Posted: 02 Mar 2017 06:32 PM PST
By David C. Gibbons & Dara Katcher Levy –
In January 2017, FDA issued two Draft Guidance documents concerning communications made by medical device manufacturers about information not expressly contained within a product’s labeling:
Promotional Communication Guidance
Overview of the Guidance
FDA stated that medical product manufacturers have expressed an interest in communicating data and information concerning approved or cleared uses of their products that are not contained in such products’ FDA-required labeling—an understatement for sure, but a recognition of the views expressed in various fora over the past several years, including the recent public hearing on manufacturer communications regarding unapproved uses of approved or cleared medical products, held by FDA on November 9 and 10, 2016.
FDA’s position, as expressed in the Promotional Communication Guidance, is that product promotional communication by a pharmaceutical or medical device manufacturer that is consistent with its FDA-required labeling and truthful and not misleading in any particular would not subject a manufacturer to FDA enforcement action, even if such information were not expressly included in FDA-required labeling. FDA defined “FDA-required labeling” as the “labeling reviewed and approved by FDA as part of the medical product marketing application review process,” such as the approved U.S. prescribing information for human drugs or biologics or approved labeling for medical devices. While beauty may be in the eye of the beholder, consistency with FDA-required labeling seems to be only in the eye of the regulator. However, FDA articulated a number of factors that the agency would use to determine whether a medical product communication is consistent with its FDA-required labeling. These include:
Analysis
The Promotional Communication Guidance contains some helpful clarifications regarding FDA policy on communications consistent with FDA-required labeling (think “near-label” promotion) that industry should find helpful. Pursuant to the Promotional Communication Guidance, manufacturers may engage in certain types of communications, such as that regarding longer-term safety and efficacy and convenience, which are now subject to FDA enforcement discretion if they comply with the requirements imposed by this guidance.
However, given the recent spate of First Amendment litigation (see, e.g., here and here) concerning off-label promotion, it is unclear why any communications made by medical product manufacturers that are rendered truthful and non-misleading by being grounded in fact and science and appropriately contextualized would be unlawful, and thereby subject to enforcement in the first place. First Amendment issues were not addressed in this guidance, as FDA continues to vacillate on developing and implementing a workable policy (see our post here) in light of the relevant judgments and settlements that have not gone its way.
Overall, we think the Promotional Communication Guidance is helpful in understanding FDA’s current thinking regarding communication of information that is not included in a medical product’s labeling. We also believe the Promotional Communication Guidance will enable manufacturers to promote their products with additional types of product information (e.g., patient testimonials) compared to what they chose to disseminate previously.
We do not think the Promotional Communication Guidance goes far enough with respect to truthful and non-misleading medical product communications protected by the First Amendment. However, we recognize that many companies were hesitant to test the boundaries of FDA’s willingness to take enforcement action, even in light of First Amendment litigation that appeared to limit FDA’s ability to curb off-label promotion.
Payor Communication Guidance
Overview of the Guidance
Congress provided a statutory safe harbor for Health Care Economic Information (“HCEI”) communicated to payors, formulary committees, or other similar entities when exercising their responsibilities for selecting approved drugs for coverage or reimbursement. See Food and Drug Administration Modernization Act of 1997, Pub. Law No. 105-115, § 114, 11 Stat. 2312; 21st Century Cures Act, Pub. Law No. 114-255, § 3037, H.R. 34-73. Pursuant to this safe harbor, claims by pharmaceutical manufacturers meeting the statutory definition of HCEI and presented to payors, formulary committees, or other similar entities were held to the “competent and reliable scientific evidence” standard, as opposed to the more stringent substantial evidence standard that FDA requires for safety and efficacy claims under the Federal Food, Drug, and Cosmetic Act. The Payor Communication Guidance, issued twenty years after the original HCEI safe harbor was enacted, provides guidance regarding the communication of HCEI to payors about both approved drugs and investigational drugs and medical devices.
In the Payor Communication Guidance, FDA provided additional clarity regarding the audience for HCEI communications. First, FDA further explained that “payors” refers to any entity “responsible for the financing or reimbursement of costs associated with health care services.” Second, FDA explained that formulary committees are “multidisciplinary committees [responsible] for the selection of drugs and the management of a drug formulary.” These entities may range from a technology assessment panel to pharmacy and therapeutics committees that have responsibility for an entire hospital system. Falling within this definition are committees “constituted to consider HCEI” and make decisions regarding drug selection, formulary management, and/or coverage and reimbursement determinations at the population level through a “deliberative process.” In accordance with the statute, FDA has expressly excluded health care providers who make decisions for individual patients.
