FDA asks for input on postmarketing ER/LA opioid trial requirements

Last fall in light of the prescription opioid abuse epidemic, FDA informed pharmaceutical companies that make opioids that they would be required to conduct postmarketing studies of extended-release/long-acting (ER/LA) opioid analgesics. FDA explained that more data are needed on misuse, abuse, hyperalgesia, addiction, overdose, and death with these formulations.

FDA held a meeting May 19-20 with experts from academia, medical centers, the pharmaceutical industry, and even patients to help industry formulate those studies, and the discussion showed the work will likely be complex.

The agency noted there are limited data on long-term use of ER/LA opioid analgesics in part because it is difficult to ensure patients’ participation in trials longer than 12 weeks.

Among other things FDA called for “validated definitions of ‘doctor/pharmacy shopping’ as outcomes suggestive of misuse, abuse, and addiction.” One proposed study described at the meeting would formulate definitions of doctor or pharmacy shopping by grouping patients according to number of prescribers, pharmacies visited, and type of payment.

Another protocol suggested looking at the incidence of and risk factors for misuse, abuse, and addiction by clinical characteristics, product/formulation, dose and duration of use, prescriber specialty, as well as demographic, psychosocial/behavioral, medical, and genetic factors. It suggested examining outcomes by a review of the medical record for early refills, doctor shopping, emergency room visits, overdose, and death.

Another draft protocol would study whether patients with a poor response to high-dose opioid therapy may be affected by opioid-induced hyperalgesia. “If this hypothesis were valid,” according to the protocol, “poor opioid responders would have high ratings of experimental pain stimuli (e.g., ice water immersion or thermal pain) and removal of opioid therapy would result in improvement of experimental pain sensitivity compared to continuation of opioid therapy.”

Discussion at the FDA meeting included a number of topics: How to use ICD-9 or ICD-10 codes, whether and how to review social histories of patients, what patient groups and databases are good resources for information, how to ensure cancer patients are identified and separated from non-cancer patients, what dosages to examine, and how to deal with study dropouts given that these patients can be anxious about pain.

Information about the session and the proposed research is on the FDA website. The agency will accept comments through June 19 on www.regulations.gov and the docket number is FDA-2014-N-0374. A session transcript is expected on that site shortly.