Healthy Skepticism Library item: 6337

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Publication type: news

Psaty B, Burke S.
Protecting the Health of the Public — Institute of Medicine Recommendations on Drug Safety
New England Journal of Medicine ( NEJM ) 2006 Oct 26
http://content.nejm.org/cgi/content/full/355/17/1753?query=TOC

Full text:

Protecting the Health of the Public – Institute of Medicine Recommendations on Drug Safety

PERSPECTIVE

Volume 355:1753-1755 October 26, 2006 Number 17

Bruce M. Psaty, M.D., Ph.D., and Sheila P. Burke, M.P.A., R.N.

Soon after rofecoxib had been withdrawn from the market in September
2004, hearings of the Senate Finance Committee and editorials in the lay
and medical press raised serious questions about drug safety in the
United States. In response, the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA) asked the Institute of
Medicine (IOM) to assess the U.S. drug-safety system. The IOM assembled
a diverse panel of experts without ostensible bias or conflict of
interest, none of whom were pharmaceutical industry employees. The
committee, on which we served, reviewed published literature, held open
meetings, and received comments from the pharmaceutical industry, the
FDA, and nonprofit groups. In September 2006, the IOM released the
committee’s findings and recommendations.1

The drug-approval system evolved over the past century in response to
earlier drug disasters and advocacy by interest groups, including
patients and industry. Currently, new drugs undergo serious evaluations
of efficacy and safety before approval. The pre-marketing randomized
clinical trials are generally small, short-term studies. CDER uses the
information from these trials to make eventually a binary decision – to
approve or not to approve.

The Prescription Drug User Fee Act of 1992 and its 1997 renewal helped
to accelerate drug approval, but these acts also prohibited the FDA from
applying user fees to improve post-marketing drug surveillance. In the
absence of efforts to enhance drug safety, the United States became
increasingly the country of first launch, the public testing ground, for
many new drugs. Although the 2002 reauthorization of user fees permitted
their use for selected drug-safety activities, the negotiations between
industry and the FDA about performance goals have contributed to the
perception that the FDA’s client is industry rather than the public.

Under the current model, drugs are rapidly evaluated before approval and
are often aggressively marketed afterward. Direct-to-consumer
advertising can rapidly expand the use of new drugs to include patient
groups that were sparsely represented in pre-marketing evaluations. The
centerpiece of the CDER post-approval safety system is the Adverse Event
Reporting System (AERS); in this system, patients or health care
professionals submit reports of adverse events thought to be related to
drug administration. Although this collection of voluntarily submitted
case reports represents the weakest form of epidemiologic evidence, many
drugs have been appropriately relabeled, sometimes with black-box
warnings, or withdrawn from the market on the basis of AERS evidence.

CDER lacks a systematic approach to identifying possible pre-marketing
drug-safety problems and translating them into high-quality
post-marketing studies. Without an organized system to identify
potential safety signals, the studies needed to resolve them may not be
performed. The post-marketing commitments that are requested by the FDA
are often hastily assembled by sponsors, who may not have a symmetric
interest in safety and efficacy. Even so, once a drug is approved, CDER
lacks the authority to force sponsors to complete agreed-upon
post-marketing commitments or to require sponsors to initiate new
studies. As a result, hundreds of agreed-upon studies remain “pending”
in perpetuity. Since CDER lacks the resources to conduct its own
studies, when a new drug is launched, the current regulatory system
creates “an evidence-free zone.“2

According to the 2003 report of the Office of Inspector General of the
Department of Health and Human Services,3 a survey of CDER reviewers
revealed that 66% lacked confidence in the FDA’s safety monitoring of
marketed prescription drugs, and 18% had felt pressure to approve a drug
despite reservations about its quality, efficacy, or safety. In 2006,
the Government Accountability Office found that the “FDA lacks clear and
effective processes for making decisions about, and providing management
oversight of, postmarket safety issues.“4

On the basis of these reports and other evidence, the IOM committee
identified a number of serious problems, including a lack of clear
regulatory authority, chronic underfunding, organizational difficulties,
and a scarcity of post-approval data. Contributing to an urgent need for
cultural change in the FDA are a suboptimal work environment, a lack of
consistency among CDER review divisions, polarization between the
offices responsible for the pre-marketing review and post-marketing
surveillance, CDER management’s disregard and disrespect for scientific
disagreement, and politicization and a lack of stability in the office
of the FDA commissioner.

According to the committee’s vision, the FDA must embrace a culture of
safety in which the risks and benefits of medications are examined
during their entire market life. This so-called life-cycle approach
would entail evaluating risks in the context of benefits, sustaining
attention to both efficacy and safety after approval, and advancing and
protecting the health of the public. Risk–benefit analyses would
highlight key areas of uncertainty. The careful design and conduct of
post-marketing studies would help to resolve uncertainties as drug use
expanded. The committee’s recommendations focus on the central theme of
an ongoing effort to acquire, integrate, and communicate information
that will allow physicians and patients to use drugs wisely and well.

The committee sees its recommendations as an integrated package – not a
menu of options. The recommendations that focus on science include, for
instance, a thorough scientific review of the AERS system, an increase
in FDA access to large administrative databases, a systematic approach
to risk–benefit assessments, the development of an intramural research
capacity, an advisory committee review of all new molecular entities,
limitations on the proportion of advisory committee members who are
given waivers of conflicts of interest, clinical trial registration, the
reporting of summary results from all trials, and the development of a
public–private partnership for prioritizing, designing, and funding
confirmatory studies of public health importance.

