Every day the Food and Drug Administration (FDA) works to balance expeditious access to drugs with concerns for safety, consonant with its mission to protect and advance the public health. The task is all the more complex given the vast diversity of patients and how they respond to drugs, the conditions being treated, and the range of pharmaceutical products and supplements patients use. Reviewers in the Center for Drug Evaluation and Research (CDER) at the FDA must weigh the information available about a drug’s risk and benefit, make decisions in the context of scientific uncertainty, and integrate emerging information bearing on a drug’s risk-benefit profile throughout the lifecycle of a drug, from drug discovery to the end of its useful life. These processes may have life-or-death consequences for individual patients, and for drugs that are widely used, they may also affect entire segments of the population. The distinction between individual and population is important because it reflects complex determinations that FDA must make when a drug that is life-saving for a specific patient may pose substantial risk when viewed from a population health perspective. In a physician’s office, the patient and the provider make decisions about the risk and benefits of a given drug for that patient, whereas FDA has to assess risks and benefits with a view toward their effects on the population. The agency has made great efforts to balance the need for expeditious approvals with great attention to safety, as reflected in its mission—to protect and advance the health of the public.
In the first years of the 21st century, the issue of prescription drug safety came to the attention of the public with renewed intensity. Drug withdrawals, apparent delays in warning the public about important drug risks, a
perceived rush to approve drugs without sufficient attention to safety, and press coverage of internal problems in CDER may have contributed to a deterioration of public confidence in FDA. Academics, consumer organizations, professional societies, and legislators debated the possible causes and solutions of what was seen by many as a major problem (Consumers Union, 2005; Grassley, 2005; NCL, 2005; US PIRG, 2006). FDA and the Department of Health and Human Services (DHHS) announced a series of steps to address drug safety, including asking the Institute of Medicine (IOM) to convene a committee to assess the US drug safety system and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs.
In its report, the committee considered the drug safety system as the sum of all activities conducted by FDA and other stakeholders to monitor, evaluate, improve, and ensure drug safety. (See the committee’s Statement of Task in Box S-1.) Although much of the committee’s work was focused on drug review, safety surveillance, and related activities of CDER, the committee also reviewed some key aspects of the roles and considered the potential contributions of the pharmaceutical industry, the academic research enterprise, Congress, the health care delivery system, patients, and the public.
Some observers believe that drug withdrawals (which are only one potential indicator of drug safety) represent de facto failures of the drug regulatory system, or that newly identified unusual and serious adverse events indicate that someone made a mistake in approving the drug. This is not so. FDA approval does not represent a lifetime guarantee of safety and efficacy, and what is newest is not always the best. For several related reasons, even the best drug safety system would not prevent adverse reactions to pharmaceuticals on the market. It is impossible to know everything about a drug at the point of approval because drugs’ mechanisms of action are complex, and because the clinical testing that happens before approval is generally conducted in controlled settings in defined, carefully selected populations that may not fully represent the wide range of patients who will use the drug after approval, some chronically, and in combination with other drugs. Thus, the understanding of a drug’s risk-benefit profile necessarily evolves over the drug’s lifecycle. CDER staff who review regulatory submissions, such as new drug applications, must strike a delicate balance in judging the drug’s risks and benefits, and whether the need for more study to increase certainty before approval warrants delaying the release of the drug into the marketplace and into the hands of health care providers and their patients.
Legitimate questions have arisen about CDER’s handling of drug safety. Are safety signals recognized and addressed in a timely fashion? Is the public informed about safety problems in a clear and timely manner? Do the interactions of pre- and postmarketing center staff facilitate effective action
The Statement of Task
In response to growing public concern with health risks posed by approved drugs, the FDA has requested that the Institute of Medicine (IOM) convene an ad hoc committee of experts to conduct an independent assessment of the current system for evaluating and ensuring drug safety postmarketing and make recommendations to improve risk assessment, surveillance, and the safe use of drugs. As part of its work, the IOM committee will:
on drug safety? Does the center have the mix of expertise, technology, scientific capacity, authority, and resources to achieve its share of FDA’s mission, to protect and advance the health of the public? Do the political, social, and economic aspects of the external environment and the expectations of other stakeholders affect the agency’s functioning? To answer some of these questions, the committee reviewed aspects of the drug safety system that it believes can be transformed to improve the monitoring and evaluation of drug safety signals and restore public confidence in the system, including:
The organizational culture of CDER and its determinants, and how organizational culture may affect the center’s performance in assessing and acting on the evolving understanding of risk and benefit over the drug lifecycle;
Key factors of regulatory science and processes (methods, data resources, expert advice, independence) necessary to enhance drug safety;
The regulatory authorities necessary to provide for drug safety;
The communication structure needed to support an effective drug safety system; and
The financial resources required to enable CDER to meet its responsibilities in supporting the FDA mission.
