Comments by Sidney Wolfe, Ben Peck and Frank Clemente
Public Citizen’s Health Research Group and Congress Watch
The Prescription Drug User Fee Act (PDUFA)
[Docket No. 01N-0450]
The Health Research Group participated in the Food and Drug Administration’s (FDA) September 15, 2000 public meeting on the re-authorization of the Prescription Drug User Fee Act (PDUFA), due in September 2002. We submitted comments for this first meeting that are available on our web site.
Public Citizen’s position was then, and remains, that Congress must adequately fund the FDA using public money. Also, PDUFA’s second re-authorization in 1997, with its slavish deadlines and the accompanying ill-advised Food and Drug Administration Modernization Act (FDAMA) are examples of failed experiments in public policy.
The PDUFA-FDAMA combination has successfully shortened the drug development process resulting in an enormous economic benefit to the pharmaceutical industry. Consumers, on the other hand, have suffered substantial harm from a large number of redundant “me-too” drugs (e.g. Posicor, Duract, Redux and others) with known safety problems, coming on the market that were less safe and no more effective than drugs already available. PDUFA has clearly been a successful economic policy for the drug industry but at the very least it has raised a red-flag that the user fee concept as now negotiated has failed as a public health initiative.
Consumers are extremely apprehensive about the possible next re-authorization of PDUFA and the consideration of FDAMA-II.
Since the September 15, 2000 meeting, an additional three new drugs have been withdrawn from the market for safety reasons. These are alosetron(Lotronex), rapacuronium (Raplon), and cerivastatin (Baycol). This brings the total of new drugs first approved and then withdrawn from the market since 1992, the year that PDUFA-I was enacted, to 10 products. An additional three drugs approved since 1992, levacetylmethadol (Orlaam), tolcapone (Tasmar), and trovafloxacin (Trovan), have been removed from markets in other countries because of safety but remain on the market in the U.S. The majority of these 13 drugs were approved and withdrawn in the U.S., or another country, after mid-1996. And for the preponderance of these drugs the safety problems that led to their removals from the market were known before they were approved.
This number of drug withdrawals in such a short period of time is troubling and unprecedented in the Health Research Group’s 30 years of observing the FDA. PDUFA has brought the FDA too close to the industry it regulates for public comfort or safety and has raised questions about outside pressure to approve new drugs and the agency’s independence to operate in the public interest.
This concern about the FDA extends outside the borders of the U.S. A May 19, 2001 commentary appearing in one of the world’s most respected medical journals, the British publication The Lancet, was entitled “Lotronex and the FDA: a fatal erosion of integrity.” Lotronex was inexplicably granted an expedited review by the FDA. It was found to be minimally effective and before its approval to cause life-threatening adverse effects. The drug was removed from the market after nine months because of these adverse effects. The author of the commentary and editor of the journal wrote “the FDA, its Center for Drug Evaluation and Research (CDER) in particular, has become the servant of industry.”
Regular Congressional oversight of the FDA’s performance is required to ensure that the agency is acting appropriately and in a timely manner. This would include separate hearings on and investigation of each drug that has been removed from the market for safety reasons. Congress could assign the General Accounting Office or the Office of Inspector General in the Department of Health and Human Services to conduct reviews of why drugs that were approved had to be removed from the market.
We will now respond to each of the three questions asked by the FDA in turn.
1. Has PDUFA supported FDA’s mission to protect and promote public health? What should be retained or changed to enhance the program?
According to the FDA, six drugs approved in the 1980s, the decade prior to the enactment of PDUFA-I, were removed from the market for safety reasons. As mentioned above, 10 new drugs approved in the 1990s have subsequently been withdrawn. This number rises to 13 if the drugs removed from the market in other countries for safety reasons that remain on the market in the U.S. are counted.
Confusion and concern arise for consumers when, on one hand the agency steadfastly maintains that all is well since PDUFA-I, while on the other the editor of the FDA Consumer magazine observed that “PDUFA has been a Faustian bargain.” And the director of the Center for Drug Evaluation and Research is quoted as saying that PDUFA has “create[d] a sweatshop environment that’s causing high staffing turnover.” In addition, another senior FDA staff member has commented that this high staff turnover resulting from PDUFA “throws the [new drug approval] process into a tizzy.”
Public Citizen does not believe that a deal with the devil that creates a sweatshop for drug reviewers and that has thrown the drug review process into a tizzy supports the FDA’s contention that it has not faltered in its mission to protect and promote public health.
