May 3, 2012 — A report by the Institute of Medicine (IOM) instructs the US Food and Drug Administration (FDA) to make postmarketing research of drugs' risks and benefits a priority and to develop a centralized system for managing all information about drugs throughout their life cycles.

This report was prompted by several high-profile drugs found to be harmful once they were in widespread use, including Vioxx (rofecoxib, Merck), Avandia (rosiglitazone, GlaxoSmithKline), and selective serotonin reuptake inhibitors (in children). Initially undertaken as a response to these incidents, which occurred after the drugs had been approved, the IOM determined that simply looking at the issue from a postmarketing perspective was not enough and that the FDA needed to develop a way to prevent these problems in the future.

"It is no secret that the present report was born amid the challenges that FDA was facing in its consideration of the cardiovascular risks associated with the antidiabetic drug Avandia," write the authors.

The FDA Amendments Act (FDAAA) of 2007 increased the FDA's capacity to monitor drugs postapproval and to act on evidence of safety problems. Before that the act, the FDA had only 2 choices when it came to drugs it was concerned about: it could either withdraw the drug from the market or attempt to convince the manufacturer to change its label or add warnings to it.

With this increase in authority, the FDA has faced new challenges, including developing a system for identifying which drugs need postmarket studies, deciding which type of study design is most appropriate, and ensuring that studies are conducted in an ethically and scientifically sound manner.

"The committee's most important recommendation is that FDA, in its role as a public health agency, be active in shaping its postmarketing drug safety monitoring role, taking it as seriously as it does its responsibility to approve safe and efficacious drugs. The committee calls this, as did an [IOM] committee that preceded it, 'the lifecycle approach,' " write the authors in the report.

Evaluate Drug's Risks and Benefits Throughout Its Life Cycle

"To implement this life cycle approach, the committee recommends that the FDA require and maintain a comprehensive benefit and risk assessment and management plan (BRAMP) to track the medicine's benefits and harms during its entire life cycle," the authors write in a report brief.

Much of the needed information is being collected, but it is now in many different locations. This living document "would serve as a guide that supports organizational adherence to the lifecycle approach, increases the transparency of FDA's decisions, and fosters collaboration between FDA and drug sponsors," write the authors in the report.

The BRAMP would provide an ongoing record of questions and concerns about the drug as well as collect data about the drug while it is in use. Regulatory actions, if any, would also be recorded in this document.

Identify Need for Postmarket Research

Deciding when to conduct postmarketing research requires a difficult balancing act: The FDA must weigh the need for public safety against its responsibility to protect research participants.

There are too many different types of drugs and sets of circumstances to have 1 algorithm for determining when to conduct postmarketing research and what kind of research to do.

"[T]he FDA should prospectively determine and publicly identify the risk factors associated with greater uncertainty about a drug’s benefit-risk profile in the postmarketing setting," the authors write in the brief. "Where the FDA finds higher risk, the agency should seriously consider requiring timely postmarketing research and should make public the rationale either for requiring research or for not requiring research, if there is a compelling argument against it," they conclude.

These risk factors can include:

• drugs that have been approved using several surrogate endpoints, where there is conflicting evidence about probable health outcomes;
  
  
• a first-in-class drug approval that used surrogate endpoints intended for medicines belonging to a different drug class; and
  
  
• a drug associated with a troubling safety profile that could affect many people, that has to potential for severe adverse effects, or that has a strong biological rationale for a certain adverse effect.
  
  

"To aid in this effort, the FDA should maintain and update annually a list of surrogate endpoints allowed for use in drug approval, as well as maintain information on their correlation with actual health outcomes. Postmarketing research also may be required when a drug is anticipated to have a different benefit-risk profile in a subgroup of the population or in the general public, outside of clinical trials," write the authors in the report brief.

Selection of Study Design

The authors acknowledge that randomized clinical trials are the gold standard when it comes to determining a drug's efficacy before approval, but after approval, they can be difficult to conduct, in part because patients may no longer be willing to participate in research once a drug is widely available.

"By law, the FDA may require a postmarketing clinical trial only under certain conditions, such as when observational studies cannot provide sufficient information to guide agency actions," the authors write in the brief.

"Depending on the frequency, magnitude, seriousness, and timing of a suspected adverse event, in many situations observational studies may be preferred for postmarketing research to assess a drug's risks," they write.

Conduct Studies Ethically

The report also states that research should be conducted in an ethically and scientifically sound manner. "The committee concludes that the FDA may be justified in requiring studies that could expose patients to heightened risk — but only if a public health question of pressing importance is at stake, if no other study design could supply the needed evidence, and if the FDA relies on the research findings in a timely fashion in formulating its regulatory response," write the authors in the brief.

"The FDA's current approach to drug oversight in the postmarketing setting is not sufficiently systematic and does not ensure that it assesses the benefits and risks of drugs consistently over a drug's life cycle. Adopting a regulatory framework that is standardized across all drugs, yet flexible enough to adapt to regulatory decisions of differing complexity, could help make the agency's decision-making process more predictable, transparent, and proactive, allowing the FDA to better anticipate post-approval research needs and improving drug safety for all Americans," the report concludes.

Ethical and Scientific Issues in Studying the Safety of Approved Drugs . Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs, Institute of Medicine.

By Troy Brown