Experts react to FDA’s shift to single pivotal trials for most drugs

The US Food and Drug Administration (FDA) will, by default, require only one clinical trial to demonstrate that a product meets its regulatory requirements for safety and efficacy in most cases, according to two top officials. Former top FDA officials who spoke to Focus raised concerns about how the policy was developed and announced.

In an article published in the New England Journal of Medicine (NEJM) on Wednesday, FDA Commissioner Marty Makary and Vinay Prasad, director of the Center for Biologics Evaluation and Research (CBER) announced a major shift in the agency’s longstanding evidentiary standards for drugs.

“Going forward, the FDA’s default position is that one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorization of novel products,” Makary and Prasad wrote. “The FDA will carefully examine all aspects of study design with particular focus on controls, end points, effect size, and statistical protocols.

“Without examination of the quality of a study, two trials may even provide a false assurance,” they added. “The FDA expects a surge in drug development in response to our initiative.”

Last week, Richard Pazdur, the longtime director of FDA’s Oncology Center of Excellence who left the agency last year, shortly after being named director of the Center for Drug Evaluation and Research, told The Wall Street Journal that the shift to only requiring a single pivotal trial for drugs – and how the policy was made public – was one of the factors that led him to leave the agency.

In the article, the officials laid out their rationale for changing the decades-old standard requiring at least two confirmatory trials for drugs and biologics, arguing that the previous standard was based on the limited understanding of biology of the time and that there are alternative ways to ensure products meet safety and efficacy requirements.

Makary and Prasad said that the new standard will reduce the cost of drug development, noting that a single pivotal study can cost between $30-150 million, and suggested that lower development costs may lead to lower drug prices for consumers.

“Critics may argue that our initiative means that the FDA is relaxing its standards and will now permit ineffective or even harmful products on the U.S. market,” the authors said. “This is incorrect. First, the FDA has never been perfect, and even with a default requirement of two trials, the FDA has approved numerous products that were later found to have serious safety concerns or lack efficacy.

“Second, as we note, the number of clinical studies is no safeguard against valid inference if all other aspects of trial design are deficient,” they added. “If the control arm is substandard, the end points dubious, the statistical plan generated post hoc, the power inadequate, or all of the above, erroneous conclusions may be reached even with two, three, or four studies.”

They also stressed that the agency may require more than one study in some cases. “If an intervention has a nebulous, pluripotent, or nonspecific mechanism of action; if it affects a labile, short-term, or surrogate outcome; or if a trial has some underlying limitation or deficiency, additional adequate and well-controlled studies may be required,” they said. “The FDA will always reserve the right to demand the appropriate scientific study within the bounds of U.S. law.”

Peter Pitts, president of the Center for Medicine in the Public Interest (CMPI) and a former FDA associate commissioner, said the announcement raises many questions about how the policy was developed and how the agency intends to implement it. He told Focus that it is a brave but precipitous announcement that doesn't detail the science that went into the decision behind it.

"What drove the process to reach this decision, and equally important, who was part of that process?" asked Pitts. "A two-page opinion piece, even in the New England Journal of Medicine, isn't a replacement for a detailed explanation of this policy shift.

"Who was consulted? Was anyone consulted? What were the data that drove the decision? Who from CDER was part of the discussion?” he added. “Was there a discussion, or did Drs. Makary and Prasad dream it up all on their own based on their very limited FDA experience? Was there industry input? Was there patient input? Was there input of any kind from anybody other than Drs. Makary and Prasad?"

Pitts said FDA should have announced the policy through official channels, such as in a press release referencing a robust and detailed study conducted by the agency that included feedback from key stakeholders. He said if such a document exists, it should be made public so that everyone can evaluate the rationale behind the initiative.

"Usually, these announcements are matched with a release of a draft guidance explaining what they mean and I think this was a real missed opportunity to both launch an initiative and put a stake in the ground as to what the details are to drive it forward," said Pitts. "Right now, this could very easily be viewed as another nutty idea with no substance to it, and that's the last thing we need in this country."

"This proposition may have been put forward with the best intentions, but that ends up achieving the reverse, which is slowing down investment and excitement in pharmaceutical and medical technology innovation," he added.

