September 15, 2000
Comments by Larry D. Sasich, Pharm.D., M.P.H, FASHP
Public Citizen’s Health Research Group
Before the FDA’s Public Meeting on the Prescription Drug User Fee Act (PDUFA)
Public Citizen appreciates this opportunity to comment on the Prescription Drug User Fee Act (PDUFA) and what we hope will be its non re-authorization in September 2002.
When first put forth in 1992, PDUFA appeared to be a reasonable attempt to improve a drug review process reeling under chronic, imprudent under-funding of the Food and Drug Administration (FDA) by Congress. PDUFA’s re-authorization in 1997 opened the door for passage of the Food and Drug Administration Modernization Act (FDAMA). This ill-advised law included such anti-consumer protection provisions as the off-label promotion of drugs and its dangerous pharmacy compounding provisions, neither of which remotely relate to the FDA’s drug review process which is the subject of PDUFA. This highlights the dangers to the public of re-opening the Food, Drug and Cosmetic Act (the Act) every five-years giving the drug industry and its paid advocates in Congress the opportunity to play mischief with the Act. The toxic duo of PDUFA-FDAMA has weakened the FDA and for the first time rolled back consumer protection laws that had become progressively stronger during the last century.
By law, PDUFA fees can only be used for drug review. However, PDUFA-FDAMA mandated additional unfunded burdens upon the agency such as those mentioned above. Moreover, PDUFA-FDAMA requires that the amount the FDA must spend from public appropriations on the drug review process is increased by an inflation factor every year. With flat appropriations, funds for other vital FDA functions must be funneled into the new drug review process to meet PDUFA-FDAMA requirements for drug review funding. Consequently, resources for programs such as postmarketing safety surveillance, monitoring of prescription drug advertising, and manufacturer and import inspections, have dwindled.
PDUFA, via FDAMA, also resulted in a legislated “mission” for the agency that has in effect recast the FDA as industry’s partner, rather than its monitor, in new drug development with the intent to speed up the entire process a role that economically benefits the industry. This new Industry-FDA culture of collegiality is not necessarily in the interests of the public’s health.
During Public Citizen’s 29 years of observing the FDA, the essential policy issues have remained largely unchanged. Primary among these is the relationship between the pharmaceutical industry and the FDA and the extent that the industry by itself, or through Congress, can influence drug regulation and the drug-approval process for its own gain. Forty years ago, Judge Lee Loevinger, then head of the Antitrust Division of the Department of Justice, during the Kefauver hearings that produced the legal requirement that drugs be proved both safe and effective before marketing remarked that “Unfortunately, the history of every regulatory agency in the government is that it comes to represent the industry or group it’s supposed to control.” Judge Loevinger’s perspective is depressing, but we believe it is possible for the public, rather than the industry, to once again become the FDA’s primary “customer.”
When the President and Chief Executive Officer of the industry’s major lobbying group, the Pharmaceutical Research and Manufacturers of America, gives the FDA “high marks” for the implementation of FDAMA, consumers should be concerned. Consumers will not continue to have confidence in the credibility of an agency that has even the appearance of representing the interest of the industry over its own. The obvious solution is adequate public funding of what the FDA itself calls “The Nation’s Foremost Consumer Protection Agency.” Keeping the FDA adequately funded and independent is a goal that is clearly possible in an era of a trillion-dollar budget surplus.
I will now briefly respond to those aspects of the questions posed by the FDA not addressed in my opening remarks:
1. The FDA has implemented management improvements that have substantially decreased the time for new drug review and made new medications available to the public faster. Do you view this as a benefit of the user fee program that should be maintained in the future?
A distinction must be made between four categories of drugs: (1) those for serious or life-threatening conditions for which there is no adequate treatment; (2) drugs for rare disorders; (3) the majority of new drugs that are approved, which are redundant chemical modifications of drugs already marketed; and (4) drugs that are granted priority review because they work in some new way.
