REMS and Risk Management 2014: A Year in Review will begin at 12:01 pm ET

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Oswin Mills
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4 Q&A Submitting Questions:» Type question in the Q&A box WEBINAR» All submitted questions are only displayed to the Host & Presenters» Answers to your questions will be addressed verbally during Q&A Submit questions here inventiv Health. All rights reserved.

Data Sources & Definitions used for Analysis Data* derived from: FDA monthly reports of NDA and BLA Approvals http://www.fda.

7 Data Sources & Definitions used for Analysis Data* derived from: FDA monthly reports of NDA and BLA Approvals DrugandBiologicApprovalReports/ucm htm FDA Approved Risk Evaluation and Mitigation Strategies (REMS) ucm htm Currently approved individual REMS Currently approved Single Shared System REMS Released REMS *Data available as of December 19, inventiv Health. All rights reserved.

FDA.gov (Approved Risk Evaluation and Mitigation

REMS Approvals (N=221) 2008 2014 72 60 26 33 12 8 10 2008 2009 2010 2011 2012 2013 2014 REMS approvals have decreased

Products with REMS and Black Box Warnings (N=77) 2008

In 2014, all newly approved REMS had products with a

Total NDA and BLA Approvals 2008 2014 76 84 82 89

was a 10% increase of NDA/BLA approvals between 2013

Comparing NDA/BLA Approvals with NDA/BLA Approvals with REMS 2008 2014 84 82 89 103 92 102 76

14 Comparing NDA/BLA Approvals with NDA/BLA Approvals with REMS % 35% 28% 13% 11% 5% 9% inventiv Health. All rights reserved. Total NDA/BLA Approvals NDA/BLA Approvals with REMS % NDA/BLA approvals with REMS Of the 102 NDA/BLA approvals in 2014, 9 products were approved with a REMS.

Comparing NDA/BLA Approvals, NME Approvals, and NMEs with REMS 2008 2014 Since 2008, the average number of NMEs approved per

76 84 82 89 103 92 102 39 33% 42% 48% 23% 15% 15% 35 30 27 24 26 21 8 11 10 7 6 4 9 2008 2009 2010 2011 2012 2013 2014 26%

15 Comparing NDA/BLA Approvals, NME Approvals, and NMEs with REMS Since 2008, the average number of NMEs approved per year was % 42% 48% 23% 15% 15% % NDA/BLA Approvals NME Approvals NME Approvals with REMS % Novel Approvals with REMS 15 Of the 102 NDA/BLA approvals in 2014, 35 were New Molecular Entities. Of those 35 NMEs, 9 were approved with a REMS inventiv Health. All rights reserved.

2014 REMS Approvals (N=10) 2014 Jan Feb Mar Apr May Jun Jul

17 Approved Individual REMS Product Indication Risk(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) REMS Element(s) ETASU 2 Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU 3 Tanzeum (albiglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis 4 Vogelxo (testosterone) Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide 5 Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia 6 Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm 7 Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation 8 Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis 9 Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU Blincyto Philadelphia chromosome-negative precursor B-cell 10 (blinatumomab) acute lymphoblastic leukemia inventiv Health. All rights reserved. Cytokine release syndrome, neurological toxicities, preparation and administration errors

18 4 of the approved individual REMS are for products indicated to treat diabetes Product Indication Risk(s) REMS Element(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) ETASU Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU 1 Tanzeum (albiglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Vogelxo (testosterone) Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide 2 Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia 3 Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation 4 Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU Blincyto Philadelphia chromosome-negative precursor B-cell 18 (blinatumomab) acute lymphoblastic leukemia 2015 inventiv Health. All rights reserved. Cytokine release syndrome, neurological toxicities, preparation and administration errors

19 2 products are indicated to treat low testosterone Product Indication Risk(s) REMS Element(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) ETASU 1 Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU Tanzeum (albiglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis 2 Vogelxo (testosterone) Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU Blincyto Philadelphia chromosome-negative precursor B-cell (blinatumomab) acute lymphoblastic leukemia inventiv Health. All rights reserved. Cytokine release syndrome, neurological toxicities, preparation and administration errors

20 2 products are indicated to treat cancer Product Indication Risk(s) REMS Element(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) ETASU Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU Tanzeum (albiglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Vogelxo (testosterone) Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm 1 Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU 2 Blincyto (blinatumomab) inventiv Health. All rights reserved. Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia Cytokine release syndrome, neurological toxicities, preparation and administration errors

