I am president of the National Research Center for Women & Families, which is a think tank that uses research to improve the health of adults and children. I am also speaking on behalf of our Cancer Prevention and Treatment Fund, which analyzes research results that can improve the prevention, diagnosis, and treatment of cancer. Thank you for the opportunity to speak today.
My perspective is as a researcher trained in epidemiology and public health at Yale Med School, who was on the faculty at Vassar and Yale and conducted longitudinal researcher at Harvard, before moving to Washington, DC to work on Capitol Hill, at HHS, at the Institute of Medicine, and as the head of a nonprofit think tank. I am very glad to be on this consumer panel, and I strongly agree with the recommendations of my colleagues. Ours is not a consumer organization; we are a public health think tank, but our views closely align with consumer organizations and those focused on scientific integrity because of our mutual interest in better research and better health care.
My perspective is also influenced by my being a fellow at the Center for Bioethics at the University of Pennsylvania, on the Board of the Reagan Udall Foundation, and on the Board of the Alliance for a Stronger FDA.
Our Center does not accept funding from medical device or pharmaceutical companies, so that we have no financial interests in the medical products and policies we examine. However, I personally have ties to Johnson & Johnson, because my 94-year-old father spent his career there and our entire family has stock in the company.
I consider myself one of FDA’s biggest fans, because I have tremendous respect for the agency and am committed to ensuring that it has the resources it needs to keep our food and medical products safe.
User fees help the FDA to be able to do its job. I think everyone in this room agrees that we want safe and effective drugs to be on the market in the U.S. as soon as possible. Where we don’t always agree, however, is what is appropriate evidence of what is safe or effective, and how to weigh the potential risks and potential benefits. Regarding PDUFA V, we share the concerns of members of the Patient, Consumer, and Public Health Coalition, such as Consumers Union, National Consumers League, National Women’s Health Network, and the Union of Concerned Scientists, about the tone and focus.
I think it is a good idea that the proposed PDUFA V would enable companies to have more meetings with the FDA earlier in the approval process, in an effort to make the process more efficient for companies. It is not in anyone’s best interest if pharmaceutical companies don’t understand what the FDA expects or requires of them to get their products approved. However, these meetings are very resource-intensive. User fees need to be available for other important uses as well, and we are very concerned that these meetings will take up so much staff time that there will not be enough staff available for the kinds of safeguards that are needed to protect patients from the risks of the drugs being reviewed and approved.
As we outlined in an August 2011 Coalition letter to HHS Secretary Kathleen Sebelius, our main concern is that most of the recommendations are aimed at industry’s goals of reducing barriers to new drug approvals rather than protecting and promoting the health of patients. Performance goals are needed to protect patients from the risks of pharmaceuticals, not just to speed them to market.
Overall, the proposed recommendations are quite specific in terms of commitments to industry but vague on safety commitments. The proposal's section on the "Enhancement and Modernization of FDA Drug Safety System" is only 2 ½ pages out of a total of 34 pages. It states, "FDA will continue to use user fees to enhance and modernize the current U.S. drug safety system..." What does that mean? Will any of the increases in user fees be going to drug safety? Or will those amounts remain the same as in PDUFA IV? Are there any new user fees slated to increase the staff at Office of Surveillance and Epidemiology (OSE)? If the FDA is increasing the number of staff to 'expedite drug development,' won't that put even more pressure on the already smaller OSE staff
REMS and Sentinel Research
The proposal specifies that user fees will provide support for enhancing REMS and the development of Sentinel, but says almost nothing about how that will be accomplished and whether the goals are to enhance safety or other purposes. For example, the REMS section focuses on reducing the burden on industry, health care professionals, and patients. It does not talk about the importance of ensuring safety. This is especially worrisome, because in the Federal Register notice of this meeting, it refers to REMS as a strategy designed to get drugs on the market “that could not otherwise be approved because of the risks…would outweigh the benefits.”