The committee also recommended new attention to communication with
patients; new authorities and enforcement tools that enable the FDA to
require various post-marketing actions from drug companies in a timely
fashion; the use of a new symbol, such as a black triangle, on product
labels for up to 2 years after approval to signify the uncertainty
associated with new drugs; a moratorium on direct-to-consumer
advertising during that period; and a re-review of the risk–benefit
status of new drugs 5 years after approval.

According to the committee, the FDA commissioner should be appointed for
a fixed term of 6 years, and the appointee should have “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.” An external management
advisory board, noted the committee, could help to transform the
agency’s culture and develop a comprehensive strategy for sustained
cultural change. The committee recommended an interdisciplinary-team
approach to the ongoing evaluation of drugs and joint authority on the
part of the Office of New Drugs and the Office of Surveillance and
Epidemiology for postapproval regulatory actions related to safety.

To accomplish these changes, the FDA needs a substantial increase in
resources. The committee expressed a preference for these resources to
come from general appropriations, because the understanding of a drug’s
risks and benefits is a public good. If this approach is not
practicable, then the current restrictions on the use of users’ fees
should be greatly reduced. New safety-related performance goals, in
addition to rapid-approval goals, should be developed.

The current system, in which the binary decision regarding approval
essentially signals the end of information gathering, imposes a huge
responsibility on CDER to make the right decision about new drugs. New
post-marketing regulatory powers would provide the FDA with additional
opportunities to act in a timely fashion. Scientific disagreements also
tend to occur in the face of uncertainty. An ongoing systematic effort
to identify safety signals, translate them into high-quality studies,
and communicate the findings to patients and physicians can facilitate
cultural change and foster productive scientific debate.

Post-marketing evaluations of drugs can benefit all parties, including
industry. For statin drugs, for instance, large, long-term trials have
provided high-quality evidence about health benefits, extended the
indications for use, and increased market share. For some drugs, new
black-box warnings and occasional drug withdrawals are unavoidable. The
timely identification, confirmation, and communication of risks and
benefits are the best measure of regulatory success. With additional
resources, new regulatory powers, and cultural changes, the FDA can link
regulatory actions to new data in imaginative ways in an effort to
improve the health of the public as well as industry.

Toward a New Vision of Drug Safety

The increasingly complex interface between innovation and regulation has been characterized by binary opposites: speed versus safety, tight preapproval regulation versus loose postapproval regulation, active collection of data before approval versus passive surveillance after approval, and an abundance of clinical efficacy data before approval compared with much less safety data after approval. The polarity of approach and emphasis is inconsistent with the widely accepted notions that risk must be considered in the context of benefits, that understanding of the risks and benefits associated with a drug changes over a drug’s lifecycle, and that the attention paid to safety and efficacy before approval must therefore be sustained as a drug enters and diffuses through the market and is used by a growing number and diversity of patients. Timely approval and attention to safety can become complementary rather than antithetical goals as postapproval surveillance becomes more effective, and regulatory authority and its exercise are commensurate with how a drug performs in real-life conditions over its lifecycle. The approval decision does not represent a singular moment of clarity about the risks and benefits associated with a drug – preapproval clinical trials do not obviate continuing formal evaluations after approval. However, the approval decision is a critical juncture in a product’s lifecycle because it releases a drug to the market, where the public will gain broad exposure to it. In a strengthened drug safety system, that juncture should mark the beginning of another important stage in the lifecycle, when regulators, sponsors, health insurers, health care providers, and independent researchers actively pursue and manage emerging knowledge about risk–benefit relationships and uncertainty and they communicate that knowledge to patients, health care providers, and health care organizations in a timely manner. – Excerpt from “The Future of Drug Safety: Promoting and Protecting the Health of the Public.“1

Source Information

Dr. Psaty is a professor and codirector of the Cardiovascular Health
Research Unit, Departments of Medicine, Epidemiology, and Health
Services, University of Washington, Seattle. Ms. Burke is an adjunct
lecturer at the Kennedy School of Government, Harvard University,
Cambridge, MA, and deputy secretary and chief operating officer of the
Smithsonian Institution, Washington, DC. Ms. Burke was the chair of, and
Dr. Psaty a member of, the Institute of Medicine Committee on the
Assessment of the U.S. Drug Safety System.

A list of IOM committee members and staff is included in the report
brief, “The Future of Drug Safety: Action Steps for Congress” at
www.iom.edu/CMS/3793/26341/37329/37331.aspx.

An interview with Dr. Psaty can be heard at www.nejm.org.

This article was published at www.nejm.org on October 9, 2006.

References

1. Committee on the Assessment of the US Drug Safety System, Baciu A, Stratton K, Burke SP, eds. The future of drug safety: promoting and protecting the health of the public. Washington, DC: National Academies Press, 2006. (Accessed October 5, 2006, at http://www.iom.edu/CMS/3793/26341/37329.aspx.) 2. Gale EA. Lessons from the glitazones: a story of drug development. Lancet 2001;357:1870-1875. [CrossRef][ISI][Medline] 3. FDA’s review process for new drug applications: a management review. Washington, DC: Department of Health and Human Services, 2003. (Publication no. OEI-01-01-00590.) 4. Drug safety: improvement needed in FDA’s postmarket decision-making and oversight process. Washington, DC: Government Accountability Office, March 2006. (Report no. GAO-06-402.)