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U.S. Department of Health and Human Services


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Preliminary Responses to Industry Questions About Opioid REMS

FDA is providing preliminary responses to the following questions, discussed at an FDA-Industry Working Group (IWG) Face-to-Face Meeting on May 16, 2011.

Prescriber Training

1. What did FDA intend regarding the content development for prescriber training? (ACCME indicated that an approved CE1 provider should develop everything beyond the outline FDA has already provided.)  Does FDA expect the IWG to develop training materials, or should the CE provider develop this material with IWG input?  What level of cooperation is expected?

FDA expects the holders of pending and approved applications to work together to develop the content for the prescriber education:  the blueprint for CE providers to use to develop the actual course content.  The blueprint, which should be submitted as part of the proposed REMS and will be appended to the approved REMS, should expand on the outline attached to the REMS notification letter, capturing the key messages that are to be communicated to prescribers about each of the topics in the outline.  FDA will review the blueprint, suggest modifications, and ultimately approve the blueprint.  FDA’s review will ensure (1) that the blueprint contains the information prescribers need to safely and effectively manage pain with LA/ER opioids and (2) that the content is not promotional. 

2. How will the approved content be made available to accredited CE providers?

Once a REMS is approved, FDA will post the related blueprint on its web site as part of the approved REMS.  Accredited CE providers will be able to access it and turn the content into actual training materials without further involvement by the application holders. 

3. How will CE development be funded?  Will the CE training be available to prescribers free of charge?

FDA expects the application holders, through the single shared system, to issue one or more requests for proposals (RFPs) for accredited CE providers to turn the approved blueprint into CE training courses.  Chosen proposals will be eligible for unrestricted grants under letters of agreement to take the approved blueprint and develop the courses. Through this funding mechanism, FDA expects the CE training to be made available to prescribers free of charge.

4. Who will be responsible for assessing the quality of the CE training materials?

As discussed in the notification letter, FDA expects the sponsors, through the single shared system, to hire an independent auditor to evaluate the quality of the content of the CE materials developed by the accredited CE providers.  The audit should determine how well the CE materials reflect the content of the blueprint approved by FDA as part of the REMS as well as how the content meets the ACCME and other accreditation body standards for CE.

5. How will sponsors determine how many prescribers have taken the training? 

As part of the assessment of whether the REMS is meeting its goals, through the single shared system, sponsors will be expected to develop a mechanism for determining how many prescribers of LA/ER opioids have successfully completed the CE training.  Sponsors should consult with ACCE, other accreditation bodies, and CE providers to determine how this information can be collected and how to establish realistic goals for how many prescribers can be trained through an aggressive CE program.  Collecting this information could be required as part of the RFP.

6. FDA had indicated in one teleconference that they are working on a patient/prescriber agreement.  Can FDA please send the IWG a copy of this agreement so we can review and consider using it as a part of the educational material for the patient in our draft REMS?    

FDA does not expect sponsors to develop a PPA (or PPAs) as a part of the response to the REMS letter, although industry should address in the prescriber training materials how PPAs could be used to facilitate appropriate patient use of their opioid therapies. 

In addition, as a part of the ONDCP Rx Drug Abuse Plan, FDA is working with stakeholders in the health care community to develop two model PPAs that can be used, when appropriate, by physicians and patients. Two separate model documents are being discussed:  (1) for patients who are using opioids (possibly for the first time) for acute pain and (2) for those patients who are either entering into long-term pain care or who are in chronic pain care.  The documents, once completed, will be available on FDA’s Safe Use web site as well as on web sites of other stakeholders.  We can share the essential elements of the ongoing work with the IWG once we have consensus in the FDA working group.  We welcome any suggestions you have in this regard.

7. The IWG would like to organize a three-way, face-to-face meeting of FDA, the IWG, and ACCME.  Recent discussions between IWG member companies and ACCME indicate that there are several unresolved issues related to how the content that is developed by the IWG will be made available to CE providers in a way that ACCME is comfortable with.  Would the FDA participate in such a meeting? 

FDA would be willing to participate in a meeting, but FDA has had separate discussions with ACCME through which we have confirmed that the model described in the response to question 1 for developing the content of the CE for prescribers (the blueprint) as well as the development and funding of the actual CE courses will be acceptable to ACCME.  FDA intends to have conversations with other accreditation bodies to discuss the model.  

