FDA Notice of Proposed Rulemaking: “Amendments to Regulations Regarding ‘Intended Uses’”

What’s New/Significant

The Food and Drug Administration (FDA) proposes to amend its medical product “intended use” regulations to clarify the types of evidence it considers when determining a product’s intended use as a drug or device.    

The FDA’s long-standing position is that any relevant source of evidence may be considered in evaluating a product’s intended use. While the FDA has not changed this position, the proposed revisions clarify that knowledge that a health care provider has prescribed or used an approved or cleared medical product for an unapproved use, is not, standing alone, sufficient to establish intended use. 

Rationale

The FDA issued a proposed rule in 2015, and a final rule in 2017, revising the language of the intended use regulations to conform to the current practice in applying the regulations. These amendments did not reflect a change in the FDA’s approach regarding types of evidence. After receiving a petition requesting reconsideration of these amendments, the FDA delayed the effective date of the final rule and reopened the docket to invite public comment. A number of comments raised questions and concerns, and on March 18, 2018, the FDA delayed the effective date of the intended-use amendments until further notice to allow further consideration of the substantive issues raised in the comments.

After considering the issues raised in the petition and comments, the FDA is now proposing to repeal the portions of the final rule issued in 2017 and issue a new rule to provide more clarity regarding the types of relevant evidence and provide direction to regulated industry and other stakeholders.

Scope

The proposed rule includes examples of types of evidence the FDA would consider relevant in determining intended use, including a variety of direct and circumstantial evidence:

1. Express Claims and Representations
   
   Any claim or statement made by or on behalf of a firm that explicitly represents a product for a particular use, including labeling claims and representations (whether made in required or optional/promotional labeling), advertising matter, and oral or written statements by persons responsible for the labeling, or their representatives
2. Implied Claims
   
   Any claim or statement made by or on behalf of a firm that implicitly represents a product for a particular use, including: 
   
   
   • Suggestive product names such as Chronix, Shroomz or e-Cialis.
   • Statements that imply an intended use, such as “For best results, use approximately 30-45 minutes prior to engaging in sexual intercourse.”
   • Representations that the product contains a particular ingredient to imply a physiological effect, such as the inclusion of “aspirin” or “sildenafil” in the ingredient list.
3. Product Characteristics and Design
   
   The characteristics of the product and its design, including:
   
   
   • The known physiological effects (medical or recreational) of a product that is unapproved for any medical use (for example, a product containing an active pharmaceutical ingredient or an analogue of an API or controlled substance).
   • The known use (recreational or medical) of a product that is unapproved for any medical use.
   • The product’s design or technical features.
4. Circumstances of the Sale or Distribution
   
   Circumstances surrounding the distribution of the product and the context in which it is sold, including:
   
   
   • To whom and for whom the products are offered, such as a firm’s repeated proactive detailing and delivery of large amounts of complimentary product samples to a health care provider whose patient population does not fall within the product’s approved population.
   • Circumstances and the context surrounding the sale, such as balloons containing laughing gas (nitrous oxide) being sold outside a rock concert; or the repackaging of bulk products into smaller plastic bags; and using personal, not business, emails and addresses for communications and deliveries.

The proposed rule includes examples of types of evidence that, standing alone, would not be considered by the FDA to be determinative of intended use, including: 

1. Knowledge, Alone or in the Context of “Safe Harbors,” of Health Care Providers Prescribing or Using an Approved Product for an Unapproved Use
   
   A firm will not be regarded as intending an unapproved use of an approved product based solely on that firm’s knowledge that the product is being prescribed or used by health care providers for this use. The following scenarios would not, standing alone, be considered evidence of a new intended use:
   
   
   • A pharmaceutical firm tracking sales and distribution metrics notes that one of its products, approved for use only in adults, is being ordered by and distributed to many medical practices that treat exclusively pediatric populations. The firm does not direct its sales or marketing staff to disseminate samples of or information about this product to these pediatric practices.
   • A pharmaceutical firm tracking sales and distribution metrics notes that one of its products, approved for the treatment of adult patients with acute lymphoblastic leukemia (ALL), is being ordered by and distributed to many medical practices that treat exclusively pediatric oncology populations. The National Comprehensive Cancer Network clinical practice guidelines (CPG) for the treatment of ALL in pediatric patients also recommends the firm’s drug product as a treatment option. The pharmaceutical firm distributes copies of the CPG at medical conferences, following all recommendations made in the revised draft guidance “Distributing Scientific and Medical Publications on Unapproved New Uses—Recommended Practices” (Ref. 8). The firm does direct its sales or marketing staff to disseminate samples or information about this product to practices that treat pediatric cancer patients exclusively.
2. Additional Examples That, Standing Alone, Are Not Determinative of Intended Use
   
   
   • A firm disseminates safety information about an unapproved use to health care providers to minimize risk to patients. 
   • In limited instances, a firm could disseminate safety and warning information without triggering the prohibitions on distributing a product for an unapproved use and misbranding a product by failing to provide adequate directions for use. 
     
     
     • The unapproved use of a firm’s approved drug is broadly accepted by the medical community and the firm has submitted an efficacy supplement to add the unapproved use to the labeling of the drug. The boxed warning and risk evaluation and mitigation strategy (REMS) materials for the drug warn of potential risks related to the unapproved use in general terms, but the firm disseminates additional specific safety and warning information to health care providers to minimize the risk to patients receiving the drug for the unapproved use. The safety and warning information does not expressly or implicitly promote the efficacy of the unapproved use.
   • A firm’s official social media account “follows” the social media account for a 501(c)(3) nonprofit that supports patients with a rare disease for which there is no FDA-approved treatment. The firm is in the process of investigating one of its FDA-approved products for use in the treatment of the rare disease that the nonprofit account supports. The nonprofit account disseminates messages about charity events, scientific conferences, support groups, and rare disease research and drug development. The firm account does not make any comments or otherwise endorse any specific posts on the nonprofit account.
   • During an internal meeting, a firm’s CEO displays a slide of internal sales projections for its approved product that reflects potential sales for an unapproved use that is widely recognized as the standard of care.
   • A firm makes corporate filings or submissions to the U.S. Securities and Exchange Commission that include required disclosures of development activities or potential or actual sales for an unapproved use.
   • Following a clinical trial, the sponsoring firm prepares a plain-language summary of the aggregated clinical trial results and provides the summary solely to clinical trial participants to acknowledge their contributions to scientific and medical advancement (not to inform prescribing and use decisions). The summary provides a factual, balanced and complete presentation of the trial results, including relevant safety information and any limitations of the study. The summary does not make any conclusions about the safety or effectiveness of the unapproved product or the unapproved use, and it includes a conspicuous and prominent statement that the product or use has not been approved, cleared or licensed by the FDA.

Effective Date

The agency proposes that any final rule based on this proposed rule become effective 30 days after the date of publication of the final rule in the Federal Register.