In its information gathering, the committee became aware of multiple proposals to strengthen the drug safety system that have been made in the past and have addressed many of the areas outlined. In its work, the committee has attempted to develop a coherent and integrative approach to transforming drug safety programs that encompasses the categories described above. The committee made several overarching findings. First, there is a perception of crisis that has compromised the credibility of FDA and of the pharmaceutical industry (Harris Interactive, 2005; Pricewaterhouse-Coopers’ Health Research Institute, 2005). Second, the committee learned that most stakeholders—the agency, the industry, consumer organizations, Congress, professional societies, health care entities—appear to agree on the need for certain improvements in the system. Third, the committee found that the drug safety system is impaired by the following factors: serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in CDER that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement. Fourth, the committee found that FDA, contrary to its public health mission, and the pharmaceutical industry, contrary to its responsibility to the users of its products (and its shareholders), do not consistently demonstrate accountability and transparency to the public by communicating safety concerns in a timely and effective fashion.
The committee’s vision of a transformed drug safety system has at its core a lifecycle approach to drug risk and benefit—not a new concept, but one that has been implemented, at best, in a limited and fragmented manner. For FDA, attention to risk and benefit over a drug’s lifecycle would require continuous availability of new data and ongoing, active reassessment of risk and benefit to drive regulatory action (responsive to the accumulating information about a given drug), and regulatory authority that is strong both before and after approval. For the industry, attention to risk and benefit over
the lifecycle will require increased transparency toward FDA in the process of elucidating and communicating emerging information about a drug, and acceptance of changes intended to strengthen drug safety. Importantly, FDA’s credibility is intertwined with that of the industry, and a more credible drug safety system is in everyone’s best interest. For the health care delivery system, a lifecycle approach to risk and benefit implies the need to heed and follow FDA communication about drug safety matters and to exercise appropriate caution in drug-related decision making (from formularies to prescribing) in recognition of the limited information available at the time of drug approval. Also, the health care delivery system would benefit from consistently basing prescribing decisions on the science, and exercising caution in regard to the industry’s influence on the practice of medicine. Health care organizations and professional societies could contribute to prescribers’ understanding of the evolving science behind the assessment of drug risk and benefit. The academic research enterprise could enhance its contributions of data to the assessment of risk and benefit at all points in a drug’s lifecycle, continue its crucial advisory relationship with FDA, and uphold the value of complete transparency in recognition of real and perceived conflicts associated with financial involvement with the industry. Other government agencies could contribute to the lifecycle approach to drug risk and benefit by collaborating with FDA and the private sector to ensure that data streams from publicly funded health care settings contribute to an improved drug safety system. The public and patients could do their part by communicating with their health care providers about the pharmaceutical products they are using, learning about and discussing with their providers drug risks and benefits in the context of their health needs and characteristics, informing their providers about side effects they experience, and calling for more useful and timelier information about drug benefits and risks associated with new drugs. The public and other stakeholders could also urge Congress to ensure and sustain adequate funding for FDA.
Instability in the Office of the Commissioner has been a serious problem for FDA and CDER in particular. A large, complex, science-based regulatory agency cannot perform optimally in the absence of stable, capable leadership, and clear, consistent direction.
3.1: The committee recommends that the FD&C Act be amended to require that the FDA Commissioner currently appointed by the President with the advice and consent of the Senate also be ap-
pointed for a 6-year term of office. The Commissioner should be an individual with appropriate expertise to head a science-based agency, demonstrated capacity to lead and inspire, and a proven commitment to public health, scientific integrity, transparency, and communication. The President may remove the Commissioner from office only for reasons of inefficiency, neglect of duty, or malfeasance in office.
A mechanism is needed to allow the agency and CDER leadership to benefit from the advice and support of individuals experienced in changing organizational culture and leading large and complex organizations.