The statements about meetings that FDA must have with industry are very specific. The statements on the Sentinel research, in contrast, are extremely vague. We are strong supporters of the Sentinel research, but are very concerned about whether Sentinel data will be reviewed and acted upon in a timely manner – as timely as that required for the approval process under PDUFA V. Obviously, companies are very concerned that Sentinel research findings have the potential to identify risks of very popular prescription drugs worth billions of dollars in sales. The loss of those profits is therefore a major concern to industry. Of course, patients could also be harmed if safe and effective medications were erroneously identified as unsafe. But the truth is that many widely used medications are “me-too” drugs that can be easily replaced with other products on the market, and the potential harm to companies if a product is unnecessarily taken off the market is much greater than the potential harm to patients.
We know that industry wants to make sure that research findings from Sentinel are not made available to the public – including doctors or providers – unless the adverse reactions were expected based on previous knowledge or data, and only when the evidence is absolutely beyond a doubt. However, the Sentinel research was intended to be an early warning system. If information from Sentinel research is not made public unless the findings are consistent with expected mechanisms of adverse reactions or until the findings are absolutely conclusive, it will not be an early warning system; it will be a later warning system, and patients whose lives could otherwise be saved will not be saved. It doesn’t make sense that drugs can be sold based on short-term studies but can’t be taken off the market or even have new warnings without much better evidence. If that continues, patients will continue to die unnecessarily.
Up until now, consumer and public health groups have not been privy to any public discussions on exactly how the Sentinel results should or will be used, and how they won’t be used. So, we are concerned that the FDA states that Sentinel may “reduce the Agency’s reliance on required postmarketing studies and clinical trials.” Sentinel should complement but not replace postmarketing studies, especially until such time as it has established a track record that suggests other types of research are no longer needed.
Enhancing Benefit-Risk Assessment
We’re concerned with the section on “Enhancing Benefit-Risk Assessment,” which will develop a five-year plan to implement a benefits/risk assessment. It states that FDA will facilitate a “balanced consideration of benefits and risks
What does “balanced consideration of benefits and risks” mean? Does that mean that the current consideration of benefits and risks is out of balance? Judging from discussions at FDA Advisory Committee meetings, it often seems to focus more on the potential for helping one patient than the potential for harming many, but I am not confident that is the concern of those who wrote this PDUFA document. Is “balance” a code word for lowering the risk standards? Considering the large number of patients who have taken drugs that we know have harmed many of them, such as Vioxx and Avastin and Ketek, for example, I want to know what “enhancing benefit-risk assessment” means.
FDA is concerned about the accuracy of meta-analysis done outside of the Agency. It wants to conduct its own meta-analysis with “the raw clinical trail data submitted by drug sponsors that would typically not be available to outside researchers.”
I have seen meta-analyses misused many times, so I hope this would be a way to improve the accuracy of meta-analysis results. Clearly, transparency is an important issue for this proposal, and I’d like to know more about how those issues will be resolved.
There is a growing body of evidence that many biomarkers that seem absolutely logical do not necessarily predict patient outcome. For example, drugs that are extremely effective in reducing glucose levels are not always the best at saving the lives of diabetics, and drugs that are great at reducing cholesterol levels are not always the best for saving lives of people with high cholesterol. And yet, there is tremendous pressure to replace meaningful outcome measures with biomarkers that can shorten the time needed to complete clinical trials. We want more specifics on what safeguards will be in place to assure the better use of biomarkers in ways that emphasize the benefits to patients, not just getting drugs to market sooner.
Patient Reported Outcomes
We believe that patients should be evaluated objectively to determine the risks and benefits of medications. The reason why double blind clinical trials are the gold standard is that both patients and their physicians are not objective at measuring outcome. When the Women’s Health Initiative trial was ended, for example, many women who were very upset that they would no longer get their hormone pills learned that the pills that they believe had so greatly benefited them were placebos, not hormone pills. Patient surveys and interviews should be used to help researchers and physicians understand the importance of the risks and benefits of specific drugs, but safety and efficacy should be evaluated based on sound scientific evidence, not on patient perceptions.
