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The US drug regulatory system fails to address the country’s most urgent medical needs with the resources appropriate for the task. But change is possible, say Christopher-Paul Milne and Kenneth I. Kaitin.
The US drug regulatory system fails to address the country’s most urgent medical needs with the resources appropriate for the task. But change is possible, say Christopher-Paul Milne and Kenneth I. Kaitin of the Tufts Center for the Study of Drug Development.
Although prescription drugs comprise a relatively small percentage of overall healthcare expenditures at 10%, they, nonetheless, represent the primary point-of-contact between the majority of the US population and the healthcare system; while 62% of Americans fill a prescription in any given year, only 8% typically experience a hospital stay. Thus, in an era of health reform, when a primary concern for decision-makers at all levels-policymakers, public health officials, practitioners-is how well our system is meeting the medical needs of the population, focusing on the role played by prescription drugs is essential.
In the US, oversight of new drug development and approval is the responsibility of the FDA. In 1997, the FDA Modernization Act expanded the agency’s mission to go beyond protecting the public from unsafe products, to also promoting public health, by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner.
While the overall number of approvals for new molecular entities (NMEs) -i.e., innovative new drugs with active ingredients never previously approved by the FDA-has varied from year-to-year over the last three decades, a concerning trend has emerged. Among the top five therapeutic areas-infection (e.g., antibiotics, antivirals), cardiovascular (e.g., hypertension, heart failure), central nervous system disorders (e.g., Alzheimer’s disease, schizophrenia), metabolism & endocrine diseases (e.g., diabetes, enzyme deficiencies), and oncology (e.g., blood cancers, solid tumors)-approvals of NMEs have decreased significantly in two areas (infection and cardiovascular), remained static in two others (central nervous system and metabolism & endocrine), and increased in only one area (oncology). (See chart on facing page).
Why should we be concerned about this trend? For two reasons. The first is that the trend is not in sync with public healthcare needs. While cancer is certainly a major health problem, it is neither the nation’s No. 1 health concern, nor the most urgent in terms of unmet medical needs. In contrast, infection and cardiovascular disease, two therapeutic areas representing notable unmet needs, had significant decreases in the absolute and relative numbers of NME approvals. Cardiovascular disease is the nation’s No. 1 killer in terms of overall mortality, while infection is the No. 1 threat (e.g., drug-resistant pathogens and newly emergent infections such as SARS and Ebola), with the potential to impact a sizeable portion of the US population.
The second reason for concern is that the trend runs counter to FDA’s mission-which is defined by Congress, who thus shares some responsibility for supporting it. In principle, regulatory bodies should be addressing public health needs with resources proportionate to the challenges at hand-this is what agencies strive for, and what citizens should expect. If this is not being done, then agency priorities and resource allocations should be examined, and recalibrated if necessary.
The NME approval trend is perplexing, because while FDA controls how many and how fast products reach the marketplace, it is the pharmaceutical industry that controls what drug candidates enter the development pipeline. The two therapeutic areas that have remained static in recent decades-CNS and metabolism & endocrine-represent areas with substantial market potential (e.g., mental health was tied with cancer as one of the four most costly conditions in the US during the decade of the 2000s, whereas by the end of the decade, diabetes topped the charts with $40 billion more healthcare costs annually than cancer). Despite the enormous market opportunity, however, the number of NME approvals in these two therapeutic areas has been static, in each area equaling only half the number of oncology approvals. At a time when there is increasing availability of prognostic and diagnostic technology available for CNS disorders, as well as drug delivery and drug-device innovations in metabolism & endocrine diseases, the continued dominance of oncology, at 30% of the pipeline, is both economically and medically out of balance.
Economic dictates of supply and demand, and what the market will bear, explain some of industry’s high level of interest in oncology drugs. Over the last 10 years, the average price for oncology treatments has risen sharply. While high prices act as a “pull” incentive for oncology research and development (i.e., they increase the likelihood of sufficient return on investment and thereby act as an R&D incentive), regulatory initiatives aimed at speeding development and review times serve as equally powerful “push” incentives (i.e., they lower the financial and logistical barriers, and reduce the risk of entering the field of research).
Another reason for industry’s focus on oncology is that the enormous investment in basic research by the National Institutes of Health and other funding sources has led to greater understanding of the pathophysiology and genetic mechanisms of many cancers, which provides exciting new and fertile areas for commercial product development. Also, the field of cancer research, over the years, has benefitted from a very effective patient advocacy movement. The American Cancer Society, for one, has been described as “the single most effective disease-based lobby in American pharmaceutical regulation.”
