Promotion & Advertising of Combination Products: Key Postmarket Considerations

Combination Products Regulation, Policy, & Best Practices It’s A Whole New Ballgame–Are You All In? June 8, 2017

Moderated by: Heather Bañuelos & Lisa Dwyer, King & Spalding

Panelists: Glenn Byrd, Senior Director, Promotional Regulatory Affairs, AstraZeneca Suzanne O’Shea, Director, Navigant Consulting

Agenda • Recent Developments ― Consistent Communications Draft Guidance

― Application to Combination Products ― Communications with Payors

― 21st Century Cures Act ― Communications with Payors Draft Guidance

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New Draft Guidance “Consistent Communications”

Draft Guidance Communications with Payors

Draft Guidance

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“CONSISTENT COMMUNICATIONS” GUIDANCE

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“Consistent Communications” Guidance • Off-Label Background ― Last 20 years

― Debate has focused on when/ how off-label information may be shared legally with HCPs

― Scientific exchange v. promotion ― FDA focused on narrow safe harbors – e.g.,

―Reprints

―Responses to Unsolicited Requests

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“Consistent Communications” Guidance

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• Forgotten question: ― What is “off-label” speech?

• CC Guidance partially answers that question ― Communications not contained in FDA-

required labeling that are ― Consistent with FDA-required labeling ― Will not, alone, be considered evidence of a

new intended use

Conceptual Categories of Claims

• Information expressly contained in FDA-required labeling On-label

• Information that could trigger the need for a supplemental marketing application (or “adequate labeling”)

Off-label

• All other information about a medical product Out-of-label

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The Three-Factor Test

• Indication • Patient Population • Limitations and Directions for Handling/Use • Dosing/Administration

How does the “out of label” information compare to the FDA-required labeling?

Does the “out of label” information increase health risks relative to information in the FDA-required labeling?

Does the FDA-required labeling enable the product to be safely used under conditions suggested by the “out of label” information?

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Examples – “Consistent Communications” • Comparisons ― Information based on a comparison of the safety or efficacy of a

medical product for its approved or cleared indication to another medical product’s same approved or cleared indication

• Adverse Reactions ― Information that provides additional context about the adverse

reactions associated with the approved or cleared uses of the product • Onset of Action ― Information about the onset of action of the product for its approved

or cleared indication and dosing or use regimen • Long-term safety and/or efficacy data ― Information about the long-term safety and/or efficacy of products

that are approved/cleared for chronic use

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Examples – “Consistent Communications” • Specific Patient Subgroups ― Information about the effects or use of a product in specific

patient subgroups that are included in its approved/cleared patient population

• Patient-reported Effects ― Information concerning the effects of a product that comes

directly from the patient • Product Convenience • Mechanism of Action ― Information that provides additional context about the mechanism

of action described in FDA-required labeling

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Examples – Information That Is Not a “Consistent Communication”

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Types of information that is viewed as not consistent with FDA-required labeling (i.e., off-label): ― Treat or diagnose a different disease or condition ― Treat or diagnose a different patient population’ ― Treat a different stage, severity, or manifestation of a

disease ― Use of product as monotherapy when only approved for

adjunctive treatment ― Different route of administration or tissue type ― Different strength, dosage, or usage regimen ― Different dosage form

Substantiation: Evidentiary Standard • Less than substantial evidence ― “Scientifically appropriate and statistically

sound” • Must be truthful and not misleading

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Additional Considerations “Consistent communications” should also: ― Accurately represent underlying study results,

data and information and disclose material aspects and limitations of the study design and methodology

― Disclose and contextualize unfavorable or inconsistent findings

― Disclose information from FDA-required labeling to help contextualize the communication

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Consistent Communications Guidance: Application to Combination Products

Consistency with Labeling

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• Drugs/Biologics approved with Companion or Complimentary diagnostics ― Key issues:

1. Drug label – Companion says: “…as detected by an FDA approved test…”

2. Drug label – Complimentary: may have information in the Clinical Studies section of the PI that describes the test used and the results from those patient sub-groups

Consistency with Labeling - Example

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• One aspect of the new guidance had an impact on our companion/complimentary diagnostic example ― Effects or use of a product in specific patient subgroups

that are part of the larger approved population (e.g., effects on diagnostic populations within the pivotal trial cohort)

― Gave us clarity on our ability to communicate important information to HCPs about how patients perform based on their diagnostic status – even if the diagnostic test is not required for drug eligibility

― But be careful – still cannot mislead the audience by performing all kinds of sub-group analyses!!!

Consistency with Labeling – Example (cont.)

