New pain meds pose tricky PR test, as FDA gaffe shows

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A patient education kit for Covidien pain drug Exalgo
A patient education kit for Covidien pain drug Exalgo

Reformulations of prescription pain drugs designed to reduce abuse potential are arriving on the scene, just as substance misuse, particularly among teens overdosing on potent opioid analgesics, reaches frightening levels nationwide. But whether the innovative treatments can help stem this epidemic remains to be seen. Until community-based evidence builds, the FDA is grappling with the best way to encourage manufacturers to communicate risks vs. benefits and ensure safety.

Underscoring the problem, four parents who lost children to prescription drug abuse filed a citizen petition with the FDA this week regarding a recently approved, controlled-release version of pain drug oxycodone. The FDA's announcement on the approval claimed the drug, OxyContin, “will likely result in less abuse by snorting or injection,” however, manufacturer Purdue Pharma did not conduct in vivo (human lab) studies to determine whether the new formulation really reduced that potential. Likely working off the agency's press release, media coverage of the new pill has suggested that it's less addictive or less abusable than its predecessor. The parents implored the FDA to issue a statement clarifying that there is actually not enough human clinical evidence to say as such.

As the agency's communication misstep shows, extended-release prescription opioid drugs designed to curb misuse pose a new communications challenge, especially in ensuring benefits continue to outweigh risk without burdening pain patients, who already face a stigma of being labeled an addict or criminal for their long-term use of these drugs. How regulators guide marketers to express features like deterrence and pain relief, along with side effects like overdose and death, really matters.

“It is critical that we find ways to intervene that will limit the increasing problems of addiction, overdose and death associated with the long-acting and extended-release opioids, while maintaining the necessary balance to assure continued access to these important analgesic drug products for people with chronic pain,” wrote Bob Rappaport, director of FDA's division of anesthesia and analgesia products, in a proposed set of risk evaluation and mitigation strategies (REMS) for long-acting opioid drugs issued by the agency in June.

A two-day FDA advisory panel meeting designed to build consensus around the REMS got under way Thursday. (Click here for a recap of the panel's vote.) Sponsors of long-acting and extended-release opioids were notified last year that their products would require a REMS. In 2009, FDA says, it received well over 2,000 submissions to an initial REMS outline and held a series of meetings to gather additional input.

The inclusion of a host of national health agencies at this week's REMS meeting—the DEA, US Public Health Service, CDC and the White House's Office of National Drug Control Policy (ONDCP)—reflects the gravity of the issue. Millions of patients are prescribed extended-release or long-acting opioids each year. Last year 16 million prescriptions were written. The CDC says nonmedical use of prescription opioid painkillers was associated with approximately 306,000 emergency department visits in 2008—on par with ED visits for cocaine and heroine.

And research shows that prescription drug abuse is a particularly distinct problem among teens. The proportion of all substance abuse treatment admissions of those aged 12 and older involving abuse of prescription pain relievers rose by over 400%, from 2.2% in 1998 to 9.8% in 2008, according to a new study by the Substance Abuse and Mental Health Services Administration (SAMHSA).

“These findings should serve as exclamation points to punctuate what we already know—abuse of prescription drugs is our country's fastest-growing drug problem, the source of which lurks far too often in our home medicine cabinets,” said R. Gil Kerlikowske, director of the ONDCP.

There are 18 manufacturers of long-acting opioid products, including 27 brand and generic drugs. In the absence of a class-wide REMS, each company is doing its own style of risk communications. To help reach consensus, the agency has asked industry for input.

“The advice I would give would be to really embrace the risk of these products,” Dr. Herbert Neuman, chief medical officer for Mallinckrodt, the pharmaceutical segment of drug firm Covidien, told MM&M. He is one of four industry employees to present during the FDA meeting. “These products are vital. They treat severe pain in patients and yet they have risks. The key to success around this is embracing the risk and coming up with a valid scientific method for evaluating the tools that you use, or don't, and whether or not those tools are working.”

