Letter from the Steering Committee
Introduction
The CERTs Program
CERTs Projects
Peer-reviewed CERTs Publications
Dear Fellow Citizens:
Neither patients nor their caregivers should have to guess which therapies are the best, or live in fear that a mistake was made in treatment. This is the basis of the CERTs program.
The U.S. system of developing and marketing medical products has produced great benefits. This system requires that adequate, well-controlled studies show that products are safe and effective for their intended use.
The system has some drawbacks, however. For example, to meet the requirements for marketing approval, clinical studies of a new therapy may have a very narrow focus—testing it, say, only in male adults. Information often is lacking about how it may work in other groups.
Further, studies may not test medical products in combination with other therapies often used by the same patients, with occasionally fatal results.
Once approved, drugs and devices often are used for purposes other than those for which they were approved. Sometimes these uses are supported by studies, but not always. It is hard for caregivers and patients to find information about such uses, except through personal experience, which can be risky.
Finally, some side effects of medical products emerge only after they have been approved for sale, when large numbers of people begin to use them. The systems used to capture these events may not be as effective as they could be.
No wonder caregivers and patients in the real world are left with doubts about therapies.
The CERTs program fills several gaps. It aims to answer important questions that have not been addressed. It provides its results, positive or negative, for all to see. It sets out to develop a learning curriculum for current and future caregivers. Finally, it represents a major step toward giving people the information they need to make the best choices possible.
The participants in CERTs—government agencies, academic organizations, managed-care organizations, drug and device companies, practitioners, commercial research groups, and consumer groups, among others—have voluntarily committed to seeking answers together, putting society's interests first.
People of all ages deserve the benefits of the CERTs program. We are committed to establishing a national network of centers that will investigate and educate. We hope that this collaboration will improve health for us all.
Hugh Tilson, MD, DrPH (chair); Lynn Bosco, M.D., M.P.H.; Robert M. Califf, MD; William H. Campbell, Ph.D.; Lisa Egbuonu-Davis, MD; Linda Golodner; Peter Honig, M.D., M.P.H.; Judith M. Kramer, MD, MS; Richard Platt, M.D., M.Sc.; Wayne A. Ray, Ph.D.; Kenneth G. Saag, M.D., M.Sc.; Marcel Salive, M.D., M.P.H.; Brian L. Strom, M.D., M.P.H.; Karen Williams; Raymond L. Woosley, MD, Ph.D.
People need objective, complete, accessible information about the best ways to use medical products, so that they can take action to improve health.
The Centers for Education and Research on Therapeutics (CERTs), administered by the Agency for Healthcare Research and Quality (AHRQ), aim to provide just such information.
Although drugs, medical devices, and biological products improve health for thousands of people, side effects, misuse, and overuse of products seriously impair the health of many others. In addition, many who could benefit from a therapy do not receive it, through lack of information, oversight, or in the mistaken belief that it will do them harm.
We need more guidance about to how to choose and use products most appropriately, how to prevent errors and adverse effects, and how to use products in a cost-effective way.
Drug and device companies, medical education programs, professional groups, and medical journals provide some information, but it may have a narrow focus, may be slanted, and may not consider the risks and benefits of interactions with other therapies. Even when valuable information is available, it often does not get into the hands of the people who need it most.
We are conducting research and educating people about the best uses for drugs, medical devices, and biological products, in the public interest. Armed with knowledge from CERTs, people can take action to improve health.
This Annual Report for Year 1 both introduces the CERTs program and reviews its accomplishments to date. We have made much progress so far but recognize the tremendous challenges and opportunities still before us.
"The great aim of education is not knowledge but action."
—Herbert Spencer
Since 1992, AHRQ, formerly the Agency for Health Care Policy and Research, has studied outcomes associated with prescribed drugs. Their Pharmaceutical Outcomes Program has addressed many important questions about the use of therapies, but critical issues remain.
To address these issues, Congress authorized a CERTs demonstration program in the Food and Drug Administration (FDA) Modernization Act of 1997 (Public Law 105-115). AHRQ, with its expertise, was chosen to administer the program.
In November 1998, AHRQ asked the community to nominate research topics. AHRQ then selected topics on the basis of several criteria:
The demonstration program began in September 1999, when AHRQ awarded $7.7 million over 3 years to support four research centers and a coordinating center. Congress authorized the permanent CERTs program in December in the Healthcare Research and Quality Act of 1999 (Public Law 106-129). A fifth center was added in July 2000, and two more in September 2000.