21 7 of the 10 approved REMS in 2014 contain a Communication Plan Product Indication Risk(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) REMS Element(s) ETASU Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU 1 Tanzeum (albiglutide) Vogelxo (testosterone) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide 2 Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia 3 Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm 4 Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation 5 Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis 6 Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU Blincyto Philadelphia chromosome-negative precursor B-cell 7 (blinatumomab) acute lymphoblastic leukemia inventiv Health. All rights reserved. Cytokine release syndrome, neurological toxicities, preparation and administration errors

22 only 2 of the 7 approved REMS with a Communication Plan have identical risks Product Indication Risk(s) Myalept (metreleptin) Adjunct to diet as replacement therapy to treat complication of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Serious adverse sequelae (severe infections, excessive weight gain, glucose intolerance, diabetes mellitus) REMS Element(s) ETASU Aveed (testosterone undecanoate) Testosterone replacement in adult males with primary hypogonadism or hypogonadotropic hypogonadism Pulmonary oil microembolism and anaphylaxis ETASU 1 Tanzeum (albiglutide) Vogelxo (testosterone) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Treatment in adult males for low or no testosterone Transference/exposure to women or children MedGuide Symlin (pramlintide acetate) Type 1 or type 2 diabetes in patients who use mealtime insulin and failed to achieve desired glycemic control Severe hypoglycemia Afrezza (insulin human) Improve glycemic control in adult patients with diabetes Acute bronchospasm Zydelig (idelalisib) Relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-hodgkin lymphoma, relapsed small lymphocytic lymphoma Fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, intestinal perforation 2 Trulicity (dulaglutide) Type 2 diabetes mellitus Medullary thyroid carcinoma, acute pancreatitis Lemtrada (alemtuzumab) Relapsing forms of multiple sclerosis Autoimmune conditions, infusion reactions, malignancies ETASU Blincyto Philadelphia chromosome-negative precursor B-cell (blinatumomab) acute lymphoblastic leukemia inventiv Health. All rights reserved. Cytokine release syndrome, neurological toxicities, preparation and administration errors

23 Communication Plan Materials Product HCP REMS Letter Prof Society RPh Fact Sheet Website Tanzeum X X X X Symlin X X X X Afrezza X X X X Journal Piece Patient Info Card Zydelig X X X X X X Trulicity X X X X Lemtrada X X Blincyto X X X X X The majority of the Communication Plan elements are identical inventiv Health. All rights reserved.

Communication Plan Example: Zydelig REMS REMS

quarterly in 6 publications Patient Info Card

Accompanied by REMS Fact Sheet and PI Available on

after approval With REMS Letters By Sales & Medical

website Distributed by Sales or Medical Reps to

24 Communication Plan Example: Zydelig REMS REMS Letters REMS Fact Sheet Journal Piece Published quarterly in 6 publications Patient Info Card Distributed within 30 days after approval Accompanied by REMS Fact Sheet and PI Available on REMS website Distributed during the first 12 months after approval With REMS Letters By Sales & Medical Reps Displayed at scientific mtgs Available on REMS website Distributed by Sales or Medical Reps to prescribers Available on REMS website inventiv Health. All rights reserved.

Communication Plan / ETASU Example: Lemtrada REMS RPh certification HCP certification Review the

complete the REMS Knowledge Assessment Complete and sign the Prescriber Enrollment Form Enroll

Information Care Submit REMS Prescription Ordering Form for each Rx Perform baseline and period

Report any AEs Notify Genzyme if an enrolled patient is no longer under care within the last 48

Overview and REMS Education Program Ensure all staff are educated and trained Verify a REMS

is enrolled HC facility certification Designate an authorized rep Submit completed REMS

the risks and provide What you Need to Know about Lemtrada Treatment and Infusion Reactions

2015 inventiv Health. All rights reserved.

25 Communication Plan / ETASU Example: Lemtrada REMS RPh certification HCP certification Review the Prescribing Information Review the Lemtrada REMS Overview and REMS Education Program Successfully complete the REMS Knowledge Assessment Complete and sign the Prescriber Enrollment Form Enroll each patient and provide What you Need to Know about Lemtrada Treatment and Patient Safety Information Care Submit REMS Prescription Ordering Form for each Rx Perform baseline and period monitoring Submit Patient Authorization and Baseline Lab Form Complete REMs Patient Status Form Report any AEs Notify Genzyme if an enrolled patient is no longer under care within the last 48 months Designate an authorized rep Submit completed REMS Enrollment Form Review the Lemtrada REMS Overview and REMS Education Program Ensure all staff are educated and trained Verify a REMS Prescription Ordering Form is received Verify prescriber and infusion site is certified; patient is enrolled HC facility certification Designate an authorized rep Submit completed REMS Healthcare Facility Enrollment Form Review the Lemtrada REMS Overview and REMS Education Program Ensure all staff are educated and trained Verify a REMS Prescription Ordering Form is received Verify prescriber and infusion site is certified; patient is enrolled Counsel patients about the risks and provide What you Need to Know about Lemtrada Treatment and Infusion Reactions Monitor patients during and for 2 hours after each infusion Complete a REMS Infusion Checklist inventiv Health. All rights reserved.