3.2: The committee recommends that an external Management Advisory Board be appointed by the Secretary of HHS to advise the FDA commissioner in shepherding CDER (and the agency as a whole) to implement and sustain the changes necessary to transform the center’s culture—by improving morale and retention of professional staff, strengthening transparency, restoring credibility, and creating a culture of safety based upon a lifecycle approach to risk-benefit.
3.3: The committee recommends the Secretary of HHS direct the FDA commissioner and Director of CDER, with the assistance of the Management Advisory Board, to develop a comprehensive strategy for sustained cultural change that positions the agency to fulfill its mission, including protecting the health of the public.
The Office of Drug Safety, now the Office of Surveillance and Epidemiology (OSE), has not had a formal role in drug regulation—neither formal opportunities to learn from and participate in relevant aspects of the review process nor the authority to take action regarding postmarketing safety.
3.4: The committee recommends that CDER appoint an OSE staff member to each New Drug Application review team and assign joint authority to OND and OSE for postapproval regulatory actions related to safety.
The Prescription Drug User Fee Act (PDUFA) mechanism that accounts for over half of CDER’s funding and the reporting requirements associated with the user-fee program are excessively oriented toward supporting speed of approval and insufficiently attentive to safety.
3.5: To restore appropriate balance between the FDA’s dual goals of speeding access to innovative drugs and ensuring drug safety over the product’s lifecycle, the committee recommends that Congress should introduce specific safety-related performance goals in the Prescription Drug User Fee Act IV in 2007. (See Chapter 3 for suggested goals.)
Science and Expertise
FDA’s Adverse Event Reporting System (AERS) is outdated and inefficient, and although CDER has begun a technological overhaul of the system, more work is needed to improve its usefulness in postmarketing surveillance.
4.1: The committee recommends that in order to improve the generation of new safety signals and hypotheses, CDER (a) conduct a systematic, scientific review of the AERS system, (b) identify and implement changes in key factors that could lead to a more efficient system, and (c) systematically implement statistical-surveillance methods on a regular and routine basis for the automated generation of new safety signals.
In addition, CDER’s ability to test drug safety hypotheses is limited.
4.2: The committee recommends that in order to facilitate the formulation and testing of drug safety hypotheses, CDER (a) increase their intramural and extramural programs that access and study data from large automated healthcare databases and (b) include in these programs studies on drug utilization patterns and background incidence rates for adverse events of interest, and (c) develop and implement active surveillance of specific drugs and diseases as needed in a variety of settings.
The report makes several recommendations (4.3, 4.5, 4.8, and 5.4 below) intended to help CDER develop a more structured way to determine the level of postmarketing scrutiny and data requirements, in other words, to match the evaluation of drugs with the way that they will be used in the population. Short-term preapproval trials do not provide adequate information about the balance of risks and benefits of drugs that are used by many people for many years.
Various public- and private-sector organizations possess increasingly high-quality data resources and scientific capacity, and a concerted effort is
needed to ensure that those resources are used efficiently and effectively in the service of drug safety.
4.3: The committee recommends that the Secretary of HHS, working with the Secretaries of Veterans Affairs and Defense, develop a public-private partnership with drug sponsors, public and private insurers, for-profit and not-for-profit health care provider organizations, consumer groups, and large pharmaceutical companies to prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health importance. Congress should capitalize the public share of this partnership.
4.4: The committee recommends that CDER assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs).
The assessment of risks and benefits is an activity that does not end at approval, and risk and benefit cannot be considered in isolation of one another.
4.5: The committee recommends that CDER develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the preapproval and postapproval settings.
The committee has made several recommendations to expand the data on drug risks and benefits to improve those decisions. However, in order to plan and use those data, appropriate expertise must be brought to bear. This expertise comes from the CDER staff as well as their advisory committees and other non-governmental experts. The committee believes there is a need to expand this expertise to take on the new responsibilities laid out in recommendations made in this report. CDER will need more expert staff, deeper expertise in the staff it already has, and different kinds of expertise.
With this expanded expertise and resources CDER can be a more effective steward of postmarketing safety and a more credible scientific partner with industry and academia by actively participating in defining important research questions and designing appropriate studies.
4.6: The committee recommends that CDER build internal epidemiologic and informatics capacity in order to improve the postmarket assessment of drugs.