Public Citizen supports early access to experimental drugs for patients with serious or life-threatening illnesses or for those with rare disorders that have no effective treatments. Even prior to PDUFA, the FDA had a policy of expediting access to experimental drugs through a compassionate release program and the creation of treatment-Investigational New Drug Applications. For example, the FDA expedited the review and approval of the early AIDS drugs before the advent of user fees and these drugs came on the market in the U.S. before they did in any other country. Clearly, PDUFA was not necessary to hasten the approval of these important drugs.
In contrast, the effect of PDUFA on the last two categories of drugs is very troubling. Public Citizen is as concerned about what we perceive as a pressure to approve new drugs that would not have been approved before PDUFA, by lowering drug approval standards, as it is about the speed at which drugs are now being cleared for marketing since the advent of user fees.
Our survey of the attitudes of FDA Medical Officers completed in December 1998 revealed disturbing opinions about both the pressure and speed to approve new drugs. Thirty-four Medical Officers stated that the pressure on them to approve new drugs was “somewhat greater” or “much greater” compared to the period prior to 1995.
Three recent examples from category 3, where there was an apparent pressure to approve, are the heart drug Posicor, Duract, an anti-inflammatory painkiller, and the antibiotic Raxar. These drugs were approved between June and November 1997, just prior to the re-authorization of PDUFA. All had known safety problems prior to approval. All were redundant and there were multiple options available to patients and physicians for the indications for which these drugs were approved. All received standard reviews, and all killed and injured before they were withdrawn from the market between June 1998 and October 1999. We do not believe that these drugs would have been approved in the pre-user fee era.
With respect to the speed of drug approval, priority reviews are now being inappropriately granted for new drugs with, at best, modest effectiveness simply because they work by a new mechanism of action. Recent examples of drugs in category 4 are the type-2 diabetes agent Rezulin, the flu drug Relenza, and Lotronex, approved for the treatment of irritable bowel syndrome in women with diarrhea as the main symptom. Rezulin has been banned and the other two drugs have required significant changes to their safety labeling. Twelve Medical Officers in our survey identified 25 new drugs that they reviewed in the past three years that in their opinion had been approved too fast.5 The recent experiences with these drugs suggest that priority reviews are being abused and that drugs with new mechanisms of action raise the possibility of new mechanisms of toxicity.
2. Should the FDA continue to have performance goals for the drug and biological review process?
PDUFA-FDAMA’s performance goals are in fact legislated deadlines that leave the agency with little flexibility. Reviewing new drug research is not a “cookie-cutter” affair. It is a process that is too important to the health and safety of the public to be constrained by time lines dictated by industry and enforced by the possibility that these funds will be cut off. This places enormous pressure on FDA reviewers whose decisions may affect the safety of millions.
Dr. Janet Woodcock the Director of the Center for Drug Evaluation and Research recently remarked that the intense PDUFA-FDAMA schedules “create a sweatshop environment that’s causing high staffing turnover.”
Companies can now “game” the system, knowing that reviewers are under a deadline, by procrastinating in producing information requested by the reviewers, this is a phenomenon we term “PDUFA compression.” Reviewers may not have adequate time to analyze important data before a final decision must be made to approve or not approve an application.
One example of PDUFA compression was the priority review of tamoxifen (Nolvadex) to reduce the incidence of breast cancer in women at high risk for the disease. The application was submitted on April 30, 1998, creating a PDUFA deadline of October 31, 1998. The draft Medical Officer Review had to be completed on August 18, 1998 for distribution to the advisory committee, a period of 3.5 months after submission. The Medical Officer review for this drug chronicles repeated requests for information from the company and reveals the medical officer’s frustration in not receiving the information in a timely manner. The Medical Officer wrote:
The section [Administrative correspondence] documents the lack of a complete set of primary data for review until August 4, 1998, despite an initial agreement to provide the data and repeated requests for submission. Data submission was not complete until August 4, 1998, 1.5 weeks before the deadline for review submission to ODAC [Oncology Drugs Advisory Committee]. Until July 16, 1998, response times to FDA Requests for Information ranged from 2 weeks to one month, representing significant delays in the highly compressed timeframe of the review of this application.
Public Citizen believes that the drug review clock must be in the hands of an independent FDA. Performance goals are an important managerial tool as long as they serve the public’s interest and are flexible enough to accommodate the requirements of the FDA’s review staff. The PDUFA-FDAMA time lines lack flexibility placing additional pressure on reviewers.
