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Health Outcomes Data Communications, Market Access and Value Based Contracting

David Layfer

Senior Counsel

AbbVie

Utilizing Real World Evidence (RWE) in

Communications with Payers and in Promotional

Materials

Meredith Manning

Partner

Hogan Lovells

Julie Locklear

Vice President &

Head, Health

Economics &

Outcomes Research

EMD Serono

January 26 – 27, 2017

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The content and opinions presented here are those of the speakers and do not necessarily reflect those of their employers. The presentation is not intended to be, and should not be taken as, legal advice.

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Agenda

• What is real world evidence

• Sources of real world evidence

• Creating value across the product lifecycle

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What is Real World Evidence?

“While the definition of Real World Evidence (RWE) is still evolving, most proponents associate RWE with data that is derived from medical practice among heterogeneous sets of patients in real life practice settings, such as insurance claims data and clinical data from electronic health records.”

Issue Brief. The Network for Excellence in Health Innovation (NEHI);

September 2015.

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Sources of RWE

Patients are being pushed into consumerism

with decisions on insurance (trading off on network

access and formularies for lower premiums) and

evaluating the potential benefit products and

services providers recommend against

out-of-pocket costs

Patient Centricity on the Rise

Health information technology moves beyond

paper files and billing codes and into global health

management and decision making

Real-world evidence creates efficiencies in the

drug value chain development, patient centric

approach, properly identifying unmet needs to

ensure EMD Serono is developing meaningful

products to create, improve and extend life

Big Data Is Becoming Reality and

Real-world Evidence Takes Center

Stage

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Trends in RWE over Time

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RWE Value Along Lifecycle of Products

Discovery Pre-ClinicalClinical

Phase I-III

Regulatory Approval

Post-Approval

• Identification of target

population for clinical trials

• Evaluate natural

history/epidemiology of

disease/unmet medical need

• Defining appropriate

comparators (per region) and

epidemiologic profile

• Market sizing and

forecasting

• Defining pre-market risk

assessment

• Identification of patient-

reported outcomes

• Evaluate natural

history/epidemiology of

disease/unmet medical need

• Treatment

pathways/standard of

care/adherence

• Drug utilization and clinical

effectiveness

• Safety signals (Planning of

Risk Management (RMP))

• Identification of patient-

reported outcomes

• Supporting regulatory

submissions (identifying

control arm)

DEVELOPMENT PHASE REGULATORY REVIEW LIFE CYCLE MANAGEMENT

• Evaluating

safety signals

• Supporting

RMP

• Supporting life

cycle

management

plan (new

indications)

• Long term

patient

outcomes

• Product

differentiation

• Real world data

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How and Where Can We Find Efficiencies in Clinical Trials?

• Identification of patient population (including recruitment)

• Clinical trial designs (hypothesis generation)

• Selection of appropriate comparator

• Selection of appropriate clinical trial endpoints

• Augment and/or complement RCT data on safety and efficacy of new drugs and medical devices

• Further clarity on safety and efficacy profile, potentially impacting labeling and approved indications (post-approval)

• Identification of sub-populations

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Challenges associated with RWE

• Standardization of data quality

• Privacy & patient rights

• Access to data and data sharing

• Peer review and publications

• Internal understanding of RWE value

• Cost

• Legal and regulatory compliance

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Estimates of RWE Value

“…applying big-data strategies to better inform decision making could generate up to $100 billion in value annually across the US health-care system, by optimizing innovation, improving the efficiency of research and clinical trials, and building new tools for physicians, consumers, insurers, and regulators to meet the promise of more individualized approaches.”

The McKinsey Global Institute1 1.Our work builds on insights from several reports and articles, all available on

mckinsey.com: James Manyika et al., Big data: The next frontier for innovation, competition, and productivity,

McKinsey Global Institute, May 2011; Peter Groves et al., The ‘big data’ revolution in healthcare: Accelerating value

and innovation (PDF–1.4 MB), January 2013; and Ajay Dhankhar et al., “Escaping the sword of Damocles: Toward

a new future for pharmaceutical R&D” (PDF–1.8MB), McKinsey Perspectives on Drug and Device R&D 2012.

