Two FDA advisory committees voted 23-1 Thursday that the drug should not be approved, even though they recognized the need for abuse deterrence in IR formulations, especially since IR opioids are prescribed more than three times as often as extended-release (ER) formulations.
After casting their vote, several members of the Anesthetic and Analgesic Drug Products and the Drug Safety and Risk Management advisory committees thanked the Stamford, Conn.-based Purdue for trying to push abuse-deterrence technology forward. But in the end, all they saw was “just a promise of progress,” as one member put it.
Abuse deterrence is a complicated field still in its infancy, said Gary Walco, a professor of anesthesiology and pain medicine at the University of Washington School of Medicine. A lot of clarification is still needed, he added.
Avridi was developed as a 505(b)(2) drug referencing Roxicodone (oxycodone hydrochloride, Mallinckrodt plc), which is not abuse-deterrent. Apparently because of the precautions Purdue took to reduce the potential for crushing, intranasal and intravenous abuse of the drug, Avridi showed significant absorption delays when taken with food. The delay in getting relief with initial dosing could lead to pain-wracked patients taking more than one tablet within a four-hour period.
Patients want immediate pain relief, said Anita Gupta, vice chair and associate professor of the Division of Pain Medicine & Regional Anesthesiology at Drexel University College of Medicine. What are patients to do if they have breakthrough pain right after they’ve eaten?
Jim Kiefert, the lone patient representative on the two committees, said in voting no, he asked himself if he would have wanted his wife to take Avridi when she was alone and suffering from intense pain.
Because of the effect food had on the pain relief offered by Avridi, the drug would need labeling instructions that it should be taken on an empty stomach. How to word the labeling led to more discussion as panel members debated the meaning of words like “food,” “fasting” and “empty.” For instance, would patients consider a high-calorie drink food? one panelist asked. And what about patients who have to take a number of medications?
The problem with labeling is that patients don’t think they need an instruction manual to take a pill, Michael Wolf, a professor at Northwestern University Feinberg School of Medicine, told the committees in a presentation on labeling and patient behavior. When patients are used to taking their drugs a certain way, they often don’t look at the changes required for a new drug, he said, adding that 52 percent of patients misinterpret the auxiliary information on a label.
Given the necessary complexity of Avridi labeling when other IR opioids have straightforward use instructions, the committee members said the Purdue drug wouldn’t get much use. Thus, its abuse-deterrent properties wouldn’t make a dent in the opioid problems facing society.
Those concerns were voiced time and time again throughout the day-long meeting, as panelists asked why patients would want Avridi when other effective IR opiates are already available. While Avridi may be abuse-deterrent, it offers no improved treatment for the patient. And it likely would cost patients a higher co-pay, one committee member noted.
Arthur Kibbe, a retired professor of pharmacy sciences at Wilkes University, was the lone yes vote. He called Avridi a good first step and reminded his colleagues that it’s not the FDA’s job to protect Purdue from launching a drug that would have minimal use.
Another recurring question raised by some panelists was whether Avridi was truly bioequivalent to Roxicodone since it had slower absorption with food. “It just stretches the definition of bioequivalency too far,” said Steven Passik, vice president of clinical research and advocacy for Millennium Health. He, like other committee members, wanted to see data from an efficacy clinical trial.
Going into the meeting, the FDA seemed receptive to approving Avridi. None of the questions it asked the committees related to bioequivalency. Instead, the agency wanted to know about the food effect and how to address that in labeling.
The FDA has faced intense congressional pressure to approve abuse-deterrent opioids in light of a growing problem with prescription drug abuse and misuse. If the agency ignores the advisory committees’ recommendation and approves Avridi, the drug would be one of the first abuse-deterrent IR formulations on the market.
To date, the FDA has approved four ER, long-acting painkillers with abuse-deterrent properties: Oxycontin (oxycodone, Purdue), Targiniq (oxycodone and naloxone, Purdue), Embeda (morphine sulfate and naltrexone, Alpharma Inc.) and Hysingla (hydrocodone, Purdue).
Friday, the FDA will ask the committees to look at another ER abuse-deterrent formulation – Collegium Pharmaceuticals Inc.’s Xtampza (oxycodone). Like Avridi, Xtampza would need labeling instructions. But instead of being taken on an empty stomach, it would have to be taken with consistent amounts of food.