gain marketing approval relieves InterMune of other possible payments to Marnac.</p><h3>In conclusion</h3><p>In summary, things look bleak for InterMune right now and decisive action is needed by the board. Management appears to have failed shareholders in not capitalizing on the opportunity to raise funds after an FDA advisory panel voted in favor of the drug. The company took an extremely risk approach with its FDA NDA submission and lost. Management needs to answer tough questions.</p><p>Just one more comment: InterMune appears to be overvalued at its current price of $11.10. There's too much uncertainty surrounding this company to call it an investment. Without major changes, I'd avoid this company right now. I'd be more comfortable if the stock traded lower, certainly under $10 a share.</p>

<p>InterMune suffered a major setback recently when the FDA rejected marketing approval for pirfenidone, a novel treatment for idiopathic pulmonary fibrosis. All is not lost: the agency asked for one more phase III clinical study. The big question is “Whither InterMune?” What's next for this company? Are there lessons to be learned?</p><h3>Introduction</h3><p>InterMune is an emerging pharmaceutical company based on Brisbane, CA—a short drive from San Francisco. InterMune suffered a major setback this week when the FDA rejected marketing approval for pirfenidone, a treatment for idiopathic pulmonary fibrosis. InterMune submitted two phase III clinical trials in its NDA: one study met the endpoint; the second did not. Traditionally, the FDA asks for at least two phase III studies, so it wasn’t surprising that a request was made for a second trial. Many people hoped that given the approval of the drug in Japan with successfully trials for that effort; the fact that there is no other treatment for this fatal complaint and that the second, unsuccessful trial was a “near miss,” the agency might give marketing approval under strict conditions, insisting on a third phase III trial to broaden the use of the drug. It wasn’t to happen: the agency followed the process used for decades and rejected the drug, requesting a second phase III trial. By the way, pirfenidone would have been marketed as Esbriet had it received approval.<br /><br />So, what happens next and what lessons can be learned?</p><h3>The CEO and some people in senior management need to go.</h3><p>InterMune messed up in a few areas, but the response to the agency earlier this week was, well, strange.<br /><br />"After the positive FDA Advisory Committee meeting of March 9 at which the Committee recommended the approval of the pirfenidone NDA by a 9-3 margin, we are disappointed by this outcome," said Dan Welch, Chairman, Chief Executive Officer and President of InterMune. "We will meet with the FDA as soon as possible to understand their points of view and to determine the most appropriate path forward to expeditiously make Esbriet available to the approximately 100,000 patients with IPF and their families who suffer from this terrible disease and for whom no FDA-approved medicines exist." <br /><br />This last comment wasn’t necessary. Embedded in its mission, the FDA has concerns for the 100,000 patients with IPF and their families. It was a poorly measured comment unworthy of a CEO of a pharmaceutical company. To those of us in the pharmaceutical industry, it raises questions about the corporate culture within InterMune: what was the CEO thinking? It’s by no means the worst of his sins, but it is symptomatic of something untoward in the corner office of InterMune.</p><h3>Why didn’t InterMune file another shelf registration last month?</h3><p>The company did well by raising closing $100 million in January, but why didn’t it go back to the trough? It’s a perplexing lack of ambition. The share price of emerging companies spends its early days in one of two places: intensive care or fantasy world. InterMune enjoyed a six week visit to fantasy world, it should have grabbed everything it could while good judgment deferred to greed. The share price on January 20 peaked at $14.82; it recently peaked in the mid to high 40s. With close to a quarter billion dollars in debt, a plausible argument could have been made for yet another offering to raise $250 million to pay down debt. Last week, when the company had a market cap of $2.5 billion, such an offering would have had minimal dilutive impact. In the optimism that surrounded the company, the shares would have been snapped up. There was no downside to raising more money: if the drug were approved, the company would have more R&D funds—important to keep the party going. If the FDA said no, which it did, the company would have funds to finish another trial. Management should have been prepared for the possibility of a run up months ago and filed an additional shelf registration; they didn’t, so it makes one wonder if they know how the world of biotech financing operates.