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Regulatory Affairs : May 15, 2009 (Vol. 29, No. 10)

GEN's Spotlight on the FDA

  • Bruce Mackler

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.

IVD Update

By Jeffrey Gibbs, J.D.

FDA regulation of in vitro diagnostics (IVDs) continues to present industry with major uncertainties. Some of the major issues include:

  • The In Vitro Diagnostic Multivariate Index Analysis guidance document represents FDA’s largest effort to regulate laboratory-developed tests. Although not released by the Bush Administration and criticized by many, the guidance document may be put into the public domain by the Obama Administration.

    Questions surrounding the guidance document include: when might it be released? Has it been modified and if so, in what manner? How will it be implemented? And, what impact will it have on laboratories, kit manufacturers, investors, and patients? These uncertainties can impede product development, as well as raise investment risks during these troubled economic times. 
  • How will FDA expand its regulation of laboratory-developed tests (LDTs)? The Genentech citizen petition requested that FDA actively regulate a much broader segment of LDTs than covered by the IVDMIA proposal. Moreover, Congress may adopt, or at least consider, legislation that will lead to more FDA regulation of LDTs. 
  • The FDA has recognized the importance of the development of personalized medicine and companion diagnostics. Yet, FDA’s lack of clear policies has made it difficult for these IVDs to successfully complete the FDA review process.

The agency also has not adhered to the “least burdensome” mandate established by Congress for devices. Without clear, predictable, reasonable regulatory requirements, innovative IVDs will have a difficult time entering the market, and investment in them will lag. It remains to be seen what steps the new FDA administration will take to address these issues.

With some device reviewers complaining about FDA/Center for Devices and Radiological Health management to Congress, even greater regulatory stringency seems more likely.

As a result of these ongoing developments, companies whose interests are affected by FDA regulation of diagnostics will need to monitor events carefully. Diagnostic firms that are seeking to market new IVD assays in the U.S. will want to take steps to maximize the likelihood of a successful outcome perhaps by understanding their regulatory options, (GEN, July 2008), carefully crafting the intended use statement (GEN, November 15, 2008), and properly using the pre-IDE process to better understand the regulation requirements (GEN, March 1, 2009).

Recent FDA Guidance Note

  • Q10 Pharmaceutical Quality System (April 2009) describes what FDA believes is an effective quality-management system across the entire life cycle of pharmaceuticals (drugs and biologics). This is a good predictor of the programs that FDA inspectors will be looking for, especially in the cGMP area, as well as an indicator of what FDA considers as adequate risk-based regulatory management. 
  • Somatic Cell Therapy for Cardiac Disease (March 2009) describes the level of preclinical and clinical data that will be necessary to move stem cell products into clinical development. Although, the document addresses cardiac disease, it is a harbinger of what FDA/Center for Biologics Evaluation and Research/Office of Cellular and Gene Therapies will also require for other cell regenerative therapies.

    Companies should look carefully at the FDA requirements for preclinical testing, the type of clinical study endpoints, and whether a control arm is necessary versus a “trial of sufficient size.”   

About the Bruce F. Mackler, Ph.D., J.D.

Bruce F. Mackler’s, Ph.D., J.D. (bmackler@brucemackler.net), has 28 years of FDA legal and regulatory experience in biomedical products. As an FDA adviser, he assists financial groups like venture funds that are performing due diligence on biomedical opportunities prior to making an initial investment. He consults on integrated FDA, technical, and business issues by assessing portfolio companies and conducts approval risk analyses for analysts and investors.

His business acumen stems from working in sales/manufacturing in a family business, owning several bioservice businesses, holding management roles like interim COO and regulatory affairs vp in various start-up companies, and being a university/NIH researcher for 15 years.

Dr. Mackler has a Ph.D. from the University of Oregon Medical School (1970) in the area of immunology/microbiology and has authored more than 100 published scientific papers and abstracts. He has written/edited the Life Science Due Diligence and Regulatory Newsletter and the TVM-Capital Regulatory Bulletin.

He also advises early- and late-stage biomedical companies, serves on several boards of directors and scientific advisory boards of biomedical companies, and is an active investor. His areas of expertise include FDA regulatory approval strategies, pre-INDs/IDEs, 510ks, PMAs/ NDAs/BLAs, manufacturing/QA/QC, and how to effectively interact with FDA.

Dr. Mackler co-founded the Association of Biotechnology Companies (ABC) with six small biotech firms and helped it grow to over 250 members. ABC later merged to form the Biotechnology Industry Organization (BIO).