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February/March 2009, Vol 2, No 2 - FDA Approvals, Perspectives
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Prominent Cardiologist Hammers the FDA: Insufficient Funding Compromises the Science of Drug Approvals

At a January 2009 Speaker Series sponsored by Cleveland State University, Steven Nissen, MD, Chairman of the Department of Cardio vascular Medicine at the Cleveland Clinic, said that inadequate funding and an approval system that encourages the development of noninnovative drugs has contributed to a US Food and Drug Administration (FDA) that is ineffective at ensuring the safety of drugs. It has also led to an environment that has resulted in a shortage of drugs to meet the medical needs of consumers. According to Dr Nissen, the FDA's budget, currently at $2.2 billion annually, needs to double for proper staffing and for thorough reviews of drugs, in addition to ensuring the safety of the food supply. By comparison, the Centers for Disease Control and Prevention's budget is 4-fold bigger. A larger FDA budget would pave the way for more inspectors, enhanced testing of generics, and potentially more independence of the agency overall.

To partially make up for that, the FDA must rely on user fees from the pharmaceutical industry in exchange for expedited review of certain new drug applications. "User fees make the industry the client, not the American public," said Dr Nissen.

Too Many "Me Too" Drugs

The plethora of noninnovative products, known as "me too" drugs that are only slight variations of existing drugs, can be partially attributed to the FDA's willingness to approve these molecules based on noninferiority studies, he says. These studies are designed to show that the new version of an existing drug is not more than 50% worse than the existing drug. Once approved, these products are heavily promoted directly to the consumer, creating demand for their use, while diminishing the market for generic drugs that often work just as well. "Where are the drugs we need to treat Alzheimer's disease or antibiotic-resistant bacterial infections?" he asks. "If the enormous biomedical enterprise is focused on 'me too' products,'our real medical problems go unsolved."

To promote the development of new molecular entities to treat unmet medical needs, the FDA should use a sliding scale of evidence for approval, Dr Nissen emphasizes. Noninferiority trials should not be used as the basis for approval for a new entry into a category of drugs that has existed for decades, such as sleep-promoting medicines, in which case the new entry would have to be proved better or safer than the old choices. Rather, the FDA should consider less robust evidence for drug approvals for difficult-to-treat cancers, which would force pharmaceutical manufacturers to divert research money to innovative products.

Safety Concerns

The FDA has lost its way ethically, Dr Nissen believes. "The current FDA policy is a consequence of a misguided philosophy that views clinical trials as proprietary; this approach is morally and ethically indefensible."

Much of what the FDA knows about drugs is never revealed publicly, he says. "This atmosphere of secrecy is antithetical to good science and good government," he said. The problem of FDA secrecy is exacerbated by "publication bias," the common practice of suppressing and never publishing drug studies with unfavorable results, Dr Nissen claims.

Drug safety is compromised through 2 other phenomena that lack sufficient oversight: off-label marketing of drugs and the voluntary Adverse Event Reporting System (AERS). Current estimates are that 35% of pharmaceutical sales represent off-label prescribing. The risk for unexpected harm rises exponentially when drugs are prescribed for indications for which they have not been approved, said Dr Nissen. The outgoing Bush administration relaxed rules on promoting drugs for offlabel uses just before its term expired.

The concern is that AERS is an insufficient tool to detect serious side effects. Because this reporting system is voluntary, "only 1% to 10% of adverse events are ever reported to the FDA," Dr Nissen said. "Accordingly, serious drug safety problems go unrecognized for many years," as in the case of serious muscle toxicity with cerivastatin that prompted its eventual removal from the market.

The budget shortfall at the FDA has also compromised the safety and possible efficacy of imported generic drugs, as evidenced by many recalls of generics made in India. "The FDA needs to be constantly testing the generics, verifying that they are containing the amounts of the drug that they are supposed to, and they work as advertised," he said. "It takes more resources and more vigilance on the part of the FDA."

Funding for the FDA

Nirav R. Shah, MD, MPH, Assistant Professor of Medicine, New York University, New York City, and Senior Investigator, Center for Health Research, Geisinger Health System, Danville, PA

Dr Steven Nissen has an ax to grind with the FDA. Although the general principles he espouses are correct, such as the need for greater transparency and for improvements in the evidence base underlying FDA decisions, not all his arguments make sense in today's environment.