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Health Outcomes Data Communications, Market Access and Value Based Contracting

Meredith Manning

Partner

Hogan Lovells

Real World Data under FDAMA 114An available path?

January 26 – 27, 2017

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FDAMA 114

• Since 1997, FDA has refused to interpret FDAMA 114 in a way to permit its widespread use

– In 2012, Dr. Temple gave “podium policy” that was very conservative and effectively limited FDAMA 114 to those drugs approved through head to head studies

• The 21st Century Cures Act addresses some of these concerns:

– Expressly allows clinical inputs to be used in an analysis of healthcare economic information

– It permits HCEI that is “related” to an approved indication (instead of “directly related”)

– On January 18, 2017, OPDP released a long-sought guidance on communications to payors that permits analyses that were previously criticized or even prohibited

• Thus, FDAMA 114 may be coming into its own

• And, now the question is whether it is a viable option for expanded use of “real world” evidence

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Communications Regarding Unapproved Uses

FDA Public Meeting, Nov. 9-10, 2016 – FDA requested comments on:

• How increased communications about unapproved uses could impact public health, and whether the impact would differ across different categories of medical products;

• Factors manufacturers consider when making decisions about providing information on unapproved uses;

• Standards that should apply to unapproved use communications to minimize the potential for these communications to be misleading;

• How FDA could monitor manufacturers’ communications about unapproved uses; and

• What types of regulatory and policy changes may be appropriate to provide greater certainty and clarity to regulated industry

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FDA could permit RWE under 114 and SCE

• OPDP has an option that allows interpretation of current regulations but stops short of permitting wholesale promotion of unapproved uses

– The advertising regulation permits claims based on “substantial clinical experience”

– FDAMA 114 permits claims based on “competent and reliable” evidence

• Real world evidence (or observational data) could be used under each standard

• Hogan Lovells filed a comment to FDA’s docket advocating this approach

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What and why Real World Evidence?

• The comment defines RWE as clinical data about a drug product derived from sources other than randomized controlled trials (RCTs)

– Focuses less on isolating a treatment effect on efficacy and more on how actual use of a drug affects a variety of outcomes

• Various agencies and payors call for RWE in making approval, coverage, and other decisions

– US Agencies: CDRH,CMS, AHRQ

– Other Agencies: NICE (UK), EMA (European Union)

– Private Payors: Academy of Managed Care Pharmacy

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FDA’s Current Regulatory Framework

• Therapeutic claims: must be supported by “substantial evidence or substantial clinical experience” (21 CFR 202.1(e)(6)(i))

– “Substantial evidence” = RCT data (21 USC 355(d))

– “Substantial clinical experience” not yet defined, but FDA currently equates this to substantial evidence and RCT data

• Health Care Economic Information (HCEI): must be supported by “competent and reliable” scientific evidence (CARSE) under FDAMA 114

– Standard has not been explicitly invoked, and FDA issued enforcement interpreting “adequate evidence” for HCEI to mean RCT data

– FTC defines “competent and reliable” as objectively-evaluated evidence based on relevant professional expertise yielded by generally-accepted procedures in the profession

– The agency’s January guidance defines HCEI to “pertain to the economic consequences related to the clinical outcomes of treating a disease or of preventing or diagnosing a disease. HCEI may include comparative analysis of the economic consequences of a drug’s clinical outcomes.” Answer 1.

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Why Real World Evidence?

