21st Century Cures Act An overview and a focus on Real World Evidence Section 3022 January 18, 2017 | Presented by Kimberly Belsky, Sr Director Regulatory Intelligence Mallinckrodt Pharmaceuticals

Agenda Background and Overview 21st Century Cures Act Real World Evidence Section 3022 How Used Today FDA’s NEJM Publication RWE and PDUFA VI RWE Drug v. Device Related Happenings Additional Information References

21st Century Cures Act Overview

Overview The Cures bill has been in development since early 2015 On December 13, 2016, President Obama signed into law the 21st Century Cures Act (the Act), just days after it passed in the U.S. House of Representatives and Senate The majority of lawmakers in Congress viewed as positive for patients and supported its passage   With an overarching goal of advancing biomedical innovation, the Act makes numerous changes to laws that govern: Food and Drug Administration (FDA) programs, Clinical research regulations, Medicare coverage and reimbursement rules The bill provides $500 million to FDA over 10 years to implement “Development” provisions to accelerated patient access to drugs, while maintaining safety and effectiveness standards

Overview 21st Century Cures Act Organized into Five Titles: Innovation Projects and State Responses to Opioid Abuse Discovery Development Delivery Savings

Overview – Most Relevant to Pharma/Biologics Patient Experience Data (Section 3001) Patient-Focused Drug Development (Sections 3002-3004) Qualification of Drug Development Tools (Section 3011) Priority Review Vouchers (Sections 3013, 3014, & 3086) Human Research Protections (Sections 3023 & 3024) Expanded Access Policies (Section 3032) Limited Population Pathway (Section 3042) Health Care Economic Information (Section 3037) Real World Evidence (Section 3022) Regenerative Advanced Therapies (Sections 3033-3036) Hiring Authority (Section 3072) Targeted Drugs for Rare Diseases (Section 3012) Novel Clinical Trial Designs (Section 3021) Also, medical device provisions but these will not be addressed today

Overview Not all provisions are new But, some are! Many support or expand upon existing FDA initiatives (e.g., Patient Focused Drug Development, Novel Clinical Trial Design, Real World Evidence) alone and/or under PDUFA initiatives Also, MDUFA but devices provisions will not be addressed herein What’s new for some of these are timelines to develop and/or finalize guidance, etc. Refer to end of presentation for an overview of defined timelines in the Act

Expanded Access Policy – Section 3032 Time sensitive!! By February 11, 2017 Requires manufacturers and distributors of investigational drugs for serious diseases publicly post their expanded access policy The public posting must be readily available, such as on an internet website. The posting must include, among other information: The firm’s contact information, requesting procedures, and the criteria used to evaluate requests The posting does not guarantee a patient access to an investigational product under the firm’s policy. The Act broadens recent legislation that required expanded access policies to be posted on www.clinicaltrials.gov for certain studies.3

New and Supports PDUFA VI Modern Trial Design And Evidence Development Real World Evidence for Drugs – Section 3022 New and Supports PDUFA VI

Background: Current Uses of Real World Data FDA already uses real-world data to support post-market surveillance efforts FDA Amendments Act of 2007 required FDA to develop a system for post-market risk identification and analysis of drugs (Sentinel Initiative) Use of real-world data is less common when generating evidence through clinical trials to support drug approval Use of real-world data in pre-market evidence development is not specifically prohibited by law It is not widely used due to the lack of clarity regarding evidence requirements associated with its use views that only RCTs will be accepted by the FDA to support drug approvals

Real World Evidence: Provision 3022 This provision focuses on Drugs “Real world evidence” is defined as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”   The new provisions require FDA to establish a program to evaluate RWE to: Support the approval of a new indication for an approved drug under section 505(c); and Support or satisfy post-approval study requirements

Real World Evidence: Provision 3022 Within 2 years (December 2018) FDA must implement a framework for the RWE program Within 5 years (December 2021), FDA must issue draft guidance describing (1) “the circumstances under which sponsors of drugs may rely” on RWE, and (2) acceptable standards and methodologies for collecting and analyzing RWE This provision states that the new RWE requirements do not limit FDA’s use of RWE for other purposes and do not change the standards of evidence required under sections 505(c) and (d) of the FD&C Act or section 351(a) of the Public Health Service Act.

Real World Evidence: Provision 3022 Approval of a new indication or PMR with use of RWE alone? Wording in the Act is “supports” Interpretation to advance approvals is yet to be defined (RWE data only or in addition to other clinical evidence like a ‘small’ study) The framework will be determined by subsequent public workshops, regulation, and guidance Some of the references suggest RWE as something other than a standalone. There are references to "expand[ing] on previous studies, use of the evidence to "supplement", etc. Other references might, however, suggest a standalone element, at least in narrow contexts. For instance, the reference to RWE "in certain cases where randomization is unethical"

RWE Timelines - Big Picture July 27, 2016 (FDA Draft Guidance on RWE for Medical Devices) Oct 25, 2016 (Comment close on Device Draft Guidance) Dec 13, 2016 (21st Century Cures Enacted) By Dec 2018 (FDA to develop draft framework on RWE) By Dec 2021 (FDA to issue draft guidance on RWE for Drugs) By June 2023 (FDA to Finalize Guidance) – 18 months after issuance of draft

FDA Says

FDA’s RWE for Drugs Article in The New England Journal of Medicine On December 8th, FDA published a commentary on RWE in The New England Journal of Medicine titled Real-World Evidence—What Is It and What Can It Tell Us?  The definition in the article is equivalent to Cures Act and the Device RWE Draft Guidance “information on health care that is derived from multiple sources outside typical clinical research settings, including [EHR], claims and billing data, product and disease registries, and data gathered through personal devices and health applications.” FDA states: Unlike clinical trial strict eligibility criteria and controlled procedures, RWE can provide useful data about actual use in a clinical setting Clinical trial methodologies, such as randomization and planned intervention, are not inconsistent with methods for collection and analysis of RWE Many RWE sources are not organized or optimized for supporting research or regulatory assessments Developing an RWE framework must use relevant RWE that are generated through reliable methods that limit the effect of bias and confounding factors