Increasing the scientific sophistication of the CDER staff should not happen in isolation. Since the goal is to support good science-based regulatory decision making, a corollary goal is to support the research infrastructure of the agency. Expanded research opportunities should be linked explicitly to FDA’s regulatory mission.
4.7: The committee recommends that the Commissioner of FDA demonstrate commitment to building the Agency’s scientific research capacity by:
Appointing a Chief Scientist in the office of the Commissioner with responsibility for overseeing, coordinating, and ensuring the quality and regulatory focus of the agency’s intramural research programs.
Designating the FDA’s Science Board as the extramural advisory committee to the Chief Scientist.
Including research capacity in the Agency’s mission statement.
Applying resources to support intramural research approved by the Chief Scientist.
Ensuring that adequate funding to support the intramural research program is requested in the Agency’s annual budget request to Congress.
The fast pace of review does not allow CDER reviewers to solicit consistently needed input from the appropriate FDA advisory committee(s) on issues such as postmarketing safety and the need for additional studies.
4.8: The committee recommends that FDA have its advisory committees review all NMEs either prior to approval or soon after approval to advise in the process of ensuring drug safety and efficacy or managing drug risks.
4.9: The committee recommends that all FDA drug product advisory committees, and any other peer-review effort such as mentioned above for CDER-reviewed product safety, include a pharmacoepidemiologist or an individual with comparable public health expertise in studying the safety of medical products.
FDA’s credibility is its most crucial asset and recent concerns about the independence of advisory committee members (who advise CDER in its regulatory decision making), along with broader concerns about scientific independence in the biomedical research establishment, have cast a shadow on the trustworthiness of the scientific advice received by the agency.
4.10: The committee recommends FDA establish a requirement that a substantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee’s deliberations.
The committee believes strongly in the importance of increasing the availability of information about risks and benefits, whether specific study results or CDER staff analyses of concerns, to the public and to researchers. The National Library of Medicine hosts a Web site for registration of clinical trials, but with few exceptions, this is voluntary. In 2002, pharmaceutical companies that are members of the Pharmaceutical Research and Manufacturers of America (PhRMA) committed to voluntary disclosure of the results of hypothesis-testing clinical trials for marketed and investigational drugs and in 2004 PhRMA launched a Web site (ClinicalStudyResults.org) for this purpose. A review of the site shows great variability in the ease of accessibility and completeness of the information.
4.11: To ensure that trial registration is mandatory, systematic, standardized, and complete, and that the registration site is able to accommodate the reporting of trial results, the committee recommends that Congress require industry sponsors to register in a timely manner at clinicaltrials.gov, at a minimum, all Phase 2 through 4 clinical trials, wherever they may have been conducted, if data from the trials are intended to be submitted to the FDA as part of an NDA, sNDA, or to fulfill a postmarket commitment. The committee further recommends that this requirement include the posting of a structured field summary of the efficacy and safety results of the studies.
4.12: The committee recommends that FDA post all NDA review packages on the agency’s Web site.
4:13: The committee recommends that the CDER review teams regularly and systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information.
FDA lacks the clear, unambiguous authority needed to enforce sponsor compliance with regulatory requirements and instead relies on the prospect of productive negotiations with industry. Although the agency historically has made effective use of its “bully pulpit” to compel sponsor compliance,
this process leaves potentially critical regulatory action vulnerable to a subjective and highly variable process of exercising individual or agency influence, and to the vicissitudes of changing politics and attitudes toward regulation. That is why FDA’s authorities must be clarified and strengthened to empower the agency to take rapid and decisive actions when necessary and appropriate.
5.1: The committee recommends that Congress ensure that the Food and Drug Administration has the ability to require such postmarketing risk assessment and risk management programs as are needed to monitor and ensure safe use of drug products. These conditions may be imposed both before and after approval of a new drug, new indication, or new dosage, as well as after identification of new contraindications or patterns of adverse events. The limitations imposed should match the specific safety concerns and benefits presented by the drug product. The risk assessment and risk management program may include:
Distribution conditioned on compliance with agency-initiated changes in drug labels.
Distribution conditioned on specific warnings to be incorporated into all promotional materials (including broadcast direct-to-consumer [DTC] advertising).
Distribution conditioned on a moratorium on DTC advertising.
Distribution restricted to certain facilities, pharmacists, or physicians with special training or experience.
