Implications of REMS for NPs

1. Implications of REMS for NPs A panel presentation.

2. Panel Members • Lt. Commander Kendra Worthy, PharmD • FDA • Marsha Stanton, PhD, RN • Pfizer, Inc. • Jan Towers, PhD, NP-C, CRNP, FAANP, FAAN • AANP • Deb Kiley, DNP,NP-C, FNP-BC, FAANP • Private Practice

3. MODERATED BY: JoEllen Wynne, RN, MSN, FNP-BC, FAANP

4. AANP 2011 Disclosures • Kendra Worthy, Jan Towers, Deb Kiley and JoEllen Wynne have nothing to disclose. • Marsha Stanton is employed by Pfizer, Inc.

5. AANP 2011 Objectives • Describe the basic elements of Risk Evaluation and Mitigation Strategies (REMS). • Describe the factors FDA considers in determining whether a REMS is required. • Discuss current legislative proposals specific to REMS for long acting and sustained release opioids. • Review provider response to current legislative proposals specific to REMS for long acting and sustained release opioids.

6. AANP 2011 Lt. Commander Kendra Worthy Risk Management Analyst Team Leader Division of Risk Management Office of Surveillance and Epidemiology, FDA.

7. Outline • Define REMS • Determining the need for a REMS • ER/LA Opioid REMS • TIRF REMS • Implications for Nurse Practitioners

8. Food and Drug Administration Amendments Act (FDAAA) of 2007 • FDAAA Title IX – enhanced authorities regarding postmarket safety of drugs • New authorities to • Require postmarketing studies and clinical trials • Require sponsors to make safety related labeling changes • Require applicants to develop and comply with Risk Evaluation and Mitigation Strategies (REMS) if necessary to ensure that the benefits of the drug outweigh its risks • Provisions took effect on March 25, 2008

9. What is a REMS?Risk Evaluation and Mitigation Strategy • FDAAA term • A risk management plan that utilizes tools beyond routine labeling “to ensure that the benefits of a drug outweigh its risks.” • FDA can require a REMS: • Before approval if FDA determines a REMS is necessary • Post-approval if FDA becomes aware of new safety information and determines that a REMS is necessary • Applies to New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologic License Applications (BLAs) • Requirements differ slightly for ANDAs

10. REMS Elements • A REMS can include: • Medication Guide • Communication plan • Elements to assure safe use • Prescriber training/certification • Pharmacy training/certification • Dispensed only in certain health care settings • Dispensed to patients with evidence of safe-use conditions • Each patient is subject to monitoring • Patient enrollment in a registry • Implementation system • Must include a timetable for submission of assessments of the REMS

11. REMS Are Not Exactly New 16 drugs approved with restrictive risk management programs before FDAAA Products with restrictions prior to FDAAA were deemed to have a REMS (e.g., thalidomide, isotretinoin) FDAAA clarified FDA’s authority to require enforceable risk management programs (REMS) REMS built on previous experience with risk management programs and the Guidance for Industry- Development and Use of Risk Minimization Action Plans (RiskMAPs; finalized March 2005)

12. New draft Medication Guide (MG) Guidance Draft Guidance for IndustryMedication Guides — Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS) Issued February 25, 2011 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM244570.pdf

13. When a Medication Guide Must Be Distributed If drug is dispensed in outpatient settings to be used by patient without direct supervision by a HCP The first time a drug is dispensed to a HCP for administration to patients in an outpatient setting The first time a drug is dispensed in any outpatient setting after Medication Guide is materially changed If a patient or patient’s agent requests a MG If the MG is part of a REMS that includes specific requirements for the review of the MG

14. When a Medication Guide is Not Required to be Distributed – With Exceptions FDA will not require distribution of a MG to a patient when a drug is dispensed to a HCP for administration to a patient in an outpatient setting, such as clinic, dialysis, or infusion center EXCEPT if pt or pt’s agent requests a MG EXCEPT if the MG is part of a REMS that includes specific requirements for the distribution of the MG EXCEPT for the first time the drug is dispensed EXCEPT when the MG is materially changed

15. Determining the Need for a REMS

16. How does FDA determine that a REMS is required? • Decisions to require a REMS are made on a case-by-case basis • OND and OSE decide together • FDA considers the factors outlined under FDAAA • Size of the population likely to use the drug • Seriousness of the disease • Expected benefit of the drug • Expected duration of treatment • Seriousness of known or potential adverse event • Whether the drug is a new molecular entity

17. How does FDA determine that a REMS is required? • Other considerations include but are not limited to the following: • What is the risk that has been identified? • What is the risk in context of other drugs in its class, among other drugs used to treat the disease? • What is prescribers’ familiarity with risk, monitoring, and management? • How is the risk managed for other drug products and/or disease states? • What population(s) are at risk? • Has the risk been fully characterized? • Can the risk be managed through an intervention? • Is the adverse event reversible? • How is the product likely to be used in the post-marketing setting?

