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Negotiating the Critical Path: the FDA’s Initiative to Streamline the Drug Development Process

The U.S. Food and Drug Administration (FDA), which officially exists, in large part, to “protect the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices,” has been the object of a great deal of criticism over the years from medical patients, drug and biomedical device developers, pharmaceutical companies, and analysts who view the looming shadow of the administration’s bureaucracy as an impediment to real market-based reform of the drug development and distribution process.

The federal agency, which also bears responsibility for “advancing the public health by helping to speed innovations that make medicines more effective, safer, and more affordable,” has often been accused of being “institutionally incapable of striking a proper balance between speed and caution,” as the Cato Institute’s director of health policy studies, Michael Cannon, phrased it. “The FDA’s drug-approval process costs lives by requiring too much time and testing before a drug can be brought to market,” said Cannon, “and we would be better off without it.”

While their prescription for reforming the process may be a bit more moderate than Cannons, many of those in the business of designing, developing, and marketing comfort-giving, and in some cases lifesaving, pharmaceuticals and biomedical devices share his and fellow analysts’ frustration with the administration, which has taken a number of steps in recent years to improve its methods of operation despite claims by defenders that the agency has been deprived of necessary assets by the federal bureaucracy.

A Drug Approval “Bubble”

In the 1990s, the FDA made significant improvements to its notoriously slow drug approval process, causing the average number of drugs approved annually to double from 20 at the beginning of the decade to, by 1998, 40.

The reasons for this included a fast-tracking of lifesaving drugs in the wake of the AIDS epidemic and an increase, thanks to several successful drug releases in the 1980s, in financial capital that could be allotted to researching and developing future drugs. Perhaps the greatest impact on the number of drugs and devices entering the production pipeline then and now, though, came from improvements in the discovery process itself. Advances like combinatorial chemistry, recombinant protein manufacturing, X-ray crystallography, magnetic resonance imaging, and sophisticated computer modeling have enabled researchers to optimize lead compounds (or molecules with the potential to become effective drugs), improve design to better bind to their target to alter or prevent disease courses, and synthesize the new compounds more quickly than in the past. As health care economist J.D. Kleinke wrote in the October 1998 edition of the British Medical Journal, “More money plus better science equals more new drugs.”

However, as might be expected in a world governed by the law of averages, the increase in approved drugs in the 1990s was accompanied by an increase in the real number of recalled drugs, leading some to question whether the FDA’s standards had become lax and its approval pipeline too easy to negotiate.

By 2004, though, that momentum had been lost, and the number of drugs and medical therapies reaching patients had sharply declined once again. FDA administrators looked into the causes of this “pipeline problem” – or slowdown (in the face of positive momentum) of innovative drugs and therapies reaching patients – and were surprised by what they found.

The problem, administrators found upon further inquiry, was largely the result of a decrease not in the number of drugs and biomedical devices gaining approval from the evaluating agency, but in the number of innovative medical products being submitted to the FDA for approval in the first place. This was despite the fact that between 1994 and 2003, funding for biomedical research nearly tripled (from $37 to $94 billion) in the U.S. alone, with 57 percent of that total coming from the private sector.
According to a March 2006 FDA report (“Innovation Stagnation: Critical Path Opportunities Report”), “a new compound entering human trials in 2000 was no more likely to reach the market than one entering human testing in 1985.” In fact, the number of new medical therapies released in 2004 was the lowest total in twenty years (though the 17 approved in 2006 and 2007 surpassed 2004 to set a new nadir).

“Innovation Stagnation”

A major reason for this, according to another agency report (“Innovation Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products”), was that the “development path” of drug and biomedical devices was “becoming increasingly challenging, inefficient, and costly.”

“During the last several years, the number of new drug and biologic applications submitted
to FDA has declined significantly,” said the report, while “the number of innovative medical
device applications has also decreased. In contrast, the costs of product development have soared over the last decade.”

