FOCR and NPAF Respond to Senate HELP Committee Questions on Safety Issues

Full Responses to March 1st Testimony

1) In light of recent controversies, some people have proposed requiring longer-term and larger studies of drugs before they are approved. Could you comment on whether and how this might impact patients?

Time is a highly precious commodity to someone diagnosed with a life altering and/or life threatening condition like cancer, AIDS, or diabetes. The diagnosis not only impact the patient, but also their families, friends and communities. When you are suffering from a potentially fatal or severely debilitating disease, you shouldn’t have to wait any longer than is necessary for the FDA to approve new medical products. Any attempt to mandate longer or larger clinical trials would obviously increase the length of time before patients would have access to new products if they are deemed safe and effective. When you are suffering and dying, the risk/benefit ratio of significantly different than in patient populations in other circumstances.

The process for the review of new drugs draws upon the most complete and appropriate medical evidence collected through carefully-controlled clinical trials, the expert judgment of FDA staff, and the advice of patients and doctors on the advisory committees. Approval comes down to decisions about how much risk and uncertainty should be tolerated and, in turn, depends on the strength of the evidence on the benefits that a new drug or device will provide. The invariable feature of drug development is that no matter how extensive or carefully designed the pre-approval clinical trials, a full understanding of benefit and risk is possible only after millions of patients have been treated, often times, for many years.

Such decisions about the size and length of a trial should continue to be conducted on a case-by-case basis by scientific and medical experts who are the most qualified and best equipped to make decisions about the design of clinical trials and who have experience that may be very similar. That is not to say that in some cases, a longer and/or larger clinical trial might be appropriate for the proper evaluation of a proposed product’s safety and efficacy, even if that means a potentially longer waiting period for patients. For example, a longer trial may be necessary in order to detect delayed toxicities. A larger number of trial participants may be necessary in order to detect very uncommon toxicities.

However, this decision should be determined on a case-by-case basis by the clinical trial Institutional Review Board (IRB). However, in many cases, smaller and/or shorter clinical trials may be sufficient for the rigorous evaluation of a new product. . Because the appropriate clinical trial design may vary greatly depending on the specific human testing proposed and what the testing is intended to demonstrate, imposing a uniform requirement that all clinical trials should include a greater number of subjects or extend for a greater length of time would not be scientifically grounded. IRBs in both hospital and clinical settings have historically been charged with answering those questions.

Our preliminary background research on the matter revealed that current FDA regulations provide conceptual parameters for different phases of trials (i.e., Phases 1, 2, and 3), but they do not specify a standard number of subjects in, or lengths of time for, clinical trials to support a new drug application. Companies are required to justify the size and length of study in their clinical protocol, which is submitted to FDA prior to initiation of the study as well as through the IRB that will monitor and track clinical trial status. FDA does not require a particular number of patients or length of follow-up. Rather, the appropriate sample size is derived strictly from statistical calculations, and the length of follow-up is dependent on the safety and efficacy endpoints being measured. We believe these standards are sufficient to ensure that both safety and efficacy can be proven.

FDA recommends that applicants follow the “Guidance for Industry: Good Clinical Practice” in developing clinical studies. This Guidance was developed in conjunction with the International Conference on Harmonization (“ICH”), and provides unified standards applicable to studies intended to generate clinical data for submission to regulatory authorities in the United States, European Union, and Japan, thus socializing data from country to country for enhanced reporting of clinical trial activities and results. T

he exciting news for present and future patients is that scientific discovery, particularly in emerging fields such as genomics and proteomics, is laying the foundation for an ability to effectively gauge safety and efficacy through smaller and perhaps shorter clinical trials. For example, diagnostic tools are being developed that will allow physicians to identify those patients with a particular type of cancer or those who are likely to develop a particular type of cancer, and then match those patients with the best available treatment or preventive option for that specific cancer. This technology might also dramatically improve the safety of trials as well.

FDA is taking new steps to develop better information about pharmacogenomics—the differences in the way people respond to drugs and the types and dosages of medications from which they are most likely to benefit and least likely to suffer an adverse event. The application of this knowledge will provide the ability to screen patients for their level of susceptibility to certain side effects, which will help physicians determine in advance which clinical trials and/or treatment options may be the most appropriate in terms of balancing safety and efficacy. (There is a recent example of this in the approval of the Roche AmpliChip Cytochrome P450 Genotyping test; please see http://www.fda.gov/cdrh/mda/docs/k042259.html).

Thus, science is rapidly developing a capacity to identify the best candidates for particular clinical trials from both a safety perspective and an efficacy perspective, which in many cases would provide an opportunity to conduct smarter, shorter, smaller, and safer clinical trials. With the emergence of this technology already on the horizon, a requirement for longer and larger clinical trials could prevent one of the most useful applications of such advancements. Consequently, such requirements could unnecessarily expose patients to greater risk for longer periods of time and unnecessarily impose additional burdens in terms of time and resources on those who design and conduct clinical trials.

The length and size of the clinical trial is one of the most expensive aspects of the research and development process. According to recent industry estimates published by Cutting Edge Information, the average per-patient cost of a Phase I trial is about $5,500; the average for a Phase II trial is $6,500; and the average Phase III trial costs more than $7,600 per patient. A widely cited study on drug development costs conducted by Tufts University estimates that the average per patient cost to conduct clinical trials is $23,572. The National Cancer Institute (NCI) estimated that its average per patient cost for a clinical trial ranged from $3,861 to $6,202 (depending upon the year) for the DCP Cooperative Group Treatment Trials conducted between 1993 and 1999.

