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Regulatory Focus™ > News Articles > FDA Looks for Stakeholder Input on Trials Meant to Assess Abuse of Opioids

FDA Looks for Stakeholder Input on Trials Meant to Assess Abuse of Opioids

Posted 22 April 2014 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has experienced no shortage of criticism in recent years about its regulation of opioid-based painkillers in light of the drugs' contribution to what the Centers for Disease Control and Prevention (CDC) calls an "epidemic of prescription painkiller abuse."

But while FDA's fault (or lack thereof) is a matter of intense debate, the agency has nevertheless been taking steps in recent years meant to reduce abuse while maintaining access for chronic pain patients.

Background: FDA's Opioid Policies in Brief

For example, in July 2012, FDA announced the launch of a new class-wide Risk Evaluation and Mitigation Strategies (REMS) policy for opioid products. The new policy would require all sponsors of extended-release (ER) and long-acting (LA) opioid products to make training and education available to prescribing entities starting in March 2013.

"Misprescribing, misuse, and abuse of extended-release and long-acting opioids are a critical and growing public health challenge," said FDA Commissioner Margaret Hamburg in a statement at the time. "The FDA's goal with this REMS approval is to ensure that health care professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs."

Critics, meanwhile, panned the guidance, calling the move ineffective and potentially misleading.

FDA has also been working with manufacturers to strengthen the science behind abuse-resistant and -deterrent formulations, and in January 2013 released a guidance document outlining how manufacturers can label their products as being less prone to abuse. The agency is also funding efforts to study how opioid abuse can be deterred, including through technological barriers not present in the drugs themselves.

Then, in September 2013, FDA announced it would require new studies, trials and labeling changes for ER and LA opioids. The most recognizable change was meant to explicitly state on the drug label that the ER and LA opioids are not intended for use unless alternative treatment options are ineffective, intolerable or otherwise inadequate.

Companies are also required to conduct five clinical trials, all focused on the risks of abuse associated with the drugs. Those studies are as follows:

  1. one or more studies to provide quantitative estimates of the serious risks of misuse, abuse, addiction, overdose, and death associated with long-term use of opioid analgesics for management of chronic pain, among patients prescribed ER/LA opioid products
  2. develop and validate measures of the following opioid-related adverse events: misuse, abuse, addiction, overdose and death, which will be used to inform the design and analysis for the first study and any future post-marketing safety studies and clinical trials to assess these risks
  3. conduct a study to validate coded medical terminologies (e.g., ICD9, ICD10, SNOMED) used to identify the following opioid-related adverse events: misuse, abuse, addiction, overdose, and death in any existing post-marketing databases to be employed in the studies
  4. conduct a study to define and validate "doctor/pharmacy shopping" as outcomes suggestive of misuse, abuse and/or addiction
  5. a clinical trial to estimate the serious risk for the development of hyperalgesia following use of ER/LA opioid analgesics for at least one year to treat chronic pain

FDA to Stakeholders: Speak Up

Now FDA is indicating that it wants the public to provide input on postmarketing requirements (PMRs) as well.

In a 22 April 2014 announcement, regulators said they are looking for stakeholders to weigh in on "the design and conduct of PMRs for the class-wide ER/LA opioid analgesic drug products to further assess the serious risks of misuse, abuse, hyperglasia, addiction, overdose and death associated with their long-term use."

Those risks were the same ones FDA asked opioid manufacturers to study in its September 2013 announcement, FDA confirmed in the Federal Register announcement.

So if those data requirements have already been published and explained, why does FDA feel the need to meet with stakeholders again? Simple: FDA only asked for the companies to conduct the studies. The study protocols are up to the companies, and must be submitted to the agency by August 2014-four months from now.

FDA said it wants public input on what the proper "design and conduct" of those studies should look like. FDA and New Drug Application sponsors "will consider stakeholder input when preparing final protocols to be submitted by August 2014," FDA wrote in the Register announcement.

Among the most interesting studies may be the fourth proposed by FDA, which seeks to "define and validate 'doctor/pharmacy shopping,'" a process which involves pain patients seeking treatment at multiple doctors for the same condition, thereby obtaining a large supply of opioids which can then be abused. The biggest unanswered question thus far: How will FDA use this information, and for what purposes?  FDA's authority over prescribing is decidedly limited, but a formal definition of doctor/pharmacy shopping might be the first step in instituting new REMS-based restrictions on ER/LA opioids.

Being able to differentiate pain patients from abusers/misusers is half the battle, and as FDA has found out time and again, a most difficult battle indeed.

The meeting of stakeholders will occur on 19-20 May 2014. Comments will also be accepted in advance of the meeting via FDA's Federal Register docket.

Federal Register Notice


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