In 2002, the Food and Drug Administration cleared for marketing just under 5000 new drugs, biologics, medical devices, and animal drugs, an increase of almost 400 new products over 2001. These approvals included many remarkable new medical advances, including new drugs to treat colon cancer, hepatitis B, pulmonary hypertension, and other serious diseases; a new biological drug for non-Hodgkins lymphoma and a new child vaccine for diphtheria, pertussis and tetanus; new medical devices that improve surgical outcomes and that better detect disease; and two new antimicrobial drugs for livestock.
FDA reviewed many of these products in the rapid timeframes dictated by the Prescription Drug User Fee Act, which has been estimated to have resulted in a reduction of 30% in FDA review time. A 24% decline has also been reported in the time it takes for a drug manufacturer to develop and bring a new drug to market from inception of human testing. Despite these improvements, however, FDA's 2002 experience included some concerning trends in technology development. In some important categories, such as NMEs (new molecular drug entities), the number of approved products was down significantly from previous years.
There are many potential explanations for this worldwide trend. Explanations cited include a weakened investment climate, a trend toward development of relatively minor improvements in types of drugs already on the market, concerns that companies are only interested in products that have the potential to be "blockbusters," and additional time required for product developers to cope with a "deluge" of new basic scientific findings in such advanced areas as genetics, genomics, and proteomics. FDA is also cited for the declining application rate, by some who believe that the agency is becoming more conservative in the face of recent drug withdrawals (although the rate of drug withdrawals has not risen over past years), and that FDA desires to seek increasingly more data about a drug, thus causing larger and longer study trials that consume drug development resources. In addition, recent research has shown that the cost of developing a new drug has increased considerably. Whatever the explanations, FDA can play a unique and critical role in facilitating the advancement of technology by addressing and clarifying regulatory uncertainty, by increasing predictability in product development, and by ensuring that its regulatory processes are based on the latest scientific thinking, and are designed to assure safety and effectiveness through the most efficient means possible.
As part of FDA's efforts to keep its technology review practices up to date, FDA intends to implement new approaches to reduce overall product development time and costs for safe and effective medical technologies; and to improve FDA's support for innovative types of products so that more and better products emerge from America's drug and device industries. These new initiatives will continue FDA's commitment to allowing only safe and effective products to reach the market; however, by improving the quality of the regulatory process for technology development, the goal is to encourage product development more quickly and at a lower total cost. These initiatives span all of FDA's product review centers: drugs, biologics, devices, and animal drugs.
Two major new initiatives will be launched to help decrease product development times:
In an ideal world, all new drugs would be reviewed AND approved in the review timeframes directed by the drug user fee act--6 months for "priority" drugs that are major medical advances, and 10 months for all other drugs. That would mean that a company would submit its marketing application to FDA with the required data such that after one cycle of review, FDA could approve the product for marketing. There would be no scientific deficiencies in the application that would prohibit FDA from approving the package. But too often problems are found during the FDA's review of a marketing application--such as a problem in a drug's manufacturing--that can result in total approval time that is much longer than the FDA review time. Often this results in the application having to undergo multiple cycles of review prior to FDA approval. If these problems and deficiencies can be identified earlier, approval times will fall and patients will have access to new drugs more rapidly.
To avoid this "cycling" of applications--that is, FDA waiting for an application to be corrected before review can be completed--FDA will identify and address the main causes of multiple cycle reviews. For example, in conjunction with manufacturers, FDA will characterize the most common problems that drug applications encounter, and the "root causes" of poorly designed drug studies, so that those problems can be addressed before they occur. A key element in accomplishing this will be a concentrated effort to further improve communications between FDA and a product developer when a product sponsor begins developing its product, so that a clearer understanding exists of the scientific standards that need to be met, including how the product should be studied and what pitfalls to avoid. So, for example, if a new drug in development is known by FDA scientists to pose potential side effects when taken with another drug, FDA scientists will work with the drug's sponsor to lay out the needed data at the beginning of the drug's study.
Another important component of this initiative includes the publication this year of Good Review Management Principles (GRMPs), to provide clear guidance to ensure that the goals of improved communication are met. The devices program will publish additional guidance on FDA expectations for premarket submissions. In addition, the human drugs and biologics programs will begin to implement a Continuous Marketing Application (CMA) initiative that will enhance sponsor access to guidance and feedback.
Drug and device development, and review of those products to ensure their safety and efficacy, are not static enterprises. Enormous advances have been made in recent years, by FDA, the medical products industry, and academia, in designing safety and effectiveness studies for new products, in developing new statistical and other tools to aid in the analysis of data from clinical and pre-clinical studies, in converting the fruits of basic research into life-saving therapies, and in the efficient manufacturing of new drugs and devices. The process for reviewing those therapies must likewise advance, and FDA will take the initiative to develop and implement procedures for continuous evaluation and improvement of its review processes. This will encompass continuing education and improved training of FDA review staff in the latest science and technology in their field of expertise; development of review "templates" that will greatly improve consistency and completeness of initial reviews and reduce any temptation to unnecessarily reinvent product review with every new application; and implementation of a quality assurance program that will use performance measures to ensure that reviewers are maintaining state-of-the-art processes for assessing the products they review. Inherent in this concept is an emphasis on continuously examining how the best scientific data can be obtained about a new drug or device with the least burden on its sponsor, and with the goal of the most expeditious translation of promising research into therapies for better health.