Medication Guides

8. The REMS notification letter states: “The Medication Guide should have both common content applicable to all LA/ER opioids as well as product-specific information that is necessary for safe and effective use of the drug.”  What does the FDA mean by product-specific?  Does FDA mean each product individually?  Are separate Medication Guides needed for different dosage forms and/or delivery systems?  Or can Medication Guides be developed, based on a drug’s active molecule (i.e., all oxycodone products regardless of the formulation would have the same Medication Guide)?  Please clarify what FDA expects.

Each innovator will have a Medication Guide that includes common content applicable to the class of LA/ER opioids that is to be developed as part of the single shared system as well as product-specific information (e.g., specific use instructions, warnings and precautions, or adverse experiences that may differ by product).  Generic companies are required to have the same Medication Guide as the reference listed drug.

9. Can FDA clarify their expectations regarding the Medication Guides for the class-wide REMS?  Is it FDA’s expectation that each NDA or ANDA product Medication Guide would have text that is common to the class and also NDA/ANDA product-specific information?  Should the IWG continue to focus on developing Medication Guides based on opioid categories as initiated in the IWG draft REMS (oral LAO analgesics, Methadone, LOA transdermal patches)?

FDA does not intend to approve Medication Guides based on opioid categories.

10. Can FDA discuss the preferred approach for developing Medication Guides?  Should all Medication Guides under this program use a common template?  Is there a preferred format that FDA can recommend?  In particular, is there a preferred length (i.e., preferred number of pages)?

We are currently working on a model Medication Guide for the LA/ER opioids that will contain what would be common content for all members of the class and will indicate where product-specific information should be incorporated that differs from product to product.  The model will be provided to sponsors as soon as it is available, and sponsors will have the opportunity to comment on the content and propose revisions before it is submitted as part of the proposed REMS.

11. Appendix B in the REMS notification letter to sponsors has a layout very different from Medication Guides and Patient Medication Information Sheets (PMIS) as previously proposed by the IWG in July 2010.  Is it FDA’s expectation that the patient education document be presented in the format outlined in Appendix B?  Can FDA please confirm whether the patient education document should be general to the class, specific to the active drug substance or delivery system, or be product specific?

The patient education document should be a single sheet of paper (possibly two sided) with the content outlined in Appendix B.  The patient education document should contain common general information and will include a space for prescribers to write in product-specific instructions for patients.

12. For LA/ER opioids that have Medication Guides already approved, are they acceptable as is, or will they need to be updated to reflect FDA’s final decision regarding Medication Guide requirements outlined in the final approved REMS?

Existing Medication Guides will need to be revised to include the common content as well as the product-specific information developed as part of the new REMS. 

REMS Assessment Plan

13. Item #5 of the REMS assessment plan, which refers to the surveillance plan, states “As much as possible, the information should be drug specific.”  Does “drug specific” refer to active drug substance, same dosage form/delivery system, or individual product?    

Information should be collected in as much detail as possible for each individual product, including each unique dosage form/delivery system.  For example, for some higher strength products, the patient must be opioid tolerant before the product can be prescribed.  To the extent practicable, we would like assessments to collect sufficient information at the individual product level to ascertain whether patients who are prescribed the products are, in fact, opioid tolerant. 

14. Item #6 of the REMS assessment plan states “Include methodology for monitoring patterns of prescribing to identify changes in access to these products” in regard to an evaluation of drug utilization patterns.  It will take a number of months to develop detailed methodology with a research organization that has to be approved by the IWG.  The IWG has already proposed a high-level overview of the methodology in the proposed REMS, with more detailed methodology to be developed after the REMS is approved.  Does FDA concur?

The REMS submission should include your proposed methodology for monitoring patterns of prescribing.  Although the methodology proposed in the REMS submission may be preliminary, the REMS submission should provide a timetable for expeditious completion of the methodology. 

15. Item #7 of the REMS assessment plan states “e.g. prescriptions to non-opioid tolerant patients.”  Since the full prescribing information/labels of individual products differ in the indication for the product and since the black box warnings vary in what they include with regard to use in non-opioid tolerant individuals, it might be complicated to conduct a shared REMS assessment of this issue.  Can FDA please comment and explain what the intent is?