Pitts said that FDA staff rely on high evidentiary standards grounded in solid scientific and policy research, which is lacking in the NEJM article. He also noted that the staff needs to understand how the new decision was reached if they’re going to effectively implement it.

“It concerns me that two guys wrote a two-page editorial and it's going to completely change the dynamic of the FDA review process,” said Pitts. “I think that's very dangerous.”

Pitts noted that conducting a single pivotal trial could also be a pathway to faster rejection and noted that the agency has other expedited development pathways. Pitts also questioned whether the default proposition should shift to requiring only a single pivotal study, without a transparent and in-depth conversation about what drove that decision, what evidence was considered, and who was consulted.

“I'm very concerned, especially in the midst of the [Prescription Drug User Fee Act (PDUFA)] negotiations, that the article made no mention of stakeholders of any kind being asked for their feedback, whether those are internal FDA stakeholders or pharmaceutical industry or patient groups or any group other than Drs. Prasad and Makary,” said Pitts.

Pitts questioned whether FDA considered the global impact of the new decision. He noted that FDA has generally been the global regulatory standard for the biopharmaceutical industry and questioned how that status will be affected by the change.

“The question now is, will all other countries in Europe, Australia, Japan, etc., choose to lower their standards or change their standards, or require less evidence based on this move by the FDA?” asked Pitts. “Did the FDA speak to its global regulatory partners to discuss where this might lead? ... Will this cause more chaos than it does excitement?”

Pitts also worried that the way the policy was developed and put forward might not instill confidence in investors, patients, or payors.

“A bold idea presented inappropriately, kills a bold idea, and my concern is that this announcement can very easily stifle what the FDA really requires, which is a new and dynamic view of reviewing drugs so that decisions can be reached more rapidly,” he added. “This seriously dilutes predictability, which is not what developers, patients, physicians, and payers need. We need the reverse of that.”

Former FDA Commissioner Robert Califf said that all the factors in addition to the single pivotal trial approach mentioned in the article are reasonable.

"Over half the approvals were already based on one trial plus supportive evidence (accelerated approvals)," Califf told Focus. "Many of the programs I worked on as an academic were large, pragmatic trials in heart attack, unstable angina and heart failure—essentially meeting the statistical criteria of the two-trial thinking.

"My major concern is that a NEJM perspective is not enough room to cover all the clarifications needed in a policy, so I hope something more is coming," he added. "The post-market surveillance pronouncement is interesting and will be important, but there are no details in the perspective."

A pharmaceutical industry expert who spoke to Focus on the condition of anonymity, as they were not authorized by their company to speak publicly about the policy, said that industry wants more clarity on when FDA exercises flexibility in determining whether a product requires two pivotal trials or one but noted that the announcement doesn't really provide such clarity. If the plan goes ahead, the expert said there will be more data to compare the two-trial model with the single-trial model.

"The argument being articulated is that we don't necessarily need a second trial to show reproducibility. We're using results from other sources such as real-world evidence, whatnot, to augment that […] to make a decision," they said. "There may be cases where it's very clear and they can make that decision with... [But] I don't know that that solves the problem of ambiguity, but we'll see with data over time, if the decisions they reach under this new model result in better outcomes for patients, while maintaining the same safety standard."

They also questioned whether the policy would reduce burdens for industry and lead to lower drug prices.

"If accelerated drug development also coincides with increased safety events, that's not a good policy," the source cautioned. "If that proves to be true over the next five years or so, of operating under this policy, I would hope that the administration would be willing to make a change back or put additional controls in place to prevent those safety events.

"I'm willing to be open-minded of new ways of doing things, but I also think with any system of flexibility, you're going to make choices that differ from what the policy says, and anytime that happens, people are going to question it, and there's going to be ambiguity," they added.

The source also questioned what the policy means for drug companies that market in other regulatory regimes that don't follow the single-trial model and whether that means the US becomes an experimental playground that takes on additional risks. The source also noted that there is reputational risk to FDA and industry if things don't go well, as well as financial risk to manufacturers if products end up going to market with safety concerns.

NEJM

Experts react to FDA’s shift to single pivotal trials for most drugs

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