FDA also addressed the scope of HCEI protected by the safe harbor in the Payor Communication Guidance. One of two major changes to the HCEI statutory safe harbor enacted under the 21st Century Cures Act was the loosening of certain limitations to the analyses protected thereunder. Broadly speaking, under 21st Century Cures, HCEI must “relate” (as opposed to “directly relate” in the original statutory text) to an on-label indication. Furthermore, as long as an HCEI analysis does not only relate to an off-label indication, the analysis (and communications associated with the analysis) is protected under the safe harbor.
In the Payor Communication Guidance, FDA clarified its thinking, through various examples, on what “relates to an approved indication” means. Examples of HCEI that relate to an approved indication include:
One other important 21st Century Cures-related change to the safe harbor included clarification of what is included in HCEI. Prior to 21st Century Cures, FDA created confusion by suggesting that clinical outputs of a health economic analysis were held to the substantial evidence standard even though the economic outputs were held to the lower standard of competent and reliable scientific evidentiary standard. 21st Century Cures expressly included, within the definition of HCEI, the “clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis.” This significant change addressed what had been a fundamental problem with the safe harbor as originally enacted—health economic endpoints cannot be completely disentangled from clinical endpoints in an HCEI analysis and, now, both are protected. In the Payor Communication Guidance, FDA acknowledged that the competent and reliable scientific evidence standard applies to “all components of HCEI,” including safety and efficacy.
FDA stated that when medical product manufacturers present HCEI in accordance with the safe harbor provisions, information regarding the study design and methodology, generalizability, limitations, sensitivity analyses, and other information “relevant to providing a balanced and complete presentation” should be clearly and conspicuously presented.
Concerning presentations by medical product manufacturers regarding investigational products, FDA stated that certain types of information may be presented to payors prior to approval or clearance of a drug or medical device. This information may include:
It is important to note that FDA stated in the Payor Communication Guidance that it views HCEI as promotional and, therefore, expects that such information will meet FDA’s requirements for the submission of promotional materials, including submission on FDA Form 2253 at the time of first use.
Analysis
The most significant changes to a manufacturer’s ability to communicate HCEI to a payor or similar entity came with the passage of 21st Century Cures, which addressed certain fundamental problems with the safe harbor as originally enacted. That is, 21st Century Cures loosened the restrictions regarding whether aspects of an HCEI analysis could relate to off-label uses of the drug and whether the clinical outputs of an HCEI analysis were held to the lower evidentiary standard. The Payor Communication Guidance acknowledges and operationalizes these changes, along with providing clarity on FDA’s thinking concerning various elements of the safe harbor.
We found the amendments to the HCEI safe harbor enacted under 21st Century Cures to provide welcome and necessary relief from issues created by the safe harbor as originally enacted. To a large extent, the Payor Communication Guidance furthers the legislative intent of 21st Century Cures and, therefore, not much has changed with respect to our advice to clients preparing these presentations. The ability to expand the scope of HCEI analyses and include underlying clinical data and outputs in HCEI presentations under the protection of the safe harbor removes some of the risk in HCEI presentations carried out by manufacturers.
Arguably, the most significant change that the Payor Communication Guidance outlines is the opportunity for manufacturers to provide HCEI for investigational products. We see this as a big win for patients and hold out hope that earlier communications between manufacturers and payors may lead to earlier coverage determinations, which, in turn, may improve patient access.
As these are Draft Guidances, comments may be submitted to the docket at any time, but FDA requests that they be posted no later than April 19, 2017.
In January 2017, FDA issued two Draft Guidance documents concerning communications made by medical device manufacturers about information not expressly contained within a product’s labeling:
- Medical Product Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers: Guidance for Industry [Draft] (January 2017), hereinafter “Promotional Communication Guidance;”
- Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers: Guidance for Industry and Review Staff [Draft] (January 2017), hereinafter “Payor Communication Guidance.”
Promotional Communication Guidance
Overview of the Guidance
FDA stated that medical product manufacturers have expressed an interest in communicating data and information concerning approved or cleared uses of their products that are not contained in such products’ FDA-required labeling—an understatement for sure, but a recognition of the views expressed in various fora over the past several years, including the recent public hearing on manufacturer communications regarding unapproved uses of approved or cleared medical products, held by FDA on November 9 and 10, 2016.
FDA’s position, as expressed in the Promotional Communication Guidance, is that product promotional communication by a pharmaceutical or medical device manufacturer that is consistent with its FDA-required labeling and truthful and not misleading in any particular would not subject a manufacturer to FDA enforcement action, even if such information were not expressly included in FDA-required labeling. FDA defined “FDA-required labeling” as the “labeling reviewed and approved by FDA as part of the medical product marketing application review process,” such as the approved U.S. prescribing information for human drugs or biologics or approved labeling for medical devices. While beauty may be in the eye of the beholder, consistency with FDA-required labeling seems to be only in the eye of the regulator. However, FDA articulated a number of factors that the agency would use to determine whether a medical product communication is consistent with its FDA-required labeling. These include:
- Factor 1: Different Conditions of Use; whether information in a medical product communication is different from the information in the FDA-required labeling regarding:
- Indication,
- Patient Population,
- Limitations and Directions for Handling, Preparing, and/or Using the product,
- The recommended dosage or use regimen or route of administration.