We expect companies to work together on a shared REMS assessment.  Although some of the information will be product specific, it should still be collected and included in the shared REMS assessment.

16. The FDA notification letter does not include the usual element of assessment regarding distribution and dispensing of Medication Guides, reports on failure to adhere to the distribution and dispensing requirements, and corrective actions taken to address non compliance.  Is this a deliberate omission by FDA? 

Yes.  These elements are not necessary for these assessments. 


17. Does FDA plan to continue to review and approve ANDAs and NDAs that fall into the category of LA/ER opioids? 


18. What is FDA’s expectation concerning IWG involvement for those companies who do not have an approval but have received a preapproval letter as part of the review of their NDAs/ANDAs?

FDA expects companies with pending applications for an LA/ER opioid to contact the IWG and participate in development of the single shared system for implementing the REMS.

19. Can FDA please clarify what is meant by “stepwise approach”?  This is in reference to Janet Woodcock’s comment at the teleconference when she stated that the agency views the opioid class-wide REMS as being a “stepwise approach.”  

This is apparently a reference to Dr. Woodcock's statements made on April 20 during conference calls with members of the media and agency stakeholders, respectively.  The "step-wise approach" relates to evaluating the need for a potentially more restrictive REMS if this approach doesn’t work. 

In this REMS, we are requiring drug sponsors to develop educational content that will be approved by FDA and made available to prescribers through accredited CE providers, but we are not, at this time, requiring a system to ensure that prescribers have completed this training before they write a prescription for a LA/ER opioid, or before such a drug is dispensed.  Instead, we are working with the Administration to seek legislation that would make prescriber education mandatory under the Controlled Substances Act (CSA) as a precondition for DEA registration.  If the voluntary program under the current REMS is found to be ineffective, FDA will also consider the possibility of developing a mandatory educational program or other measures under the Food and Drug Administration Amendments Act (FDAAA).  We would take into account any mandatory system that might have been put in place under the CSA. 

20. Can FDA please send the IWG a list of companies who have products that fall into the category of LA/ER products so that we can ensure that they are part of the process for finalizing the shared LA/ER class-wide REMS program?

We can provide a list of the companies who have approved products, but we cannot share the names of companies who have pending applications.  We will provide the companies with pending applications with the IWG contact information and ask them to contact the IWG to participate in the development of the single shared system REMS.

21. The ANDA REMS notification letters did not indicate that assessments were a requirement.  Can FDA confirm that assessments are not required for ANDA holders?  If they are required for ANDA holders, is it FDA’s expectation that the assessments conducted by the brand and generic companies be the same?  

FDA expects ANDA holders to participate in the assessments of the REMS to be conducted under the single shared system.  ANDA holders’ products will be considered in the assessments, and ANDA holders have a stake in the outcome of the assessments because any action taken as a result of the assessments will affect both NDAs and ANDAs.

22. The REMS notification letters for NDA holders do not require REMS assessment, stating “FDA strongly recommends that sponsors make provision in the single shared system for joint assessments of the effectiveness of the REMS.”  Is it FDA’s expectation that the NDA holders conduct REMS assessments of the class of LA/ER and share the results with the ANDA holders?

See the response to 21, above.

23. What are FDA’s filing expectations regarding the draft REMS proposal that is due in 120 days?  Does FDA expect that each company file proposed REMS for review or would individual companies be able to submit one common draft REMS program until FDA and the IWG have finalized what the final plan will look like?

FDA expects each company to submit a proposed REMS and REMS supporting document to their own application within 120 days that will reflect the single shared system to implement the REMS that is being developed.  FDA expects the proposed REMS, the REMS supporting documents, and most of the appended REMS materials will be identical for all members of the class.  We expect that Medication Guides will be the only product-specific documents, and as discussed in the responses to the Medication Guide questions, FDA intends to provide a model Medication Guide to be used to develop product-specific Medication Guides. 

In the past, when class-wide REMS have been developed, FDA has seen a wide variety of formats for submitting the REMS.  This has made reviews inefficient.  To ensure efficiency during the review process, FDA will soon be providing more specific guidance for how to structure the electronic submission of the REMS. 


1The training will be provided by accredited CME and other CE providers.  For ease of reference in this document, we refer to the training as CE.