Safety Concerns and Shortages Challenge Pharma Manufacturing - Industry struggles to curb drug abuse, diversion, and disruptions in supply to ensure access to quality products. - BioPharm


Safety Concerns and Shortages Challenge Pharma Manufacturing
Industry struggles to curb drug abuse, diversion, and disruptions in supply to ensure access to quality products.

BioPharm International
Volume 24, Issue 6


Although FDA advisory committees rejected such a voluntary educational campaign last July as too weak to curb abuse, the agency is adopting this moderate approach as a first step in trying to tackle the problem. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research (CDER), noted that the agency can require drug manufacturers to develop educational materials, but lacks the authority to control physician prescribing. A limited distribution system for opioids with mandated physician and patient registration would create an oversight responsibility far beyond FDA's capabilities and generate fierce opposition from the medical community.

Instead, the Obama administration is asking Congress to enact legislation that mandates training on opioid use for physicians to obtain the DEA registration number needed to prescribe opioids and other controlled substances. But for now, the educational component of the national plan is optional for the 600,000 doctors and other health professionals licensed by DEA to prescribe controlled substances. In 2000, Congress approved the Drug Addiction Treatment Act, which requires 8 hours of special training for physicians to prescribe and dispense buprenorphine (Subutex and Suboxone) for treating opioid addiction, but this involves much more limited drug use and far fewer physicians. The prospect of additional Congressional action in the near future is fairly dim because both the medical pain-management community and pharmaceutical industry oppose mandatory training or other initiatives that could limit access to pain medications.

At the same time, drug-abuse groups would like to expand the scope of the REMS to include immediate-release pain medications, such as short-acting Vicodin (hydrocodone), which is the most widely prescribed drug in the US (131 million prescriptions were written for Vicodin in 2010, according to IMS Health). The current program is limited to extended-release opioids, such as hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol, because these drugs contain a stronger dose of active ingredient and, thus, are more dangerous when abused.

Just how some 16 brand and generic-drug firms will devise a singled shared system for educating prescribers and patients and for monitoring the program's impact is unclear. While components of the educational materials and Medication Guides will apply to all drugs in the class, each manufacturer also will have to provide drug-specific information. A common approach for assessing the effectiveness of the REMS will involve independent audits of training quality, evaluation of providers' understanding of opioid risks, and a broader surveillance plan to detect misuse, abuse, overdose, addiction, and death resulting from specific drugs.

CDER's Office of Surveillance and Epidemiology may play a role by tapping data bases on prescribing, emergency room visits and other indicators that could help evaluate the program's impact. In the end, all affected manufacturers may submit a similar REMS to FDA, with appendices on their specific drug. FDA wants to receive the industry REMS plan by fall 2011 so that the program can go into effect in early 2012.

The ultimate solution to the opioid misuse problem is for manufacturers to formulate pain killers more resistant to abuse. The White House plan calls on FDA and the National Institute on Drug Abuse (NIDA) to collaborate on research for developing and testing abuse-deterrent formulations, as well as pain therapies less attractive to nonmedical users. FDA also is charged with issuing guidance in two years on developing and testing such products and on ways to assess performance in the real world.

Clearer standards for studying tamper-resistance and for conducting clinical trials would be useful to manufacturers developing medicines with anti-abuse features, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), which testified before an April 2011 Energy & Commerce subcommittee hearing on combating prescription drug abuse. PhRMA also noted the importance of obtaining adequate reimbursement and coverage for addiction treatments.

In fact, formulating abuse-resistant products can be challenging. King Pharmaceuticals (now part of Pfizer) had to recall painkiller Embeda (morphine/naltrexone) several times after it was approved in 2009 due to stability and dissolution problems related to its anti-abuse formulation; apparently it may not return to the market. Purdue Pharma's extended-release Palladone (hydromorphone) was associated with serious adverse events and pulled in 2005. Pain Therapeutics is developing abuse resistant Remoxy as a substitute for oxycodone. To demonstrate that its unattractive taste and texture will discourage abuse, the company designed a clinical study to document lower "drug liking" by potential abusers, which it hopes will pass muster with FDA.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,

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