Elements of Current Individual REMS* 14% 49% 27% 10% MedGuide MedGuide + Communication

Released REMS (N=145) 99 33 1 1 7 4 2009 2010 2011 2012 2013 2014 68% of the

30 Data Source Discrepancies: January 2014 through December Nucynta ER Original REMS approval on 8/25/2011 Joined the ER/LA SSS REMS in 2012 Added to the released REMS list in 2014, although the data source depicts that it had been released of its REMS on 7/ Metoclopramide Oral Solution (ANDA ) Added to the released REMS list in 2014, although the data source depicts that it was released on 7/31/ Metoclopramide Oral Solution (ANDA ) Added to the released REMS list in 2014, although the data source depicts that it was released on 9/10/ inventiv Health. All rights reserved.

31 Single Shared System REMS = Isotretinoin ipledge REMS Transmucosal Immediate-Release Fentanyl (TIRF) Products REMS Extended-Release and Long-Acting (ER/LA) Opioid Analgesics REMS Est Est Est Mycophenolate REMS Est Rosiglitazone REMS Est Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) REMS Est Each Single Shared System REMS is shared by multiple sponsors and contains 31 elements including MedGuides and Elements to Assure Safe Use inventiv Health. All rights reserved.

32 Current Products within Single Shared System REMS = Isotretinoin ipledge REMS Transmucosal Immediate-Release Fentanyl (TIRF) Products REMS Extended-Release and Long-Acting (ER/LA) Opioid Analgesics REMS Mycophenolate REMS Rosiglitazone REMS Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) REMS = Number of products (NDAs or ANDAs) in each Single Shared System REMS as of December 31, inventiv Health. All rights reserved.

Trends observed in 2014 Increased percentage of newly approved REMS with Communication Plan s versus any other REMS element 70% of the new REMS for 2014 were approved with a Communication Plan 88% of

33 Trends observed in 2014 Increased percentage of newly approved REMS with Communication Plan s versus any other REMS element 70% of the new REMS for 2014 were approved with a Communication Plan 88% of the new REMS for 2013 were approved with ETASU (including the two single shared system REMS) 10 for 10 in black box warnings 100% of the REMS approvals in 2014 were approved with a black box warning More REMS targeted toward one indication versus any other 40% of the new REMS for 2014 were indicated to treat diabetes Decreased rate of releasing REMS obligations by 57% compared to 2013 Only 4 REMS were released of their REMS requirement in inventiv Health. All rights reserved.

34 FDA and industry are working to standardize REMS FDAAA REMS Guidance CDER Issue Paper: REMS Assessments PDUFA V Reauthorization IOM Report ISPE Response to FDA Questions Public Meeting: Standardizing & Evaluating REMS Public Workshop: Survey Methodologies Expert Workshop: Strengthening REMS through Systematic Analysis, Standardized Design, & Evidence-Based Assessment Report: Standardizing & Evaluating REMS inventiv Health. All rights reserved.

35 FDA and industry are working to standardize REMS FDAAA REMS Guidance CDER Issue Paper: REMS Assessments PDUFA V Reauthorization IOM Report ISPE Response to FDA Questions Public Meeting: Standardizing & Evaluating REMS Public Workshop: Survey Methodologies Expert Workshop: Strengthening REMS through Systematic Analysis, Standardized Design, & Evidence-Based Assessment Report: Standardizing & Evaluating REMS inventiv Health. All rights reserved.

36 PDUFA V Reauthorization Goals By the 1 st quarter of FY 2014, FDA will: Issue a report of its findings (related to standardization) and identify at least one priority project including a work plan for project completion By the end of FY 2014, FDA will: Issue guidance on methodologies for assessing REMS, including methodologies for determining whether a specific REMS with ETASU is commensurate with the specific serious risk and not unduly burdensome on patient access Ref: PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 through inventiv Health. All rights reserved.