Administrators found one result of the aforementioned rising costs was that innovators were spending a disproportionate amount of research and development (R&D) time on products with “potentially high market return,” meaning that broader-based, less lucrative drugs and therapies such as “targeted for important public health needs (e.g., counterterrorism), less common diseases, prevalent third world diseases, prevention indications, or individualized therapy” were being left by the wayside.

With this, the FDA was acknowledging the need for greater investment in medical development sciences and communication with product developers about which potential drugs were worth greater investments of time and capital, as well as about the types of clinical trials that would best set new products up for approval “If the costs and difficulties of medical product development continue to grow,” the report said, “innovation will continue to stagnate or decline, and the biomedical revolution may not deliver on its promise of better health – and, without a new generation of product development tools, the biomedical revolution may not deliver on its promise of better health.”

A Need for Coordinated Effort

Along with the rising costs involved in R&D, and the capital-allocating effect of those costs, the FDA found another speed bump in the “critical path,” or the path between drug conception and final product distribution. This was the fact that, while there had been huge advances in recent years in the basic sciences used to optimize potential drug molecules and to work with lead compounds, these advances had not been met with similar steps forward in the applied sciences necessary to actually develop and effectively test these new medical products.

In other words, in the FDA’s view, “not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs. In many cases, developers have no choice but to use the tools and concepts of the last century to assess this century’s candidates.”

Whether because of this or because of a combination of other factors, such as FDA’s strict clinical testing standards, the “vast majority,” according to the agency, of new drugs and devices that entered clinical trials failed, often after a great deal of time and capital had been invested in their discovery and development. The growing costs of R&D were further augmented by the failure rate, creating a situation in which, as the FDA put it, “developers [were] forced to use the profits from a decreasing number of successful products to subsidize a growing number of expensive failures.”

In other words, according to the FDA, “the medical product development process” was “no longer able to keep pace with basic scientific innovation.”

In an effort to address the problems found in the drug discovery and delivery process, FDA administrators suggested that public and private participants in the development process engage in a “collaborative effort to create a new generation of performance standards and predictive tools.”

The goal of this effort was to use those tools to achieve and improve on new scientific innovations and advances for the purpose of increasing efficiency and streamlining the critical path between drug discovery and approval – or, in the FDA’s words, to make “a concerted effort to apply the new biomedical science to medical product development” for the purpose of “moderniz[ing] the critical path.” Advances in bioinformatics, genomics, imaging technologies, and materials science were to be harnessed by this initiative, spearheaded by an FDA which would be responsible for “identifying and prioritizing” issues clogging the drug development pipeline and opportunities for improved public health benefits.

Advent of the “Critical Path Initiative”

In March 2004, in accordance with this plan, the FDA launched a program called the “Critical Path Initiative,” which acting FDA commissioner Andrew von Eschenbach in 2006 called “the vehicle that will take us into the 21st century” through “fostering strong, sustained scientific advances that will enhance the health and well-being of all Americans.”
One of the agency’s “top priorities,” according to Eschenbach, the Critical Path Initiative sought to improve the drug discovery and approval process in two ways: by aiding in the development of new biomarkers and disease models to improve clinical trials and medical therapy, and by streamlining the clinical trials themselves.

Its effort to do so required collaboration between all involved in three major areas, or “dimensions,” along the critical path between drug and biomedical device discovery and distribution: assessing the proposed product’s safety, evaluating medical utility, and industrializing the end product. The proposal was met with a great deal of support by those in the development field, who largely agreed with the FDA’s diagnosis of scientific shortfalls and an outdated regulatory environment, as well as with its call for increased collaboration and a modernization of standards.

With the Critical Path Initiative, the FDA hoped to provide a set of tools specially targeted to improve predictability and efficiency along the development pathway. This “development toolkit,” as the administration called it, contained new scientific and technical applications and methods, from predictive modeling, to biomarkers and electronic monitoring to help determine and monitor product safety and effectiveness, to improved clinical evaluation techniques.
Since the initiative’s inception in 2004, the FDA has striven to modernize its regulatory and communication infrastructure in small ways, such as creating a portal for the electronic transfer of product information and standardizing the electronic submission of proposed prescription drug labels. However, a great deal of room for improvement remained.

