by William D. Schwieterman, MD, PhD; and Steven D. Targum, MD

Dr. Targum is on the editorial board of Psychiatry 2007. Presently, he is Chief Medical Officer at Brain Cells Inc., an executive-in-residence at Oxford BioScience Partners, and a consultant in psychiatry at the Massachusetts General Hospital, Boston, Massachusetts; and Dr. Schwieterman is an independent consultant to Tekgenics, Inc., Mobile, Alabama.

Introduction

New medications must progress through arduous preclinical and clinical stage testing prior to achieving approval for commercialization (sales and marketing). In the United States, the ultimate hurdle preceding approval is the Food and Drug Administration (FDA). Interactions between the FDA and pharmaceutical drug developers are intended to provide a reasonable, balanced review system to assure safety as well as efficacy for the public good. This direct relationship is affected by public perception and legislative actions, which are, in turn, constantly influenced by the media for better or worse. In fact, a recent New York Times editorial bluntly stated that the FDA regulators, “have too cozy a relationship with manufacturers.”[1] Allegations of this sort fuel greater conservatism at the FDA. Beyond these external pressures, the personnel at the FDA and the pharmaceutical companies are very distinct cultures representing government (public) interests versus private interests. This brief review will describe the current state of the FDA approval process and consider some of the anticipated changes within the agency that will affect how new drugs get to clinical practice.

The article is cowritten with William D. Schwieterman, MD, an independent consultant for biotech and pharmaceutical companies who spent 10 years at the FDA in the Center for Biologics from 1992 to 2002. While at the FDA, Dr. Schwieterman was Chief of the Medicine Branch and later Chief of the Immunology and Infectious Disease Branch in the Division of Clinical Trials.

There has been an increased focus on safety, including proposals for the development of an independent Office of Drug Safety (OSE). Why?

Dr. Schwieterman: Historically, a high profile safety issue is a catalyst for criticism and change at the FDA on how drugs are developed and reviewed. The obvious trigger this time was the cardiovascular deaths from Cox-2 inhibitors that resulted in allegations of misconduct and the perception of unfair marketing practices. A recent General Accounting Office (GAO) report[2] stated that the FDA lacked a clear and effective process for making decisions about and providing management oversight of drug safety issues that arise after a medicine is on the market.

The immediate impact at the FDA were regulatory actions that will mean increased safety requirements (longer and bigger clinical trials), increased conservatism during phases 1 and 2, an increase in the number of drug warnings (black boxes), and an increased focus on post-marketing surveillance studies.

Is the increased focus on safety justified?

Dr. Schwieterman: Obviously, safety is important and post-marketing surveillance has not been well conducted in the past. However, my experience has been that the FDA has never compromised its scientific standards and that there has been no perceptible change in safety of the currently available drug supply. In fact, the irony of this increased vigilance is that drugs have never been more effective or safer. However, the FDA could not ignore the heavy criticism from the public and Congress about the apparent lack of adequate safety oversight.

What is PDUFA?

Dr. Schwieterman: PDUFA is the Prescription Drug User Fee Act established by Congress to enhance the drug review process via good review practices, increased electronic submissions, review of direct to consumer advertising, and increased FDA staff. While pharmaceutical companies must pay this user fee, it does not afford them any undue influence at all. Unfortunately, some articles in the media have implied that these payments do afford influence resulting in broad public misconceptions and increased pressure on the FDA.

What impact does public pressure have on the FDA?

Dr. Schwieterman: Frankly, public pressure is the biggest influence at the FDA and congress. The FDA reaction has been to dramatically increase the focus on product safety of both investigational and marketed products. Legislative action created an independent safety oversight office which will inevitably increase drug development hurdles by adopting more conservative standards.

Has the increased FDA conservatism affected currently marketed psychiatric drugs?

Dr. Schwieterman: In 2004, FDA advisory committee meetings reviewed safety of the entire class of antidepressant drugs resulting in a new “suicidality” warning for all SSRIs. Another example was the decision by FDA in 2006 to establish new warnings for the entire class of ADHD drugs for psychosis and other behavior problems, as well as new warnings for cardiovascular adverse events. Just this year, FDA wrote to manufacturers that “medication guides” be made available to patients using these therapies.[3]

Following advisory committee deliberations on ADHD, the FDA made a decision not to approve Sparlon (modanifil) for pediatric ADHD. Now, Sparlon is essentially the same drug as Provigil, which is already on the market for narcolepsy with a safety database of more than 2 x 106 patient exposures in adults. Despite this extensive safety database for modafinil, FDA was concerned about a few severe skin reactions occurring in kids, and decided not to grant approval for the new ADHD indication.

I’m not suggesting that the FDA was wrong about these warnings and decisions; however, these examples demonstrate that the FDA is more conservative and will be more restrictive in the near future.

Would a new independent Office of Drug Safety (ODS) improve safety surveillance?

Dr. Schwieterman: It is really too soon to tell, especially since legislation on this is still pending, but the ODS could divorce assessments of benefit from risk, which could be a problem. Safety can never be viewed alone in medicine. In my opinion, benefit/risk is a complicated issue, but the only meaningful assessment at FDA and in medicine. On the other hand, The ODS will bring more resources to safety, which will allow for full review of post-marketing safety and could, if managed well, bring credibility back to the FDA and the pharmaceutical industry.

What can we expect from the FDA in the near future?

Dr. Schwieterman: Expect increased scrutiny over drug labeling, increased conservatism with narrower labels and more safety warnings, more focus on patient subpopulations, and much more attention to post-marketing data. In the short run, new drug approvals will be slower to achieve and physicians will need to be more diligent with the drugs they currently prescribe. Until the Congress and the public perceive a more open pharmaceutical industry and more transparent review process, it is likely that external pressure on the FDA will continue to necessitate a conservative posture.

References

1. Misdirected studies on Avandia. New York Times. June 12, 2007:A22.
2. US Governament Accountablility Office. Drug Safety: Improvement Needed in FDA’s Post-Market Decision-making and Oversight Process, March 2006.
3. FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html. Access date: July 19, 2007.