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505(b)(2) – Part 2: The Assessment: Safety Review

Of course my product is safe! – the RLD was shown to be safe.

Perhaps so.  The FDA approves products based on a risk/benefit; is the risk of taking the drug outweighed by the benefit?  Would FDA approve the RLD using today’s standards?  What changes from the RLD are we proposing to make in this development program and how would these changes alter the risk/benefit?

Recently, Bayer pulled Trasylol from the global market due to results from a Canadian study sponsored by a third party.  The FDA “cannot identify a specific patient population where we believe the benefits outweigh the risks,” said John K. Jenkins, director of the FDA’s office of new drugs.  This action shows that information coming after a drugs approval can be helpful to ascertain the needed study(s) to show that the proposed product is safe.

Indeed, many 505(b)(2) drug products are designed to reduce the adverse events associated with the RLD.  Some companies are founded on this premise:

Evan M. Levine, ADVENTRX president and CEO stated “…. product candidates fit well with our mission to develop less toxic drugs that address specific medical needs and improve patient care. For example, the novel formulations of paclitaxel and docetaxel were developed without formulation vehicles Cremophor(R) or polysorbate 80 which can cause severe hypersensitivity reactions.”

Camargo conducts a comprehensive review of safety information available for the proposed (and, perhaps, closely related) product.  Potential sources from which this information is obtained include: (1) published randomized placebo-controlled trials [PubMed]; (2) cohort studies; (3) meta-analyses; (4) voluntary notifications to national regulatory authorities of adverse events [MedWatch]; (5) published individual case reports; and (6) summary basis of approval documents.   Individual studies are examined and summarized on the basis of dose, patient population, indication, duration of use, and other relevant factors (e.g., drug-drug interactions, genetic factors).  Additionally, all relevant studies are integrated into a comprehensive summary table listing incidence of adverse events.

Much of the information we find and collate is used in the IND submission to support the Phase 1 study and is also used in the NDA filing.