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Are 'breakthrough' drugs as safe as other FDA-approved medicines?

New research questions the quality of drugs given the "breakthrough therapy" designation by the US Food and Drug Administration. In late 2012, the FDA created this designation to speed the process for reviewing not-yet-approved experimental medicines intended to treat serious or life-threatening conditions.

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Susan Scutti (CNN)
(CNN) — New research questions the quality of drugs given the "breakthrough therapy" designation by the US Food and Drug Administration. In late 2012, the FDA created this designation to speed the process for reviewing not-yet-approved experimental medicines intended to treat serious or life-threatening conditions.

Commonly, the clinical trials supporting breakthrough drugs lack some of the scientifically rigorous features found in the research backing drugs that have not been granted that designation, a new study published in Tuesday in JAMA found.

"I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions," said Dr. Joseph S. Ross, a co-author of the study and associate professor at the Yale University School of Medicine.

"Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs."

'Greater uncertainty'

Ross and his co-authors began their study by identifying all new drugs and biologics approved by the FDA from January 2012 through December 2017. During that time period, 46 "breakthrough" drugs were approved. Examples of breakthrough drugs approved during that time are Bristol-Myers Squibb's Opdivo (nivolumab) for Hodgkin lymphoma and Pfizer's Ibrance (palbociclib) for certain types of breast cancer.

Next, the researchers examined the scientific features of the pivotal clinical experiments that led to each approval of these 46 drugs: namely, randomization (when study participants are randomly assigned to receive either the experimental drug or placebo), blinding (when both participants and the people conducting the study don't know who is assigned the placebo), comparator group (where a control group of participants receiving a placebo is used for comparison purposes), primary end point (the main result measured by a clinical trial) and number of patients.

What did the study authors find? The clinical trials supporting breakthrough approvals commonly lacked randomization, double-blinding, and control groups and enrolled small numbers of patients. The also used surrogate markers -- a substitute result, such as a lab test, for actual medical benefit -- as primary end points.

Meanwhile, prior research suggests that use of randomization, double-blinding, control groups and actual medical outcomes are more common among pivotal trials supporting FDA approval of non-breakthrough drugs -- even those undergoing accelerated approval, another form of FDA expedited approval, according to the study. (The FDA-approved breakthrough drugs examined in the study are different from right-to-try drugs, which are unapproved drugs that have not completed their clinical trials, though they have passed Phase 1 of the FDA's approval process.)

Add to that, more than half of the breakthrough drug approvals were based on a single pivotal trial. Plus, premarket development times were approximately five years on average, compared with seven to 12 years for non-breakthrough drugs. FDA regulatory review and approval required less than seven months on average, compared with 2½ years for non-breakthrough drugs.

"When approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval," Ross wrote in an email. "Uncertainty over whether the effect observed in the single small trial will be observed in a larger population or replicated in another trial; uncertainty over whether the effect observed over the short-term will persist over the longer-term, or whether new risks (or even benefits) might be observed over the long-term."

And uncertainty whether the effect on a surrogate marker of disease "will be confirmed by eventual demonstration of benefit and safety based on clinical outcomes like improved mortality or improved symptoms," Ross said.

Ross and his co-authors concluded that both patients and physicians might have misconceptions about the strength of evidence supporting breakthrough approvals.

"We must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarket trials are conducted within a reasonable period of time, resolving some of this uncertainty and making sure that the drugs are associated with the benefit/safety profile that we expect," Ross said.

How much evidence

Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said the study findings are "not surprising."

Given that "breakthrough" is a designation for drugs treating life-threatening diseases that affect few people, the clinical trials would naturally have fewer participants compared with clinical trials for drugs treating conditions that affect many people, such as hypertension.

Also, when you're testing a drug and patients have, for example, a fatal cancer that has spread throughout their body, "generally speaking, you wouldn't put those people on a placebo," Woodcock said, as it is considered inhumane to deprive them of the experimental drug's potential benefits. "So you don't have, sometimes, randomized trials," she said.

Since it is known that these seriously ill cancer patients will die, if they are given an experimental drug and then have a "durable response" -- their tumors shrink; they live longer than expected -- researchers know that "this wouldn't happen by chance," Woodcock said. "So we do have a control group; it's just called external control -- what would have happened. ... So we're able to judge that these treatments are making a big difference."

Accelerated approvals, which came into effect with the AIDS epidemic in the late '80s, are for drugs treating serious or life-threatening illness and are decided based on surrogate endpoints, Woodcock explained.

"Breakthrough designation is just that: It's a designation. And what it confers is more attention paid to a very promising therapy in early development," she said. "It doesn't change the standards."

"When people are dying, they don't want to wait till every 'I' is dotted and every 'T' is crossed, because they don't have that much time," she said. Yet, once a few effective drugs are approved, then "the bar slowly raises."

"It's a natural evolution over time. But for those untreatable diseases, patients do not want us to wait until they're dead, and we have a giant package of evidence; they are willing to accept more uncertainty."

Whether the clinical trials contain a large number of people or are randomized or not are "very important trial design issues," Woodcock said.

Today, scientists have more knowledge about drugs and disease. "We're doing these targeted therapies a lot where we understand exactly what the drug is supposed to do right and we can measure whether it's doing it or not," she said.

"We always have to walk that line between getting enough evidence -- appropriate amount of evidence -- and then not having a drug be available to people who have very serious illnesses who it could help, right?" Woodcock said. "We listen to the patients, and we listen to their treating physicians, and we listen to the medical community, but we also listen to those who urge caution."

Alex Ebied, a clinical assistant professor at the University of Florida College of Pharmacy, said it is "important" to know that the FDA reviews breakthrough drugs "faster than the standard process" with two main questions asked: "Does this drug benefit the public? Is it safe?"

Ebied, who was not involved in the new study but has also published on the topic of FDA regulation, said that "Each drug must prove that it works safely for a specific medical condition.

"The science is the same between fast-tracked and non-fast-tracked drugs. Each drug must demonstrate efficacy and safety in clinical trials. These trials are not skipped but reviewed faster with the same threshold of grading criteria," Ebied said. "That being said, many of the conditions that are treated with these fast-tracked/orphan drugs are rare and represent a small portion of the population. Thus making it difficult, or in most cases not feasible, to expect the same type of robust data and information as we would like to see."

To ensure that "the reward outweighs the risks," Ebied said, "It is important that the FDA is selective with the medications that they allow to be approved via this expedited pathway."

Ultimately, Ross believes the FDA is doing what the public wants: "More novel therapies coming to market as quickly as is reasonably possible, while the FDA is doing its best to assure drug safety and efficacy."

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