To conduct research and provide education that will advance the optimal use of drugs, medical devices, and biological products.
To serve as a trusted national resource for people seeking to improve health through the best use of medical therapies.
Public Interest: Research must be conducted to answer important questions that otherwise may not be addressed, with higher priority given to projects that offer better opportunities to achieve our mission and vision.
Public-Private Partnership: For our results to apply to the "real world," the research must reflect a collaboration of groups with different perspectives and resources: patients, caregivers, government, academia, delivery systems, payers, purchasers, and manufacturers of medical products.
Multidisciplinary Alliances: The best research harnesses the collective expertise of medical practitioners, clinical pharmacologists, health services researchers, clinical epidemiologists, pharmacists, clinical researchers, and others involved in health care.
Communication: The information from CERTs must be made readily available to all relevant audiences.
Education: Education of current and future caregivers, policymakers, and patients is critical to improving health.
Public Policy: Policymakers must be provided with the best available scientific evidence upon which to base policies.
Accountability: Americans should expect CERTs to be a permanent, trusted resource when they need answers to questions about therapies.
We achieve our mission through activities that:
Within the U.S. Department of Health and Human Services, AHRQ is the lead agency supporting research into how to make health care better, more cost-effective, and more accessible. It sponsors and conducts research about outcomes, quality, cost, use, and accessibility of health care.
AHRQ's Center for Outcomes and Effectiveness Research, consulting with the FDA, oversees the CERTs program and provides technical assistance and research support to the centers.
There is a Steering Committee composed of a chairperson; the CERTs principal investigators; representatives from AHRQ, the FDA, and the National Institutes of Health (NIH); and three at-large members.
Representatives from all centers have formed work groups to address broader issues related to the CERTs effort, such as quality of care and the use of databases in research.
Duke University coordinates CERTs activities among the seven centers, each of which focuses on therapies for one group or disease area.
The Seven CentersDuke University
Principal Investigator: Elizabeth R. DeLong, Ph.D.;
Therapies for disorders of the heart and blood vessels.
Georgetown University
Principal Investigator: Raymond L. Woosley, M.D., Ph.D.;
Drug interactions, particularly in women.
HMO Research Network
Principal Investigator: Richard Platt, M.D., M.Sc.;
Usefulness of HMOs for studying drug use, safety, and effectiveness.
University of Alabama at Birmingham
Principal Investigator: Kenneth G. Saag, M.D., M.Sc.;
Therapies for disorders of the joints and bones.
University of North Carolina at Chapel Hill
Principal Investigator: William H. Campbell, Ph.D.;
Therapies for children.
University of Pennsylvania
Principal Investigator: Brian L. Strom, M.D., M.P.H.;
Therapies for infection.
Vanderbilt University
Principal Investigator: Wayne A. Ray, Ph.D.;
Prescription drug use in a Medicaid population.
We have organized our efforts around four themes, which guide the interactions of the entire program.
We are developing knowledge about therapies and how best to use them. Our research examines both basic mechanisms (through clinical pharmacology and genomics research) and medical outcomes.
Children and Adolescents
More than 80 percent of the prescription drugs given to children have not been tested in children and are not labeled for pediatric use. But children are not "small adults." They have different metabolic rates, their bodies are changing rapidly, and their ability to understand and express information varies widely. For these reasons, assessment of therapeutics in children is critical.
We have two projects assessing how drugs move and work in the bodies of children and adolescents, one examining children with cystic fibrosis, and another assessing the levels of drugs called protease inhibitors in the blood of children with human immunodeficiency virus (HIV) infection. The goal is to identify how children's bodies handle drugs differently from adults', which may result in more tailored (and thus more effective) treatment.
Drugs to treat attention deficit/hyperactivity disorder (ADHD) and depression in children have been used more and more in recent years, despite a lack of supporting evidence for their safety and long-term effectiveness. During Year 1, we assessed how the use of these drugs has changed among doctors and patients, in preparation for more detailed future studies.
The incidence of Type 2 diabetes in adolescents may be increasing because of lifestyle changes. We are gathering the data needed to determine whether this is true. The earlier this disease is diagnosed, the sooner treatment can begin.