18. Approved REMSMarch 25, 2008- May 18, 2011 ETASU 19 MG-Only REMS 124 More than MG 58 Communication Plan 39 Deemed 6

19. Opioid REMS

20. Opioid REMS – Background • Prescription opioid abuse increasing problem • CDC: drug overdose death rates in the US increased approximately five-fold since 1990 • Largely due to prescription opioid drug abuse and misuse • For deaths attributed to drugs, the most common drug categories are cocaine, heroin, and opioid prescription drug products • By 2006, data showed that prescription opioids were involved in more overdose deaths than heroin and cocaine combined

21. Opioid REMS – Background • 2009/2010: FDA held several public meetings to hear different perspectives on management of opioid abuse • Effort to address opioid abuse included • ONDCP, DEA, FDA, SAMHSA, and CDC • Balance between continued access to opioids and stronger measures to reduce risks For more information: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm

22. 12 branded products Fentanyl transdermal (Duragesic) Methadone Hydrochloride (Dolopine) Morphine Sulfate (Avinza) (Kadian) (MS Contin) (Oramorph) Morphine Sulfate and Naltrexone (Embeda)* Oxycodone Hydrochloride (OxyContin) Oxymorphone Hydrochloride (Opana ER) Hydromorphone Hydrochloride (Exalgo) (Palladone)* Burprenorphone transdermal (Butrans) * Not currently marketed 17 generic products Fentanyl transdermal (7) Methadone (3) Morphine (4) Oxycodone ER (3) Extended Release/Long-Acting (ER/LA) Opioid REMS

23. ER/LA Opioid REMS • Medication Guide • Working on new template • Element to Assure Safe Use • Sponsor to ensure training is provided • Training will be conducted by accredited, independent continuing medical education provider • Sponsor must provide prescribers information that prescribers can use to educate patients (outline included) • Inform prescribers of the existence of the REMS and the need to successfully complete the voluntary training

24. Content of Education Program for ER/ LA Opioid REMS • Patient Selection and Assessment • Considerations when prescribing opioids • Managing patients taking opioids • Initiating and modifying dosing of opioids for chronic pain • Maintenance (reassessment & tolerance) • Monitoring patients for misuse and abuse • Product Specific Information • Patient counseling

25. Transmucosal Immediate Release Fentanyl (TIRF) REMS • Products • Fentanyl Citrate sublingual tablet (Abstral) is the only approved “TIRF REMS” • Fentanyl Citrate transmucosal troche/lozenge (Actiq) • Fentanyl Citrate buccal tablet (Fentora) • Fentanyl Citrate buccal film (Onsolis) • Goal • Mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors

26. Transmucosal Immediate Release Fentanyl (TIRF) REMS • Medication Guide • Elements to assure safe use • Prescriber Enrollment for outpatient use • Pharmacy Enrollment • “Documentation of safe use conditions” via a Patient-Prescriber Agreement • Linkage to dispensing

27. Implications for Nurse Practitioners

28. Implications for Nurse Practitioners • Will vary depending on state • May be subject to certain conditions if prescribing drug subject to a REMS • Complete duties within standard clinical practice • Distribute MG and patient counseling materials • Appropriate patient selection • Screening for patients at risk for abuse/addiction

29. Fentanyl Citrate sublingual tablet Darbopoetin Alfa (Aranesp) Rosiglitazone Maleate and Metformin Hydrochloride (Avandamet) Rosiglitazone Maleate and Glimepiride (Avandaryl) Rosiglitazone Maleate (Avandia) Buprenorphine transdermal Alvimopan (Entereg) Epoetin Alfa (Epogen/Procrit) Drugs with REMS that include Prescriber Certification or Training

30. Drugs with REMS that include Prescriber Certification or Training (cont’d) • Icodextrin (Extraneal) • Isotretinoin • Ambrisentan (Letairis) • Alosetron (Lotronex) • Alglucosidase Alfa (Lumizyme) • Mifepristone (Mifeprex) • Romiplostim (Nplate) • Fentanyl Citrate buccal tablet

31. Oxycodone controlled-release tablets Eltrombopag (Promacta) Lenalidomide (Revlimid) Vigabatrin (Sabril) Buprenorphone and Naloxone Sublingual Film (Suboxone) Thalidomide (Thalomid) Bosentan (Tracleer) Vandetanib Olanzapine Extended Release Injection (Zyprexa Relprevv) Drugs with REMS that include Prescriber Certification or Training (cont’d)

32. Sources of Information • Food and Drug Administration Amendments Act (FDAAA) of 2007: http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm • DRAFT Guidance - Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf • Approved Risk Evaluation and Mitigation Strategies (REMS) available on FDA website: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm • Deemed REMS Federal Register Notice: http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-6201.pdf

33. AANP 2011 Marsha Stanton, Ph.D., R.N., Sr. Director of Advocacy and External Affairs for Pfizer, Inc.

34. A duty of care • Opioids are an essential component of the management of patients with moderate-to-severe pain • Opioids can be used very effectively with optimal results in the appropriate patients • However: • Opioids are associated with significant risks • There has been a continued rise in the non-medical use of opioids each year • There has been a significant increase in the rates of misuse, abuse and diversion of opioids causing great concern in all communities and at the Federal level (ONDCP document) • These factors have led to a significant public health crisis