A plausible conclusion for consumers to draw, given the facts that are available to the public, is that PDUFA’s main purpose has been to benefit the pharmaceutical industry.
The agency asks what should be changed to enhance the program? We offer the following suggestions:
- Ideally, Congress would adequately fund the agency using public money, and PDUFA with its rigid timetables for agency action would be abolished. However, if Congress does reauthorize PDUFA, there are several things that could be changed that would give the agency the flexibility it needs to effectively carry out its mission to assure the safety of the nation’s drug supply. For example, drug reviewers could be given the ability to exempt a drug they are reviewing from the time frame regime because of its complexity or other circumstances that require more time to complete a thorough review. Finally, if performance goals are to continue, all stakeholders, not just industry, must be at the table when they are negotiated with the FDA.
- A condition for the agency to collect user fees under the new law is that it must commit a set amount of appropriated funds to the new drug approval process. That amount increases each year by an inflation adjusted amount. In an era of flat-line Congressional appropriations, the FDA has had to shift money from other areas to meet this requirement for collecting fees. This requirement should be abolished.
- Extension of current fees and establishment of a relicensing fee. Currently, there are three types of user fees collected by the FDA: (1) application fees; (2) annual establishment fees; and (3) an annual product fee. Application fees should be extended to include Investigational New Drug (IND) applications, supplemental New Drug Applications (sNDA), and manufacturing supplements. A re-licensing fee must be established that could be used to cover the cost of postmarketing safety monitoring. This fee could be assessed annually, every three years, or every five years.
- Future re-authorizations of user fees must be done without incorporating recommendations from industry to the Food, Drug and Cosmetic Act (FDCA) which would lessen protections for patients as occurred in 1997. Giving the pharmaceutical industry access to FDCA every five years for the re-authorization of user fees allows too much opportunity for mischief from both sides of the political aisle.
Senior FDA officials made an important disclosure in late 1999 concerning PDUFA and the safety of new drugs that must be addressed:
As for the concern that the FDA should not be approving multiple versions of the same class of drug, we believe that it is an interesting public policy debate, but as the law now mandates, the FDA can only judge a product’s safety and efficacy, not its uniqueness of comparative efficacy or its social value. For the agency to apply new, more stringent requirements to a “me-too” drug would require congressional legislation to change the legal framework under which the FDA operates.
The current legal standard for approving new drugs in the U.S. is now 40 years old. The recent spate of new drug safety withdrawals is clear evidence that new drugs can come on the market that are less safe and no more effective than drugs already available. The current standard is woefully inadequate and the Health Research Group accepts that it is a partial explanation for many of the recent drug safety withdrawals, but not the entire explanation. A more appropriate standard for the 21st century would be proof of therapeutic superiority, using clinical endpoints, as a requirement for new drug approval. We urge the FDA to make such a recommendation to Congress.
2. Should PDUFA allow the use of user fee funding to monitor safety after new drug or biologic approval?
Our strong opposition to the use of user fees for postmarketing safety surveillance is based on the fact that the user fee program is not the simple transfer of funds from industry to the agency to cover part of the cost associated with the new drug approval process. Instead, to gain industry cooperation, user fees required the establishment of deadlines that have left the FDA with little flexibility. It is chilling to consider what influence might be negotiated away for allowing user fees to be expended for postmarketing safety monitoring.
Would there be requirements for industry-FDA meetings to resolve disputes about whether or not the agency could release a drug safety warning to the public? Or, would the industry require negotiating its standard for causality before listing adverse drug reactions in professional and patient labeling? Both are possible if the re-authorization of PDUFA to include postmarketing safety monitoring requires negotiation with and the consent of the industry.
The timely distribution of drug safety information to the public is far too important to consider any program that would allow industry influence that may delay the rapid dissemination of such information.
Public Citizen is not opposed to the establishment of other types of user fees such as mentioned in Question 1, but there must be no strings attached. For example, the annual re-licensing fee suggested above could be used, in part, for postmarketing safety monitoring.
3. How can FDA ensure that PDUFA goals are met if there continues to be a funding shortfall? If the funding shortfall persists, should FDA, in order to best protect and promote the public health, set review priorities and, if so, how? Should there be flexibility in setting user fees to cover the increased cost of the program?
