1. Purpose
This paper aims to further policy development in the American Public Health Association relating to the safety and effectiveness of medications for the treatment and prevention of disease. APHA last addressed this policy area in 19991 but more recent developments justify re-examination. The paper examines the key policy, programmatic and ethical issues pertinent to the licensing, marketing and use of such medications. The paper takes a public health perspective, namely, to assure that information on the effectiveness and safety of marketed medication is scientifically based and is disseminated to professionals and consumers in a timely and intelligible way to assure valid, credible benefit-risk assessments including cost-benefit. It provides information and recommendations for APHA, the public health community and other stakeholders to promote development of more effective, science-based regulatory and information processes. The paper starts with a review of the limitations of the current drug regulatory review process and proceeds to strategies for addressing areas in need of change.
2. Problems
2.1. The Current Regulatory Process and Its Limitations
The FDA mandate to protect the health of Americans has evolved over the past 100 years and has grown gradually as the capability for assessing the efficacy and safety of drugs has expanded. There is much to be proud of in this history.2 Federal law codifies the authority of the FDA,3 and legislation in 1962 clarified FDA's role in mandating the studies needed to market a medication for use in humans. Significantly, in the history of drug safety, human tragedies have been major triggers for reform: for example, sulfanilamide formulation errors and children's deaths in 1938, and European pregnant women's use of thalidomide and subsequent birth defects in their offspring in 1960.4
Efficacy and pre-market safety assessment were featured in 1962 revised regulations in an attempt to reduce the risk that unsafe or ineffective drugs would reach the market. In addition, the agency is responsible for pre-clinical assessment of the quality of product formulation, pharmacokinetics (fate of the drug in the body) and animal toxicology. The current regulations for bringing a product to market are extensive, and a product must successfully complete three phases of clinical study, which are facilitated by FDA guidance documents and procedures.5 Phases I, II and III pertain to pre-marketing studies, with the phases advancing from safety in volunteers (I), to treatment effects in patients (II), to large scale randomized clinical trials (III). Efficacy is required to be shown in comparison with an inert product (placebo) in one or more studies. Typically this results in knowledge of experience with the drug in 500-3000 volunteer patients before marketing. After marketing, Phase IV (post-marketing surveillance) activities take place, although with far less priority and rigor than pre-marketing. Critics call for greater FDA authority to require Phase IV safety and effectiveness studies.6
2.1.1. Lack of Transparency
Notwithstanding positive aspects of the regulatory system, a lack of transparency is all too often evident in the actions and responsibilities of FDA in regard to drug decision-making. For example, FDA has unpublished clinical trial findings submitted by manufacturers that are available to the agency but not to the public. These trial findings could revise the benefit to risk assessment in a specific situation and lead to different conclusions. This was the case for the use of antidepressants in the selective serotonin reuptake inhibitor (SSRI) class for the treatment of depression in youth.7 When the public learned of the existence of unpublished negative findings, there was much criticism of the failure to make this information available earlier. As a result, FDA is now less willing than in the past to accept arguments about the proprietary rights of manufacturers as justification for withholding information on trials outcomes. Moreover, trial registration is now demanded by leading academic journals as a pre-condition for publication,8 as is the maintenance of a national database of human trials (www.clinicaltrials.gov). Yet, throughout the gradual revelation of a regulatory environment that favors proprietary interests, FDA failed to provide the needed leadership on this issue of publication bias or on the consequent misleading interpretation of efficacy findings that could result from a failure to publish negative trial findings.
2.1.2. Factors Tending to Compromise Scientific Integrity in the Drug Approval Process
There are concerns about the existence and influence of financial conflicts of interest and the intrusion of political and/or ideological pressures to influence regulatory processes, to the detriment of scientific integrity and ultimately of public health. The nature of appointments to advisory bodies, including technical advisory committees,9 in recent years has raised the level of such influence on public health related functions throughout the federal government10 and has been a matter of great policy concern for APHA.11 The extensive prevalence of disclosed financial conflicts on the part of members of FDA drug advisory committees, and its relation to voting patterns at committee meetings, have been shown in a recent study.12 This section outlines the key ways in which financial conflicts and political pressures have been manifested in the FDA.
