December 17, 1998: Raymond L. Woosley, Georgetown University Medical Center
Response to AHRQ on CERTs
Thank you for the opportunity to respond to the Notice in the Federal Register of November 3, 1998. I have responded to each of the questions as requested.
How should the Center for Education and Research on Therapeutics (CERTs) be organized?
Because of the broad scope of the work authorized in the legislation, it will be necessary for the demonstration program of CERTs to focus on one aspect of therapeutics. Because of the relative proportion of therapeutics devoted to drugs. The demonstration program should focus on the basic and clinical research and educational programs that will improve the quality of healthcare through the optimal and appropriate use of medications.
The CERTs should be organized to effectively focus on the most important part of the mission as stated in the legislation. This will require access to broad expertise in the appropriate use of medications. Access to the recent databases on medication usage and access to the educational programs that serve the healthcare providers and the public. No single agency or entity currently has all of the requisite expertise or resources to effectively carry out the mission. Therefore the RFA should create a mechanism to gather this expertise together and facilitate access to the necessary data and educational elements.
The CERTs could be most effective by using the organizational structure shown in the accompanying diagram. AHCPR should create and make appointments to a CERTs Steering Committee. The CERTs Steering Committee would provide general guidance and oversight to the activities of the entire program and therefore should have a strong emphasis on clinical pharmacology and representation from the disciplines of pharmacology, medicine, clinical pharmacy, pharmacy, nursing, and relevant governmental agencies (Agency for Health Care Policy and Research [AHCPR], Food and Drug Administration [FDA], Center for Disease Control [CDC], and National Institutes of Health [NIH]). Non-voting representatives from the pharmaceutical and biotechnology industry (Pharmaceutical Research Manufacturers Association Foundation [PhRMA] and BIO) should be invited.
AHCPR should award a contract through a competitive mechanism for funding three CERTs and one would also serve as a Coordinating Center for CERTs. The Coordinating Center for CERTs would be expected to perform the following activities:
- Establish and plan biannual meetings of a Steering Committee for CERTs.
- Coordinate monthly conference calls between the three CERTs to review new data and approve elements of the educational program.
- Create a forum for communication between the CERTs that would prevent duplication of effort and maximize synergy.
- Evaluate the scientific information that is generated in the CERTs or that becomes available from any reliable source, develop a consensus opinion on the data and establish communication and educational programs to effectively translate the information into clinical practice.
Is it appropriate for AHCPR or these centers to seek additional funding partner?
Yes, the activities of CERTs can serve the mission of other governmental agencies and could therefore qualify for broad support. The basic and clinical research activities could be funded with support from the NIH, especially the National Center for Research Resources and the General Clinical Research Centers. The National Institute of General Medical Sciences could provide valuable support for clinical investigator training at the CERTs. The Center for Disease Control could provide support for evaluation of drug safety using field operatives trained to evaluate rare cases of drug toxicity. Foundations, the FDA Orphan Drug program and patient advocacy groups could be asked to support research to evaluate orphan indications for marketed drugs. The FDA could be asked to support some of the basic and clinical research on drug safety, especially where it would assist in the performance of FDA's regulatory role. For example research to identify the mechanism of toxicity with a therapy such as Phen-fen could assist the agency in deciding how to evaluate NDAs for new drugs for obesity. Although the Pharmaceutical Research Manufacturers Association Foundation could be asked to contribute support for CERTs, the pharmaceutical companies themselves should not be allowed to support CERTs so that they remain free of conflict of interest.
What should be the initial areas of emphasis?
There are several compelling reasons why the CERTs research program should focus on drug safety. Because new drugs are now being approved in the US before they are available in other countries, we have had and will continue to have an inordinately large number of drugs withdrawn from the market. CERTs could play a vital roll in buttressing the post-marketing surveillance of newly marketed drugs. A recent study found that drug-induced death is one of the leading causes of death in this country. CERTs should help quantify the harm that occurs with drug use and identify the most effective means of preventing this harm. There are ample convincing data showing that the prescribing practices of physicians are less than ideal. As examples, the second leading cause of a malpractice suite is a prescription error. Twenty three percent of prescriptions for the elderly were found to he either dangerous or inappropriate. For these reasons, the educational programs of CERTs should focus on methods to improve the prescribing of drugs by physicians and the monitoring of therapy by physicians and other health care providers.
What are high priority research topics?
- Clinical research and educational programs to prevent dangerous drug interactions.
- Magnitude and mechanism of drug toxicity, e.g. Phen-fen.
- Identification of reliable predictors of drug-induced hepatitis.
- Pharmacogenetic approaches to reduce the incidence of drug toxicity.
- Mechanisms of gender differences in clinical response to drugs.
- Development of improved methods to test drugs in children. e.g. non-invasive assessment of plasma drug concentrations using transdermal capture as indices of drug exposure.
- Clinical importance of QT prolongation by tamoxifen: does it result in torsades de pointes arrhythmias and is it seen with other antiestrogens or sex hormones?
- Rapid assessment of the magnitude and mechanism of drug toxicity newly discovered by the FDA Office of Post Marketing Drug Risk Assessment (OPDRA).
Should the Agency include a list of specific topics in the RFA or focus on the infrastructure and capacity of applicants to identify research issues?
The CERTs should be chosen based upon their proven ability to identify problems with drug usage at the bedside and in clinical or basic research programs and then conduct: the necessary research to correct the problem or answer the questions and translate the research into medical practice. Successful applicants would be expected to conduct the needed basic laboratory and clinical research needed to address the types of problems/questions that are listed above. There should be asked to identify the infrastructure needed to conduct the type of work described above. The grant should provide the infrastructure for conducting this type of work and salary support for the investigators so they can remain free of perceived or real conflicts of interest.
Major related issues in creating these centers are the need for a critical mass of expertise and the need for financial independence. It is very doubtful that this program can be very effective or even successful unless adequate funds are rewarded. I encourage the agency to award the fully authorized amount of $3 million for this program. This could fund three CERTs at a reasonable level and allow them the independence needed for objective evaluation of drugs. Since the Government Accounting Office has estimated that $20 billion is lost annually from less than optimal utilization of medications and because drug-induced death is estimated to be the fifth leading cause of death in the nation, $3 million seems the minimal investment that should be made to begin to improve the use of medications in the nation.
Another issue that must be addressed is the scientific training and qualifications of those awarded the responsibility of conducting this work. While the work will require an interdisciplinary team of clinical scientists, I believe the proper environment for optimal productivity and quality would be a well-functioning Division of Clinical Pharmacology that has an active clinical investigator training program, access to a General Clinical Research Center and a proven record of conducting clinically relevant hypothesis-based research. The faculty must be in a medical center in which they have the full support of the Departments of Medicine. Pharmacology and Pediatrics to assure access to patients and a broad spectrum of teaching opportunities.
I thank you for the opportunity to comment on this very important new program and I thank you for your consideration of my remarks.
Raymond L. Woosley, M.D., Ph.D.
Professor and Chairman
Department of Pharmacology
Georgetown University Medical Center
3900 Reservoir Road NW
Washington, DC 20007-2195
Telephone: (202) 687-1064
Fax: (202) 687-4872