The FDA has already partially answered Question 3 for itself in the supplementary information it provided in the Federal Register notice soliciting these comments. The agency stated:
Although FDA has been able to meet most of its performance goals, we do not believe this will continue in the future [emphasis added]. We do not foresee increasing or even maintaining performance levels until resources are available to meet the increased workload.
In the present political environment and for the foreseeable future, unless Congress commits to adequately funding the agency through the appropriations process, the FDA must set its own review priorities. The priority of a new drug review must be based on the best interests of the public health. This was something that the agency managed well before the enactment of PDUFA.
Consumers will not be concerned about a delay in approving an additional non-sedating antihistamine, the ninth fluoroquinolone antibiotic, or the tenth calcium channel blocker for treating high blood pressure. Consumers are concerned about valuable FDA resources being used to expedite the review of the 20th nonsteroidal anti-inflammatory drug, or Viagra for erectile dysfunction, or a drug to treat flu that was no different than a placebo when tested in North American patients. Consumers are most concerned about the recent approval and subsequent withdrawal of a substantial number of redundant “me-too” drugs that offer no therapeutic advantage over older drugs, only an increase in the risk of harm or death.
Public Citizen would support allowing the FDA flexibility in setting user fees. The FDA has been placed in an untenable position. After responding to the flood of new drugs approved in 1996 and 1997, a total of 92 New Molecular Entities, the number of New Drug Applications (NDAs) has since steadily fallen. Fewer NDAs translates to lower revenues for the agency. Uncertainty in the amount of funds available can not be conducive to recruiting and retaining the best talent for the agency to ensure the highest standards possible in the drug review process.
The FDA’s message to the public about PDUFA has been confusing because it has maintained people have benefitted because more products are available more quickly, yet so many people have been needlessly been harmed by these new products. The public is not interested in more drugs more quickly. Rather they are interested in better drugs.
The form and tone of the three above questions asked by the FDA indicate to us that the agency does have an important message for Congress and the public, though not clearly stated. By suggesting that it be allowed to set its own new drug review priorities and asking for more flexibility in setting user fees, the agency is saying that user fees as conceived under PDUFA-II are degrading the FDA’s ability to fulfill its legislative mandate to protect the public health. The agency, in fact, in the absence of adequate congressional funding, is asking for public support for the authority to collect user fees without “strings” – such as rigid procedures for decisions on NDAs and meeting documentation – being attached by the pharmaceutical industry. User fees then simply become drug licensing fees.
In the absence of adequate public funding, which would be the best solution, Public Citizen would support authorizing the collection of licensing fees without conditions to maintain the FDA at the highest level. However, to gain public support the FDA must be very clear in its message.
 U.S. Food and Drug Administration. FDA Talk Paper: Glaxo Wellcome Decides to Withdraw Lotronex From the Market, November 28, 2000.
 U.S. Food and Drug Administration. FDA Talk Paper: Injectable Anesthesia Drug Being Withdrawn From Market, March 29, 2001.
 U.S. Food and Drug Administration. FDA Talk Paper: Bayer Voluntarily Withdraws Baycol, August 8, 2001.
 The European Agency for the Evaluation of Medicinal Products. EMEA Public Statement on the Recommendation to Suspend the Marketing Authorization for Orlaam (Levacetylmethadol) in the European Union, April 19, 2001.
 The European Agency for the Evaluation of Medicinal Products. Press Release: Recommendation for the Renewal of the Suspension of the Marketing Authorization for Tasmar (Tolcapone), September 26, 2001.
 The European Agency for the Evaluation of Medicinal Products. Public Statement on Trovan/ Trovan IV/ Turvel/ Turvel IV Withdrawal of the Marketing Authorizations, March 21, 2001.
 Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001;357:1544-1545.
 Friedman MA, Woodcock J, Lumpkin MM, et al. The safety of newly approved medicines. Journal of the American Medical Association 1999;281:1728-1734.
 Thompson L. User fees for faster drug reviews. FDA Consumer 2000 Sep-Oct:25-29.
 Friedman MA, Woodcock J, Lumpkin MM, et al. Safety of FDA-approved drugs. Journal of the American Medical Association 1999;282:2297-2298.
 Department of Health and Human Services, Food and Drug Administration. Prescription Drug User Fee Act (PDUFA); Public Meeting. Federal Register Vol. 66, No. 223, Monday, November 19, 2001, pages 57967-57970.
 Friedman MA, Woodcock J, Lumpkin MM, et al. Safety of FDA-approved drugs. Journal of the American Medical Association 1999;281:1728-1734.