2.1.2.1 Conflict of Interest
Conflict of interest with the FDA's mission is the focus of many recent critical appraisals of FDA performance.13,14 In the past, although U.S. drug development has traditionally been the realm of profit-making drug companies, this was thought to be balanced by the FDA's authority to regulate marketing. A clear wall of separation between business interests and the FDA's responsibility for the health of the public was apparent. Consequently, public confidence was generally high. In the mid-1970s, concern was expressed that FDA authority over the drug approval process was unnecessarily delaying access to new products and the notion of a "drug lag" was put forward.15 By 1992, the Prescription Drug User Fee Act (PDUFA) was passed and a new era began. Now, pharmaceutical manufacturers would provide funds directly to increase the work force of the Office of New Drugs at FDA, with the goal of decreasing the approval time and eliminating the so-called drug lag. While funds have been allocated to speed new products to market, it appears that accelerated approval is too often achieved at the expense of the new drug's safety. While median approval time on a new drug application (NDA) decreased from 23 months in the early 1990s to 12 months in 1996, at the same time, a relatively greater incidence of rapid withdrawal of new products has occurred since 1995.16 Moreover, several of these represented products that were marketed in the United States well after safety concerns were apparent from the post-marketing experience in other countries. Events such as these suggest that a rush to the marketplace, now enhanced by PDUFA and since 1997 by the FDA Modernization Act (FDAMA), reflects a marketing perspective that has more to do with profitability than with advancing public safety and health. The loss of independence of the FDA became most apparent when FDA began to describe the drug industry applicant as a customer for its services.
.1.2.2 Influence of Political and Ideological Bias
In recent years, ideology-driven advocacy has on occasion become a means of forcing political rather than scientific decision-making at the FDA. For example, the delay in approving the marketing of morning-after contraception is seen as politically motivated.17,18 This prompted the resignation of a senior FDA scientist.19 There is clear evidence that a recent FDA commissioner, for reasons not based in science, took the highly unusual course of overriding senior professional staff by stalling the decision on switching the product status from by prescription-only to over-the-counter.20,21
2.1.3. Safety Concerns
Although new problems regarding FDA's independence regarding drug efficacy decisions have arisen particularly since PDUFA and FDAMA were enacted in the 1990s, concerns about drug safety are not new. Consumers and professionals often fail to appreciate that drug safety is a relative concept and is mainly relegated to Phase IV, the post-marketing surveillance (PMS) phase of drug development. Until a drug is used in several hundred thousand individuals, it is not possible to identify rare adverse events associated with its use.22 Consequently, a drug has only partial safety information when it enters the market.
Unfortunately, the high level of demands made by the FDA to assure adequate pre-marketing assessment is not complemented by a similarly strong mandate for the post-marketing phase. Until legislation changes that situation, the system will rely on MedWatch, the spontaneous reporting process. MedWatch, is an FDA-sponsored, voluntary, passive surveillance program.23 MedWatch is not often used by practitioners, so only a small proportion (an estimated 1 percent of all serious adverse drug events) are reported by physicians, other health professionals or consumers; most reporting comes from the pharmaceutical industry and little systematic assessment is possible because reports tend to be incomplete and lack clinical follow up.4 As a result, MedWatch is unable to assess the incidence of adverse drug events. This lack of infrastructure and analytic procedure results in doubt and dismissal of many MedWatch signals of a possible risk. There is no incentive for the industry to invest in phase IV studies once the drug is already available in the marketplace. Furthermore, FDA requests for phase IV studies have been relatively rare, and serious delays in requested studies have recently come to light.24
When one considers the expansive use of pharmaceuticals in U.S. populations including youth,25 pregnant women,26 and the elderly,27 it is evident that the need for an active surveillance drug safety system has never been greater. APHA has recommended that Congress mandate and fund a program of active surveillance of marketed pharmaceuticals.28
2.1.4 All-or-None Licensing
In some instances, the risk attendant on a new drug's approval may be so great that conditional approval might be a more responsible way for FDA to make new products available while retaining authority to call for further study.6 Suitable candidates for conditional approval would be new categories of drugs where little is known before the first agent in the class is marketed. Marketing of the drug would be restricted until it earned greater confidence.
