RARE Daily

Putting Scientific Standards Under the Microscope

January 24, 2020

On the eve of this year’s JPMorgan Healthcare Conference, The New York Times published an editorial that argued the U.S. Food and Drug Administration’s standards have been slipping and action was needed to ensure the agency carry its mission of protecting the public.

The newspaper noted the agency’s susceptibility to political interference and special interests, a lack of resources and power, and the frequent loss of staffers to companies it regulates as being  among the issues that impede the FDA from carrying out its mission and undermine its credibility.

Among the steps the editorial calls for is a fresh look at some of the “shifting standards” at the agency, such as the use of real-world evidence and surrogate endpoints. It calls on the agency to abandon ones that don’t work, even if it means slowing down the approval process, which they say would be okay. It also argues for the need for the agency to stand up for science.

“Scientific evidence (or the lack thereof) needs to be the deciding factor in any final regulations from the FDA. That means saying no to politicians and drug and device makers—as well as patients’ groups—when their demands are not supported by the agency’s own findings,” the editorial board wrote. “It also means holding companies to account when they fail to complete postmarket studies, or when their products prove faulty or dangerous.”

This week, the FDA seemed to breathe life into The New York Times argument with the release of a complete response letter it had issued to Sarepta Therapeutics in August when the agency declined to approve the company’s antisense oligonucleotide golodirsen for patients with the rare neuromuscular disease Duchenne muscular dystrophy who have a mutation amenable to exon 53 skipping. The agency later reversed itself in December and granted approval for the drug, a decision widely viewed as surprising at the time.

Though complete response letters are normally treated as confidential and not made public by the agency, the agency published the letter as part of the approval package for the drug. It not only provides insight into concerns within the agency about the safety and efficacy of Sarepta’s drug, but also sheds light on a dispute within the agency over the evidence presented by the Sarepta.

The letter, signed by Ellis Unger, director of the Office of Drug Evaluation-I in the FDA’s Center for Drug Evaluation and Research, expressed concern about serious infections related to the delivery of the drug from use of an implanted port and about the potential for the drug to cause kidney damage. Part of Unger’s concerns related to significant infections, bacteremia, sepsis, septic shock, and deaths reported to the FDA relating to the use of a central intravenous infusion port for delivering Sarepta’s exon-skipping drug eteplirsen, which won accelerated approval in 2016 despite an internal fight within the agency between staff and leadership over the decision. Some 11 cases of 469 exposed patients have been reported and Unger argued that even though no similar infections were reported in the approximately 30 patients treated with golodirsen, this points to a similar risk of serious infections with golodirsen.

He also noted that renal toxicity is a known risk of antisense oligonucleotides and nonclinical studies of golodirsen showed evidence of “significant renal toxicity.” This is complicated by the fact that serum creatinine can’t be used as a way to monitor renal function in DMD patients because they have reduced muscle mass with attenuated creatinine productions. Though other biomarkers have been suggested as an alternative, Unger said no practicable proposals was made for renal monitoring of these patients. While he acknowledges no renal toxicity was noted in the clinical data, the patient population was small and such a program would be unlikely to detect infrequent adverse events.

Unger argued that golodirsen was shown to result in only a modest increase in truncated dystrophin—the protein lacking in DMD patients—by a mean of 0.9 percent of normal. “If one accepts the premise that a small increase in truncated dystrophin, on the order of 9 parts per thousand, is reasonably likely to predict clinical benefit,” he wrote, “it seems reasonable to assume that the clinical benefit would be commensurately small.”

He concluded that the “small benefit” offered by the drug did not outweigh its risks.

In communications with the FDA seeking an appeal to the decision by the agency to issue the complete response letter, Sarepta disagreed with Unger’s assertion that a small increase in dystrophin would result in only a “commensurately small” clinical benefit. It argued the letter overstated the risks the drug posed to patients and failed to recognize that the patients who would use the drug are in dire need of treatment.

Sarepta said it has conducted a number of analyses of patients using eteplirsen and the data show it is delaying the time to loss of the ability to walk by 3.4 years and that patients using the drug also experience less deterioration or respiratory muscle function compared to patients in a natural history.

In a November letter to Sarepta, Peter Stein, director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research, granted the company an appeal to the complete response letter. He broke with Unger on key points. He said he disagreed with the assessment that the benefit from golodirsen would necessarily be very small. He also disagreed with Unger that DMD patients could not be monitored appropriately to detect injury to kidneys and noted that, to date, there was no observed signal for renal injury associated in the golodirsen studies. He said that a panel of standard, commercially available measures of renal function could be used.

Stein said Sarepta’s 4053-101 study “convincingly demonstrates” golodirsen increases dystrophin levels. “Patients with DMD are looking for improvement in muscle strength, even if only a modest increase in handgrip or arm strength, or respiratory muscle strength that might allow them some improvement in their ability to perform daily tasks, such as dressing or typing, or even reduce their time on mechanical ventilation,” he wrote. “As I discussed above, the extent of increase in dystrophin varied in Study 4053-101, which suggests that clinically meaningful benefits may not be obtained in all treated patients but may be seen in a subset of higher responders.”

“Boys with Duchenne usually lose the ability to walk during adolescence and most don’t live past their mid-to-late 20s. These kids are losing muscle function every day that they will never get back,” said Tracy Sorrentino, senior director at Sarepta. “They don’t have time to wait.”

She said the company is now focused on completing its confirmatory trials.

The rare disease community has been fighting to accelerate drug approvals, use surrogate endpoints, use real-world data, and get regulators to rebalance risk-benefit equations in the face of progressive and fatal conditions that move faster than the process of drug discovery, development, and approval.

But both The Times editorial and the differing viewpoints within FDA that have come to light through the Sarepta case should put the rare disease community on notice. Meeting standards of scientific proof should be in everyone’s interest, but what constitutes adequate proof will likely come under greater scrutiny.

Patients and their advocates are leading the way in devising and validating new clinical measures that can demonstrate what constitutes meaningful benefits to patients. But there will be increased pressure to produce more robust data to demonstrate the benefits outweigh the risks of experimental therapies.

The Times is right in saying scientific evidence needs to be the deciding factor. That can be a challenge in small clinical trials of heterogenous populations. But in a world of ever-expanding biomarkers and digital health devices, the opportunity to demonstrate whether new therapies provide meaningful benefits is expanding as well. It will be critical for drug developers and patient groups to address this at the earliest stages of drug development and ensure there are validated measures that demonstrate true benefits to patients.

This will not only be an issue of approval, but of access. Expensive therapies will be scrutinized not just by regulators, but payers as well, who will demand proof that the therapies they pay for work.

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