</p><h3>Why did InterMune file an incomplete NDA?</h3><p>I outlined the reasons earlier why many hoped the agency would grant approval—even restricted marketing approval—to pirfenidone. However, there are scores of competent consultants in the industry, including many dozen FDA veterans that likely would have cautioned InterMune on their strategy. InterMune didn’t appear to hire the correct consultants: a fault of management. I can’t think of an example where the FDA has granted marketing approval to a drug without two complete, phase III trials. Why did InterMune management think that their company would be treated differently?</p><h3>Where is Plan B?</h3><p>Why didn’t InterMune have another, phase III trial running after the NDA submission? Why was there no plan B? Understanding how the agency works, one would think a company would have another phase III trial running as a backup. It does run the risk for forcing the hand of the reviewers: the FDA might just wait until the trial is completed. However, it does speak to a lack of understanding of how the FDA, a very conservative agency, works.</p><h3>What’s next for InterMune?</h3><p>Expect a downsizing. The company has negative cash flow and earnings; its balance sheet is reasonable for an emerging pharma company, but problematic for a company in its position. Without a fresh infusion, it doesn’t have sufficient cash to run a phase III clinical trial without inject sizeable risk into the long-term viability of the company. InterMune will have to downsize considerably—perhaps losing at least half of its employees.</p><h3>Get new management</h3><p>The company needs fresh management; for the reasons I annunciated earlier, I don’t have confidence in the management of InterMune and a major shake-up is necessary. There’s no guarantee that a new management team will be able to pull the company out of its current problems, but I would hold out little hope for the future of InterMune if the current team is left in place.</p><h3>InterMune might lose pirfenidone</h3><p>There’s a chance that InterMune will sell its assets. InterMune may not be able to pay for a new trial, but other companies could help. In return, ITMN would have to surrender substantial upside: bad for current investors. One way for the company to move forward would be for InterMune to license pirfenidone to another party. It would surprise me if this effort isn’t currently underway. This option shouldn’t be alien to InterMune as it bought the rights from Marnac, Inc. in 2007. In fact, it’s not clear to me that InterMune currently owns all the rights to pirfenidone. The agreement with Marnac: since the drug is not approved, they many actually owe Marnac $14.5 million. On a bright side, failure to gain marketing approval relieves InterMune of other possible payments to Marnac.</p><h3>In conclusion</h3><p>In summary, things look bleak for InterMune right now and decisive action is needed by the board. Management appears to have failed shareholders in not capitalizing on the opportunity to raise funds after an FDA advisory panel voted in favor of the drug. The company took an extremely risk approach with its FDA NDA submission and lost. Management needs to answer tough questions.</p><p>Just one more comment: InterMune appears to be overvalued at its current price of $11.10. There's too much uncertainty surrounding this company to call it an investment. Without major changes, I'd avoid this company right now. I'd be more comfortable if the stock traded lower, certainly under $10 a share.</p> 2010-05-07T17:14:18Z 2010-05-07T17:14:18Z /index.php?option=com_content&amp;view=article&amp;id=4118:arena-nasdaqarna-may-10-2010-webcast&amp;catid=39:biotechnology-companies&amp;Itemid=64

