FDA's "Breakthrough Therapies" Designation Often Misleading

In 2012, Congress passed legislation creating a new "breakthrough therapy" designation to expedite the testing and Food and Drug Administration (FDA) approval of new drugs intended to treat serious or life-threatening diseases. The designation — which can be requested by companies developing new drugs — is supposed to be reserved for new drugs that preliminary evidence indicates "may demonstrate substantial improvement over existing therapies."[1]

However, researchers at Harvard Medical School, who recently analyzed drugs that were approved under the breakthrough designation, have concluded that patients and doctors are being misled about the benefits of these drugs.[2]

When the 2012 law was passed, the FDA expected that about two drugs per year would receive the breakthrough designation.

But unsurprisingly, because the breakthrough designation affords manufacturers many advantages — including intensive guidance from FDA staff during a drug’s development; faster review times; and approval based on smaller, less rigorous clinical trials — the FDA has been inundated with hundreds of requests for this designation. Since 2013, the agency has approved 29 drugs that were designated as breakthrough therapies.

The Harvard researchers emphasized that unlike other congressionally mandated FDA expedited-review programs for drugs — like "fast track," "priority review" and "accelerated approval" — the "breakthrough" label "appears to signify an exceptional magnitude of therapeutic benefit."

They noted that when drugs are designated as "breakthroughs" by the FDA, they often are described by the popular press as "game-changers," "miracles" and "cures," and that the public in turn may reasonably expect the drugs to offer cures or dramatic improvements.

But these perceptions are, in many cases, wrong. The Harvard researchers found that the evidence of benefit for breakthrough drugs compared with existing treatments often was at best very modest or limited. For example, of 16 cancer drugs approved under the breakthrough designation, seven resulted in a complete remission of the targeted cancer in no more than 3 percent of subjects during clinical testing.

Likewise, for one drug approved for treatment of a serious lung disease called idiopathic pulmonary fibrosis, one key clinical trial showed no evidence of benefit; two other trials showed slightly slower rates of decline in lung function when compared with a placebo, but these differences were not considered by the FDA to be clinically important.

The Harvard researchers proposed that Congress should revise the law by eliminating the term "breakthrough." This simple step would go a long way toward preventing patients and doctors from being misled about the actual benefits of such drugs. But Congress should go further by tightening the standards for approving drugs reviewed under the FDA’s other expedited-review programs.

References

[1] Pub. L. No. 112-144, 126 Stat. 993 (2012). https://www.congress.gov/112/plaws/publ144/PLAW-112publ144.pdf. Accessed April 13, 2018.

[2] Darrow JJ, Jerry Avorn J, Kesselheim AS. The FDA breakthrough-drug designation — Four years of experience. N Engl J Med. 2018;378(15):1444-1453.