Skip to content

New England Journal of Medicine – New FDA Breakthrough-Drug Category — Implications for Patients

New England Journal of Medicine – New FDA Breakthrough-Drug Category — Implications for Patients

To the Editor:

Darrow et al. (March 27 issue)1 present an incomplete and misleading review of the Food and Drug Administration (FDA) programs that are available to expedite drug development, review, and approval. As the authors note, drug regulation involves balancing the potential benefits of access to a therapy against the potential risks associated with the drugs and the prognoses of patients with the diseases that the therapies are intended to treat, on the basis of evidence of safety and effectiveness. Any evaluation of drug regulation should present a complete picture of the available evidence regarding the effect of reforms, including their impact on facilitating the generation and effective use of evidence.

The FDA has four distinct mechanisms to speed the development and availability of drugs for treating serious or life-threatening conditions: priority review, accelerated approval, fast-track review, and most recently, breakthrough therapy.2 Although these approaches all aim to advance the availability of safe and effective products, they use different selection criteria and target different parts of the drug-development process.

Darrow et al. claim that the FDA applies expedited-approval programs too liberally, noting that 56% of drugs approved in 2012 used expedited-approval pathways. However, the authors offer no analysis of these drugs and do not acknowledge that almost half the new drugs that were approved in 2012 were for orphan diseases or cancers, many of which had no effective treatment option.

Most drugs that have received accelerated approval have completed rigorous postmarketing studies, been converted to full approval, and often become standard of care. Furthermore, the FDA has taken notable steps, including its Sentinel Initiative, to enhance the availability of postmarketing safety evidence that is very difficult to obtain in the premarket setting.3

Nothing in law or FDA guidance indicates that the breakthrough-therapy designation lowers the standards for approval, nor do the authors provide evidence to support this claim. The breakthrough-therapy designation was created to facilitate a collaborative “all hands on deck” approach between the FDA and the drug sponsor on the basis of preliminary clinical evidence of substantial improvement over existing therapies for a serious or life-threatening disease.4 This approach does not confer a less rigorous path to approval. The majority of the drugs receiving the designation are still undergoing clinical trials, and only four have received FDA approval. All four are clear advances in the treatment of life-threatening diseases that previously lacked effective therapies. FDA programs have evolved over recent years to support the development and review of products that have had a lasting effect on disease treatment in the United States, positively affecting thousands of lives.

Mark McClellan, M.D., Ph.D.
Brookings Institution, Washington, DC

Ellen Sigal, Ph.D.
Friends of Cancer Research, Washington, DC 

Dr. McClellan reports receiving payment to serve on the board of directors of Johnson & Johnson. No other potential conflict of interest relevant to this letter was reported.


4 References

To the Editor:

The Infectious Diseases Society of America (IDSA) is concerned that the article by Darrow et al. misrepresents new legislation that would allow the FDA to approve antibiotic agents on the basis of small clinical trials in limited populations — specifically, in patients with serious or life-threatening infections and no other treatment options. New antibiotics that are approved through this pathway must be shown to be safe and effective and would carry a special label telling clinicians to use them with extreme care and only for patients with unmet needs. The bill also directs the FDA to review marketing materials in advance and directs the Centers for Disease Control and Prevention to monitor the use of these drugs.

As an infectious diseases physician, I share the authors’ concern about approving potentially risky drugs. But that concern must be balanced with the reality that patients are dying because we lack effective antibiotics to treat the infecting organisms. For years, the IDSA has been fearful of a return to a preantibiotic era. Sadly, for more and more patients, that fear is today’s reality because the antibiotic pipeline is nearly dry.

Barbara E. Murray, M.D.
University of Texas Medical School, Houston, TX 

Dr. Murray reports serving as the president of the Infectious Diseases Society of America; receiving consulting fees from Rib-X Pharmaceuticals, Durata Therapeutics, the Medicines Company, Achaogen, GlaxoSmithKline, Theravance, and the Innovative Medicines Initiative Joint Undertaking (European Union grants review); receiving lecture fees from Pfizer; and receiving research funding from Johnson & Johnson, Astellas Pharma, Cubist Pharmaceuticals, Forest Pharmaceuticals, and Theravance. No other potential conflict of interest relevant to this letter was reported.