<p>Arena Pharmaceuticals had a webcast for analysts and other interested parties this morning; notes and comments on this webcast are included below.</p><ul><li>No agreement with major pharma company yet;</li><li>No advisory committee (also referred to as a panel) meeting scheduled; ARNA will announce if and when they hear it; they will get a 55 day warning from the agency</li><li>Last patient later this month and results later this year</li><li>Supplement to the NDA will be filed post approval</li><li>APD 916 in phase 1; results will be announced in the third quarter</li><li>APD 997 is being evaluated by JNJ</li><li>First quarter financials: R&D expenses have decreased significantly by $24.3 million due to a decrease in clinical trial expenses<br />x Manufacturing costs are included in R&D expense</li><li>They will present more data on lorcaserin in future conferences, including the diabetes meeting in Orlando and in Arlington, VA in July</li><li>They will present at a meeting in San Diego a few weeks before the lorcaserin PDUFA date</li><li>Question on the panel: has the FDA suggested a panel is likely? Lief said no, but that September 15 and 16 there is a meeting of the panel, but he hasn't heard anything form the FDA from the FDA.</li><li>The company should hear in late July if they're going to be on the September panel.</li><li>Lief probed on commercial agreement on the company; Lief said he couldn't comment on it. Lief reiterated that Arena has always said that they are ready to launch on their own.</li><li>Worried: if they cannot form a partnership, would there be a soft launch. Lief said he doesn't like soft launches. 7500 physicians account for half of weight loss prescriptions. Arena could reach all of them with a modest sales force of 100 people. He then made a stronger statement: "as I said earlier, we do expect to sign a partnership agreement." He later said that "we expect to form an agreement before approval and before launch."</li><li>Lief commented that nothing has changed in the supplemental data for the ongoing clinical trial of the lorcaserin BLOOM trial; they will file the data as a supplement;</li><li>A competitor (Vivus) suggested that the benchmark for approval, the 5% average weight loss could change; Jack Lief said he didn't want to speculate on the thinking of the FDA and that lorcaserin meets the published efficacy standards. Lief joked that it's nice that "our competitor is changing the FDA guidance for the FDA."</li><li>Additional data on the 120 safety update. The data were submitted; it did include blinded data of an ongoing study; it summarized the most significant adverse events;</li><li>They were asked about the number of major cardiovascular adverse events in the BLOSSOM study; some cardiovascular AE data were presented and more detailed information will be presented in upcoming meetings; the data in the Phase 3 trial show that the AE is low as would be expected from the low risk people selected from the phase 3 study; the company is confident in previous statements that lorcaserin has "really good safety profile."</li><li>Guidance for the 2010 income statement is unchanged</li><li>On the $150 million shelf registration: the spend assumes no partnership with a commercial entity, so the company expects to do "a lot better than that." Lief said they need to be well advanced in anticipation of the PDUFA date and they plan to raise money opportunistically;</li><li>How long will the current cash last? Debt to Deerfield is due in July of 2011; they have already paid the $10 million due in July of 2010. It was paid last year.</li><li>If the BLOOM data is filed before the PDUFA date, will it extend approval by six months? Lief said he won't speak for the FDA: the current NDA was accepted by the FDA for a robust review; Lief doesn't feel that the BLOOM data is necessary to making a decision; the initial submission was acceptable;</li><li>Other companies are waiting until after approval to get a better deal; Lief said that the timing of any agreement is highly speculative; he doesn't think he is compromising anything by signing an agreement before approval; when we see a commercial agreement it "will be a very nice approval for both parties."</li><li>If the PDUFA date is October 22, the launch can happen within 12 weeks after approval; Q1 2011;</li><li>Will the CV data be adjudicated by the fall? Lief said that there would be no adjudication; a colleague said that there would be adjudication if there were certain AE and they don't expect such adjudication to be necessary;</li><li>How are discussions with "reimbursers" going? Ten states cover weight management for Medicade today; Lief believes there is a chicken and edge situation in that once a good drug is available, the value of such a drug will be seen; note that at least two thirds of those that took the drug lost at least 5% and that figure represents 26 pounds, so parties would benefit from reimbursement;</li><li>Is the FDA ok with filing the BLOOM data post approval? Lief said they have discussed the plan with the FDA and they are in agreement;</li><li>As the competitor already has a panel date, has it pushed back partnership discussions for Arena? Lief said that he doesn't think so.</li></ul><p>I would view this webcast as being very positive. I drew a number of conclusions from what I heard in the discussions.