We argued that this presents a middle ground that permits progress post- Amarin

• Closely tracks RCT data for determinations of efficacy and incidence of side effects

• Provides valuable information for payors, physicians, and patients that RCT data cannot

– Cost, utilization, and cost-effectiveness

– Impact on quality of life

– Comparative information across treatment options

– Effect of confounding factors on patients using a drug

– FDA appears to have accepted that RWE can meet the standard

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Payor Guidance Answers 5-7

• FDA will consider the evidence to meet the CARSE standard if it “has been developed using generally-accepted scientific standards appropriate for the information beying conveyed that yield accurate and reliable results.” A.6

• FDA will consider existing current good research practices from authoritative bodies – ISPOR and PCORI.

• FDA expressly states that indirect treatment comparisons can be acceptable. A. 5

• This is a huge change from the Temple presentation in 2012

• Materials should set out numerous factors such as the study design, methodology, type of analysis, modeling, patient population, and “perspective/viewpoint”

• FDA does not discuss the types of data that are required• Which is also a major departure from past statements on the topic

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FDA Officials’ Statement

Published an editorial in NEJM on December 9, 2016 which is useful in assessing limitations of the analysis

• FDA recognizes usefulness of RWE but has concerns on its use

– Confounding: statistically-significant effect due wholly or in part to non-treatment factors

– Special concern where RWE used to show efficacy, particularly in accelerated review for precision medicine and rare disease treatment products

– Data quality: especially where existing data not originally collected to support research is used, e.g. EMRs and registry data

– Bias

• RWE can and should still incorporate randomization and planned interventions

– E.g., Salk polio vaccine field trials, ADAPTABLE (aspirin dosing) study

• FDA “is committed to robust policy development” on RWE under PDUFA VI

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Health Outcomes Data Communications, Market Access and Value Based Contracting

David Layfer

Senior Counsel

AbbVie

Communication of RWE

January 26 – 27, 2017

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What is Real World Evidence? How Can It be Communicated?

• Definition of Real World Evidence: Data collected outside of controlled clinical trials and used to understand burden of illness, treatment patterns, patient behaviors and product performance in settings and populations that are representative of routine clinical practice.

• Communication of RWE studies could potentially occur in:

• Promotional use by sales/marketing

• Market access communications with payers

• Publications or presentation at scientific conferences

• Scientific exchange by Medical Affairs

• Media communications (e.g., press releases)

• Ongoing consideration by FDA of how RWE may be used in regulatory filings (e.g., label expansions, new indications, support new drug approvals)

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Potential Framework for Considering Promotional Use of RWE

•Generally, three standards of evidence govern promotional communications:

Substantial Evidence

Competent and Reliable Scientific

Evidence

Truthful and Non-Misleading

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Potential Framework for Considering Promotional Use of RWE

•FDA generally considers “substantial evidence” to be two well-controlled, randomized clinical trials, which has historically posed a challenge to use of RWE.

•Even if RWE did not meet the substantial evidence standard for promotion, consider whether RWE could be used where:

1)Substantial Evidence is not required to support the claim; or

2)Substantial Evidence to support the claim already existsand the RWE further supports the claim

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Sample Claims Utilizing RWE

Claim Type #1: Safety or efficacy

• Under FDA regulations, promotional claims are false or misleading if they represent a drug as safer or more effective than has been demonstrated by “substantial evidence.” (21 CFR 202.1(e)(6))

• FDA may not interpret RWE studies evaluating safety/efficacy to meet the substantial evidence standard

• However, where substantial evidence separately exists for a promotional claim (e.g., the efficacy or safety is demonstrated as the primary endpoint in pivotal trials), consider whether RWE that is consistent may be appropriate for promotional use

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Sample Claims Utilizing RWE

Claim Type #1: Safety or efficacy

• “In a real world study, Drug X lowered cholesterol in 75% of high risk patients – which is consistent with the percentage of patients demonstrating lower cholesterol in pivotal trials of Drug X.” OK?

• “In a real world study, Drug X lowered cholesterol in 85% of high-risk patients, which exceeded that seen in pivotal trials of Drug X.” OK?

