December 18, 1998: Richard C. Dart, Rocky Mountain Poison and Drug Center
Response to AHRQ on CERTs
Thank you for the opportunity to nominate topics and ideas for implementation for the Demonstration Program Regarding Centers for Education on Therapeutics (CERTs). We have followed the literature on this topic and offer the following suggestions regarding the CERTs.
Centers for Education and Research on Therapeutics
The United States has the good fortune of approving numerous new therapeutic agents every year. Manufacturers of new drugs, biologicals and devices rightly focus on demonstrating safety, efficacy and manufacturing quality in order to obtain U.S. Food and Drug Administration (FDA) approval. However, these new therapies often raise new issues regarding the appropriate use and adverse effects associated with that product. For example, it is common for new applications to be proposed immediately after introduction of a new product. In addition, widespread use often reveals adverse effects that were not noted in clinical trials. Currently, these issues are not addressed in a anticipatory manner. The over-the-counter pain relievers are an excellent example. Aspirin, other non-steroidal agents and acetaminophen are used by millions of patients every year and yet there is no systematic and independent analysis of the new adverse events that have been proposed. Concern has emerged regarding the use of acetaminophen by the 110 million persons who drink alcohol in the United States. The fear of liver injury from the combined use of acetaminophen and alcohol has generated myriad articles and debates in the press and in the lay population. Despite the impressive and sustained level of interest, no effective effort to develop the information needed nor to address the issues involved has developed. In other words, the current system addresses the general needs of the population well, but does not address well the needs of sub-groups such as patients who drink alcohol.
The current system also fails many patients with rare illnesses. While the FDA orphan programs have facilitated the introduction of dozens of products, a large number of therapeutic agents remain undeveloped because the cost of development exceeds the potential profit. A tremendous example is an intravenous formulation of N-acetylcysteine (NAC) for the treatment of acetaminophen poisoning. N-acetylcysteine for oral administration is the only form of the drug approved for use in the United States. However, it is not tolerated well orally and the use of NAC in patients with fulminant hepatic failure has been proven only using the intravenous product. The American health system is justly ridiculed for its inability over 20 years to make available a drug that is already available in every other country in the world. Other outstanding omissions include antidotes for cyanide poisoning, beta-blocker poisoning, scorpion envenomation, calcium channel blocker poisoning and many others. These special populations are not large individually. When considered as a class, however, over 100,000 patients per year suffer from poisonings that have potential treatments available, but not approved for clinical use. The unmet need here is for the academic and professional groups to develop the pre-clinical and clinical information needed for the drug to be submitted for FDA consideration. CERTs could create a public-private partnership that would provide the information and new products needed to meet the needs of these special populations.
Proposed Focus: We therefore suggest that CERTs should have a dual focus: the Special Needs of the general population and the needs of Special Populations. These are areas often neglected by clinically relevant research. These topics provide many examples that would allow AHCPR and FDA to highlight the important contribution that CERTs can make in a relatively short time. Indeed, due to the amount of therapeutic information already available, CERTs could produce clinically meaningful information in a very short time period.
Using the acetaminophen example described above, a CERT would likely find that anecdotal reports suggest that acetaminophen may be toxic in certain patients who have experienced induction of certain enzymes in the cytochrome P450 system. However, data generated in animals conflict with the anecdotal reports involving humans. From this analysis, a study describing the relationship in cytochrome P450 induction and acetaminophen metabolism in humans could be developed. A clinical trial could easily establish whether induction actually occurs and, if so, whether liver injury in patients developed. Once this information is developed, however, it is critical that it be effectively delivered to both health care professionals and their patients. The recipients of this information are diverse. To fulfill this goal, the organization will need to have access and credibility with all levels of health care practitioners, pharmacy benefit managers, all type of health maintenance organizations, health care insurers and governmental agencies.
Proposed Boundaries: The CERTs concept describes focused research that effectively delivers meaningful information to health providers as well as patients. The delivery of this information is a critically important aspect of CERTs. Consumers and health care professionals are desperate for accurate and meaningful information to guide them. This need mandates that CERTs applicants should demonstrate that they can encompass the continuum from the research department to the bedside and also include education. This indicates that successful CERTs applicants should demonstrate that they can fulfill each of the steps needed: determine which topics to investigate, perform meaningful research and deliver the results with appropriate clinical interpretation to patients and their health care providers throughout the United States.
The need for a continuum of activities that end with the delivery of understandable and meaningful information indicates that CERTs may take two forms. First, it may be possible for one organization to provide the integrated package including research, interpretation and evidence-based integration of that research into clinical practice and then delivery of that information to health care providers and consumers. However, such facilities may not exist. Therefore, optimal performance may come from closely integrated operations of organizations that specialize in one of the needed areas. Perhaps there should be several CERTs, each with a special area of emphasis. This type of arrangement could allow the CERTs concept to be initiated with the small amount of financial support currently envisioned. However, the coordination and integration of such a system would be critical.
We would prefer that the program focus on development of infrastructure, however, there should be careful coordination so that CERTs can share and rapidly disseminate emerging information. Since the infrastructure of evidence-based analysis is much less that for laboratory or clinical research, this approach would also allow a more substantial start-up than the alternatives.
Since the initial financial support is limited, it may also be wise to focus initially on analysis, interpretation and application of information that has already been developed. This would take advantage of information created by other programs. It would also provide perspective for CERTs. In the process of analyzing information on therapeutic agents, it would become apparent where future research was needed. Furthermore, the process of working with professional and lay organizations would create relationships that will support the CERTs program admirably in the long run.
Federal Health programs or underserved populations; or an indication of how the research results or Center activities might be used within the professional or organizational setting.
One strength of the Special Needs and Special Populations concept is that it inherently addresses the need of underserved populations.
Richard C. Dart, M.D., Ph.D.
Director, Rocky Mountain Poison and Drug Center
Associate Professor of Surgery, Medicine and Pharmacy
University of Colorado Health Sciences Center
Appendix 1. Emerging Issues Without Adequate Support for Research, Development and Education
Therapeutic Agent Number of Patients Involved (est.) ____________________________________________________________________________________ Acetaminophen 110 million Role of metabolism in clinical disease 11 million Alcohol-drinking population Tens of thousands Alcoholic patients Patients on anticonvulsant therapy Repeated supratherapeutic ingestion (a common therapeutic misuse syndrome) ____________________________________________________________________________________ "Ultra-orphan" therapeutic agents 4000 new cases per year Scorpion antivenom 5000 new cases per year Calcium channel blocker antibody ____________________________________________________________________________________ Safety of Newly Introduced Therapeutic Agents ____________________________________________________________________________________ New Applications of Newly Introduced Therapeutic Agents