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May 15, 2009 (Vol. 29, No. 10)

GEN's Spotlight on the FDA

  • Sometimes, during the course of new biotech drug development, the sins of a clinical investigator wind up being visited upon the sponsor. Here are some examples:

    • The integrity of a Phase IIIb trial supporting an NDA was recently called into question by a FDA warning letter that  observed that a U.S. principal investigator failed to adequately supervise individuals to whom he delegated tasks. There were, allegedly, fabricated signatures on informed consents from minors, a case of a minor above the age of seven who did not sign the consent form, and an instance of a nonenglish speaker signing a consent form written in English.

      These problems also indicated poor sponsor monitoring and resulted in lingering sponsor liabilities, especially with pediatric patients. In addition, the integrity of the Phase IIIb data to support the NDA was lost.

    • Pfizer recently settled a Nigerian government-initiated lawsuit in which Nigeria alleged that Pfizer, through its Nigerian principal investigator, failed to gain informed consent or Nigerian governmental approval for a particular clinical trial. The Nigerian government sought $9 billion in damages and criminal prosecution of Pfizer executives. 

    • India is investigating the death of an infant who died in a vaccine study. Developing countries, which in some respects represent attractive places for carrying out clinical studies, have increasing liabilities, especially if companies rely on monitoring groups that lack depth, necessary quality assurance oversight, and an understanding of local practices.
    • Criminal charges were made against an investigator for failing to prepare and maintain an adequate case history during a clinical study (US v. Palazzo and US v. Garfinkel). Where the clinical investigator fails, the sponsors have inherently failed and are now exposed to potential FDA and product-liability risks.

    The lesson here is simple: sponsors must invest more to educate investigators and improve quality control of clinical studies, whether they take place in the U.S. or not. This is easy to say, but hard to do. In today’s regulatory environment, the failure to make adequate investment in both has negative FDA and civil consequences.

    Artfully drafted Clinical Investigator Agreements may not protect a company, especially where the firm has failed in its education and monitoring of the investigator.

    And, if you think clinical investigators are the only problem, look at the GAO’s report (GAO-09-448T) on IRB’s vulnerability to unethical manipulations. It is likely that Congress may act on clinical investigator and IRB oversight in the future. Companies would be wise to now anticipate such a move.

  • Navy Broadsides FDA for Blocking Clinical Trials

    Companies frustrated with the FDA can now sympathize with the U.S. Navy, which released an internal report blasting FDA for blocking clinical trials on an investigational blood substitute. The April 4 edition of The Boston Globe published an article detailing the Navy’s allegations, which concluded that the FDA reviews were “faulty,” and showed a consistent pattern of erroneous, misleading, and anecdotal statements, reporting bias, changing requirements, no sense of urgency, and conflicts of interest.

    While it is uncommon for another governmental agency to attack FDA with such ferocity, it is more unusual to also include 13 university medical professors as coauthors, as did the Navy’s internal report. The Boston Globe article makes interesting reading, especially in an environment where private industry complaints mirror those voiced by the Navy.

    To paraphrase an old saying, where there is Navy smoke, there must be fire among the senior officers to allow this internal publication to surface. Obviously, this presents a challenge to the new FDA management, especially the allegation that soldiers who suffer from severe blood loss on the battlefield were the intended patients for the blood substitute clinical study. Ironically, cancer patients and others have frequently voiced the same complaint about the lack of FDA sensitivity or urgency, with a number of them dying during what appears to be laborious clinical development and review cycles.