Looser Efficacy Standards Could Waste Taxpayer Dollars On Useless Drugs, NEJM Says
Executive Summary
Editorial cites Lilly's failed Alzheimer's candidate solanezumab to argue that looser efficacy standards could result in Medicare paying for ineffective drugs, but it's unlikely that a Scott Gottlieb-led FDA would have approved the drug.
The imposition of less-demanding efficacy requirements associated with the likely incoming US FDA commissioner Scott Gottlieb could have the consequence of costing taxpayers billions on useless drugs, three Harvard Medical School professors argue.
In a May 4 New England Journal of Medicine (NEJM) article, Chana A. Sacks, Jerry Avorn and Aaron S. Kesselheim write that current regulatory standards have in certain instances "prevented ineffective medications from reaching patients and averted unnecessary spending."
The authors in particular detail the case of Eli Lilly & Co.'s failed Alzheimer's disease candidate solanezumab, which failed meet the primary endpoint of demonstrating a statistically significant slowing in cognitive decline in patients with mild dementia due to Alzheimer's disease compared with placebo. (Also see "Lilly’s Solanezumab Fails, But The Surprise Would Have Been Success" - Scrip, 23 Nov, 2016.) Cognitive decline was measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), which is regarded as the gold standard outcome measure in most Alzheimer's trials. (Also see "Alzheimer's Endpoint ADAS-Cog Likely Here To Stay Despite Clinical Failures" - Pink Sheet, 31 Oct, 2016.)
Lilly opted to forgo pursuing a regulatory submission as a result of the failure to demonstrate efficacy.
"As the FDA’s role and drug-approval standards undergo new scrutiny, it’s instructive to assess instances in which current regulatory standards prevented ineffective medications from reaching patients and averted unnecessary spending (as well as unanticipated side effects)," the authors write. "The public and private funds not spent on a useless drug remained available for other interventions that have been proven to work."
The authors note that Lilly never determined what the list price for solanezumab would have been if it was approved, but they speculated it would have been high, pointing to the costs of other monoclonal antibodies like AbbVie Inc.'s Humira (adalimumab), which cost Medicare $1.7 billion in 2015.
Most of the solanezumab costs would have fallen on Medicare, as 96% of people with Alzheimer’s dementia are 65 years or older, they write.
Concerns About Surrogates, Gottlieb
The authors expressed concerns about provisions of the 21st Century Cures Act that embrace the use of surrogate endpoints, as well as an apparent willingness to embrace uncertainty by Gottlieb.
The Cures legislation allows FDA to grant accelerated approval for regenerative therapies, and also establishes a review pathway at the agency for biomarkers and other drug development tools that can be used to help shorten drug development. (Also see "The Evolution Of 21st Century Cures Legislation" - Pink Sheet, 29 Nov, 2016.)
Gottlieb has touted the 21st Century Cures Act for expanding the use of surrogate endpoints to help more quickly provide an indication of a drug's efficacy. The nominee has also spoken in favor of embracing uncertainty more broadly. He previously suggested placing approval decisions into the hands of more senior scientists rather than the junior staff, since the more experienced members are more willing to embrace uncertainty. (Also see "Gottlieb Nomination As US FDA Chief Could Signal Changes To Generic Approval Process" - Pink Sheet, 13 Mar, 2017.)
"According to the bill, decisions to allow the use of these tools should be based on factors that 'may include' scientific merit — phrasing that opens the door to future fundamental changes to the type of evidence that could be considered to meet the basic efficacy requirement," the authors write. "Future FDA leadership could push for wider latitude to accept less-demanding criteria as the basis for approval rather than requiring achievement of clinical primary end points in rigorous prospective trials."
Gottlieb, however, contended at his confirmation hearing that he would uphold FDA's gold standard for approvals of safety and efficacy. (Also see "Gottlieb's Confirmation: He's Willing To Disagree With Trump, Sec. Price" - Pink Sheet, 5 Apr, 2017.)
Accelerated approval is also only a tentative approval, and requires that sponsors conduct further clinical trials to confirm the anticipated clinical benefit of a product. Failure to show a clinical benefit could result in the removal of a drug from the market.
An Apples And Oranges Comparison?
In spite of the author's criticism of surrogate endpoints, their main argument against embracing uncertainty involved a drug, solanezumab, that did not involve the use of surrogate endpoints as a primary measure of efficacy. Its primary endpoint was a slowing in cognitive decline as measured by the ADAS-cog, a meaningful endpoint.
It is difficult to imagine that even a Gottlieb-led FDA would approve a drug like solanezumab, which failed to even demonstrate qualities that could be indicative of efficacy, as surrogates do.
The authors did not mention the case of FDA's accelerated approval of Sarepta Therapeutics Inc.'s Duchenne muscular dystrophy (DMD) drug Exondys 51 (eteplirsen), which included only one 12-patient controlled clinical study to support efficacy. Approval – which was based on the surrogate endpoint of dystrophin increase in skeletal muscle – came in a seemingly contentious decision with Center for Drug Evaluation and Research Director Janet Woodcock overruling the concerns of other reviewers, who had concerns about the drug's efficacy. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)
Exondys 51 still has to undergo Phase IV testing to prove its predicted clinical benefit, as a condition of accelerated approval. However, the drug will more largely be an issue of private insurance than of Medicare, in contrast with Alzheimer's drugs.