Promotion & Advertising of Combination Products: Key Postmarket Considerations

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1 Combination Products Regulation, Policy, & Best Practices It s A Whole New Ballgame Are You All In? June 8, 2017 Promotion & Advertising of Combination Products: Key Postmarket Considerations Moderated by: Heather Bañuelos & Lisa Dwyer, King & Spalding Panelists: Glenn Byrd, Senior Director, Promotional Regulatory Affairs, AstraZeneca Suzanne O Shea, Director, Navigant Consulting

2 Agenda Recent Developments Consistent Communications Draft Guidance Application to Combination Products Communications with Payors 21 st Century Cures Act Communications with Payors Draft Guidance 2

3 New Draft Guidance Consistent Communications Draft Guidance Communications with Payors Draft Guidance 3

4 CONSISTENT COMMUNICATIONS GUIDANCE 4

5 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 5

6 Consistent Communications Guidance Forgotten question: What is off-label speech? CC Guidance partially answers that question Communications not contained in FDArequired labeling that are Consistent with FDA-required labeling Will not, alone, be considered evidence of a new intended use 6

7 Conceptual Categories of Claims On-label Information expressly contained in FDA-required labeling Off-label Information that could trigger the need for a supplemental marketing application (or adequate labeling ) Out-of-label All other information about a medical product 7

8 The Three-Factor Test How does the out of label information compare to the FDA-required labeling? Indication Patient Population Limitations and Directions for Handling/Use Dosing/Administration 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? 8

9 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 9

10 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 10

11 Examples Information That Is Not a Consistent Communication 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 11

12 Substantiation: Evidentiary Standard Less than substantial evidence Scientifically appropriate and statistically sound Must be truthful and not misleading 12

13 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 13

14 Consistent Communications Guidance: Application to Combination Products 14

15 Consistency with Labeling 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 15

16 Consistency with Labeling - Example 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!!! 16

17 Consistency with Labeling Example (cont.) 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? 17

18 Consistency with Labeling Example (cont.) 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 18

19 Consistency with Labeling Example (cont.) 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 19

20 Examples from FDA Enforcement Letters: Brovana COPD drug for nebulization. Patient acquires nebulizer separately. My hands don t move as well anymore, so it s hard for me to use my inhaler. BROVANA (arformoterol tartrate) Inhalation Solution NOV Letter (Oct. 24, 2013) 20

21 Examples from FDA Enforcement Letters: Nitrolingual Pumpspray Angina drug, metered dose inhaler. Eliminates hard-to-open prescription bottles and the need to fumble with small tablets Convenient and easy-to-use Nitrolingual Pumpspray (nitroglycerin lingual spray) NOV Letter (April 26, 2011) 21

22 Questions Does OPDP confer with CDRH before expressing concerns about device constituent part? Some statements about device constituent part seem selfevidently 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. 22

23 COMMUNICATIONS WITH PAYORS GUIDANCE 23

24 Communications with Payors Draft Guidance New Safe Harbor for Pipeline Communications 24

25 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 25

26 Types of Information Covered Indication Sought Product Information (e.g., drug class, device design) Results of clinical and preclinical studies Pricing Information Anticipated Timeline for Approval / Clearance Marketing Strategies Patient Support Programs Information must be unbiased, factual, accurate and non-misleading 26

27 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) 27

28 Communications with Payors Draft Guidance Clarification of HCEI Provision 28

29 Previous HCEI Framework FDAMA 114 FDCA 502(a) (as amended by FDAMA) 29

30 21 st 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. 30

31 Definition of HCEI 21 st 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) 31

32 Covered Audience for HCEI: All Payors 21 st 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

33 HCEI Related to an Approved Indication FDAMA 114 HCEI must directly relate to an approved indication 21 st 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

34 Examples HCEI Related to Approved Indication Related to Not Related to Dosing Patient Subgroups Validates Surrogate Endpoints Comparisons Practice Setting (e.g., managed care vs. FFS) Length of Hospital Stay Patient Populations Outside Indicated Population HCEI on prevention or cure when product approved only for symptom relief Patient Reported Outcomes (e.g., work productivity) Disease Burden (e.g., cost of lost work days) Duration of Treatment FDA Draft Guidance, p

35 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 Methodology Generalizability Limitations Sensitivity Analyses FDA Approved Labeling Differences from Approved Labeling Omitted Studies / Data Sources Risk Information Financial / Affiliation Biases 35

36 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) 36

37 21 st 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. 37

38 QUESTIONS? 38