The regulatory environment has had a substantial impact on the introduction of innovative new medicines in certain therapeutic areas. Over the past 25 years, a large number of regulatory initiatives have been implemented to speed the development and review of drugs for life threatening and severely debilitating medical conditions. As one would expect, drugs to treat cancer have been some of the major beneficiaries of these initiatives.
It’s not surprising that at a time when the out-of-pocket costs to develop a new medicine exceeds $1 billion, many companies would be drawn to areas that receive favorable regulatory treatment. This has certainly been true in oncology. In the 2000s, oncology drugs represented 32% of all priority reviews (i.e., those drugs considered by the FDA to offer important therapeutic gains, and receive a six month review time, compared to 10 months for standard drugs), 53% of all accelerated approvals (i.e., drugs eligible for conditional approval based on surrogate, or indirect measures of benefit), and 50% of all fast-track designations (i.e., breakthrough drugs that receive increased access to scientific interaction with the FDA during the development period). In sum, oncology drugs received 45% of all FDA special program awards (i.e., priority review, fast-track designation, and accelerated approvals). The relationship between regulatory initiatives designed to speed access to important new medicines, and industry’s focus on oncology is supported by the fact that if you look at the number of oncology approvals during the 10-year period before FDA’s special regulatory programs were implemented (1984 -1993), oncology was not even in the top five therapeutic areas for approvals.
Unfortunately, it is a zero-sum game. FDA has often voiced concern that it has been asked to do more over the years without a commensurate increase in resources allocated by Congress. Sometimes, as FDA itself has pointed out, this imbalance results in performance deficits in one area of responsibility to the detriment of another. Nonetheless, change is possible. For example, under the Generating Antibiotic Incentives Now (GAIN) Act, antibiotics intended to treat drug-resistant pathogens may be eligible for several incentives, including fast-track designation and priority review, as well as five years of market protection from generic competition, once approved. Just two years since passage of the GAIN Act in mid-July of 2012, industry participation in the program has been robust, with 52 designations awarded for 35 unique molecule development programs, according to FDA’s Blog. Regrettably, however, not every disease area can have its own GAIN Act. Political will and patient and public advocacy are often lacking, and resources at the FDA are finite.
To address a broad swath of unmet medical needs and to boost innovation in those areas, we offer the following two-step policy recommendation. The first step is to create a National Commission on Medical Priorities. The Commission would be comprised of experts from government, academia, industry, and the medical establishment, and its responsibility would be to assess the country’s immediate and long-term health needs, and review the innovation landscape to determine whether current public and private R&D efforts are appropriately focused on those needs. One of the beneficial outcomes of the Commission would be to spark a national debate and raise public awareness of this country’s most urgent medical needs.
The second step is to create within the FDA an Office of Special Regulatory Programs. The new Office’s aim would be to design and implement a prioritization process to determine which drugs may be eligible for one or more of FDA’s fast-track programs, thereby garnering a greater share of the agency’s resources. The prioritization process would triage new drug candidates based on level of unmet medical need, using the recommendations of the National Commission on Medical Priorities as a guide. To help subsidize these activities, sponsors of candidate drugs would pay an application fee to the FDA. The application would explain why the drug candidate should be considered a priority, and why it deserves to receive special attention by the agency. If the new Office determines that a drug candidate is eligible for one or more of FDA’s special regulatory programs, the sponsor would be exempt from paying any additional application or user fees. It is likely that drug sponsors would be attracted to such a program, because it would provide an opportunity to receive FDA attention and advice during the development process, and an expedited review of the new drug application, ultimately leading to quicker time to market.
Despite the enormous public and private investment in R&D to bring new drugs to market, there are urgent medical needs in the US that remain unaddressed. In fact, in disease areas associated with some of the highest levels of morbidity and mortality (e.g., cardiovascular disease), the number of innovative new medicines approved over the last three decades has actually declined.
To address this deficit, there is a critical need for public debate about what our R&D priorities should be, and then the FDA should be authorized to use special regulatory programs to incentivize companies to devote resources and focus their efforts in these areas. The creation of a National Commission on Medical Priorities, to identify areas of urgent medical need, and an FDA Office of Special Regulatory Programs, to ensure that those drug candidates that address those needs benefit from FDA’s fast-track programs, would be two important steps in the right direction. All that is required to affect such change is political will and public support.
Kenneth I Kaitin, PhD, is Director & Professor, Tufts Center for the Study of Drug Development. He can be reached here. Christopher-Paul Milne is Director of Research, Tufts CSDD. He can be reached at email@example.com.