3. Should fees collected from industry be used to pay for other costs FDA incurs to ensure that drugs in the American marketplace are safe and effective? Such additional costs might include monitoring adverse drug reactions, monitoring drug advertising, and routine surveillance, inspection and testing of drug manufacturers.
We can only imagine what “strings” industry would have Congress attach to user fees for postmarketing adverse drug reaction surveillance. Would there be a legislated requirement for industry-FDA meetings to resolve disputes about drug safety before the agency could warn doctors about potential problems through professional product labeling changes? Could the industry be granted deference in deciding whether or not an injury or death was drug-induced? Might the FDA be required to allow the industry final editorial approval before any advisory statements about drug safety were released to the public? All are possible with user fees.
The solution is clear – to prevent further incursion into the FDA’s ability to effectively regulate prescription drugs requires public funding of the FDA. PDUFA-FDAMA is an unmistakable warning that user fees collected to finance the review of new drugs are bad public policy and that this scheme for funding the FDA must be regarded as a failed experiment.
 Posicor or mibefradil, approved in June 1997, was the ninth member of the calcium channel blocker family of high blood pressure lowing drugs. Concern was raised about the safety of this drug in patients with heart failure before it was approved. The drug was eventually banned in June 1998 because of fatal drug interactions. (Department of Health and Human Services, Food and Drug Administration. FDA Talk Paper: Roche Laboratories Announces Withdrawal of Posicor From the Market. June 8, 1998.)
 Duract or bromfenac, approved in July 1997, was the twentieth nonsteroidal anti-inflammatory drug (NSAID) on the market. Bromfenac’s liver toxicity was known before approval and it was banned in June 1998 for this reason.(Department of Health and Human Services, Food and Drug Administration. FDA Talk Paper: Wyeth-Ayerst Laboratories Announces The Withdrawal of Duract From The Market. June 22, 1998.)
 Raxar or grepafloxacin, approved in the U.S. in November 1997, was the eighth fluoroquinolone antibiotic cleared for marketing. Before it was approved this drug was known to alter electrical conduction in the heart that could lead to life-threatening heart rhythm disturbances. The drug was withdrawn in October 1999 because of deaths from heart rhythm disturbances. (Press Release from Glaxo Wellcome. Glaxo Wellcome voluntarily withdraws Raxar [Grepafloxacin]. October 27, 1999.)
 Rezulin or troglitazone was granted a priority review and approved in January 1997 for the treatment of type-2 diabetes. Numerous other drugs were available for the treatment of this disease. Troglitazone was withdrawn in March 2000 after reports of 90 cases of liver failure, including 63 deaths and seven organ transplants. (Department of Health and Human Services. HHS News: Rezulin To Be Withdrawn From The Market. March 21, 2000.)
 Relenza or zanamivir was granted a priority review and approved in July 1999 for the treatment of uncomplicated influenza. The FDA statistical reviewer wrote “Zanamivir has not been shown to be effective in this country for the treatment of influenza, and in my opinion therefore should not be approved.” (FDA Statistical Review and Evaluation. Michael Elashoff, Ph.D.) The FDA advisory committee voted 13 to 4 not to approve zanamivir, but the agency approved the drug anyway. This drug required new safety warnings in July 2000. (Dear Health Care Professional Letter, Important Revisions to Safety Labeling for RELENZA from Glaxo Wellcome, Inc. dated July 2000.)
 Lotronex or alosetron was granted a priority review and approved in February 2000 for the treatment of irritable bowel syndrome in women with diarrhea as the predominant symptom. This drug required new safety labeling and the mandatory distribution of a Medication Guide by pharmacists in August 2000. (Department of Health and Human Services. FDA Creates Medication Guide For Lotronex Health Professional Labeling Revised to Help Manage Risks. August 24, 2000.)
Public Citizen’s Health Research Group petitioned the FDA on August 31, 2000 to immediately ban Lotronex. As of August 28, 2000, it has been associated with at least 26 cases of ischemic colitis, a condition that results from a lack of blood flow to the colon, leading to death of bowel tissue. (www.citizen.org/hrg1533)