An example already cited is antidepressants in the selective serotonin reuptake inhibitor (SSRI) class Prozac is the best-known brand name in the category. Shortly after the drug's marketing in 1988, its safety was questioned for possibly causing suicidal behavior in adults.29 FDA public hearings were held with an advisory panel empowered to assist the FDA in deciding whether the signal warranted further study. No such recommendation was made, and in 2003 the same safety question reemerged, this time with SSRI use to treat depression in children and adolescents.30 Here, too, the agency's analysis of existing clinical trial data is fraught with questionable decisions, most notably, failure to call for further research on safety in the face of inadequate clinical trial data for resolving uncertainties about rare adverse clinical events such as suicide.
Two analyses were conducted at FDA. The first analysis was suppressed, but when the newspapers publicized the situation, the FDA eventually made that study public on its Web site along with a second study with a different analytic method which produced a more uncertain result.31 Nevertheless, the outcry of families with members who were harmed (but whether the drug was to blame is still uncertain) caused the panel to act and recommend a black box warning for the drug label. The black box warning is a special format on the official FDA-approved manufacturer's product label calling attention to the risk of serious or life-threatening events. If conditional approval had been given to this new and potentially better class of antidepressants, an opportunity for large scale active surveillance for safety could have been opened up promptly rather than the very uncertain clinical decision-making that has resulted in the past 15 years.
In addition, independent analysis of the efficacy data would have shown SSRIs to be ineffective for children as compared with adolescents and adults.32, 33 In contrast to the United States, the United Kingdom has a more action-oriented independent safety surveillance system. Academic-based safety units conduct analyses on national data sources and are relatively free of pharmaceutical industry influence. Consequently, agency differences for SSRI recommendations for U.S. and European children exist. The United Kingdom and the European Union recommend generally not using SSRIs in children and, if an SSRI is deemed to be needed, restricting use to fluoxetine (Prozac).34
Other examples of faulty decisions in permitting the continued marketing of questionable products include: in the case of rofecoxib (Vioxx) for arthritis pain relief, permitting the continued marketing of the product five years after cardiac safety concerns were voiced but issuing no call for additional safety studies;35 in the case of troglitazone (Rezulin) for diabetes, after multiple reports suggesting severe liver toxicity; and in the case of cerivastatin (Baycol) for hyperlipidemia, with questions regarding much greater risk of rhabdomyolysis than for existing products in the same class.36
2.2. Unmet Scientific and Organizational Needs
The development of research methods to assess drug efficacy began in 1948 with the evaluation of streptomycin for the treatment of tuberculosis.37 The effectiveness of the drug compared with standard treatment (rest) and placebo was convincing evidence of the importance of double blind rigorous methods. The drug industry adopted clinical trial methods and in the next 30 years many medications reached the market after FDA approval with greater assurance of their therapeutic value than had been the case with earlier approvals.
Progress in clinical trial methods during the past 20 years has led several nations to adopt standards that have a public health perspective. Specifically, trials with an active comparison arm (usually representing the best available current treatment) as well as a placebo arm permit inferences about the benefit of the new treatment relative to available treatments of known benefit and costs. Australia has adopted comparative trial data as essential to the government review of medications for approval for reimbursement.38 As noted above, APHA has recommended that Congress fund an independent program to expand pharmaceutical assessment with a focus on comparative effectiveness, long-term effectiveness, and cost-effectiveness.28 (Legislation along these lines, albeit without reference to long-term effectiveness, was proposed in Congress in 2003.39) In failing to develop similar new standards for the marketing of medications, the FDA fails to address important trends in the scientific methodology of drug efficacy.
Attention to the relative effectiveness for marketed medications would bring research questions with a public health dimension to a fuller focus.40 This issue received attention in the recent Medicare Part D implementation.41 The recent onset of a vast increase in medication expenditures, most of which is likely to be paid for with public funds, requires renewed attention to the comparative effectiveness and cost-effectiveness of marketed medication. This is not an FDA function per se but ideally could involve collaboration with the Agency for Health Care Research and Quality (AHRQ, the agency charged with supporting research to improve the quality of health care, reduce its cost, and broaden access to essential services) and the Center for Medicare and Medicaid Services (CMS, the agency responsible for reimbursement decisions for public programs for the poor, elderly and disabled).