To the Editor:

Darrow et al. imply that the ability of severely ill patients to make critical decisions about their therapy is impaired by their dire situations. The Leukemia and Lymphoma Society (LLS) believes that patients, in concert with their physicians, are in the best position to determine what is right for them and how much risk they are willing to take. Such treatment decisions are increasingly personalized, thus making it difficult for broad populations to be treated similarly. Therefore, the LLS is fully supportive of early-access programs, including compassionate-use programs, for patients who are out of other options. Moreover, our patients have benefited from expedited-approval pathways at the FDA, because such approaches accelerate access. We applaud the FDA for approving two breakthrough-therapy medications for hematologic cancers (ibrutinib [Imbruvica, Pharmacyclics and Janssen Biotech] and obinutuzumab [Gazyva, Genentech]) that are offering promise for patients with limited alternatives. We do agree that regulations requiring pharmaceutical and biotechnology companies to follow through on postmarketing studies to confirm data in a timely fashion should be strictly enforced and that the FDA should continue to ensure compliance with these regulations.

Mark Velleca, M.D., Ph.D.
Leukemia and Lymphoma Society, Washington, DC 

No potential conflict of interest relevant to this letter was reported.


To the Editor:

The article by Darrow et al. summarizes prior government efforts to expedite the availability of new therapeutics and discusses the implications of the breakthrough-therapy designation. It is worth clarifying that gemtuzumab ozogamicin was not approved for the treatment of pediatric leukemia.

Three trials evaluated the efficacy and safety of the single agent gemtuzumab ozogamicin. The population for the initial report included 142 patients with a median age of 61 years who had a first relapse of acute myeloid leukemia (AML).1 A total of 30% of the patients had remission. The FDA granted approval for gemtuzumab ozogamicin in the treatment of patients with a first relapse of CD33-positive AML who were 60 years of age or older and who were not considered candidates for cytotoxic chemotherapy.2,3

However, the required postapproval study, combining gemtuzumab ozogamicin with daunorubicin and cytarabine in adults under the age of 61 years with new-onset AML, did not confirm clinical benefit.4 This confirmatory study was performed in a clinical setting that differed from the setting of the original studies.2 The sponsor voluntarily withdrew the new drug application in 2010.

Alejandro D. Ricart, M.D.
Instituto Oncológico Henry Moore, Buenos Aires, Argentina 

Dr. Ricart reports owning stock in Pfizer. No other potential conflict of interest relevant to this letter was reported.


4 References

The authors reply: McClellan and Sigal overlook the fact that the FDA itself acknowledges that its innovations expediting drug approval lower the required evidentiary threshold. The agency describes the fast-track designation as a result of patients’ willingness to accept “greater risks” from products treating life-threatening illnesses1 and has noted that accelerated approval may expose patients to “drug[s] that will ultimately not be shown to provide an actual clinical benefit.”2

The new breakthrough-therapy designation may not lower evidentiary standards in the same manner as other expedited-approval programs, but it can do so indirectly by generating premature enthusiasm that increases pressure to approve and prescribe a drug. This approach can lead to uncontrolled or truncated trial designs that are less robust than standard trials, and it can normalize the regulatory use of biomarkers that are less likely to predict clinical outcome.2 These expedited-approval programs have indeed altered approval standards: although the legal standards of “safe” and “effective” remain, the evidentiary standards for meeting those criteria have been loosened. Although the FDA Sentinel Initiative can provide some postmarketing information, the agency is still learning how to use this tool,3and postmarketing surveillance should not replace adequate premarket assessment.

Although Murray’s warning of a return to a preantibiotic era is a call to action, so too is the possibility of regressing to the pre-1962 era during which ineffective drugs often received FDA approval. This concern is particularly salient for new antibiotics, which are usually approved on the basis of trials showing noninferiority (rather than superiority) to comparator agents. These agents are also withdrawn from the market more commonly than all other drug categories.4 Early access can benefit patients, as Velleca asserts, but only if the drug is in fact effective — the very question that only rigorous evidence development can answer. His contention that patients and physicians “are in the best position to determine . . . how much risk they are willing to take” may be true but minimizes the crucial role of governmental benefit–risk assessment of medications. Pressing treatment needs should be met with intensified development efforts, not new designations.

Ricart clarifies the original indication of gemtuzumab ozogamicin, which is now reflected in the online version of our article.

Jonathan J. Darrow, S.J.D., J.D.
Jerry Avorn, M.D.
Aaron S. Kesselheim, M.D., J.D.
Brigham and Women’s Hospital, Boston, MA 

Since publication of their article, the authors report no further potential conflict of interest.