Studies Raise New Concerns Over FDA's Expedited Approval Designations, Supplemental Indications

Regulatory NewsRegulatory News | 24 September 2015 |  By 

An increasing number of newly-approved drugs by the US Food and Drug Administration (FDA) have been associated with expedited development or review programs, though many of these approved drugs are not first in class and potentially less innovative, according to two new studies published in the British Medical Journal (BMJ).


Under the standard regulatory review process, FDA has 10 months to review a potential new drug's safety and efficacy based on a company's randomized controlled trials assessing validated clinical outcomes.

But over the past few decades, FDA and Congress realized that the 10-month approval window can delay access to important drugs, which can be problematic for those with serious or life threatening conditions with no other treatment options.

In response to the concerns, regulators and legislators created four programs—one pathway and three designations—to expedite approval of some promising new drugs intended for unmet medical needs.

In 1983, Congress passed the Orphan Drug Act, which created special tax breaks and market exclusivity periods for products intended to treat patients with diseases potentially too rare for large randomized trials and for which the market may not provide adequate incentives for investment. Then, in 1988, FDA formalized what is known as the “fast track” designation, which permitted approval of drugs treating life-threatening or severely debilitating diseases after a single Phase II study.

Four years later, Congress authorized an “accelerated approval” pathway, allowing drugs treating serious or life-threatening illnesses to be approved on the basis of surrogate endpoints reasonably likely to predict patient benefit. That same year, FDA launched its priority review designation, which guaranteed review of new drug applications (NDAs) within six months of submission for drugs offering a therapeutic advance over available therapies.

Key Issues

One of the BMJ studies, released Wednesday, shows that a review of the expedited approval designations and pathway from 1987 to 2014 found that they do reduce development and review timelines, and in some cases offer great advances for patients, such as with Novartis' leukemia drug Gleevec, which was approved after only 2.5 months of FDA review.

However, the study also finds that these programs have been a source of controversy, particularly as drugs have been approved on the basis of surrogate endpoints  and were later found not to accurately predict actual changes in patient health outcomes.

The study offers the example of Pfizer's Mylotarg (gemtuzumab), which benefited from all four expedited review programs and led to an approval to treat acute myeloid leukemia based on surrogate endpoints. In 2010, however, the drug was pulled from the market after studies showed the drug was not efficacious and actually increased mortality.

As far as the breakthrough therapy status -- which legislators intended to apply to only a handful of drugs each year and FDA predicted would be for about two to four drug candidates each year --  FDA received nearly 250 applications for breakthrough status in the first two years of the program, of which it granted 68. Twelve of those 68 have been approved, including four treatments for chronic lymphocytic leukemia.

"It is doubtful that a single disease condition can be the subject of four true 'breakthroughs' in such a short time frame," researchers said.

The increase in safety issues also links with an increased likelihood of post-approval changes in the prescribing information for some of the therapeutics. The researchers say that regulators "may want to ensure that the provisional nature of these drugs is well communicated to patients and physicians" as currently, the "only drugs approved through accelerated approval have this information integrated into their official labels.

"Studies have also found increased safety issues in the post-marketing phase for drugs benefiting from expedited approval, including adverse events and boxed warnings for agents receiving shorter review time," the study says.

The researchers also raise questions about the House-approved 21st Century Cures Act, which would create an even further expedited pathway for new antibiotics and antifungals.

Second Study

The other study investigated the efficacy evidence supporting the approvals of supplemental indications. The researchers found "wide variations" in such evidence, noting that additional indications expanding a drug's approved patient population were supported by the fewest active comparator trials and clinical outcome endpoints.

FDA approved 295 supplemental indications between 2005 and 2014, representing 164 unique drugs and ranging from 20 approvals in 2012 to 48 in 2006.

But almost all of the supplements expanding a drug’s patient population were for pediatric patients, and nearly half of these supplemental approvals were supported by uncontrolled studies or no additional clinical studies, with approval based on extrapolation from adult studies alone.


In an accompanying editorial, two experts from the US and Canada say these two studies "give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed."

Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study

Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review


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