Any mandate for larger and longer clinical trials would dramatically increase the overall cost of research and development. Such increases could have a chilling effect on the pace of scientific discovery.

Fortunately, the continued development of new, scientifically based capacities to enable shorter, smaller, and smarter clinical trials holds great promise for dramatically reducing the skyrocketing costs associated with the clinical trials component of research and development. Since the cost of conducting a clinical trial sometimes prevents companies from pursuing promising new products (particularly those that would be used only in certain patient sub-populations), any technological advancements that reduce the cost of clinical trials could provide a heretofore lacking economic incentive to expand the scope and scale of the research and development pipeline to include new products for diseases and conditions that would otherwise be considered too great of a financial risk. For many patients with limited to no treatment options for their particular disease, a robust research and development pipeline offers them and future patients the best hope for potential improvements in their quality of life and/or life expectancy.

2) Many have called for a greater separation between the Office of New Drugs, which is responsible for drug approvals, and the Office of Drug Safety, which is responsible for post-market surveillance of drugs that have already been approved. Are you concerned that an independent Office of Drug Safety would only look at risks and problems, potentially ignoring the benefits?

Patients and their families, physicians and caregivers must always weigh the benefits and risks associated with a particular treatment option. Similarly, we feel that the FDA must carefully weigh the benefits and risks associated with a new drug when making decisions about approval or post marketing activity.

Safety and efficacy are the inseparable foundation of the FDA’s ability to best define the appropriate risk/benefit ratio of a product. Risk cannot be considered separately from benefit, nor safety from efficacy. To review one without an equal measure of the other could easily lead to misjudgments and false conclusions. For that reason, we would advise against any effort that creates new regulations or bureaucracy that isolates or further separates the drug safety function from the overall drug review and monitoring process.

Rather than an independent drug safety office operating in isolation, we would prefer strengthening of the existing Office of Drug Safety so it can do a better job in a more timely fashion. Adding new levels of bureaucracy at FDA that only consider safety without consideration for efficacy will almost certainly discourage research on new therapies for deadly diseases like cancer and AIDS. Assuming they could even be approved, it could be difficult to keep new treatments for these diseases on the market if the regulatory hurdles for safety are too high because those drugs are likely to have some level of side effects, and they are likely to be used in patient populations that are sick and vulnerable to adverse reactions.

Of even greater concern is how an overemphasis on safety might have a devastating impact on the advancements being made in our ability to detect deadly diseases early or prevent them altogether. The conundrum is that the clinical testing and medical application of new technologies for early detection and prevention will involve people at risk for the specific disease who are not yet showing signs of advanced disease and may be entirely without symptoms. However, the tools for early detection and prevention are likely to have side effects, just like any medical intervention.

If the regulatory emphasis on safety is too great, it will be very difficult to get new tools for the treatment, prevention and early detection approved and then keep them on the market even though they may save hundreds of thousands, if not millions, of lives in the not too distant future. Such potential uncertainty can easily discourage the public and private sectors from investing hundreds of millions of dollars into the research and development of new products in this country if those products are likely to face intense scrutiny over safety concerns regardless of their benefits. We can evaluate the number of off-shore clinical trials toady, as opposed to five years ago, and see that many US clinical trials have been moved to foreign locations. The patients of the United States would benefit greatly from additional clinical trials taking part in our country.

It always has been an unfortunate but unavoidable fact that some adverse effects may not become apparent until after a drug has been in wide or extended use. We can hope to minimize such adverse effects and enhance the agency’s capacity to report them, but we must also accept certain risks associated with beneficial drug products.

With that in mind, we do feel strongly that the FDA can do a better job with its post marketing surveillance activity. We applaud Dr. Lester Crawford’s announcement that FDA will enhance the independence of internal deliberations and decisions regarding risk/ benefit analyses and consumer safety by creating an independent Drug Safety Oversight Board (DSB). The DSB will oversee the management of important drug safety issues within the Center for Drug Evaluation and Research (CDER). The DSB will comprise members from the FDA and medical experts from other HHS agencies and government departments (e.g., Department of Veterans Affairs) who will be appointed by the FDA Commissioner. The board also will consult with other medical experts and representatives of patient and consumer groups.

Another important initiative is for FDA to continue to increase the transparency of its decision-making process by establishing new and expanding existing communication channels to provide targeted and timely drug safety and efficacy information to the public. These channels can be used to help ensure that established and emerging drug safety and efficacy data are quickly available in an easily accessible form to those who will bear the risks: patients and their caregivers. The increased openness will enable patients and their healthcare professionals to make better-informed decisions about individual treatment options. To address these objectives, the FDA must stress efficient risk management — finding the least costly approach to achieving the most risk reduction for patients. Efficient risk management requires using the best scientific data, quality standards, and efficient systems and practices that provide clear and consistent decisions and communications for the public and regulated industry. Although we see it only as a first step, we are pleased that the Agency is proposing a new "Drug Watch" Web page for emerging data and risk information and increased use of consumer-friendly information sheets written especially for healthcare professionals and patients. Finally, we believe FDA will need to employ more user-friendly, automated adverse event reporting systems.

In order to achieve these objectives, we strongly believe additional financial resources will be required. Moreover, without new resources, every dollar the FDA shifts towards new regulations and infrastructure for safety is money taken away from programs that allow the agency to more effectively and efficiently evaluate risk and benefit together in the New Drug Approval process.