• “In a real world study, Drug X lowered cholesterol more than its competitor Drug Y.” OK?

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Sample Claims Utilizing RWE

Claim Type #2: Disease Awareness

• Unlike prescription drug promotional labeling and advertising, disease awareness communications are not subject to the requirements of the FD&C Act and FDA regulations. FDA regulations requiring substantial evidence do not apply.

• Disease awareness statements still need to be truthful and non-misleading.

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Sample Claims Utilizing RWE

Claim Type #2: Disease awareness

• “Based on a claims database analysis, the prevalence of Disease X has decreased.” OK?

• “Based on a claims database analysis, disability costs were more than two times higher in employees with Disease X versus employees without Disease X.” OK?

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Sample Claims Utilizing RWE

Claim Type #3: Adherence

• FDA considers adherence (the ability of a patient to take a drug as directed) and persistence (duration of time from drug initiation to discontinuation) to be impacted by many factors, including clinical factors, and therefore requires substantial evidence.

• “There are many factors that affect patient adherence, including side effects, effectiveness, dosing schedule, dosage form, and cost. An adherence claim must be supported by substantial evidence taking into account these types of determinants of patient adherence.” (2005 Warning Letter)

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Sample Claims Utilizing RWE

Claim Type #3: Adherence

• “Based on a claims database analysis, initiation of an appropriate dose of Drug X resulted in up to 90% of patients remaining on therapy vs baseline at 3 months.” OK?

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Sample Claims Utilizing RWE

Claim Type #4: Health care economic claim

• 21st Century Cures Act creates a different standard for certain health care economic promotional claims (Section 3037). Where health care economic claims (including claims based on RWE) meet certain requirements, they need only satisfy the standard of “competent and reliable scientific evidence”

• Must meet the statute’s definition of health care economic information

• Must be used with the appropriate audience, which are payers, formulary committees and similar entities

• Must be related to an FDA-approved indication

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Sample Claims Utilizing RWE

Claim Type #4: Health care economic claim

• “Drug X has a lower cost per cure as compared to Drug Y.”OK?

• “Drug X is more effective than Drug Y at reducing costs when administered to patients for a use outside of Drug X’s label.” OK?

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R&D/Medical Affairs Use of RWE

• Unlike the considerations for promotional use of RWE, Medical Affairs may involve a different determination - whether the RWE is appropriate scientific exchange.

• Scientific exchange is the bona fide exchange of scientific information or data in a scientific/non-promotional context.

• 21 CFR 312.7: “This provision [prohibiting pre-approval promotion] is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media.”

• Potential scenarios for communication of RWE as scientific exchange:

• Responding to unsolicited requests from HCPs?

• Presentation of RWE at Scientific/Medical Conferences?

• Publication of RWE in Scientific/Medical Journals?

• Proactive communication of RWE to HCPs?

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Press Releases Regarding RWE

• There are different types of press releases, and whether RWE could be shared may depend on the type. For example:

• Promotional? FDA has stated that press releases from manufacturers that make claims about pharmaceutical products are promotional, so promotional regulations may apply.

• Non-promotional? There may potentially be situations where press releases are considered non-promotional “scientific exchange”, depending on the subject matter and intent. (21 C.F.R. § 312.7(a))

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Regulatory Filings Utilizing RWE

• FDA released draft guidance in 2016 clarifying how RWE might be used in pre-market and post-market regulatory decisions for medical devices – with a focus on the relevance and reliability of the RWE

• Examples offered by FDA:• Expanded indications for use• Post-market surveillance studies (potentially as a condition of

approval)

• 21st Century Cures Act requires FDA to develop a framework and guidance for evaluating RWE in the context of drug regulation to support approvals of new indications for previously approved drugs, and to support or fulfill post-approval study requirements (Sec. 3022)

• On December 8th, FDA Commissioner Robert Califf, along with the Directors of relevant Centers and Offices, 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?”