Regulatory Focus™ > News Articles > FDA to Require New Studies, Trials, Labeling Changes for Certain Opioid Products

FDA to Require New Studies, Trials, Labeling Changes for Certain Opioid Products

Posted 10 September 2013 | By Alexander Gaffney, RAC

In a sweeping change, the US Food and Drug Administration (FDA) today announced it will require new safety labeling changes and postmarket study requirements for extended release and long-acting opioid analgesic products in a bid to curb their abuse and misuse.

Background: FDA and Opioids

FDA has taken a number of actions in recent years intended to cut down on the abuse of opioid products to counteract rising deaths from overdoses.

In January 2013, for example, FDA said a new guidance document would "incentivize" abuse-deterrence studies for opioid products, and called on manufacturers to provide it with specific data to promote the safe and proper use of their opioid products.

Sponsors of opioid products will have to take into account not just the intended use of the products but also their likely routes of abuse. The intent, FDA said, is for manufacturers to build abuse-deterrent qualities into their products.

However, each abuse-deterrence quality-be it crush-proofing or various routes of administration-will need to be backed up by data to show its safety and efficacy. Companies that successfully complete such testing and clear it with FDA might be allowed at least one indulgence: the ability to market the drug using claims that it is more "abuse-deterrent."

FDA officials noted that "so long as the claim accurately reflects data and doesn't overstep" the trial data, abuse deterrence claims would be allowed, although FDA would subject such claims to scrutiny. They also noted that such labeling is important to inform healthcare providers about the risk-deterrent properties of a particular product, and thus "encourage sponsors to seek approval" for the labeling.

[More: FDA Guidance 'Incentivizes' Abuse-Deterrence Studies for Opioids]

Another notable development was FDA's July 2012 launch of a new class-wide Risk Evaluation and Mitigation Strategies (REMS) policy for opioid products. The new policies 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 policy, calling the move ineffective and potentially misleading.

The New Policy

In its 10 September 2013 announcement, FDA said it would be building upon these two earlier policies by "invoking its authority to require safety labeling changes and postmarket studies to combat the crisis of misuse, abuse, addiction, overdose and death from these potent drugs."

"Today's action demonstrates the FDA's resolve to reduce the serious risks of long-acting and extended release opioids while still seeking to preserve appropriate access for those patients who rely on these medications to manage their pain," said FDA Commissioner Margaret Hamburg in a statement.

Notably, the policy does not affect non-LA/ER opioid product. Douglas Throckmorton, deputy director for regulatory programs at FDA"s Center for Drug Evaluation and Research (CDER), said in a press call that this category of products could come to be included under future restrictions, but no specific actions are under consideration at this time.

In letters sent to manufacturers of extended-release and long-acting opioid analgesics, FDA said it would be requiring post-marketing studies and at least one clinical trial to assess the risks of each respective product.

Under Section 505(o)(3) of the Federal Food, Drug and Cosmetic Act (FD&C Act), FDA said it determined that postmarketing adverse event reports alone were not sufficient to assess the "known serious risks" associated with opioid analgesics. "Furthermore, the new pharmacovigilance system that FDA is required to establish under Section 505(k)(3) of the FD&C Act will not be sufficient to assess these serious risks," it added, referring to a new system required under the FDA Safety and Innovation Act of 2012.

As a result, companies will need to conduct the following five studies:

  • 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
  • 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
  • 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
  • conduct a study to define and validate "doctor/pharmacy shopping" as outcomes suggestive of misuse, abuse and/or addiction
  • 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

Companies were also encouraged by FDA to "work together with the holders of other approved New Drug Approval (NDA) applications for ER/LA opioid analgesics on these studies and clinical trial to provide the best information possible." Protocols will need to be submitted to FDA through an investigational new drug (IND) filing by August 2014.

Failure to submit the studies could result in enforcement action, FDA said in its letter to manufacturers.

Labeling Changes

In addition, companies will also need to update the labeling on their respective products to reflect several new general requirements and at least one specific risk.

According to FDA, the largest change is likely set to be in the indication for which the drugs are prescribed. ER/LA opioids will now be reserved for use in patients for whom alternative treatment options are ineffective, intolerable or otherwise inadequate.

At present, the drugs are indicated for "the relief of moderate to severe pain in patients." The new labeling will state that the drugs are indicated for "the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate."

Left to be seen is whether this stricter prescribing "emphasis" will result in meaningful changes in prescribing habits. In a statement, FDA said the labeling will only "clarify" the need for further vigilance, but did not mention any further restrictions within the class-wide opioid REMS that would create more robust barriers to prescribing the drugs.

FDA said it is now aware of an association between use of opioid products by pregnant mothers and a condition known as neonatal abstinence syndrome (NAS), which occurs when a newborn experiences withdrawal from an opioid product it was exposed to in the womb.

Other changes are set to reflect new requirements in nearly all sections of the current drug labeling. Once finalized, those changes will become a formal part of the ER/LA Opioid class-wide Rise Evaluation and Mitigation Strategy, FDA said.

Throckmorton added on the press call that FDA's actions on 10 September 2013 do not represent a final step, but rather part of an ongoing process.

FDA Statement

Related FDA Documents

Tags: MedGuide, REMS

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