Medicare Part D data present an important opportunity to improve the post-marketing evidence on prescribed medication outcomes, use and safety among the elderly and disabled. This potential will be enhanced if researchers are able to merge these data with claims data on other Medicare services. However, it is currently unclear whether and under what guidelines Medicare Part D data will be available to scholars such as university-based researchers for such research.42 It is important that access to data for these purposes be clarified by regulatory and, if necessary, by legislative action, in order to bring the resources of the research community more effectively to bear on these important issues. Furthermore, community-based treatment outcomes will complement information available from randomized clinical trials on use, safety and effectiveness with additional information available from these large observational datasets. Such datasets offer statistical power to study less common outcomes that are often unavailable through randomized clinical trial data.
Study design issues involve concerns about the use of biomarkers as the primary endpoints for determining successful outcome of treatment. Proximal rather than distal endpoints are emphasized in many endpoint measurements. Typically, pharmaceutical trials have tended to restrict endpoints to symptom improvement (proximal endpoint). In acute conditions for example, serious cancers and life-threatening infectious diseases the use of proximal endpoints, such as T-cell counts, instead of distal endpoints, such as survival may conceivably be justified. However, drug company-sponsored trials have mostly ignored distal endpoints for example, increased functioning for independent living and work rehabilitation in studies on treatment of chronic conditions, such as schizophrenia. The distinction in these endpoints is critical from a public health perspective. In the past, publicly funded studies, for example, the Framingham study, could be credited with showing that blood pressure control (proximal endpoint) is associated with fewer strokes and cardiac deaths and with longer life (distal endpoint).43 In contrast, in recent years, for chronic conditions we have learned of drug effects in terms of symptom control but not necessarily in terms of increased functioning.44 In clinical trials, patient reports of improved "quality of life" may produce more pronounced, favorable assessments of drug versus placebo than clinically relevant measures- making unclear the benefits of a drug entity's coming to the market primarily on the basis of short-term subjective primary endpoints.45
In another new trend, in some recent drug company sponsored studies, reports of small effect sizes in major clinical trials are interpreted as supporting efficacy, whereas research leaders with a public-health cost-effectiveness perspective would challenge such modest effects.
The Pharmaceutical Research and Manufacturers of America (PhRMA), the pharmaceutical industry lobby, has voluntary guidelines for scientific integrity and ethical conduct.46 Nevertheless, there is a clear need for greater independence of clinical drug research in terms of funding, design of studies and interpretation of study findings.47 Independent assessment requires public funding, which could be derived from revised expenditure priorities in the NIH research Roadmap.48 This would allow Phase IV studies of effectiveness, safety and cost-efficiency to be undertaken in major pharmaceutical treatment areas with a great public health benefit to the society as well as to individual patients.
2.3. Other Issues
2.3.1. Prescription Drug Advertising
Many consumers have become increasingly sophisticated in their understanding of drug information, and a possible factor cited by the drug industry is direct to consumer advertising (DTCA) of prescription drugs. DTCA was initiated in 1997 after the pharmaceutical industry announced it would relinquish its prior voluntary restriction.49 The decision was touted by the industry as a means of increasing consumer education, but such positions are difficult to defend when current TV and radio ads are reviewed. The extensive cost of such advertising, which totaled $4 billion for TV and radio ads alone in 2004, suggests that its role in increasing market share is formidable50 even if its possible effectiveness as a tool for the education of consumers may be remote. Enthusiasm for such practices is not shared among western nations. Canadian and European pharmaceutical policies do not permit DTCA.