Adults
Heart disease has been the number-one killer of adults in the United States for all but one of the last 100 years. Although aspirin can save lives in people who have coronary artery disease (CAD), a very common form of heart disease, only about half of them take aspirin regularly. We have examined the use of aspirin in this group, tapping into the resources of a 30-year-old database for cardiovascular disease. We have found that 87 percent of the people in the database have been taking aspirin. This is better than average but still shows room for improvement, especially among women.
We have used similar methods to examine the use of beta-blocking drugs in people who have congestive heart failure (CHF). Compared with aspirin, beta-blockers cost more; they also require a prescription and, until recently, were thought to be harmful to people with CHF. Before beta-blockers can be widely used, then, educational efforts must overcome resistance based on outdated information. Only about 45 percent of the people with CHF in the database have been taking beta-blockers, and the rates of use for the individual drugs known to save lives have been extremely low.
More than 2 billion prescriptions are written in the United States every year, and two thirds of all visits to doctors result in at least one new prescription. Thus people likely are taking more than one drug at a time. Interactions between these drugs can be fatal. In fact, several drugs have been removed from the market because of fatal interactions in recent years. Further, most drugs used by adults have been studied only in men. How women process drugs taken alone or with other drugs is largely unknown.
Our initial efforts in addressing the issue of drug interactions includes studying drug usage and interaction patterns, to identify targets for further testing. This effort involves the use of large databases and collaborations with the FDA.
People over the age of 65 are the fastest-growing segment of the U.S. population, and the older a person gets, the greater the risk of having a heart attack. Several drugs can reduce the risk of death after a heart attack, chief among them aspirin, beta-blockers, and drugs to reduce cholesterol. These drugs might be greatly underused in men and women covered by managed-care plans such as Medicaid, which includes substantial numbers of elderly people.
We are studying the rates of use for these three types of drugs in a large Medicaid population, by physician and hospital, with the goal of identifying targets for future education, including policy makers.
People must have an accurate picture of the benefits and risks associated with therapies as used in practice. Our focus is on improving the ability to detect beneficial and harmful effects of therapies, then maximizing the benefits and minimizing the risks. The systems that we are developing will provide the information needed to stimulate basic research into mechanisms of disease and the effects of therapies.
Children and Adolescents
We know much more about the safety of drugs for adults than we do for children. We have begun a pilot study of a new reporting system for adverse drug events in children. For the larger issue of how many drug errors occur in children, we are studying another reporting system, MedMARx.
More than 20,000 children and teens in this country may be infected with HIV. How they respond to given doses of anti-HIV drugs such as protease inhibitors may differ from how adults respond. We are assessing the relation between the dose of protease inhibitors, the amount of drug in the bloodstream, measures of drug safety and effectiveness, and what may cause variations in the response to treatment.
Few tools exist to measure a child's health status and quality of life, which are an important part of the assessment of therapeutic effects. Existing tools typically are variations of those used in adults. We are grading and evaluating these tools, to tailor them to the needs of children. We also have proposed establishing a common definition or set of definitions for adverse medical events, to allow them to be measured consistently across studies.
Adults
Many drugs used to correct an irregular heartbeat carry an increased risk of death, especially many of the older drugs, but they continue to be prescribed in large numbers despite this risk. A newer agent for treatment of atrial fibrillation or flutter, dofetilide, appears not to increase mortality, but its use can carry an increased risk of other abnormal heart rhythms. The FDA therefore requires that doctors complete a risk-management program before using the drug.
Many prescribers may be unaware of the evidence or how to monitor therapy properly. We are now tracking the use of dofetilide at one center, before examining compliance with the FDA's rigorous requirements for education and monitoring with dofetilide use.
For our drug-interactions project, we will be testing potential interactions in the laboratory. When this is complete, we will begin verifying their relevance with studies in humans.
We are harnessing the power of the Internet to aid in our efforts to manage risk. For example, we have been working with MedWatch scientists at the FDA to analyze cases of a potentially fatal, irregular heart rhythm (torsades de pointes). People can develop torsades de pointes because of an inherited gene, but they also can develop it after taking certain drugs, and women are more susceptible than men.
We have created a Web-based registry (http://www.qtdrugs.org) for physicians to report cases of torsades de pointes that are caused by drugs. The program will help identify individual drugs, drug interactions, and genetic mutations associated with this disorder.