For example, Dr Nissen points to the reliance on user fees from the pharmaceutical industry as the reason for the FDA being "captured" by Pharma. User fees in and of themselves do not lead to being "captured"; how the money is spent, and transparency (or lack thereof) in reporting the flow of funds, may lead to such a state. What is required is smarter regulation to dictate how user fees are incurred and subsequently spent, rather than simply looking for alternative (perhaps nonexistent) sources of funding.

Dr Nissen suggests that the FDA should use a sliding scale of evidence for approval to promote the development of new molecular entities to treat unmet medical needs. The FDA's primary mission, however, is to protect public health by ensuring the safety, efficacy, and security of drugs, biologics, devices, and the food supply. Although facilitating innovation is certainly a priority, evidence standards cannot be relaxed for generics relative to "me too" drugs.

The evidence required for FDA decision-making should more closely match the specific needs in each case. For example, instead of focusing on noninferiority studies for a new entry in a category of drugs that has existed for decades, a careful review of the gaps in the evidence base should be conducted and studies in populations not initially studied may be required for FDA approval.

For orphan conditions or difficult-to-treat cancers, innovation cannot be achieved by using a less robust evidence base. Rather, stakeholder-focused means to promote innovation, such as longer periods of exclusivity or other rewards, should be used as the carrot to drive innovation.

It is true that the FDA has relied on clinical trials at the expense of other types of evidence; however, it is only recently that observational studies, registries, and associated analytic techniques have matured. The use of postmarketing surveillance registries and phase 4 studies should be encouraged. To date, only a small fraction of such studies have been completed.

As for publication bias, this problem has been solved. All trials (including phase 1) have to be registered at as per Section 113 of the FDA Modernization Act for investigational new drug regulations, and the International Committee of Medical Journal Editors now requires trial registration as a condition for publication of clinical trial results. Many sponsors, reviewers, ethics boards, and other groups also require registration before the enrollment of the first participant. Therefore, going forward, publication bias of trials will not be an issue, at least in the United States.

Dr Nissen is correct about the problems of off-label marketing of drugs and the voluntary AERS. But it is important to note the distinction between off-label marketing and off-label use. Off-label use can drive innovation, as it did with selective serotonin reuptake inhibitors for premenstrual syndrome. Although the current system for reporting adverse events is broken, it likely cannot be fixed. New ways of mining data from electronic health records hold much promise for replacing the system wholesale, with a thorough and more complete approach to reporting and surveillance.

As evidenced by the recent fiasco in peanut factories, the safety of our food and drug supply, often taken for granted, cannot be ignored. Broad calls for more resources and more vigilance on the part of the FDA focus attention away from the real issue: smarter—not just more—regulation is needed.

Innovation in Drug Development

F. Randy Vogenberg, RPh, PhD, Chief Strategy Officer, Employer-Based Pharmaceutical Strategies, and Senior Scholar, Department of Health Policy, Thomas Jefferson University, Jefferson Medical School, Philadelphia, PA

Innovation in drug development has never been easy or uncomplicated in the United States, nor has the relationship between Congress and the FDA. Going from savior to scapegoat in less than 75 years, the FDA continues to be caught between societal priorities, all of which have potent advocates for their point of view. Dr Nissen, a frequent FDA critic, continues to offer his mixed messages on this federal agency (as well as advocating for some drugs that others have argued are high-risk "me too" agents).

Although it is easy to point to the failings and problems of any government agency, offering solutions to improve programs or systems that can at least incrementally move us forward in patient care safety and outcomes of care would seem more worthwhile. The presidential election and current recession have put a momentary pause on the engine of healthcare innovation, but offer all of us an opportunity to rethink drug development. Biologic product research, along with nanotechnology and molecular medicine, will be changing healthcare delivery and finance. During the transition to this brave new world of products, we must not forget the traditional drugs and generic products that are available today. Finding the right balance between yesterday and tomorrow is the dilemma facing all industries, along with the agencies that regulate them.

For health plan sponsors, what is important remains the same as in previous years—a value proposition for healthcare products or services that meet the needs of patient populations in an affordable system reflective of our capitalist societal goals. Aligning new drug development, innovation, and regulation to that purpose is a good starting point to bring all parties together toward a meaningful, positive direction for US healthcare—refocusing on 21st-century drug product innovation.

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Last modified: August 30, 2021