2.3.2. Medical Autonomy and the Diffusion of Scientific Information
In order to prescribe and dispense medications appropriately and safely, practitioners need to have a reliable source of the best available information about the benefits and risks of medications. FDA-approved labeling is the official source of essential prescribing information and should have a major role in risk communication post-marketing. However, FDA's mechanisms for communicating this information are ineffective, and most practitioners receive critical information about pharmaceuticals through less formal channels, such as medical journals, non peer-reviewed and industry supported media, the Physicians Desk Reference- a proprietary publication- and postgraduate medical education. More recent activity focuses on Web-based media, for example, Medscape and WebMD. The information from such sources is frequently biased, due to commercial ties that authors and sponsors often have with drug companies. 51-53
The FDA-approved drug labeling (package insert) is the source of essential prescribing information. However, not only does the label's tiny print tend to discourage reading, but the amount and complexity of the information in drug labels can be overwhelming to consumers and to health care professionals. Moreover, the process of changing drug labels is slow: when the changes proposed in a label may affect the drug maker's potential liability or its drug's commercial value, lengthy negotiations ensue between the FDA and the drug company. In its attempt to raise awareness about drug safety, the FDA recently completed a several-year-long process to make labels easier to read and understand.54 The format highlights the most important risks and benefits of a drug by putting boxed warnings and other essential prescribing information first and in summary form. The new format applies only to newly marketed drugs initially, and the FDA will apparently rely on voluntary compliance with the standards and trust that the new format will be gradually phased in for other recently marketed drugs.
When the FDA recognizes that serious adverse drug reactions and/or other serious risks are associated with a drug, this is typically communicated to practitioners by "Dear Doctor" letters, boxed warnings, and other labeling changes often mandated by the FDA. "Dear Doctor" letters are sent by manufacturers to alert physicians about a risk associated with a marketed product. This reduces potential liability for failure to warn patients of risks. However, evidence suggests that these letters generally have limited effect on physicians' practices, as there are numerous examples of suboptimal or inappropriate prescribing of medications following such warnings.55,56 Another change pending at the FDA will be to provide practitioners who sign up on its Web site with daily updates and reminders about drug safety and efficacy matters.57 These changes are unlikely to have much impact, because physicians continue to be targets of heavily financed drug marketing and so these less objective resources for drug prescribing information will continue to have a dominant influence.
Almost all medical postgraduate education (commonly referred to as continuing medical education or CME) is industry funded, either directly or indirectly, through medical societies and academic institutions.52 Key congressional leaders have criticized industry support of the training of health care practitioners by awards of educational grants since exposure of abuses made it evident that such grants are basically part of a marketing strategy.58,59 The pharmaceutical industry is also a major supporter of professional societies and patient advocacy groups, all of which may endorse their products. The close connections between the drug industry and academia are particularly troublesome because these affect the way drugs are being evaluated.47,60 Such conflicts exist within FDA advisory panels as well, as indicated by the reports of pediatric panel members charged with developing recommendations on the risk of stimulants in relation to cardiovascular events.61
While PhRMA asks its members who sponsor CME to adhere to a voluntary code of conduct that was jointly endorsed by the AMA and other professional societies, these rules have loopholes. The code calls for a degree of scientific rigor and objectivity in promotional materials. It discourages discussion of only the benefits of specific drugs. The code's primary means of addressing the possibility of bias in sponsored training is to ask for disclosure of potential conflicts of interest arising from the prior receipt of honorariums or other pharmaceutical funding. 62 This process, however, fails to prevent bias in the content of oral and written presentations. The industry also fails to abide by provisions intended to limit discussion of off-label use of drugs. Finally, CME programs typically fail to place adequate emphasis on risks associated with drugs or on their comparative cost efficacy.63
There are indications many physicians believe that marketing practices do not affect them.64 Yet there is ample evidence that such persuasion does work and the drug industry continues to spend a large portion of its budget on it.65 One form used widely in recent years is paying doctors to promote a drug to other doctors by lecturing at small meetings or dinners.66 A great proportion of drug marketing still takes the traditional form of pharmaceutical "detailing," wherein company representatives have one-on-one visits with physicians. Drug companies also provide considerable direct financial support to medical societies, as well as to patient advocacy organizations in order to influence prescribing physicians, other health professionals and consumers. In the absence of more assertive oversight of pharmaceutical industry practices regarding information bias on safety and efficacy and full publication of all study findings, drug company biases will continue to dominate the information arena, largely unchallenged.