<br /><br />I believe that Arena has moved far a long in its discussions with a commercial partner--most likely a major pharma company--to launch its weight reduction drug, lorcaserin; I expect the partnership to be announced soon: certainly before the PDUFA date for the drug;<br /><br />I concluded that the safety data from the ongoing BLOOM trial is good; Arena doesn't expect to have adjudication on results--a decision by a third party--from which you could conclude that they haven't seen anything that needs explanation;<br /><br />The current, ongoing trial will conclude later this year, but I think that the results won't be submitted until after the PDUFA date, when a decision would be rendered by the FDA;<br /><br />I think that the shelf registration for $150 million announced recently is an effort to capitalize on an announcement of a commercial partner for lorcaserin. Arena will likely use the funds to pay down its debt, which has an interest rate of 7.25%.<br /><br />All in all, I think that the news--what one could infer from what was said--was very positive. I plan to buy back the stock I sold earlier this week when the self registration was announced.</p>

<p>Arena Pharmaceuticals had a webcast for analysts and other interested parties this morning; notes and comments on this webcast are included below.</p><ul><li>No agreement with major pharma company yet;</li><li>No advisory committee (also referred to as a panel) meeting scheduled; ARNA will announce if and when they hear it; they will get a 55 day warning from the agency</li><li>Last patient later this month and results later this year</li><li>Supplement to the NDA will be filed post approval</li><li>APD 916 in phase 1; results will be announced in the third quarter</li><li>APD 997 is being evaluated by JNJ</li><li>First quarter financials: R&D expenses have decreased significantly by $24.3 million due to a decrease in clinical trial expenses<br />x Manufacturing costs are included in R&D expense</li><li>They will present more data on lorcaserin in future conferences, including the diabetes meeting in Orlando and in Arlington, VA in July</li><li>They will present at a meeting in San Diego a few weeks before the lorcaserin PDUFA date</li><li>Question on the panel: has the FDA suggested a panel is likely? Lief said no, but that September 15 and 16 there is a meeting of the panel, but he hasn't heard anything form the FDA from the FDA.</li><li>The company should hear in late July if they're going to be on the September panel.</li><li>Lief probed on commercial agreement on the company; Lief said he couldn't comment on it. Lief reiterated that Arena has always said that they are ready to launch on their own.</li><li>Worried: if they cannot form a partnership, would there be a soft launch. Lief said he doesn't like soft launches. 7500 physicians account for half of weight loss prescriptions. Arena could reach all of them with a modest sales force of 100 people. He then made a stronger statement: "as I said earlier, we do expect to sign a partnership agreement." He later said that "we expect to form an agreement before approval and before launch."</li><li>Lief commented that nothing has changed in the supplemental data for the ongoing clinical trial of the lorcaserin BLOOM trial; they will file the data as a supplement;</li><li>A competitor (Vivus) suggested that the benchmark for approval, the 5% average weight loss could change; Jack Lief said he didn't want to speculate on the thinking of the FDA and that lorcaserin meets the published efficacy standards. Lief joked that it's nice that "our competitor is changing the FDA guidance for the FDA."</li><li>Additional data on the 120 safety update. The data were submitted; it did include blinded data of an ongoing study; it summarized the most significant adverse events;</li><li>They were asked about the number of major cardiovascular adverse events in the BLOSSOM study; some cardiovascular AE data were presented and more detailed information will be presented in upcoming meetings; the data in the Phase 3 trial show that the AE is low as would be expected from the low risk people selected from the phase 3 study; the company is confident in previous statements that lorcaserin has "really good safety profile."</li><li>Guidance for the 2010 income statement is unchanged</li><li>On the $150 million shelf registration: the spend assumes no partnership with a commercial entity, so the company expects to do "a lot better than that." Lief said they need to be well advanced in anticipation of the PDUFA date and they plan to raise money opportunistically;</li><li>How long will the current cash last? Debt to Deerfield is due in July of 2011; they have already paid the $10 million due in July of 2010. It was paid last year.