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• Key questions impact the regulatory path/oversight 1. What is the relationship between the drug and

device company? a. Is there a co-marketing arrangement/contract? b. OR, Are the two companies responsible for

marketing their own drugs/devices? c. Will OPDP impose drug ad-promo oversight on

diagnostic device manufacturer?

Consistency with Labeling – Example (cont.)

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Will OPDP impose drug ad-promo oversight on diagnostic device manufacturer? With our initial approval of a drug with a companion

diagnostic (i.e., diagnostic test needed to identify appropriate/eligible patients for drug), we had to navigate this question

We contacted OPDP to inquire whether they would impose their oversight on the device company

Device company had no clue about the potential for OPDP to impose drug ad-promo oversight, nor what it might mean for how they marketed their diagnostic

Consistency with Labeling – Example (cont.)

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OPDP asked to review the agreement between the drug and device companies

Our situation: separate marketing of our respective products Important to have a working agreement defined so it

is clear how to deal with product-specific questions Our reps had basic indication/intended use information and

then deferred all other questions to the device reps and vice versa.

Based on this arrangement – OPDP elected to exercise enforcement discretion and NOT impose ad-promo regs on the device company

Examples from FDA Enforcement Letters: Brovana

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• COPD drug for nebulization. Patient acquires nebulizer separately.

BROVANA® (arformoterol tartrate) Inhalation Solution NOV Letter (Oct. 24, 2013)

“My hands don’t move as

well anymore, so it’s hard for me

to use my inhaler.”

Examples from FDA Enforcement Letters: Nitrolingual Pumpspray

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• Angina drug, metered dose inhaler.

Nitrolingual® Pumpspray (nitroglycerin lingual spray) NOV Letter (April 26, 2011)

“Eliminates hard-to-open prescription bottles and the need to fumble with

small tablets”

“Convenient and easy-to-use”

Questions

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• Does OPDP confer with CDRH before expressing concerns about device constituent part?

• Some statements about device constituent part seem self-evidently true.

Eliminates hard to open prescription bottles.

• Some statements about device constituent part could have nothing to do safety and effectiveness of product.

Sleek design. Pocket-sized. Pretty Pink color.

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COMMUNICATIONS WITH PAYORS GUIDANCE

Communications with Payors Draft Guidance

New Safe Harbor for Pipeline

Communications

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New Safe Harbor for Pre-Approval Communications with Payors

• Expressly permits pre-approval communications with payors about investigational products

• Scope: Applies to investigational products (i.e., products not yet approved for any use) ― Does not cover communications about

unapproved uses of approved products • Timing: Silent as to specific timing ― Draft guidance does not expressly impose any

time-based restrictions on how early communications may occur prior to approval

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Types of Information Covered

Anticipated Timeline for Approval / Clearance

Information must be “unbiased, factual, accurate and non-misleading”

Indication Sought

Results of clinical and preclinical studies

Product Information (e.g., drug class, device design)

Pricing Information

Marketing Strategies

Patient Support Programs

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Required Disclosures • Clear statement regarding product’s investigational

status and that safety and effectiveness has not been established

• Information related to stage of product development (e.g., clinical trial phase)

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Communications with Payors Draft Guidance

Clarification of HCEI Provision

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Previous HCEI Framework – FDAMA 114

FDCA § 502(a) (as amended by FDAMA)

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21st Century Cures Act § 3037 Amendments to 21 U.S.C. § 352(a) (FDAMA § 114) (a) FALSE OR MISLEADING LABEL If its (a)(1) If its labeling is false or misleading in any particular. Health care economic information provided to a formulary committee, or other similar entity, in the course of the committee or the entity carrying out its responsibilities for the selection of drugs for managed care or other similar organizations a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement, shall not be considered to be false or misleading under this paragraph if the health care economic information directly relates relates to an indication approved under section 355 of this title or under section 262(a) of title 42 for such drug and is based on competent and reliable scientific evidence. The requirements set forth in section 355(a) of this title or in section 262(a) of title 42 shall not apply to health care economic information provided to such a committee or entity in accordance with this paragraph, is based on competent and reliable scientific evidence, and includes, where applicable, a conspicuous and prominent statement describing any material differences between the health care economic information and the labeling approved for the drug under section 505 or under section 351 of the Public Health Service Act. The requirements set forth in section 505(a) or in subsections (a) and (k) of section 351 of the Public Health Service Act shall not apply to health care economic information provided to such a payor, committee, or entity in accordance with this paragraph. Information that is relevant to the substantiation of the health care economic information presented pursuant to this paragraph shall be made available to the Secretary upon request. In this paragraph, the term “health care economic information” means any analysis that identifies, measures, or compares the economic consequences, including the costs of the represented health outcomes, of the use of a drug to the use of another drug, to another health care intervention, or to no intervention. (2)(A) For purposes of this paragraph, the term `health care economic information' means any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug. Such analysis may be comparative to the use of another drug, to another health care intervention, or to no intervention. (B) Such term does not include any analysis that relates only to an indication that is not approved under section 505 or under section 351 of the Public Health Service Act for such drug.