Medical journals are another primary resource for the reporting of clinical trials and other drug information. Most medical journals depend on funding from the pharmaceutical industry through drug advertisements and, recently, through the publication of journal supplements that report the findings of conferences or provide a series of opinions on specific medical topics. Physicians who are seen as "thought leaders" are sought after to provide postgraduate medical training and to write journal articles.58 This is arranged by sponsorship of the drug industry, jointly with medical societies and academic institutions. While disclosure of these relationships is required, some unethical practices have been exposed. Notably, physicians writing medication reviews often receive industry assistance in the form of unacknowledged "ghost writers," and these research reports are then published in supplements designed to resemble peer-reviewed journals. 60
The quality of journals' content and reporting of clinical trials is also variable. Few medical journals mandate that submissions of trials comply with the CONSORT (consolidated standards of reporting trials) requirements.67 Furthermore, the under-reporting of negative or inconclusive trials, termed publication bias, is a serious concern that is only recently being addressed. In the 1997 Food and Drug Modernization Act (FDAMA Section 113), ClinicalTrials.gov was created as a central registry of trials that involve serious and life-threatening medical conditions. While PhRMA has urged its members to report other trials voluntarily, the International Committee of Medical Journal Editors (ICJME) has mandated that authors register their trials before it will consider their papers for publication.8 Although these efforts have greatly increased the numbers of trials reported, compliance among trial sponsors remains incomplete;68 important information about drugs and other interventions studied and other important aspects of trial protocols are being left off of the registry or are not being disclosed in a timely manner.69
2.3.3. Ethical Dimensions of Medical Treatment with Marketed Medications
Since 1978, ethical concerns for the conduct of federally funded clinical trials are governed by the principles espoused in the Belmont Report.70 Human experimental studies are restricted to those that show respect for persons, beneficence and fairness. These criteria are crucial for drug assessment studies because proprietary stakeholders have much to gain if the trial results are accepted in the FDA review procedures. This strict protocol for ethical dimensions of pre-marketing data contrasts sharply with ethics in the post-marketing phase.
Traditionally, there is little problem for physicians to prescribe marketed medications for conditions not indicated on the official drug labeling information approved by the FDA.71 Such off-label use usually lacks adequate evidence of efficacy and safety and may present opportunities for an ethical breach in the physician-patient contract. FDA has upheld this off-label use of medications as within the authority of physicians to prescribe, largely because the drug industry usually has no incentive to study additional indications. In 1997, in an effort to provide such an incentive, FDA issued the Pediatric Rule. Under this rule, the industry was given the option of a six-month patent extension in exchange for studies on the efficacy and safety of drugs in children. The Best Pharmaceuticals for Children Act (2002)72 and the Pediatric Research Equity Act (2003)73 are further indications of efforts by FDA and the legislature to gain more systematic information on pediatric usage. The paucity of such information had been largely ignored by the drug industry in the past because of a lack of profitability or fear of increased liability. Consequently, there has been some improvement in studies of drugs in children, although the patent extension is given regardless of study outcome. Some of these studies have been of poor quality- for example, in the SSRI youth studies there were different methods of adverse event reporting across the studies and post-hoc combining of trial data. The net result is growing discomfort among physicians, who are discovering bias in the information on drug efficacy and safety they are receiving- particularly for off-label use.7 The information to guide the widespread off-label use of medications for children and other vulnerable groups is being challenged as inadequate in terms of efficacy and safety.72,74 The need for post-marketing effectiveness studies is being emphasized as a public health dimension largely missing from our knowledge base of drug effects. 75
2.3.4. Transparency and Reliability
A reformed regulatory system would address conflicts of interest through heightened monitoring and a stricter code of conduct for all involved. Because transparency is required if conflict of interest and bias are to be eliminated, drug companies should be required to give complete details about their relationships with all who receive their support. Communications to health care professionals and consumers should emanate from one independent drug safety and efficacy board, and the role and influence of the pharmaceutical industry in this process should be minimal. Independent centers that can conduct such drug evaluations already exist in the United States. Prominent examples are the Evidence-Based Practice Centers and the Centers for Education and Research on Therapeutics (CERTS).76 An excellent model of such an agency in the United Kingdom is the National Institute for Health and Clinical Excellence (NICE),77 which evaluates the scientific evidence supporting treatment interventions and produces practice guidelines and standards, which in turn inform funding decisions and training initiatives in the National Health Service.