Distribution conditioned on the performance of specified medical procedures.
Distribution conditioned on the performance of specified additional clinical trials or other studies.
Distribution conditioned on the maintenance of an active adverse event surveillance system.
5.2: The committee recommends that Congress provide oversight and enact any needed legislation to ensure compliance by both the Food and Drug Administration and drug sponsors with the provisions listed above. FDA needs increased enforcement authority and better enforcement tools directed at drug sponsors, which should include fines, injunctions, and withdrawal of drug approval.
The agency’s timely performance of the required postmarketing safety reviews could be listed as one of the goals associated with PDUFA and reported on in the goals letter to Congress (see Chapter 3).
5.3: The committee recommends that Congress amend the Food, Drug and Cosmetic Act to require that product labels carry a special symbol such as the black triangle used in the UK or an equivalent symbol for new drugs, new combinations of active substances, and new systems of delivery of existing drugs. The Food and Drug Administration should restrict direct-to-consumer advertising during the period of time the special symbol is in effect.
The symbol should remain on the drug label and related materials for 2 years unless FDA chooses to shorten or extend the period on a case-by-case basis.
5.4: The committee recommends that FDA evaluate all new data on new molecular entities no later than 5 years after approval. Sponsors will submit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer-reviewed journal, and will report on the status of any applicable conditions imposed on the distribution of the drug called for at or after the time of approval.
The public would benefit from more information about how drugs are studied before FDA approval, how drugs’ risks and benefits are assessed, and what FDA review entails. Patients also need timely information about emerging safety concerns and about a drug’s effectiveness. Such information would help patients make better decisions in collaboration with their health care providers. FDA does not have an adequate mechanism for seeking and receiving specific scientific and patient/consumer advice on communication matters.
6.1: The committee recommends that Congress enact legislation establishing a new FDA advisory committee on communication with patients and consumers. The committee would be composed of members who represent consumer and patient perspectives and organizations. The advisory committee would advise CDER and other centers on communication issues related to efficacy, safety, and use during the lifecycle of drugs and other medical products, and it would support the centers in their mission to “help the public get the accurate, science-based information they need to use medicines and foods to improve their health.”
6.2: The committee recommends that the new Office of Drug Safety Policy and Communication should develop a cohesive risk communication plan that includes, at a minimum, a review of all center risk communication activities, evaluation and revision of communication tools for clarity and consistency, and priority-setting to ensure efficient use of resources.
The suite of recommendations put forward in this report—to improve the culture in CDER, attract and retain highly qualified staff, improve technological capacity, obtain and benefit from access to data and innovative scientific partnerships, and so on—are all dependent on adequate resources. An agency whose crucial mission is to protect and advance the public’s health should not have to go begging for resources to do its job. Also, the effect on CDER’s work of CDER’s overdependence on PDUFA funding with the strings that are attached hurts FDA’s credibility and may affect the agency’s effectiveness.
7.1: To support improvements in drug safety and efficacy activities over a product’s lifecycle, the committee recommends that the Administration should request and Congress should approve substantially increased resources in both funds and personnel for the Food and Drug Administration.
The committee favors appropriations from general revenues, rather than user fees, to support the full spectrum of new drug safety responsibilities proposed in this report. This preference is based on the expectation that CDER will continue to review and approve drugs in a timely manner and that increasing attention to drug safety will not occur at the expense of efficacy reviews but rather it will complement efficacy review for a life-cycle approach to drugs. Congressional appropriations from general tax revenues are a mechanism by which the public can directly, fairly, and effectively invest in the FDA’s postmarket drug safety activities. However, if appropriations are not sufficient to fund these activities and user fees are required, Congress should greatly reduce current restrictions on how CDER uses PDUFA funds.
The year 2006 marks a major milestone in FDA’s history, public interest in drug safety matters has reached a high point, negotiations in advance of the September 2007 sunset of PDUFA have begun, Medicare part D has enrolled millions of senior citizens in a system that has the potential to yield useful data about experience with drugs, and congressional attention to drug safety issues has become intense. Now is the time to renew and transform
CDER’s culture, its authorities, its scientific capacity, and its ability to communicate with health care providers and the public. The committee believes that the recommendations contained in this report, implemented together and with adequate resources, will enable the center (and the agency) to function more effectively in the present and to position itself for an even more challenging future in advancing and protecting the health of patients and the public.
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