37 FDA and industry are working to standardize REMS FDAAA REMS Guidance CDER Issue Paper: REMS Assessments PDUFA V Reauthorization IOM Report ISPE Response to FDA Questions Public Meeting: Standardizing & Evaluating REMS Public Workshop: Survey Methodologies Expert Workshop: Strengthening REMS through Systematic Analysis, Standardized Design, & Evidence-Based Assessment Report: Standardizing & Evaluating REMS inventiv Health. All rights reserved.

38 FDA and industry are working to standardize REMS FDAAA REMS Guidance CDER Issue Paper: REMS Assessments PDUFA V Reauthorization IOM Report ISPE Response to FDA Questions Public Meeting: Standardizing & Evaluating REMS Public Workshop: Survey Methodologies Expert Workshop: Strengthening REMS through Systematic Analysis, Standardized Design, & Evidence-Based Assessment Report: Standardizing & Evaluating REMS inventiv Health. All rights reserved.

Standardizing and Evaluating REMS Introduction FDA announced on Sept 23, 2014 the availability of a draft report entitled Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (REMS).

39 Standardizing and Evaluating REMS Introduction FDA announced on Sept 23, 2014 the availability of a draft report entitled Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (REMS). This report describes the Agency s findings concerning strategies to standardize risk evaluation and mitigation strategies (REMS), where appropriate, with the goal of reducing the burden of implementing REMS on practitioners, patients, and others in various health care settings. FDA is requested comments to the draft report by November 24, 2014 Docket No. FDA 2013 N inventiv Health. All rights reserved.

Report Contents Executive Summary Overview» Background» REMS Integration Stakeholder Feedback» Outreach activities» Feedback Priority Standardization

40 Report Contents Executive Summary Overview» Background» REMS Integration Stakeholder Feedback» Outreach activities» Feedback Priority Standardization Projects» Patient Benefit-Risk Information» HCP Education» Pharmacy Systems» Practice Settings Conclusion inventiv Health. All rights reserved.

41 Overview REMS Integration Initiative Oversee the activities of three work groups with specific deliverables that will fulfill commitments FDA made under PDUFA V The Policy Work Group The Design and Standardization Work Group The Evaluation Work Group Developing draft guidance to determine whether a REMS is necessary to ensure benefits of drug outweigh risks Leads efforts to identify best practices to incorporate into future REMS design, standardize REMS tools, and integrate REMS into the health care delivery system Lead effort to develop an evidence-based approach to assessing the effectiveness and burden of REMS and developing draft guidance for assessing the effectiveness of REMS inventiv Health. All rights reserved.

42 Stakeholder Feedback FDA should use human factor evaluation approaches like Failure Mode and Effects Analysis (FMEA) to support and standardize REMS program design inventiv Health. All rights reserved.

Stakeholder Feedback FDA should use human factor evaluation approaches like Failure Mode and Effects Analysis (FMEA) to support and standardize REMS program design.

43 Stakeholder Feedback FDA should use human factor evaluation approaches like Failure Mode and Effects Analysis (FMEA) to support and standardize REMS program design. pharmaceutical industry and regulators can assess and manage risk using recognized risk management tools. Failure Mode Effects Analysis (FMEA) inventiv Health. All rights reserved.

44 Priority Standardization Projects As part of the PDUFA V commitments, FDA agreed to at least one priority project in each of the following areas: Project 1: Providing benefit/risk information to patients Project 2: Prescriber education Project 3: Pharmacy systems Project 4: Practice settings inventiv Health. All rights reserved.

45 Conclusion FDA remains committed to systematic evaluation and improvement of REMS program implementation, informed by stakeholder feedback and reflecting the dynamic and evolving nature of the drug development process inventiv Health. All rights reserved.

46 Q&A Submitting Questions:» Type question in the Q&A box WEBINAR» All submitted questions are only displayed to the Host & Presenters» Answers to your questions will be addressed verbally during Q&A Submit questions here inventiv Health. All rights reserved.

47 FoREMS & More Occurs the second Wednesday of every month at 12:00 pm ET Topic ideas? Guest speaking opportunities? Feedback? Contact us: Jenna Sisler Next webinar: Wednesday, February 11 th inventiv Health. All rights reserved.

Comprehensive support for your patients on MYALEPT

Comprehensive support for your patients on MYALEPT Insurance and financial assistance options (see page 3) Fulfillment support (see page 6) Co-pay assistance a,b (see page 4) Your patient Injection training