3. Reforming the Regulatory Process
A proposed reformed regulatory agency would include (1) a Center for New Drug Approval (CNDA), whose funding would be independent of the pharmaceutical industry, (2) a Center for Post-Marketing Studies, and (3) a Center for Drug Information.13,14 Other leading investigators of pharmaceutical outcomes have urged action for major reforms.78 Voices are also being heard from more traditional drug trialists.79 Leaders may differ on how the reforms should occur, but they are increasingly strong in voicing the need for reform.
The gravity and persistence of systemic deficiencies outlined in the present paper indicate a need for more far-reaching reforms than hitherto undertaken. Recent recommendations by Ray and Stein13 are noteworthy in this regard. They urge that a Center for New Drug Assessment should have authority to issue conditional approval, that is, approval for restricted marketing, which could make new products available with the Center retaining authority to call for further study. The proposed separate center for PMS emphasizes the need to minimize conflicts when previously approved drugs emerge with serious problems or safety questions after marketing. The Center for Drug Information, as Ray and Stein envision it, "would coordinate the communication of accurate information to practitioners and patients," to provide reliable information on which to base the use of medications. Beyond being responsible for accurate, effective labels, this Center would have the authority and capacity to invoke "more active methods of communication," such as academic detailing, when appropriate. Clearly the effectiveness of even the most ideally conceived agencies would depend critically on the political will of Congress and the executive branch to assure adequate funding.
Objective, public health oriented action by consumers is sometimes conflicted by personal or family treatment needs. The situation is further muddied by pharmaceutical industry support of patient advocacy groups. 80 An independent entity with recognized competence, such as Ray and Stein propose, to oversee pharmaceutical information flow, would support objectivity in consumer advocacy for drug research and reimbursement.
The Institute of Medicine has recommended requiring registration of all trials with clinicaltrials.gov.81 The recommendation would be strengthened if the sponsor of the clinical trial who fails to comply faces the threat of criminal penalties.
Apart from changes in the regulatory infrastructure for medications, its mandate, and its funding, a serious issue concerns the need for a public health perspective to be reflected in the funding of effectiveness and safety studies.82 In the prevailing regulatory framework, the United States has allowed private enterprise to be the major force in drug development activity. Federal funding priorities in agencies such as NIH and AHRQ should be revised to include more emphasis on the long-term benefits, safety and cost-effectiveness of medications, particularly those used to manage chronic conditions such as cardiovascular disease, arthritis, depression, schizophrenia, etc. What these conditions have in common is that all warrant integrated non-pharmacologic medical services, not just drug therapy.
Therefore, the American Public Health Association:
1. Supports legislation to enable FDA to require post-marketing studies and to enforce commitments for timely completion of such studies;
2. Supports legislation to require more transparency and access to data from pharmaceutical clinical trials and post-marketing studies, and other relevant information, including unpublished data;
3. Supports legislation to create the infrastructure for an effective post-marketing surveillance system. This system should include: resources for active surveillance, improved signal detection in current reporting systems, and effective communication of safety information to the general public and health care professionals;
4. Encourages the development of federal funding initiatives to engage the academic research community, together with FDA and other stakeholders, in a robust program of federally funded research on post-marketing utilization and outcomes of prescription drug therapies;
5. Supports legislation and regulations that would assure access to Medicare Part D data by federal agencies and non-federal investigators for research on prescription drug use and outcomes;
6. Supports the IOM recommendation that prescription drug user fees be utilized to support needed post-marketing studies. Such funds should be available to support post-marketing studies on prescription drug use and outcomes conducted both by FDA and through other mechanisms such as the Centers for Education and Research on Therapeutics; and
7. Calls for strengthening the FDA's authority to restore the moratorium on Direct to Consumer Prescription Drug Advertising.
References
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