Evaluating the Program

In March 2006, at the program’s two year mark, the administration issued an evaluation of the Critical Path Initiative in which they identified six areas ripe for further improvement: better developing new biomarkers and disease models to improve product safety and to better predict human responses; further streamlining clinical trials through innovative trial design and incorporating automation; harnessing bioinformatics to enhance the agency’s regulatory decision making for the purpose of getting “safe and effective” products to patients; modernizing the manufacturing process; developing more products for mass public health use; and better providing for at-risk populations like children.

Though the FDA was relatively objective in its two-year evaluation of the initiative, the years since that progress check have shown that the Critical Path has a ways to go before it approaches accomplishment of its initial goals. The major shortfall has been in one of the critical areas addressed by the program at its inception: facilitating the development, submission, approval, and distribution of new drugs and biomedical devices.

In 2007, the FDA approved only 17 novel molecular entities, or new products. As noted above, this total tied with the year before for the lowest total of newly approved drugs since 1983. While some in the development industry have been quick to accuse the FDA of tightening its standards in a too-cautious effort to ensure only the safest, highest-quality products reach patients and consumers, spokespersons for the administration say criteria for drug and device approval are unchanged.

Other explanations for the miniscule number of new pharmaceuticals reaching patients, as suggested by Jacob Goldstein, writer for The Wall Street Journal’s health weblog, include the adoption of a risk-averse mindset by developers, a dearth of recent scientific breakthroughs, and an industry that “has shifted its focus away from novel drugs and toward tweaking existing medicines to maximize sales during the research drought.”

In the end, though, the bureaucratic and regulatory nature of the FDA means that it will bear the brunt of the blame for an environment perceived to be unfriendly to novel drugs and biomedical products. The administration has admitted that, as a government bureaucracy, it lacks the ability “to keep up with scientific advanced” – a fact its leaders acknowledge “means that American lives are at risk.”

Further, the administration has been forced to deal with conflicting directives from its Congressional overseers, which have demanded high performance from programs like the Critical Path Initiative while simultaneously diverting funding from the program (in 2008, Congress lowered the funding for the agency’s Reagan-Udall foundation, which exists to promote the type of interagency and public-private communication and cooperation that initiative success requires, by $1 million because the chair of the House appropriations subcommittee tasked with overseeing the FDA believed pharmaceutical industry representatives affiliated with the foundation were corrupting it from within).

An Initiative Worth Keeping

Despite the speed bumps the FDA has encountered in its attempts to achieve its goal of unclogging the drug development pipeline, the Critical Path Initiative remains incredibly popular with the American public as a whole. A 2008 survey conducted by the Center for Medicine in the Public Interest (CMPI) found that nine in ten Americans supported the FDA initiative overall, and nearly 80 percent approved of the agency’s use of biomarkers to identify which drugs were best suited to individual patients. Biomarkers are a sore spot between FDA scientists and Congress. Dr. Francis Collins, director of the National Human Genome Research Institute at the National Institutes of Health, has called biomarkers “the next revolution in medicine.” Representative Rosa DeLauro (D-CT), chairperson of the House subcommittee overseeing the FDA, disagrees that biomarkers have value in medicine – a position which appears to reflect the all-too-common habit on the part of legislators of overruling experts based on opinion rather than evidence.

CMPI President Peter Pitts summed up the sentiment expressed by respondents to his organization’s poll by saying, “Day in and day out, Congressional lawmakers bash the FDA. That may score political points, but the public’s support for this program should send a strong message to Congress: Don’t cut funding from the Critical Path Initiative.”

To date, the initiative has not accomplished all – nor even most – of its goals. However, as long as it receives small but necessary changes in course and tactics along the way to better facilitate the discovery, development, approval, and distribution of new lifesaving and comfort-giving biomedical products, the communication and collaboration the Critical Path Initiative fosters with all who have a stake in the process of drug and biomedical device discovery make it a program that is worth keeping.

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