Improving FDA Performance Management
As the FDA develops programs to improve access to internal and external expertise, what conflict of interest rules will be in place for external experts?We need more information about that.
We agree with the proposal to increase accountability for the use of user fee revenues. We’d like to see it broken down by category-especially the safety-related categories. And, we’d like to see a comparison to PDUFA IV spending. This section also recommends an assessment of FDA’s performance by an independent contractor. We have not been impressed with some previous selections of independent contractors, many of whom seemed to have limited understanding of the kinds of research that the FDA relies on for drug approvals. For examples, contractors who examined post-market studies tended to evaluate whether the studies were completed, but not whether they were conducted correctly or provided useful data. This should be an open and transparent process, with clear requirements and guidelines for the selection process and the type of evaluation needed.
Recommendations That are Missing
In addition to the vague statements on important safety matters, we are very disappointed that several important proposals put forward by the FDA were not included in PDUFA at all. For example, there is growing evidence that advertisements, including ads aimed at physicians as well as ads aimed directly at consumers, have an enormous impact on prescriptions, including off label prescriptions. And yet, there is no mention of the need to carefully review all advertising to reduce the misuse of prescription drugs. At the same time that Kentucky Fried chicken had to take an TTV commercial off the air for stating that it was a healthy choice for families compared to a Big Mac – a statement that was misleading rather than completely false–drug companies were advertising atypical antipsychotic drugs as if they were antidepressants, and the FDA did nothing about that. The Seroquel ads were much more dangerous, because consumers had no way to realize how misleading they were, whereas the Kentucky Fried Chicken commercial was obviously ridiculous to many consumers.
Somehow, the standards for misleading advertisements are much better at the FTC – which regulates food ads – than at the FDA, which is supposed to be regulating drug ads but is apparently in dire need of better trained staff and more resources to review ads appropriately and in a timely manner. User fees could save lives if used to reduce misleading ads. We will be urging Congress to include such safeguards in PDUFA V.
Other recommendations that were apparently rejected by industry and therefore did not get included in PDUFA V include safeguarding human subjects in clinical trials, building quality systems into trial oversight and increasing the inspection of trial sites. We will also be urging Congress to include these additional patient safety proposals in PDUFA V.
We are also concerned about adequate resources being available for FDA inspections of manufacturing plants. According to news reports, “FDA found violations at 54 percent of plants inspected last year, up 20 percent from a decade low in 2007…And 80 drugmakers failed more than half of their inspections.” Will user fees be used for that purpose, or will most be dedicated to increasing the number of meetings between sponsors and FDA and speeding up the approval process.
In today’s budgetary climate, user fees are necessary, especially since the FDA has been under-funded for years. FDA is struggling to manage expanded demand with inadequate appropriations, but the demands are growing and the fees are not growing enough.
Do patients and consumers and the groups that represent them have a right to influence how user fees are spent? We don’t pay the fees, but we pay for the medications – directly when we use our own money to buy the products or pay for the health problems that may ensure when they don’t work well, or indirectly when we pay for our insurance coverage. And of course, as taxpayers we are paying for the appropriations that are still supporting a major proportion of FDA resources. We will continue to advocate that Congress increase funding for the FDA, and that user fees and appropriations be combined to strengthen the agency in general.
The bottom line is: user fees should not be considered a payment by companies for FDA approval or services. It is a fee for participation, just as entrance fees for national parks allow us to visit but don’t allow us to do whatever we want when we are there.
Thank you for the opportunity to speak on this panel.
1. Federal Register Volume 76, Number 176 (September 12, 2011). Prescription Drug User Fee Act; Public Meeting.
2. Food and Drug Administration (2011). PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 (Draft).
3. Silverman E, (March 2, 2011). Which Drugmaker Fails Most FDA Inspections? Pharmalot. http://www.pharmalot.com/2011/03/which-drugmaker-fails-most-fda-inspections/