Finally, FDA will implement the Common Technical Document this year. This document, a common format for submissions to regulatory agencies in the United States, the European Union, and Japan, will also include an electronic version and will replace the multiple region-specific documents now required. This will help streamline the technology development process worldwide.
Over the past decade, improvements in the sciences of medical product development and review have been continuous, and resulted in readier patient access to more life-enhancing therapies than ever before. The FDA has reviewed steps that it can take to more actively support the development of innovative new technologies. Although FDA has not traditionally been focused on such technology development, the agency can play a unique and critical role in facilitating the advancement of technology by addressing and clarifying regulatory uncertainty and by increasing predictability in product development. Thus, the agency is developing plans to enhance innovation in three key areas of emerging technology:
FDA plans to establish development "pathways" for cell and gene therapy that will help guide innovators and sponsors in their quest for evidence that such therapies can safely combat disease. Within the next year and a half, FDA will sponsor a series of conferences and workshops, in partnership with the National Institutes of Health and/or scientific societies, aimed at designing standards for the human study and manufacturing of these potentially vital new technologies. For example, FDA and the American Society for Gene Therapy will bring together gene therapy researchers from around the nation to discuss and define how studies can be designed and executed to support licensure of gene therapies. FDA and the National Cancer Institute will expand their joint programs on proteomics and genomics to help develop standards for safety, purity, and potency of tumor vaccines. These initiatives, along with more guidance to sponsors, will enable sponsors to focus studies to yield maximum information during product development.
Promising new technology is emerging that will combine drug therapies and diagnostic devices to both treat the patient as well as identify certain critical needs of the patient. For example, genomics may detect if a given patient needs a different dose of the drug than most patients, or if a patient is prone to a side effect from the drug. Development of these test/therapy combinations must be facilitated, because they have the potential to maximize drug benefits while minimizing toxicity. However, their regulatory path has been fraught with uncertainty. Over the next 18 months, FDA will issue guidance on when and how to submit pharmacogenomic information to FDA during drug development; hold a workshop on issues involved in co-development of a pharmacogenomic test and a drug; and issue joint guidance by FDA review components for sponsors of these products that guide them through the regulatory process.
An exciting area of drug discovery is engaged in finding ways of better delivering a drug to the site of infection or disease. For example, scientists have learned that applying a drug "coating" to a stent used in opening a blocked artery can have a substantial impact on the stent's success and in preventing complications from its use. Other novel systems in development include new transcutaneous insulin injectors, and monitoring systems that automatically dose anesthesia drugs in response to a patient's vital signs. Understanding early on how to study such a product, first in animals, then in humans, can greatly boost the product's successful development, thus improving its chances of receiving marketing approval and early access by patients to a lifesaving product.
FDA intends to seek assistance from the academic, patient and industry communities in developing the best methods for animal and human testing of these novel drug delivery systems. Because these "combination" therapies must be reviewed for safety by two different components within FDA, it is important to facilitate that joint review. FDA has recently created an Office of Combination Products that will ensure such facilitation. But it is also important to give sponsors of these products clear and adequate guidance on what data FDA will need to review these products and how that data might best be collected. Under the auspices of the Office of Combination Products, FDA will begin the process of developing and issuing guidance to drug and device manufacturers on these regulatory pathways.
A fourth area that FDA has learned can greatly help in technology development is the collaborative published "guidances" for developers." Guidances are simple in concept--they advise drug or device sponsors on a host of issues important to developing a new product: defining studies needed to assure product purity, consistency and potency, how to conduct studies with patients receiving placebos vs. patients receiving another drug for other diseases; statistical guidance about study size, scope and patient enrollment; factors related to a specific disease, such as concomitant conditions that might affect a study's outcome, when to exclude or include certain patients and populations in a study, and many other areas.
These guidances can prove invaluable to a drug or device sponsor by, for example, helping them structure the claims they intend to make for the drug; offer standardized approaches to evaluating a drug's effectiveness; and give the sponsor insights into carrying out safety tests. That knowledge can, in turn, help the sponsor design studies with the least burden and with the greatest likelihood of acquiring dispositive data about his product. In an effort, to provide greater focused attention on diseases that are most in need of improved therapies, FDA will form working groups to oversee guidance development for priority areas including oncology products and products to treat diabetes and obesity. Utilizing a wide range of collaborative techniques (e.g., workshops, advisory committee meetings) and with support from the relevant scientific community and other interested groups, FDA will endeavor to have a range of oncology guidances completed within one year, and within 2 years for diabetes and obesity.
Improving Innovation in Medical Technology: Beyond 2002