- Factor 2: Increases the Potential for Harm; whether the representations or suggestions in a medical product communication negatively alter the benefit-risk profile of the product.
- Factor 3: Prevents Safe and Effective Use; whether the medical product can still be used safely and effectively in accordance with the directions for use in the FDA-required labeling, given the representations or suggestions in a medical product communication.
- A head-to-head study comparing the safety or efficacy of a manufacturer’s medical product to another medical product approved/cleared for the same, approved indication, when such study does not appear in the FDA-required labeling;
- Additional context regarding adverse reactions listed in the FDA-required labeling and associated with the approved/cleared uses of the product;
- Onset of action for the product’s approved/cleared indication and dosing/use regimen;
- Long-term safety and/or efficacy for those products approved/cleared for chronic use (e.g., longer duration than the product was studied in the clinical trials described in the FDA-required labeling);
- Effects or use of a product in specific patient subgroups included in its approved/cleared patient population, even when such subgroup analyses were not included in the FDA-required labeling;
- Patient-reported outcomes when the product is used for its FDA-approved/cleared indication in its approved/cleared patient population;
- Convenience (e.g., convenient dosing schedule); and
- Additional context about the mechanism of action described in the FDA-required labeling.
- Indication;
- Patient population;
- Stage, severity, or manifestation of disease;
- Use alone versus in combination with other product(s);
- Route of administration;
- Strength, dosage, or use regimen; or
- Dosage form.
Analysis
The Promotional Communication Guidance contains some helpful clarifications regarding FDA policy on communications consistent with FDA-required labeling (think “near-label” promotion) that industry should find helpful. Pursuant to the Promotional Communication Guidance, manufacturers may engage in certain types of communications, such as that regarding longer-term safety and efficacy and convenience, which are now subject to FDA enforcement discretion if they comply with the requirements imposed by this guidance.
However, given the recent spate of First Amendment litigation (see, e.g., here and here) concerning off-label promotion, it is unclear why any communications made by medical product manufacturers that are rendered truthful and non-misleading by being grounded in fact and science and appropriately contextualized would be unlawful, and thereby subject to enforcement in the first place. First Amendment issues were not addressed in this guidance, as FDA continues to vacillate on developing and implementing a workable policy (see our post here) in light of the relevant judgments and settlements that have not gone its way.
Overall, we think the Promotional Communication Guidance is helpful in understanding FDA’s current thinking regarding communication of information that is not included in a medical product’s labeling. We also believe the Promotional Communication Guidance will enable manufacturers to promote their products with additional types of product information (e.g., patient testimonials) compared to what they chose to disseminate previously.
We do not think the Promotional Communication Guidance goes far enough with respect to truthful and non-misleading medical product communications protected by the First Amendment. However, we recognize that many companies were hesitant to test the boundaries of FDA’s willingness to take enforcement action, even in light of First Amendment litigation that appeared to limit FDA’s ability to curb off-label promotion.
Payor Communication Guidance
Overview of the Guidance
Congress provided a statutory safe harbor for Health Care Economic Information (“HCEI”) communicated to payors, formulary committees, or other similar entities when exercising their responsibilities for selecting approved drugs for coverage or reimbursement. See Food and Drug Administration Modernization Act of 1997, Pub. Law No. 105-115, § 114, 11 Stat. 2312; 21st Century Cures Act, Pub. Law No. 114-255, § 3037, H.R. 34-73. Pursuant to this safe harbor, claims by pharmaceutical manufacturers meeting the statutory definition of HCEI and presented to payors, formulary committees, or other similar entities were held to the “competent and reliable scientific evidence” standard, as opposed to the more stringent substantial evidence standard that FDA requires for safety and efficacy claims under the Federal Food, Drug, and Cosmetic Act. The Payor Communication Guidance, issued twenty years after the original HCEI safe harbor was enacted, provides guidance regarding the communication of HCEI to payors about both approved drugs and investigational drugs and medical devices.
In the Payor Communication Guidance, FDA provided additional clarity regarding the audience for HCEI communications. First, FDA further explained that “payors” refers to any entity “responsible for the financing or reimbursement of costs associated with health care services.” Second, FDA explained that formulary committees are “multidisciplinary committees [responsible] for the selection of drugs and the management of a drug formulary.” These entities may range from a technology assessment panel to pharmacy and therapeutics committees that have responsibility for an entire hospital system. Falling within this definition are committees “constituted to consider HCEI” and make decisions regarding drug selection, formulary management, and/or coverage and reimbursement determinations at the population level through a “deliberative process.” In accordance with the statute, FDA has expressly excluded health care providers who make decisions for individual patients.