RWE and PDUFA VI

RWE and PDUFA VI (FY 2018-2022) Commitment Letter Conduct a public workshop to gather input related to the use of RWE for regulatory decision-making By no later than the end of FY 2018, FDA will complete one or more public workshop(s) to gather input into issues related to RWE use in regulatory decision-making. Initiate appropriate activities to address key issues in the use of RWE for regulatory decision-making purposes. By no later than the end of FY 2019, FDA will initiate (or fund by contract), appropriate activities (e.g., pilot studies or methodology development projects) to address key concerns and considerations in the use of RWE for regulatory decision making Publish draft guidance on how RWE can contribute to the assessment of safety and effectiveness in regulatory submissions By no later than the end of FY 2021, considering available input, FDA will publish draft guidance on how RWE can contribute to the assessment of safety and effectiveness in regulatory submissions, for example in the approval of new supplemental indications and for the fulfillment of postmarketing commitments and requirements. FDA will work toward the goal of publishing a revised draft or final guidance within 18 months after the close of the public comment period.

RWE: Drug v. Medical Device

RWE – Drug v. Medical Device Medical devices are developed in an iterative fashion, RWE is generated throughout the life-cycle of a device and relevant confounding factors are typically recognized and compensated for in the data analysis  In the context of accelerated approval of precision molecular treatments, RWE to confirm clinical benefit will need to be generated quickly and reliably to support the regulatory approval process  Real-world data sources for both drug and device use are essentially equivalent and criteria for collection and analytical methodologies (e.g., accounting for confounding factors, establishing consistent definitions, and controlling data capture) can be applied to both. The Device RWE Draft Guidance was released July 27, 2016 only released about six months ago (comment close Oct 2016)

Real World Evidence – Medical Devices/ MDUFA IV FDA included a proposal in the MDUFA IV negotiations to add 15 FTEs to a coordinating center who will work on implementing the use of RWE in premarket decision-making In July 27, 2016, FDA released a draft guidance entitled Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices  with recommendations on acceptable uses for RWE in the established medical device regulatory scheme  The Device RWE Draft Guidance defines two terms that are essentially equivalent to the singular RWE definition in the Cures Act: RWD – “Data collected from sources outside of traditional clinical trials” RWE – “Evidence derived from aggregation and analysis of RWD elements” FDA identifies potential sources of device RWD, including “large simple trials, or pragmatic clinical trials, prospective observational or registry studies, retrospective database studies, case reports, administrative and healthcare claims, electronic health records, data obtained as part of a public health investigation or routine public health surveillance, and registries,” FDA states that data from these sources, if appropriately validated, can provide valuable insight into the performance of medical devices used in actual clinical settings and in routine medical practice

Also to consider… FDA Public Workshop Nov 2016 and PhRMA/BIO Principles Truthful and Non-Misleading

FDA Public Working Communication of Unapproved Uses for Approved/Cleared Products (Nov 2016) Meeting Goal: For FDA to receive public input (industry, physician groups, consumers, patients, law firms, academic researchers, etc.) on communication about unapproved uses of approved/cleared medical products impact on public health from increased communications about unapproved uses current information or systems to help FDA determine impact on prescribing and medical product development and research; distinctions between communications for categories of medical products, or for different disease areas or patient populations; standards to minimize being misleading or cause harm; standards to determine if communications are truthful and non- misleading, including disclosures (quality and validity of data) transparency and FDA monitoring / surveillance

PhRMA/BIO Principles on Truthful and Non-Misleading Communication In July 2016, PhRMA and BIO endorsed new Principles on Responsible Sharing of Truthful and Non-Misleading Information about Medicines with Health Care Professionals and Payers  to guide the establishment of responsible, science-based parameters for accurate and trusted information-sharing under a modernized regulatory framework Following are three key concepts of the PhRMA and BIO principles: Commitment to Science-Based Communication: There are many types of data and analyses that are scientifically and statistically-sound, and which can help improve patient care. We must increase access to these types of communications. Commitment to Provide Appropriate Context about Data: Communications should clearly disclose appropriate contextual information about data that are presented, including limitations on statistical methods and study design, to ensure that health care professionals and payers are clearly informed about emerging data on the safety, effectiveness and value of medicines. Commitment to Tailoring Communications to the Intended Audience: Communications should keep the sophistication of the intended audience in mind to ensure that new information is clearly communicated and incorporated into existing knowledge and expertise.

Additional Information 21st Century Cures Act Drug Provision Timelines

Drug Guidance Development and Implementation Overview Pharmaceutical Requirements and Implementation of the 21st Century Cures Act.

Drug Guidance Development and Implementation Overview Pharmaceutical Requirements and Implementation of the 21st Century Cures Act.

Drug Guidance Development and Implementation Overview Pharmaceutical Requirements and Implementation of the 21st Century Cures Act.

Drug Guidance Development and Implementation Overview Pharmaceutical Requirements and Implementation of the 21st Century Cures Act.

References

References 21st Century Cures Act https://www.congress.gov/bill/114th-congress/house-bill/6 Real-World Evidence — What Is It and What Can It Tell Us? http://www.nejm.org/doi/full/10.1056/NEJMsb1609216 Historically Controlled Trials (Presentation by Dr. Temple) See slide 20 + within http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM500821.pdf