What's Missing In Intellipharmaceutics' Opioid Filing? FDA Panel Offers List

Advisory committee notes missing pieces in sponsor's data for abuse-deterrent oxycodone extended release opioid; excipients to deter abuse also need toxicity testing.

During an advisory committee review of its application for Rexista (oxycodone extended-release), Intellipharmaceutics International Inc. was unable to answer numerous questions about the safety and efficacy of the opioid, prompting panelists to question why the company had filed an application with limited data.

The committee's July 26 discussion provided a blueprint of sorts on what the company should do as it will likely have to go back to the drawing board to conduct more studies – and also offers lessons for other firms hoping to avoid a similar fate.

Intellipharmaceutics submitted only in vitro studies for the product and only for intravenous abuse deterrence. The product has several features to deter abuse. The tablet gels when put into an aqueous solution, which is intended to deter intravenous abuse. It also includes a nasal irritant (sodium lauryl sulfate) to deter intranasal abuse, and a blue dye in the core of the pill that leaves blue stains on the hands and nose when it is chewed or crushed. Intellipharmaceutics is conducting further studies to seek abuse deterrence labeling for the oral and nasal routes.

At the joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, panelists voted 22-1 against approval of the opioid, saying the company had not conducted sufficient studies to support its safety and efficacy. (Also see "FDA Panel Rejects Intellipharmaceutics' Opioid For Missing Data, Blue Dye Safety Concern" - Pink Sheet, 27 Jul, 2017.)

The US FDA does not have to follow the committee's recommendation but it was clear from the agency's presentations that it also felt the package was insufficient.

Advisory Committee Voting Questions

1. Has the applicant demonstrated that oxycodone extended-release tablets have properties that can be expected to deter abuse by the IV route of administration? Vote: No: 19, Yes: 4
2. Are there sufficient data for this product to support inclusion of language regarding abuse-deterrent properties in the product label for the IV route of administration? Vote: No: 23, Yes: 0
3. Should the drug product oxycodone HCl extended-release tablets be approved? Vote: No: 22, Yes: 1

Intellipharmaceutics conducted in vitro studies (Category 1) but not pharmacokinetic (Category 2) and clinical abuse potential (Category 3) studies for its 505(b)(2) application referencing Purdue's OxyContin (oxycodone extended-release).

Terri Warholak, of the University of Arizona, expressed the overall view of the committee that there was not enough information to recommend approval.

Rexista may be an incremental advance, but "we don’t have the evidence. We don't know what's going to happen with the blue dye. We don’t know what's going to happen with the additional viscosity and the synringeability of the PEO [polyethylene oxide]," she stated. "If we have additional viscosity does that mean more TPP [thrombotic thrombocytopenic purpura]? We don't know. And then without the Category 2 and 3 studies, we don't have information on that either."

Follow The Guidance

Panelists offered numerous suggestions as to what the company could do to provide a complete package, including conducting studies to show the safety of the gel when it leaks into the mucosa; the safety of the blue dye; how easy it is to remove the blue stain from the hands and nose with a variety of substances; studies in those aged 11-17; drug liking studies; and studies on multiple routes of abuse.

The committee members repeatedly said the company should follow FDA's 2015 draft guidance on the evaluation and labeling of abuse-deterrent opioids. The guidance states that a complete abuse deterrence assessment should cover multiple routes of administration and consider Category 2 and 3 studies as part of the abuse deterrent assessment.

Excluding the incomplete data, the panelists were asked whether the company had shown that the product has properties "that can be expected to deter abuse by the IV route of administration." They voted 19 to 4 that it would not be expected to deter IV abuse. (See box of voting questions.)

Panelists questioned the data on the product's gelling property. They asked why the company only tested two of the most common solvents in the syringeability studies and what happens when the material in the gel is leaked into the body.

FDA's Sharon Hertz, Director of the Division of Anesthesia, Analgesia, and Addiction Products, noted that syringeability testing indicated that up to 40% of the active pharmaceutical ingredient could be syringed under certain conditions.