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Definition of HCEI

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21st Century Cures

― Expanded HCEI beyond economic “analysis”

― Includes: “clinical data, inputs, clinical or other assumptions, methods, results and other components underlying or comprising the analysis”

― Includes comparative analyses to another drug or intervention

Guidance

― Permits a variety of formats (e.g., evidence dossier, reprint, software model)

Covered Audience for HCEI: All Payors 21st Century Cures Act Clarified Covered Audience

“a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out

its responsibilities for the selection of drugs for coverage or reimbursement”

Examples Payors

Formulary / P&T Committees Drug Information Centers

Technology Assessment Panels Pharmacy Benefit Managers

Other Requirements ― Healthcare decision maker ― Consider HCEI through a

“deliberative process” ― “Appropriate range of

knowledge and expertise in . . . HCEI”

FDA Draft Guidance, p 4-5

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HCEI “Related to” an Approved Indication

FDAMA § 114 HCEI must “directly relate”

to an approved indication

21st Century Cures HCEI must “relate” to an approved indication

What does it mean to be “related to” an approved indication? Related to “the disease or condition, manifestation of the disease or

condition, or symptoms associated with the disease or condition in the patient population for which the drug is [approved].”

FDA Draft Guidance, p 5-6

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Examples – HCEI “Related to” Approved Indication

“Related to”

Patient Reported Outcomes (e.g.,

work productivity)

Not “Related to”

HCEI on prevention or cure when product approved only

for symptom relief

FDA Draft Guidance, p. 6 - 9

Dosing

Patient Subgroups

Validates Surrogate Endpoints

Comparisons

Practice Setting (e.g., managed care

vs. FFS)

Length of Hospital Stay

Duration of Treatment

Disease Burden (e.g., cost of lost

work days)

Patient Populations Outside Indicated Population

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HCEI Must Be Based on CARSE: “Competent and Reliable Scientific Evidence”

Competent and Reliable Scientific Evidence

“Generally-accepted scientific standards, appropriate for the

information being conveyed, that yield accurate and reliable

results.”

Consider standards and good research practices developed by other authoritative bodies (e.g.,

International Society for Phamacoeconomic and Outcomes

Research)

Accompanied by Appropriate Context

Study Design

Generalizability

Limitations

Sensitivity Analyses

Methodology

FDA Approved Labeling

Differences from Approved Labeling

Omitted Studies / Data Sources

Financial / Affiliation Biases

Risk Information

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Other Key Points from Draft Guidance • CARSE standard applies to all components of

the HCEI, including all inputs and assumptions

• Proactive dissemination of HCEI will be considered promotion

― Must be submitted under Form FDA 2253 (drugs and biologics)

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21st Century Cures Act § 3037 • (a) . . . . Health care economic information provided to a payor, formulary committee, or other

similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of DRUGS for coverage or reimbursement, shall not be considered to be false or misleading under this paragraph if the health care economic information relates to an indication approved under SECTION 355 OF THIS TITLE or under SECTION 262(a) OF TITLE 42 for such DRUG, is based on competent and reliable scientific evidence, and includes, where applicable, a conspicuous and prominent statement describing any material differences between the health care economic information and the labeling approved for the DRUG under SECTION 355 OF THIS TITLE or under SECTION 262 OF TITLE 42. The requirements set forth in SECTION 355(a) OF THIS TITLE or in subsections (a) and (k) of SECTION 262 OF TITLE 42 shall not apply to health care economic information provided to such a payor, committee, or entity in accordance with this paragraph. Information that is relevant to the substantiation of the health care economic information presented pursuant to this paragraph shall be made available to the Secretary upon request.

• (2) (A) For purposes of this paragraph, the term “health care economic information” means any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a DRUG. Such analysis may be comparative to the use of another DRUG, to another health care intervention, or to no intervention.

• (B) Such term does not include any analysis that relates only to an indication that is not approved under SECTION 355 OF THIS TITLE or under SECTION 262 OF TITLE 42 for such drug.

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QUESTIONS?

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