Devices used in the treatment of heart disease generally undergo even less study than drugs, especially after the devices have been approved for use. We are working with the FDA, device manufacturers, and professional societies to develop models for learning more about cardiovascular devices. One model is to use existing databases.
We are working on a program to monitor outcomes of transmyocardial laser revascularization (TMR), a new device used to bring more blood to the heart muscle. In this case, the Society for Thoracic Surgeons (STS) holds the database. This project is partly funded by the Women's Health Initiative and includes partners from the FDA's Center for Devices and Radiological Health (CDRH) and the STS.
The elderly take an average of 16 prescription drugs each year and three to four of them at any given time. The likelihood that one is a drug that combats an inflammatory condition, such as arthritis, is high. Traditional anti-inflammatory drugs (but not steroids) carry increased risks of bleeding and ulcers in the gut, especially in older people. Newer agents, such as the cyclo-oxygenase (COX)-2 inhibitors, are presumed to cause less bleeding and fewer ulcers than the older drugs while being just as effective, but they also are much more expensive than over-the-counter drugs such as ibuprofen.
We are comparing the rates of ulcers among elderly men and women taking these new agents, those taking another anti-inflammatory drug, and people taking no such drug. We also are measuring the costs associated with disorders of the gut in these same three groups.
"To believe with certainty we must begin by doubting."
—King Stanislas I of Poland
We aim to improve practice by educating people about the best ways to use therapies and aiding them in their efforts to translate such knowledge into action. Through research and demonstration projects, we are learning the best ways to achieve these aims.
Children and Adolescents
The prevalence of asthma increased by 38 percent from 1982 to 1996 in those under age 18, and even more among black children and teens. With several partners, we aim to bring to local physicians and their patients the tools they need for the best management of asthma.
We are offering a Summer Institute, Using the Evidence on Therapeutics to Enhance Quality of Care, that introduces pediatric caregivers to the process of evaluating the quality of evidence in the literature and provides practical ways to use evidence and decisionmaking tools in their practices. Our Web site also provides information for patients and caregivers.
Adults
About 1 million Americans at any given time are taking drugs called glucocorticoids. These drugs treat inflammatory conditions such as rheumatoid arthritis, asthma, and certain bowel disorders. Although helpful, glucocorticoids also can cause bone loss leading to osteoporosis. In fact, glucocorticoid use is the second-commonest cause of osteoporosis, after menopause.
Osteoporosis caused by glucocorticoid drugs is being underrecognized and undertreated among adults taking these drugs. We are planning an intervention to aid in prevention and treatment of this disorder.
A Web site (http://georgetowncert.org) is providing information for patients, pharmacists, and physicians about drug interactions and prescription drug use. Other sites offer tools to aid in prescribing. We also will be developing comprehensive educational programs for patients and caregivers about known interactions.
We have conducted a national survey of physicians in training, to identify the needs of such training programs in educating future caregivers on the prevention of drug errors. We already have identified an educational target: how to prevent adverse drug effects.
We aim to provide policymakers with the information needed to make informed choices, by describing the scientific underpinnings for possible policies designed to improve the use of therapies. For example, Investigator Dr. Lucy Savitz testified about the CERTs program in September at the National Summit on Medical Errors and Patient Safety Research, organized by AHRQ.
Children and Adolescents
Unlike drugs, devices, and biological products, the clinical effects of policy changes typically don't undergo prospective evaluation. Our project in a Medicaid population will assess the effects of losing insurance coverage on clinical outcomes in children with asthma.
We have published a preliminary CERTs study that shows a link between a lack of vitamin D supplementation and the development of rickets in breast-fed children, especially among black infants. As a result of this study, the North Carolina Department of Health and Human Services has begun making vitamin D available free to breast-feeding women throughout the State.
Adults
We are examining the effects of two policy changes on clinical outcomes in a large Medicaid population:
To carry out our activities as a cohesive entity, CERTs has developed working groups to enhance communication and scientific efficiency:
We are linked to the public through a Web site (http://www.certs.hhs.gov), hosted by AHRQ and maintained by the CERTs Coordinating Center to provide information about our mission and progress.
We have detailed our common vision and integrated approach in a manuscript, "A Call To Arms," submitted to a peer-reviewed medical journal.