Blue Dye Needs Toxicity Testing

The committee was particularly concerned about the blue dye, aluminum lake blue No. 1, and said the excipients in the opioid should be evaluated just as drug products are with similar toxicity testing.

Members asked numerous questions that pinpointed what information is needed:

• Is there data on GI distress associated with the excipients and is it dose-related? (No, there is no such data, the sponsor replied)
• Did you try to remove the blue dye stain with anything other than water, such as Vaseline or makeup remover? (No)
• Are there data that shows someone who knows they will have dye on their nose or hands is enough to deter abuse and outweigh potential risks? (No)
• Do you know what happens when you ingest blue dye intranasally? Will you turn blue and for how long? (A speaker for the company cited an IV injection study in cats and a subcutaneous study in mice conducted in the early 1960s.)
• Did you do a study to look at whether there are methylene blue side effects, which would affect resuscitation with anesthesia? (No)

Hertz stated that the blue dye is novel and that there has been no assessment of its deterrent effect. She asked the committee members for their thoughts on how it could be assessed.

One panel member said it would be good to interview those who abuse drugs to get their views on whether the dye would deter abuse. Several panelists expressed concern that the dye's shaming effect could hurt patients or be attractive to some.

Melinda Campopiano, from the Center for Substance Abuse Treatment at the Substance Abuse and Mental Health Services Administration, suggested conducting a focus group or surveying people in recovery, active users, families and treatment providers about "this type of scarlet letter approach to deterring substance use" to see whether it might be harmful and if there is a way to mitigate the harm.

"It's a double-edged sword," she said. "I can see Smurf parties and blue lollypops suddenly becoming very popular."

Purdue Postmarketing Data Is Not Definitive, FDA Cautions

Scott Novak, of RTI International, a nonprofit research institute, was the only committee member to vote in favor of approval of Intellipharmaceutics' oxycodone product. "It comes down to the equivalence to OxyContin. I don't think it's going to be any more effective, but I also don't think it's going to by any less effective," Novak stated.

He also said he did not think it was any less safe than OxyContin and that he did not see any major concerns with the blue dye. And if the data is incomplete, he said he "would hope FDA would rectify that."

In addition to assessing the data submitted by Intellipharmaceutics, FDA is also likely to look at the oxycodone product in the context of the overall market, as a recent agency-commissioned report by the National Academies of Sciences, Engineering, and Medicine recommended. (Also see "New Opioids: FDA Should Ditch 'Product-Specific Approach,' Science Report Says" - Pink Sheet, 14 Jul, 2017.)

An Intellipharmaceutics speaker cited epidemiologic data from Purdue's postmarketing studies saying it showed that the abuse deterrent formulation of OxyContin, which was introduced in 2010, reduced misuse and abuse.

Later in the day, Judy Staffa, FDA's associate director for public health initiatives in the Office of Surveillance & Epidemiology, cautioned the committee about how to interpret Purdue's data.

"If you look at these publications with a critical eye they can look rather appealing at first blush. For example, what was presented was just decreases in Oxycontin but there were a lot of other things going on in 2010 and 2011 as well. There were a lot of decreases in abuse of other products," Staffa said.

Staffa noted that FDA is struggling with what advice to give sponsors on how to do post-marketing studies and noted that the agency recently held a public meeting to talk about the methodologies and data resources to evaluate the impact of abuse deterrent formulations in the real world. (Also see "Abuse Deterrent Opioids: Which Studies Will Show Real World Effect?" - Pink Sheet, 19 Jul, 2017.)

At the end of the advisory committee meeting, the chair asked W. Joseph Herring, the non-voting industry representative from Merck Research Laboratories, for closing comments. Herring noted the takeaways for industry.

"We have to keep in mind the level of evidence required for inert excipients that may be added as innovations in abuse deterrent formulations," Herring said. "As we've learned from the discussion about the blue dye, it's also important to recognize if you have non-inert ingredients in your product, that may require a higher level of evidence to support efficacy and safety of the approach."