</li><li>If the BLOOM data is filed before the PDUFA date, will it extend approval by six months? Lief said he won't speak for the FDA: the current NDA was accepted by the FDA for a robust review; Lief doesn't feel that the BLOOM data is necessary to making a decision; the initial submission was acceptable;</li><li>Other companies are waiting until after approval to get a better deal; Lief said that the timing of any agreement is highly speculative; he doesn't think he is compromising anything by signing an agreement before approval; when we see a commercial agreement it "will be a very nice approval for both parties."</li><li>If the PDUFA date is October 22, the launch can happen within 12 weeks after approval; Q1 2011;</li><li>Will the CV data be adjudicated by the fall? Lief said that there would be no adjudication; a colleague said that there would be adjudication if there were certain AE and they don't expect such adjudication to be necessary;</li><li>How are discussions with "reimbursers" going? Ten states cover weight management for Medicade today; Lief believes there is a chicken and edge situation in that once a good drug is available, the value of such a drug will be seen; note that at least two thirds of those that took the drug lost at least 5% and that figure represents 26 pounds, so parties would benefit from reimbursement;</li><li>Is the FDA ok with filing the BLOOM data post approval? Lief said they have discussed the plan with the FDA and they are in agreement;</li><li>As the competitor already has a panel date, has it pushed back partnership discussions for Arena? Lief said that he doesn't think so.</li></ul><p>I would view this webcast as being very positive. I drew a number of conclusions from what I heard in the discussions.<br /><br />I believe that Arena has moved far a long in its discussions with a commercial partner--most likely a major pharma company--to launch its weight reduction drug, lorcaserin; I expect the partnership to be announced soon: certainly before the PDUFA date for the drug;<br /><br />I concluded that the safety data from the ongoing BLOOM trial is good; Arena doesn't expect to have adjudication on results--a decision by a third party--from which you could conclude that they haven't seen anything that needs explanation;<br /><br />The current, ongoing trial will conclude later this year, but I think that the results won't be submitted until after the PDUFA date, when a decision would be rendered by the FDA;<br /><br />I think that the shelf registration for $150 million announced recently is an effort to capitalize on an announcement of a commercial partner for lorcaserin. Arena will likely use the funds to pay down its debt, which has an interest rate of 7.25%.<br /><br />All in all, I think that the news--what one could infer from what was said--was very positive. I plan to buy back the stock I sold earlier this week when the self registration was announced.</p> 2010-05-06T22:56:30Z 2010-05-06T22:56:30Z /index.php?option=com_content&amp;view=article&amp;id=4117:arena-pharmaceuticals-nasdaqarna-shares-on-the-move&amp;catid=39:biotechnology-companies&amp;Itemid=64

Arena Pharmaceuticals May 6, 2010<br /><br />The stock has been nose-diving since 90 minutes after the opening. It opened at $3.22, hit a high of $3.24 and is now (1451 ET) at $2.90. Interestingly, the $4 July call has bounced back from its low.<br /><br />Jack Lief and other executives from ARNA will host a webcast tomorrow morning.<br /><br />It's now 1453 ET and shares of ARNA have bounced back, sharply, from a low of $2.90; the company is now trading at $3.07: it looks like $3 May calls won't execute!<br /><br />Just to be clear: I own ARNA so have a personal, vested interest in this company.  It should also be noted that today was the day of that strange 1,000 dive in the DOW.

Arena Pharmaceuticals May 6, 2010<br /><br />The stock has been nose-diving since 90 minutes after the opening. It opened at $3.22, hit a high of $3.24 and is now (1451 ET) at $2.90. Interestingly, the $4 July call has bounced back from its low.<br /><br />Jack Lief and other executives from ARNA will host a webcast tomorrow morning.<br /><br />It's now 1453 ET and shares of ARNA have bounced back, sharply, from a low of $2.90; the company is now trading at $3.07: it looks like $3 May calls won't execute!<br /><br />Just to be clear: I own ARNA so have a personal, vested interest in this company.  It should also be noted that today was the day of that strange 1,000 dive in the DOW.