A Question of Significance: Dr Hamburg & FDA Enforcement

Since January of 2001 FDA has been lax in protecting the public and enforcing their regulations. I will let you put 2 and 2 together to figure out why. However, FDA enforcement needs to be relevant and meaningful. It needs to be for the right reasons, not just because someone wants to come across as tough.

Saturday I had a disturbing phone call from a client and friend who had just received a Form FDA 483, Inspectional Observations, at the conclusion of an FDA inspection. In reviewing the 483 with my client it was obvious that the FDA inspector had overstepped his bounds and that the 483 should not have been issued. However it is now part of the public record and available through the Freedom of Information Act. Without knowing the background, one of the observations could seem very serious and could result in FDA issuing a Warning Letter. The Warning Letter would then be posted on the internet for the entire world to see.

I am one of those that feel that FDA enforcement was lax during the past eight years. Part of the reason I left FDA after 17 years was a concern that the Agency just wasn’t doing its job. However, I also spent the summer of 2004 working at FDA headquarters reviewing inspection reports (EIRs) and found many of them to be lacking. Many field investigators were not technical experts in the area they were inspecting and cited violations that were not “clear and significant” violations of the regulations. Since leaving FDA I have seen a number of FDA 483s written that just didn’t rise to the level of significance necessary for a 483 to be issued or enforcement action taken. Many times this is because the front line supervisors do not have the technical and legal skills to properly review the 483s.

In the previous post (see below) I discuss the new enforcement climate at FDA. Although I am happy that Dr. Hamburg is taking her job seriously I have some concerns. We all want safe drugs, medical devices and food. We all want clinical trials to adequate and well-controlled. But we need clear enforcement standards and a well trained inspectional force for that to happen. And I fear that small companies and clinical trial sites will bear the brunt of a tough new enforcement climate. The larger firms have the legal resources to prevent Warning Letters and other enforcement actions. A small firm bringing their first product to market or a clinical investigator who has never been inspected by FDA may find themselves in a lot of trouble. This could be an unintended consequence of the new “effective enforcement” that Dr. Hamburg mentions in her recent speech to FDLI (see below).

The country needs a well-financed FDA to protect consumers from fraudulent and unsafe products. But we also need modernized regulations and a well-trained workforce to accomplish this. Dr. Hamburg needs to first look inside FDA before a wholesale enforcement campaign. She needs to take on the really significant problems, including internal problems, first. I would suggest quality control of FDA 483s as a good place to start. And that means properly training supervisors and middle management in the Office of Regulatory Affairs (the FDA field organization that conducts inspections).

UPDATE: An interesting comment is listed under: Enforcement

One Response to A Question of Significance: Dr Hamburg & FDA Enforcement

  1. Tania Johnstone Issa says:


    I fully agree with your position. Over the years I have worked closely with sites as a CRA/monitor, project manager, program manager, and QA auditor. I have seen investigators who have been terribly negligent in regards to patient safety. Just as bad, I have seen investigators who enroll marginally eligible or ineligible subjects or keep subjects on drug/device beyond the safety parameters in the protocol, enticed by enrollment incentives and other site payments. Yet when these same sites were inspected by FDA, many of the obvious and dangerous deficiencies went unnoticed, allowing the drug to be approved and the investigator to continue managing patients in other clinical trials. I have also seen excellent investigators receive 483s for minor deficiencies which had no impact on patient safety or data integrity. Enforcement is terribly absent and, at the same time terribly misplaced.

    Carl has correctly emphasized that the FDA workforce inspecting sites and sponsors needs a thorough overhaul. Many of the basic principles of site monitoring, which are focused on (and quite adept at)ensuring patient safety and data accuracy, should be incorporated into FDAs inspection program. Well-trained monitors/CRA regularly identify lack of protocol adherence and patient safety issues, documenting these in reports. Because these reports are ultimately buried in paperfiles into perpetuity, rarely requested by the FDA, the agency charged with ensuring we have a safe drug supply, inspects sites but does not bother to read the eye-account written story of the site’s participation and the experience of their patients. Absurd, considering the FDA requires biopharmaceutical companies to perform this monitoring.

    Many FDA inspectors lack any clinical experience and cannot comprehend what is written in study protocols, case report forms, medical charts, and monitoring reports. If biopharmaceutical companies are bound by FDA to select monitors “qualified by training and experience”, the FDA should do even better with the FDA staff responsible for Site/Sponsor inspections.

    Because the clinical trials industry continues to express sincere concerns about the safety of investigational products, and bemoans lack of meaningful regulation from FDA, the industry has been self-disciplined enough to collaboratively identify and incorporate best practices (beyond regulations) truly designed to protect patient safety. Now it is time (pastdue) for REAL REFORM which should include a serious review of existing regulations against industry best practices.

    Luckily, the ICH has by and large, has avoided the many constaints of political party affiliations, changing administrations, and lobbyists, using their efforts along with public input to provide meaningful guidance/regulation. Since the FDA references ICH as guidance instead of adpoting ICH as regulation, drugs and other investigational products approved for commercialization in the US are not approved against the highest standards already in use by many countries around the world. Luckily, however, many US companies have adopted the higher standards of ICH while they wait and wait for FDA to……..

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