The critical path

The critical pathDrugs recently approved by the Food and Drug Administration help children with rheumatoid arthritis walk, prevent or halt heart disease, slow the progression of multiple sclerosis, and cure infectious diseases. New medical devices improve the heart's blood-pumping ability in patients with heart failure, and the latest vaccines protect against the threat of bioterrorism.

Advances in medical products ultimately can shorten hospital stays, lengthen life expectancies, and reduce overall health care costs. New classes of drugs--a few pills, for--example have virtually replaced major surgery for treating ulcers.

But the recent slowdown--instead of the expected acceleration--of new medical treatments actually reaching patients concerns the FDA. Products fail before they reach the market because they could not be proved safe or effective, or they could not be manufactured commercially at a consistently high quality.

Despite recent innovations, many serious and life-threatening diseases still lack effective treatments. In the agency's view, the scientific tools needed to develop medical products have not kept pace with the rapid advances in product discovery. As a result, fewer of the sound ideas spawned in medical laboratories are becoming safe and effective treatments.

In the interest of public health, the FDA says that action is needed to modernize the product development process.

In March 2004, the agency issued a major report that identifies both the problems and the potential solutions for bringing more breakthroughs in medical science to patients as quickly and efficiently as possible. The report, "Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products," examines the crucial steps that determine whether and how quickly a discovery leads to a reliable treatment for patients.

The report, which looks at the development processes for drugs, biologics, and medical devices, calls for a joint effort of industry, academic researchers, product developers, patient groups, and the FDA to identify key problems and to develop solutions.

The Problems

Despite notable advances in basic biomedical research, such as the studies of gene structure (genomics), proteins in living cells (proteomics), and of miniaturized equipment (nanotechnology), there has been a downward trend in the number of new drug and biologic marketing applications being submitted to the FDA for review. This means that the new sciences are not yet having a substantial impact on patient care.

"We can see from our reviews that these products aren't being moved along," says Kathy Carbone, M.D., acting associate director for research in the FDA's Center for Biologics Evaluation and Research. She adds, "Sometimes candidate medical products get presented to us where we simply lack the tools to easily determine the safety and effectiveness of these products that are based on exciting, but edge-of-the-wedge, technologies."

As a result, many of the investigational products that enter clinical trials fail. And sometimes product development programs must be abandoned after extensive investment of time and resources. This high rate of failure can drive up costs, and the critical path to market--even for successful product candidates--is costly, timely, and unpredictable. And researchers are forced to rely on cumbersome, often imprecise assessment methods.

For example, product developers use scientific tools, such as laboratory tests, computer models based on past experiences, and animal studies, to predict a high probability of safety and effectiveness. Other tools for making these predictions include knowledge of blood markers that accurately predict disease remission or the benefits of devices, or that can be used in early human trials to indicate effect and guide dose and regimen decisions. Developers also use scientific tests to demonstrate the biocompatibility of implanted devices.

But in many cases, product developers have no choice but to use the tools and concepts of the last century to assess this century's potential products.

"We are dealing routinely with novel products--novel technology," says Carbone, and part of the difficulty is predicting ultimate success with a novel candidate. If industry and the FDA could make these predictions more accurately, fewer products would fail on the critical path from laboratory to consumer. Similarly, new tools to measure product quality in process would mean more efficient, higher quality manufacturing.

"We think we have a way to fix it," says Carbone, "and we're asking industry, academia and others to help us focus on the gaps."

The Solutions

To meet the challenge, the FDA is calling for a new focus on modernizing the tools that researchers and product developers use to assess the safety and effectiveness of potential new products and to mass-produce high-quality therapies. New scientific and technical tools--including assays (tests), standards, computer modeling techniques, biomarkers, and clinical evaluation techniques--will improve predictability and efficiency of products along the development path, more likely resulting in safe products that benefit patients.

For example, the FDA rapidly developed standards and calibration tools that enabled product developers to design and produce test kits to screen donated blood for the presence of West Nile virus. This work involved extensive collaboration with public health laboratories, industry, and U.S. blood banks, as well as using applied research. During 2003, roughly 8.6 million blood donations were tested. Of these, more than 1,000 donations confirmed positive for West Nile virus were identified and removed from the blood supply.

The FDA also developed and implemented a more flexible and innovative approach to the clinical trials needed to evaluate medical screening devices. This new trial design allows small companies, which often cannot afford the large trials needed to evaluate screening devices, to use common protocols so that their data can be pooled for analysis. The design currently allows manufacturers to test the effectiveness of digital mammography for screening use.

Such success stories can only be accomplished through a concerted and joint effort by industry, academia, patient groups, and the FDA. Key to this effort will be the development of a "Critical Path Opportunities List" that will identify and prioritize the most pressing development problems and the areas that provide the greatest opportunities for rapid improvement and public health benefits.

To create this list, the FDA is consulting and soliciting suggestions from all interested parties to identify and address specific defined critical path opportunities to make product development more efficient and predictable. The agency will publicize the list and encourage collaborations to address the problems and create new product development tools.

In addition, the FDA intends to refocus its own activities and take on new partnerships, as needed, to fulfill these priority opportunities. These actions promise not only to bring medical breakthroughs to patients more quickly, but also to do so in ways that ensure greater understanding of how to maximize patient benefits with a minimum of risk.

The Opportunities

The FDA is uniquely suited to take a major role in these efforts because of its experience overseeing medical product development, its vast clinical and animal databases, and its close interactions with all the major players in the critical path process. The agency sees the product development problems industry-wide.

Building on the agency's proven "best practices" for expediting the availability of promising medical technologies, there is an urgent need, for example, to develop tools to accurately assess the risk that a new drug will cause heart rhythm abnormalities. Ongoing international efforts include developing, testing, and validating nonclinical tools such as computer models that may be useful in predicting human risk. Examples of tools that the FDA says are urgently needed include better predictors of human immune responses to foreign substances, methods to further enhance the safety of transplanted human tissues, and new techniques for assessing drug-induced liver toxicity.