FDA Regulatory and Compliance Monthly Recap — March 2018

• CBER’s advertising branch ends enforcement letter lull with untitled letter to CSL Behring over hemophilia treatment promotions
• FDA updates standards for acceptance of clinical investigation data for medical devices
• FDA publishes draft guidance outlining pre-request for designation process
• FDA issues draft guidance on data standardization practices for DSCSA product tracing requirements

CBER’s advertising branch ends enforcement letter lull with untitled letter to CSL Behring over hemophilia treatment promotions

The untitled letter raises concerns about promotional material depicting a man playing soccer, which is a moderate- to high-risk activity for hemophilia patients. The letter says the material misleadingly overpromises the effectiveness of the treatment.

The Advertising and Promotional Labeling Branch (APLB) of the Center for Biologics Evaluation and Research (CBER) sent its first enforcement letter since 2015, to CSL Behring over misleading material for hemophilia B treatment Idelvion. The untitled letter takes issue with online material, a patient brochure, an exhibit panel and a sales aid overpromising the effect the drug has on hemophilic patients’ activities and quality of life.

Per the letter, images of a man heading or kicking a soccer ball while jumping, along with captions about 14-day dosing, misleadingly suggests a hemophilic patient can play soccer when using the treatment. Soccer is considered a dangerous moderate- to high-risk activity for such patients because of bleeding associated with cuts, scrapes or other injuries. The impact of heading a ball could result in intracranial bleeding or concussion, while the secondary impact from landing after a jump could cause joint or bone injuries. The APLB says patients treated with Idelvion, even when their hemophilia is well-controlled, will be at serious risk for bleeding when taking part in such activities. The material misleadingly suggests hemophilia patients taking Idelvion can take part in dangerous moderate- to high-risk activity without consequences and that such activities are appropriate for patients using the product.

These misleading representations about the treatment render it misbranded under the Federal Food, Drug, and Cosmetic Act (FDCA) and make its distribution violative. As such, the APLB is requesting that CSL immediately stop disseminating the material and provide a plan for discontinuing its use of the material.

FDA updates standards for acceptance of clinical investigation data for medical devices

In recognition that more multinational clinical investigations are being carried out, the FDA issued a final rule and corresponding guidance document updating its standards for accepting clinical data from clinical investigations conducted both in and outside the U.S. The rule requires that good clinical practice (GCP) be adhered to for these investigations, though it doesn’t reference a specific GCP standard.

The FDA issued a final rule updating its standards for accepting clinical data for medical devices and amending medical device regulations to provide consistency in data acceptance criteria regardless of application or submission type. The rule finalizes a proposed rule issued in 2013, which was generally supported by industry. Although concerns were raised on the proposed rule about the lack of an international GCP standard for medical devices and the potential of resistance from foreign regulators, the FDA said the requirements in the rule provide the flexibility needed to accommodate the laws of other countries and don’t require that a specific standard be applied.

The rule amends FDA standards to require that data submitted from investigations conducted outside the U.S. to support an investigational device exemption (IDE) or device marketing application or submission adhere to GCP, which requires review and approval by an independent ethics committee (IEC) before and continual review throughout an investigation. The rule applies to clinical data submitted to support an IDE, premarket notification 510(k), requests for De Novo classification, premarket approval, product development protocol or humanitarian device exemption (HDE). Under the rule, sponsors must obtain and document the review and approval of the clinical investigation by an IEC. Sponsors conducting investigations outside the U.S. must provide statements and information about how the investigations conform with GCP. They must also secure and document freely given informed consent, including from participants whose specimens are used in the investigations.

The rule also includes requirements for the acceptance of data from clinical studies conducted in the U.S. and updates IDE, 510(k) and HDE regulations to reflect the requirements. The changes require that sponsors provide a statement about compliance with FDA regulations (21 CFR parts 50, 56 and 812) for human subject protection, institutional review boards and IDEs for studies conducted in the country. Although the FDA says it lacks data to quantify the benefits of the rule, it anticipates it will provide improved assurance of clinical data quality and integrity and protection of human subjects. It anticipates costs of compliance to be between $0.8 million and $22.1 million over ten years with a 7% discount rate. The effective date for the rule will be one year after the publication of the final rule.

In conjunction with the final rule, the agency published a Q&A guidance document to provide recommendations on how stakeholders can ensure investigations comply with the rule and revised regulations. The guidance notes that there may be cases in which investigations that don’t fully adhere to GCP are submitted in support of an IDE, marketing application or submission. In such cases, a sponsor may provide a brief explanation for not conducting the investigation per GCP, and a description of what steps were taken to ensure data and results are credible and accurate and the well-being of subjects has been protected. Alternatively, a sponsor may request a waiver if it can explain why a requirement is unnecessary, can’t be met or can be satisfied in a different way. Per the guidance, such waivers will be reviewed on a case-by-case basis.