Indeed, metrics are one of the required components in FDA's draft REMS, along with a medication guide and HCP education materials. In April when Covidien launched Exalgo, a long-acting form of the opioid hydromorphone, it did so with what it says was a program nearly identical to the FDA's proposed class-wide REMS.

Separately, the St. Louis company, which also makes products containing the opioids morphine, methadone and oxycodone, plans to deploy more than 60 voluntary tools to help ensure appropriate prescribing, dispensing and use of Exalgo. For instance, a website,, educates patients about the risk of abuse in their household and appropriate use. A dose alert timer, part of a patient welcome kit, is placed on top of the pill bottle and sounds an alarm reminding patients when it's time for their next dose. On the commercial side, Covidien also does journal advertising to a targeted group of doctors.

While Neuman said he thinks the FDA's proposed REMS does a nice job of striking a balance between access and safety, “We don't believe there is a one-size-fits-all solution that can just be applied across all products. We believe there is a combination of tools, education and programs that will maximize safety across this platform. Each sponsor has a responsibility to evaluate their products and see how they can best maximize safety.”

All manufacturers in the class are “looking very, very carefully in terms of how we can provide education on these products without overstepping the bounds,” Dr. Eric Carter, chief science officer for King Pharmaceuticals, maker of the Avinza and Embeda long-acting opioids, told MM&M.

King ran up against those boundaries last year with two VNRs for Embeda. FDA's DDMAC told King in a warning letter that the VNRs presented misleading claims, among them about the drug's abuse-resistant properties. King agreed to pull the VNRs, and the firm had to disseminate corrective messaging.

Carter said King is conducting human clinical trials of Embeda to determine whether it in fact decreases the rate of abuse in the community. “We know the risks of prescription opioid abuse are very real and in need of urgent attention,” he said. “At the same time, opioids are gold-standard analgesics and there are many millions of patients who depend on these medicines to get by and treat their chronic pain, so we've got to make sure that whatever strategy we put in place through the REMS doesn't inappropriately impede patients' access.”

King has also been working closely with other companies since last year to provide perspective on what REMS should look like and has interim strategies for Embeda and for Avinza. “We see things quite similarly to the approach that FDA is taking,” Carter said.

Once a class-wide REMS is approved, business for marketing communications agencies with expertise in this area—med ed, promotion and web, to name a few—is set to expand. As future innovations in the opioid class come on line, they should also drive agency business, as new expertise is needed to convey products to doctors and patients.

Carter said King has looked mostly to an advisory board of experts it convened for REMS support, in addition to some vendors. “Any time there is a nationwide requirement for enhanced education, then clearly that creates a significant need.” Out of the roughly 18 companies for which the class-wide REMS applies, many are generic companies that are typically not involved in these activities and so don't have in-house capabilities. These firms, Carter added, would need to look to outsource a lot of work.

Covidien's Neuman said his firm used a combination of internal resources, outside consultants and experts in the field to develop its REMS and voluntary programs. The company is assessing the programs implemented for Exalgo and plans to take a product-by-product approach with the rest of its pain portfolio. “As interest in REMS programs and other educational efforts increases, we would expect there to be a greater need for communications support.”

Carter said King has a number of other potentially abuse-deterrent formulations in development, including one for immediate-release opioids like Vicodin. While these formulations have not inspired the same level of concern in terms of opioid abuse, the short-acting drugs are much more widely prescribed than the long-acting variety, and are highly abused. Last year, out of 254 million prescriptions for opioids, 94% were for immediate-release products, according to Carter.

“If we can introduce limits through innovative technology, that will contribute to reducing the rate of abuse, addiction and death,” Carter said. “We need to take ownership of this because it is a societal problem.”

The two FDA advisory panels are set to vote today on the proposed REMS. If the agency can mobilize companies around clear communications to minimize and prevent abuse—while also encouraging them to develop safe and effective pain medications that also have some element of abuse deterrence as demonstrated by human clinical trials—it may lead to more consistency in risk communications among drug marketers.

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