The Food and Drug Administration (FDA) heard testimony on May 27 and 28, 2009, regarding the effort to develop a class-wide Risk Evaluation Mitigation Strategy (REMS) for long-acting opioids products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone or oxymorphone. The public hearing was held to get input from industry, healthcare providers, researchers, patient advocates, and pharmacies on what a REMS should like for these products, how to minimize the burden on the health care community and patients while achieving the objective of ensuring that the benefits of these drugs outweigh the risks, and how FDA should evaluate the REMS to determine whether it is achieving these objectives. Under the FDA Amendments Act of 2007 (FDAAA; Public Law 110-85), the FDA has the authority to require a REMS when necessary, to ensure the benefits of a drug outweigh the risks.

Opioid drugs are a beneficial and necessary component of pain management in patients who suffer from chronic pain. However, these drugs have serious risks when not used properly. Previously, the FDA and drug companies have taken steps to prevent misuse and abuse of opioid drugs. Despite these efforts, the rates of misuse, abuse, and over-dosage continue to increase. Establishing a REMS for opioids is intended to reduce these risks, while ensuring that patients who legitimately need these medications maintain appropriate access to them.

According to Gregory Terman, MD, PhD, a representative from the American Pain Society, a REMS should: 1) cover all opioid classes; 2) have no required patient registry; 3) contain components that are measurable and easily reversible, when necessary; 4) require prescribers and dispensers to demonstrate their knowledge of opioid pharmacology; and 5) contain education programs targeted toward the public (eg, the dangers in sharing opioids).

Representatives from the Industry Working Group, which consists of 25 companies who market short- and long-acting opioids, presented the following points: 1) a successful REMS should not interfere with effective treatment of patients; 2) success needs to be defined; and 3) it is necessary to ensure that the outcomes of REMS can be measured. The Industry Working Group proposed that the REMS include: 1) product specific medication guides written in plain language, including tear-away wallet cards; 2) specific communication plans for healthcare providers, pharmacists, professional societies, DEA, FDA, trade journals, state licensing boards, Federation of State Medical Boards; 3) elements to insure safe use including prescriber education, training, certification, dispenser education, training and certification, and signed prescriber-patient agreements.

In the opinion of representatives from the generic companies Roxane Laboratories and Covidien, the REMS process has favored innovator companies. For example, the medication guides follow the “brand first” labeling process and prescriber training is conducted through the “brand” sales force. In addition, they stated that current surveillance measures do not identify products by dosage form, strength, or manufacturer. In their opinion, there should be a single-shared system and REMS should be grounded in patient safety, where prescriber training is not provided by the sales force and ANDA holders have input into the patient medication guide.

Representatives from Roxane Laboratories and Covidien also argued that methadone should have its own REMS for the following reasons: it is not formulated as a sustained-release product; it has both pain and addiction treatment indications, while other opioids are only indicated for pain; methadone prolongs the QTc interval, which does not occur with other products.

Several groups (eg, American Pain Foundation, risk management professionals, the Industry Working Group) recommended that the REMS should begin with a pilot. A representative from a company that implements and tracks REMS predicted that the development of such a program with participation by approximately 25 companies would probably take at least 1 year.

Throughout the 2-day meeting, the FDA panel members repeatedly expressed concerns about:

1. What should the metrics for the REMS be and how should success be measured?
2. What baseline data for the REMS exist?
3. What educational measures have been used successfully?
4. What data exist to support the success of educational measures?
5. How do we find a balance between the “need for immediate action” and the call to “not do anything until we can do it right”?

How will this opioid REMS affect drug companies considering using the 505(b)(2) regulatory pathway for development of opioid products (eg, modified release, change in formulation, novel combination)?

• A REMS for opioid products will likely result in a delay in product approval while a class REMS is under development
• This REMS could facilitate or discourage new drugs and dosages from development
• This REMS is likely to place restrictions on prescribing, distribution, and dispensing of opioid drugs
• There will likely be an increased cost for REMS compliance, a possible need to contribute to databases, possible registries for patients using opioids, mandatory certification for prescribers and dispensers, increased patient education, and increased continuing education requirements

FDA maintains a web site summarizing actions to date.