FDA publishes draft guidance outlining pre-request for designation process

The guidance is designed to help sponsors secure a preliminary assessment through the pre-request for designation process, which provides information feedback on the classification of human medical products. The process is meant to provide more transparency and consistency to the informal interaction, which the FDA says may be preferable to formal feedback.

The FDA issued guidance outlining the pre-request for designation (pre-RFD) process at the Office of Combination Products (OCP) and describing the information needed in a pre-RFD. Under the pre-RFD process, sponsors may request informal feedback about whether a human medical product will be regulated as a drug, device, biologic or combination product. According to the FDA, this informal process provides a more flexible approach to interacting with the OCP and has become customary, or even preferable, to the more formal RFD process.

Sponsors may submit a pre-RFD to request a preliminary, nonbinding assessment of the regulatory identity or classification of a product and/or which center will be responsible for regulating it. Per the guidance, the OCP will provide within 60 calendar days a preliminary assessment based on the information provided in the pre-RFD. Pre-RFDs may be submitted at any time during product development but may be particularly beneficial when the classification or center assignment is unclear or in dispute and a product is in early development. Per the guidance, if a sponsor disagrees with the OCP’s preliminary assessment, the sponsor can contact the OCP to discuss its findings and may provide additional information or new data. Sponsors may also choose to submit an RFD for consideration.

A pre-RFD should include a description of the product, including the name of the product and all component products and regulatory submission numbers associated with the product. It should also include an explanation of how the product works and how it will be marketed. The guidance recommends that additional information describing details of relevant testing be provided, though this is optional. Requests should also include a list of all components and ingredients, including the amount and reasoning for each. In addition, a statement of proposed or intended use/indications for use should be provided along with instructions and conditions for use and a list of claims the sponsor plans to make about the product.

FDA issues draft guidance on data standardization practices for DSCSA product tracing requirements

The guidance is designed to help trading partners standardize the data contained in product tracing information by outlining data elements that should be included. It provides specific recommendations for cases in which trading partners are permitted by law to provide tracing information that omits certain elements.

The FDA published draft guidance describing standards for the interoperable exchange of information for product tracing, per Section 582 of the FDCA, as added by the Drug Supply Chain Security Act (DSCSA). Effective since 2015, the product tracing regulation requires that trading partners, such as manufacturers, repackagers, wholesale distributors and dispensers exchange transaction information, history and statements when taking part in transactions for certain pharmaceutical drugs.

The draft guidance provides recommendations on standardizing the data contained in product training information and addresses the data elements that should be included in this information. Section 582 applies to entities meeting the definition of a manufacturer, wholesale distributor, dispenser or repackager. In instances in which an entity meets more than one definition, all applicable requirements under Section 582 must be met but duplication is not required. The guidance provides recommendations for certain specific situations for manufacturers and dispensers:

• Manufacturer—When there are business relationships that involve multiple entities that may meet the definition of a manufacturer, such as a colicensed partner, these entities should determine and specify in a written agreement which of them will be responsible for product tracing activities.
• Dispenser—The guidance addresses three situations that may arise for dispensers:
  • Although a dispenser is required to provide product tracing information in transactions in which it transfers ownership of a product, it’s not required to so do when the sale is to another dispenser to meet a “specific patient need.” Per the guidance, this occurs when ownership is transferred from one pharmacy to another to fill a prescription for an identified patient.
  • Healthcare practitioners licensed to prescribe or administer medication are excepted from product tracing requirements for dispensers, but trading partners must be authorized trading partners.
  • Dispensers may enter into a written agreement under which a third party, such as an authorized wholesale distributor, maintains the product tracing information on the dispenser’s behalf. Per the guidance, when such an arrangement is in place, a dispenser must retain a copy of the agreement and be aware that such agreements do not relieve it of statutory obligations under Section 582. When a dispenser requests that a trading partner provide trading information directly to a third party, the trading partner transferring ownership has met its obligation to provide and the dispenser has met its obligation to capture and maintain product tracing information by providing the information directly to a third party.

The guidance outlines distinct elements of transaction information that trading partners are required to exchange:

1. Proprietary or established name—The first entity that creates the transaction information should use the proprietary or established name, and subsequent trading partners should use the same name.
2. Strength and dosage form—The strength and dosage form as written on the product label should be used.
3. National Drug Code number—Three-digit segment number composed of labeler code, product code and package code.
4. Container size—This should reflect packaging configuration of the individual salable unit rather than larger shipping units.
5. Number of containers—The quantity of individual salable units of the same lot number included in a transaction.
6. Lot number of the product—A set of alphanumeric characters assigned by the manufacturer or repackager to identify a batch or specific identified portion of a batch.
7. Date of the transaction—Date on which ownership is transferred.
8. Date of the shipment (if more than 23 hours after the transaction).
9. Business name and address from whom ownership is being transferred.
10. Business name and address of person to whom ownership is being transferred.

In cases in which a trading partner receives information that omits certain elements, trading partners should use the product information on the product label to complete the transaction information provided to a subsequent buyer.