35. The Manufacturer Role in REMS • FDA advisory committee December 4, 2009, IWG provided their plan to FDA • FDA advisory committee July 22-23, 2010, to discuss FDA REMS proposal • April 19, 2011 – FDA held teleconferences with all stakeholders and sent letters to 20 companies with instructions for completion of the opioid REMS plan • Sponsors have 120 days to complete submissions – August 17, 2011 sponsor plans submitted to FDA • The plan is expected to take effect in early 2012 • Sponsors are working to complete their requirements, which include funding of CME/CE, new medication guides, updated product information and all supporting documentation

36. Specific products’ existing REMS Timetable for Assessment Implementation System Communication Plan Medication Guide ETASU http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. Accessed January 2010.

37. Elements to assure safe use Draft Guidance. Guidance for Industry: Format and content of proposed Risk Evaluation and Mitigation Strategies (REMS), REMS assessments, and proposed REMS modifications. US Department of Health and Human Services. Food and Drug Administration, September 2009. • Are required if the drug is associated with a serious adverse event and an assessment plus medication guide, PPI or communication plan are not sufficient to mitigate these risks • Will require some of the following: • Training/certification of prescribers • Training/certification of pharmacies and hospitals • Restrictions on where drug is dispensed • Evidence of patient safe use conditions • Patient monitoring • Enrollment of patient in a registry

38. Communication Plan • Dear Healthcare Provider Letter • Product Specific Information • Patient-Provider agreement • Patient Medicine Information Sheet • Revised Medication Guides for the Pharmacists • Other supporting documents

39. Training/certification of prescribers • Certification of training or specific experience/knowledge required before enrollment in a REMS program • Providers will be required to demonstrate that they: • Can diagnose the condition for which the product is indicated • Understand the risks and benefits of the drug and have read the educational materials • Can diagnose and treat potential adverse reactions associated with the drug • Prescribers will have to periodically recertify and re-enroll • DEA may be the best option – currently being considered Draft Guidance. Guidance for Industry: Format and content of proposed Risk Evaluation and Mitigation Strategies (REMS), REMS assessments, and proposed REMS modifications. US Department of Health and Human Services. Food and Drug Administration, September 2009.

40. Training/certification of prescribers and pharmacists Draft Guidance. Guidance for Industry: Format and content of proposed Risk Evaluation and Mitigation Strategies (REMS), REMS assessments, and proposed REMS modifications. US Department of Health and Human Services. Food and Drug Administration, September 2009. In general, more emphasis will be placed on education of medications and their risks/benefits There will be more utilization of PDMPs – more state to state connectivity is desired Prescribers in hospitals/clinics/long term care, etc. will not be excluded from training requirements Those with special training in pain management will not be excluded from the new requirement – no “Grandfathering” at the current time No training or certification at present for pharmacists, however there may be a need in the future

41. Evidence of patient safe use conditions Draft Guidance. Guidance for Industry: Format and content of proposed Risk Evaluation and Mitigation Strategies (REMS), REMS assessments, and proposed REMS modifications. US Department of Health and Human Services. Food and Drug Administration, September 2009. • There will need to be documentation that shows: • Counseling patients about the risks and benefits of the product • Patients provided with a copy of the educational materials and have demonstrated understanding of the risks and benefits of the product • Monitoring patients’ laboratory tests on a periodic basis to prevent serious risk (e.g., pregnancy test) • Re-evaluation that shows patients are still appropriate candidates - periodically after beginning treatment • Monitor and follow up patients at regular intervals to ensure they did not experience any serious risk associated with the use of the drug

42. Jan Towers, PhD, NP-C, CRNP, FAANP, FAAN Director of Health Policy/Federal Government and Professional Affairs, AANP

43. Deb Kiley, DNP,NP-C, FNP-BC, FAANP The Pain Management Balancing Challenge Feeling like Goldilocks What is an NP to do?

44. Reality Patients have pain They need care They need advocates There is an increased focus on opioid - related deaths as well as drug abuse and diversion Government regulation is increasing Change will continue

45. Challenges and Rewards Knowledge Practice processes Networking Documentation

46. Important to Remember: “There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But, there are also unknown unknowns. There are things we don't know we don't know.” Donald Rumsfeld

47. Strategies • Do a SWOT • Internal • Strengths • Weaknesses • External • Opportunities • Threats

48. Strategies Consider non pharmaceutical approaches- use all of your skills when managing pain Be Proactive • Watch for policy changes, opportunities to comment • Educate your colleagues- tell 2 NPs what you learned here today

49. Strategies Educate yourself • Appropriate use of opioids • Current standards for pain management • Assessing for addiction , diversion • Alternative therapies • What are the state and federal regulations • Does your state have a PDMP?

50. “Things turn out best for the people who make the best of the way things turn out” Coach John Wooden