FDA also addressed the scope of HCEI protected by the safe harbor in the Payor Communication Guidance. One of two major changes to the HCEI statutory safe harbor enacted under the 21st Century Cures Act was the loosening of certain limitations to the analyses protected thereunder. Broadly speaking, under 21st Century Cures, HCEI must “relate” (as opposed to “directly relate” in the original statutory text) to an on-label indication. Furthermore, as long as an HCEI analysis does not only relate to an off-label indication, the analysis (and communications associated with the analysis) is protected under the safe harbor.
In the Payor Communication Guidance, FDA clarified its thinking, through various examples, on what “relates to an approved indication” means. Examples of HCEI that relate to an approved indication include:
- Duration of treatment; if approved for chronic use and no limitations on its use beyond the duration that the drug was studied in clinical trials, HCEI analyses considering use beyond the duration of such trials;
- Practice setting; use of a drug in a practice setting different than the setting in which clinical trials were conducted;
- Burden of illness;
- Dosing; HCEI analyses that include actual patient use (for approved indications) where the dosing regiment differs from the recommended dosing schedule in the FDA-required labeling;
- Patient subgroups; HCEI analyses of patient subgroups that were not analyzed in the pivotal clinical trials;
- Length of hospital stay;
- Validated surrogate endpoints; HCEI analyses derived from clinical study data using validated surrogate endpoints; and
- Clinical outcome assessments or other health outcome measures; HCEI analyses derived from studies with patient-reported outcomes or other health economic measures.
One other important 21st Century Cures-related change to the safe harbor included clarification of what is included in HCEI. Prior to 21st Century Cures, FDA created confusion by suggesting that clinical outputs of a health economic analysis were held to the substantial evidence standard even though the economic outputs were held to the lower standard of competent and reliable scientific evidentiary standard. 21st Century Cures expressly included, within the definition of HCEI, the “clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis.” This significant change addressed what had been a fundamental problem with the safe harbor as originally enacted—health economic endpoints cannot be completely disentangled from clinical endpoints in an HCEI analysis and, now, both are protected. In the Payor Communication Guidance, FDA acknowledged that the competent and reliable scientific evidence standard applies to “all components of HCEI,” including safety and efficacy.
FDA stated that when medical product manufacturers present HCEI in accordance with the safe harbor provisions, information regarding the study design and methodology, generalizability, limitations, sensitivity analyses, and other information “relevant to providing a balanced and complete presentation” should be clearly and conspicuously presented.
Concerning presentations by medical product manufacturers regarding investigational products, FDA stated that certain types of information may be presented to payors prior to approval or clearance of a drug or medical device. This information may include:
- Product information, such as drug class or device design;
- Indication sought, including the clinical endpoints studied and populations included in clinical investigations;
- Results of preclinical or clinical studies;
- Anticipated FDA approval timeframe;
- Product pricing information;
- Marketing strategies; and
- Product-related programs or services provided by the manufacturer, such as patient support programs.
It is important to note that FDA stated in the Payor Communication Guidance that it views HCEI as promotional and, therefore, expects that such information will meet FDA’s requirements for the submission of promotional materials, including submission on FDA Form 2253 at the time of first use.
Analysis
The most significant changes to a manufacturer’s ability to communicate HCEI to a payor or similar entity came with the passage of 21st Century Cures, which addressed certain fundamental problems with the safe harbor as originally enacted. That is, 21st Century Cures loosened the restrictions regarding whether aspects of an HCEI analysis could relate to off-label uses of the drug and whether the clinical outputs of an HCEI analysis were held to the lower evidentiary standard. The Payor Communication Guidance acknowledges and operationalizes these changes, along with providing clarity on FDA’s thinking concerning various elements of the safe harbor.
We found the amendments to the HCEI safe harbor enacted under 21st Century Cures to provide welcome and necessary relief from issues created by the safe harbor as originally enacted. To a large extent, the Payor Communication Guidance furthers the legislative intent of 21st Century Cures and, therefore, not much has changed with respect to our advice to clients preparing these presentations. The ability to expand the scope of HCEI analyses and include underlying clinical data and outputs in HCEI presentations under the protection of the safe harbor removes some of the risk in HCEI presentations carried out by manufacturers.
Arguably, the most significant change that the Payor Communication Guidance outlines is the opportunity for manufacturers to provide HCEI for investigational products. We see this as a big win for patients and hold out hope that earlier communications between manufacturers and payors may lead to earlier coverage determinations, which, in turn, may improve patient access.
As these are Draft Guidances, comments may be submitted to the docket at any time, but FDA requests that they be posted no later than April 19, 2017.
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