The Federal Government attempts to ensure the availability of opioid analgesics for legitimate medical and scientific purposes while controlling the abuse and illegal diversion of such substances. The Food and Drug Administration, (FDA), is charged with the task of approving medications that are deemed as safe and effective for medical use. Once approved by the FDA, a drug may be prescribed as labeled, or in an “off-label” manner, at the prescribing clinician’s discretion based on a therapeutic risk/benefit evaluation and conformity to community standards of good medical practice.

In 2002, Congress reauthorized, for the second time, the Prescription Drug User Fee Act (PDUFA III). One of the goals of PDUFA was to produce guidance for the pharmaceutical industry on risk management activities for drug and biological products. The intent of the FDA was to create a plan that would encompass the idea of medication risk management.

Specifically, the FDA describes medication risk management as an iterative four-part process that should be continuous throughout a medication’s lifecycle, with the results of risk assessment informing the manufacturer’s further decisions regarding risk minimization:

1. Assessing a medication’s benefit-risk balance

2. Developing and implementing tools to minimize risks while preserving benefits

3. Evaluating tool effectiveness and reassessing the benefit-risk balance

4. Making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance

Within the context of medication risk management, part of the application to the FDA for approval may require submission by the manufacturer of a Risk Minimization Action Plan or RiskMAP.

RiskMAP

The FDA defines a RiskMAP as the “strategic safety program designed to meet specific goals and objectives in minimizing known risks of a medication while preserving its benefits”. For the majority of FDA-approved products, labeling and routine reporting requirements of adverse events are sufficient to mitigate risks and preserve benefits. In a relatively small number of cases, when additional measures are deemed needed to ensure that the benefits of a drug outweigh the risks, a RiskMAP is required. The intent of a submitted RiskMAP is to lay out a plan (processes or systems) to minimize known safety risks, including risks of adverse effects, aberrant drug-related behaviors, and negative outcomes relative to the risk. The submitted plan is to include processes such as:

1. Targeted education and outreach to healthcare practitioners or patients to communicate risks and appropriate safety behaviors

2. Reminder systems, processes, or forms to foster reduced-risk prescribing and use

3. Performance-linked access systems that guide prescribing, dispensing, and use of the product to target the population and conditions of use most likely to confer benefits and to minimize particular risks

In September 2007, the President signed into law H.R. 3580, the Food and Drug Administration Amendments Act of 2007 (FDAAA). This new law represented a significant addition to FDA authority.

Among the many components of the FDAAA law, the PDUFA which was expiring was reauthorized and expanded. The resulting law contained numerous provisions designed to:

• Better inform the public about drug safety
• Provide new tools for the FDA to reduce risks and unsafe drug use

REMS

The passage of the FDAAA:

• Enhanced the FDA's authority to require drug labeling changes and additional post-market studies

• Gave the FDA the authority to require Risk Evaluation and Mitigation Strategies (REMS) for new products and already approved products, if it becomes aware of new safety information and determines that a REMS is necessary to “ensure the benefits of the drug outweigh the risks of the drug”.
  • REMS expanded assessment of medication risk management, previously built into RiskMAPs, to include periodic reassessment and modification as necessary

  • Contents of REMS include:
    • A Medication Guide
    • A patient package insert if such insert may help mitigate a serious risk of the drug
    • Elements to assure safe use of the medication
    • A communication plan to convey to health care providers information that supports the mitigation strategy

• Grants FDA the authority to require additional post-approval studies and if marketed medications are found to be associated with new potential risks, the FDA can require labeling changes or additional research to address these risks

• Stopped short of requiring REMS for all new drugs, as was originally proposed, and the FDA will therefore decide on a case by case whether a drug that is pending approval warrants a REMS

The FDAAA, REMS, and pain management with chronic opioid therapy crossed paths in early 2009³, when the FDA sent letters to manufacturers of all extended release opioid drugs, indicating that these drugs will be required to have a REMS in addition the to their RiskMAPs to ensure that the benefits of the drugs continue to outweigh the risks of:

1. Use of certain opioid products in non-opioid-tolerant individuals
2. Abuse
3. Overdose, both accidental and intentional

The FDA stated in this letter that:

• “The agency has long been concerned about adverse events associated with this class of drug and has taken steps in cooperation with drug manufacturers to address these risks. We intend to use the agency’s REMS authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA) to mitigate the risks of these drugs”

• “Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients”

• “Opioid drugs have serious risks when used improperly”

• “The FDA, drug manufacturers, and others have taken a number of steps in the past to prevent misuse, abuse and accidental overdose of these drugs, including providing additional warnings in product labeling, implementing risk management plan (RiskMAP), conducting inter-agency collaborations, and issuing direct communications to both prescribers and patients.”
  • “Despite these efforts, the rates of misuse and abuse, and of accidental overdose of opioids, have risen over the past decade”

• “The FDA believes that establishing a REMS for opioids will reduce these risks, while still ensuring that patients with legitimate need for these drugs will continue to have appropriate access”

• “The REMS would be intended to ensure that the benefits of these drugs continue to outweigh certain risks”

All companies that make extended-release opioids have been asked by the FDA to work together as opposed to separately, to create a single, broad-application REMS program that will encompass all extended-release medications in this class. Although individual medications have been required to submit a REMS as part of their application, or to implement one post-FDA approval, this is the first time that the FDA has indicated that a REMS will be needed on a class-wide basis. The likely impetus is the number of drug-related deaths associated with extended-release opioids.

Once a clear direction exists, the FDA will likely consult with the DEA on the class-wide REMS. The Controlled Substances Act and DEA regulations that require manufacturers and registrants of controlled substances to maintain effective controls against diversion and compliance with REMS, could arguably be viewed as a part of this duty. Drug manufacturers will need to consider that DEA will evaluate compliance with REMS as a factor in determining ongoing compliance with DEA requirements.

Clinical Implications

The REMS for extended-release opioids needs to provide mechanisms that will likely include a variety of elements to assure safe use of these medications, and to ensure that prescribers, dispensers, and patients are all aware of, and understand the risks and appropriate use of these products.

There is little doubt that the finalized program will likely have requirements that have some degree of clinical impact at all stakeholder levels:

• Ongoing, opioid-specific training and possibly certification for clinicians and pharmacists
• A higher level of clinician vigilance than previously required
• Expanded use of doctor-patient opioid agreements
  • Detailing the responsibilities of both clinician and patient
  • Including review and confirmation of patient comprehension of the Medication Guide for the specific medication
  • Dissemination of information about the safe and appropriate use of opioid medications, and the dangers of sharing medications
• A plan that outlines continued monitoring of these initiatives to ensure that the goals are being met

The challenge will be to ensure access to patients in need that are appropriate candidates for extended-release opioids, while achieving the desired goals.

References:

1. Model Policy for the Use of Controlled Substances for the Treatment of Pain. Federation of State Medical Boards of the United States, Inc. Adopted as policy by the House of Delegates of the Federation of State Medical Boards of the United States, Inc., May 2004.

2. The Comprehensive Drug Abuse Prevention and Control Act of 1970, Pub. L. No. 91-513, 84 Stat. 1236 (Oct. 27, 1970).

3. Federal Register / Vol. 74, No. 74 / Monday, April 20, 2009 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2009–N–0143] Risk Evaluation and Mitigation Strategies for Certain Opioid Drugs; Notice of Public Meeting.