No More Opioid Enriched Enrollment Studies: Califf
FDA commissioner Robert Califf told a Senate Appropriations Committee hearing 5/8 that the agency is advising against enriched enrollment studies for opioid products going forward. Califf had been asked by Senator Joe Manchin (D-WV) what the agency’s position is following a 4/2023 advisory committee meeting that expressed concerns about enriched enrollment designs because they cannot determine whether an opiate is better than a non-opiate.
“I don't think you’ll see enriched enrollment as a practice in the routine management of the affairs of opioids,” Califf responded. However, he noted that “there are other circumstances in medicine and healthcare where it’s a very important constituent of the armamentarium of clinical trial methods that are important to have available.”
As recently as last September, Manchin and Sen. Ed Markey (D-MA) called on FDA to curb the use of enriched enrollment randomized withdrawal (EERW) studies, which they say have been used to investigate opioid treatment options for patients with chronic pain but carry the risk of biasing outcomes in favor of opioid approvals. In a 9/19/2023 letter (see story)to Califf, the lawmakers noted that an FDA-commissioned report found that EERW studies underestimate opioids’ adverse impacts. Last year, members of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee criticized EERW studies for their potential to harm participating patients by introducing opioid use to people who were previously not using opioids, prescribing and maintaining opioid doses at their highest tolerance level, and then abruptly stopping opioid use, which can induce withdrawal.
At the appropriations hearing, Manchin also raised concerns with FDA’s recent moves to curb voting at advisory committee meetings. He said he was fearful that without required voting, it is possible more dangerous opioids could enter the market. Califf assured Manchin that reduced voting applies to when an advisory committee is convened for advice about a scientific field and not about a particular product. “In addition to that, what FDA is most interested in is what the advisory committee is thinking, and what’s behind the reasoning for the way they feel the way they do,” Califf said. “That’s much more important than the sort of excitement of having a vote from people that have convened for one day, without all of the background that the FDA has from looking at the data for months.”
Additionally, Manchin said FDA should only allow opioid products on the market if they are an improved product that will reduce the suffering of humans and be better for society. “These products keep coming at you all, but we are not taking anything off the market if something is going to improve and be better,” he said, asking Califf if he thinks that some products should be removed from the market?
“We need a legal construct if we’re going to pull things off the market,” Califf responded. “We at FDA are primarily referees and the rulebook is written by Congress. So when you write a law, we follow the law… The rulebook that we referee upon says if the drug is better for the indication than nothing, then it’s allowed on the market.” Manchin assured Califf that he will craft legislative language stating that if an opioid drug is approved that is better than a previously approved drug, then FDA can request that the original drug be removed from the market.