Life Science Compliance Update

February 24, 2017

Medical Device Parallel Review Program Made Permanent

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A few months back, the U.S. Food and Drug Administration and the Centers for Medicare & Medicaid Services announced they are making permanent their “Program for Parallel Review of Medical Devices,” which is now operating as a pilot program.  The parallel review initiative allows concurrent FDA and CMS review of a medical device with the goal of reducing the time between FDA marketing approval or granting of a de novo request and Medicare coverage decisions, thereby “facilitating earlier access to innovative medical technologies for Medicare beneficiaries.”

Announcement of Extension

In the notice announcing the extension of the parallel review program, the agencies observe that the pilot program benefitted manufacturers by providing feedback to help design pivotal trials that can answer both agencies’ evidentiary questions. The notice also cites the program’s success in facilitating issuance of a Medicare national coverage determination less than two months after a medical technology received FDA premarket approval. The agencies are soliciting nominations from manufacturers of additional innovative medical devices to participate in the parallel review program. However, the agencies will only accept five candidates per year.  

Federal Register

In the official announcement, FDA and CMS describe the Parallel Review program is a collaborative effort that is intended to reduce the time between FDA marketing approval or FDA’s granting of a de novo request and Medicare coverage decisions through CMS’s National Coverage Determination (NCD) process. This program is intended to ensure prompt and efficient patient access to safe and effective and appropriate medical devices for the Medicare population

Parallel Review allows both FDA and CMS to review information about a medical device concurrently, rather than sequentially, while continuing to make their premarket review and coverage decisions consistent with their respective statutory authority. FDA works to ensure that only safe and effective medical devices are marketed in the United States. CMS makes coverage decisions for medical technologies, which are reasonable and necessary for the Medicare population. Neither FDA’s premarket review criteria nor CMS’s coverage processes criteria change when a medical device is accepted into the parallel review program.

Lessons Learned From the Parallel Review Pilot Program

The FDA and CMS write that they learned two primary lessons from the Parallel Review pilot program. First, they found that manufacturers benefit from engaging both Agencies at the pivotal clinical trial design phase. The feedback that manufacturers receive from both Agencies at the pivotal clinical trial design stage can assist manufacturers in designing pivotal trials that can answer both Agencies’ evidentiary questions. Thus, it is more likely that manufacturers will only need to conduct a single pivotal clinical study rather than several pivotal clinical studies to satisfy both Agencies. Second, concurrent review by the Agencies of clinical evidence can reduce the time from FDA premarket approval or the granting of a de novo request to an NCD. For example, on August 11, 2014, FDA approved a medical device that was part of the Parallel Review Pilot Program. On the same day, CMS initiated its national coverage analysis (NCA). CMS published a favorable final NCD on October 9, 2014, less than 2 months after the medical device received its premarket approval and 7 months before the NCD statutory due date.

Parallel Review Process

The program has two stages: (1) The pivotal clinical trial design development stage, and (2) the concurrent evidentiary review stage. The manufacturer should submit a request for parallel review prior to the start of the first stage by sending an email to Parallel-Review@ fda.hhs.gov, which indicates their interest in the program and includes the following information:

  1. Nomination of manufacturer:
  • Name of the manufacturer and relevant contact information;
  • name of the product;
  • succinct description of the technology and disease or condition the device is intended to diagnose or treat; and
  • state of development of the technology (that is, in pre-clinical testing, in clinical trials, currently undergoing premarket review by FDA)
  1. A statement that the manufacturer intends to meet jointly with FDA and CMS using FDA’s Pre-Submission program, or other mechanisms that allow for meetings of the three parties to gather and incorporate feedback from both Agencies about the design and analysis of their pivotal clinical trial, to support a marketing application and a National Coverage Determination.
  1. A statement that the medical device will require an original or supplemental application for premarket approval (PMA) or the granting of an FDA de novo request.
  1. The medical device is not excluded by statute from Part A and/or Part B Medicare coverage (and the request for parallel review includes a list of Part A and/or Part B Medicare benefit categories, as applicable, into which the manufacturer believes the medical device falls).
  1. A statement that the medical device addresses the public health needs of the Medicare population (and the request for parallel review includes an explanation of how).

Upon completion of the pivotal trial and submission of an original or supplemental PMA, or a de novo request, the Agencies intend to review the pivotal clinical trial evidence concurrently. Both Agencies will independently review the data to determine whether it meets their respective Agency’s standards and communicate with the manufacturer during their respective reviews.

February 22, 2017

Citizens Petition Challenges FDA’s Off-Label Rule

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On February 8, 2017, three organizations called on the United States Food and Drug Administration (FDA) to overhaul a newly finalized regulation giving the agency wide latitude to police off-label promotion, saying it contains abrupt and unconstitutional policy changes. The three organizations include: Pharmaceutical Research and Manufacturers of America, the Biotechnology Innovation Organization, and the Medical Information Working Group (a coalition of pharmaceutical manufacturers).

The three organizations collectively represent essentially all major drugmakers, and the petition challenges a January 9, 2017, final rule issued by the FDA. The final rule revised the definition of “intended use” to include a new “totality of the evidence” standard that wasn’t in the proposed rule. The final rule caught the pharmaceutical and medical device industries off guard because the proposed rule simply deleted the knowledge-based labeling directive without hinting at a change to a totality-of-evidence standard.

The Citizens Petition

The three groups filed a citizens petition because they believe that the FDA violated the Administrative Procedure Act (APA) because stakeholders were not given fair notice of the revision and opportunity to comment. It also undercuts the FDA’s reasoning for implementing a totality-of-evidence standard, stating that such a standard is overly vague and not supported by relevant case law.

The petition states that, among the consequences resulting from the revised definitions, the open-ended, subjective totality of the evidence standard will result in: (1) increased False Claims Act (FCA) litigation because qui tam relators will be emboldened to use circumstantial evidence to allege that manufacturer communications caused the government to pay for off-label uses of medical products; and (2) a chilling of free speech about legitimate scientific data related to off-label uses of medical products.

According to Bloomberg, some attorneys agree with the three organizations that the FDA violated the APA when it made the change to the final rule.

Stay of Rule Requested

The industry groups said in the petition the FDA should indefinitely stay the final rule, reconsider it and use a final definition of “intended use” that is consistent with the proposed rule issued in 2015.

The final rule, published in the Jan. 7 Federal Register, also describes when a product made or derived from tobacco intended for human consumption will be subject to regulation as a drug, device or a combination drug/device product under the Federal Food, Drug and Cosmetic Act. The rule’s effective date was Feb. 8, but the FDA postponed it until March 21 in a Feb. 7 Federal Register notice.

The FDA has 180 days to respond to a citizen petition, but the agency can respond by saying it is still considering the issue, Bradley Merrill Thompson, a Washington-based attorney with Epstein Becker & Green PC, told Bloomberg BNA. Therefore, the deadline is not really that effective.

Totality of the Evidence

In the proposed rule, the FDA deleted from the “intended use” definition a provision that said if a manufacturer has knowledge that a drug or device is used for off-label conditions, the manufacturer is required to provide adequate labeling for that use. But in the final rule, the FDA replaced that provision with languages saying it would consider “the totality of the evidence” when deciding whether a company needs to provide labeling for an off-label use.

The petition said that under a totality of evidence standard, “everything may be considered to establish a product’s intended use. This standard would allow FDA to rely even on non-promotional scientific exchange as evidence of intended use” and could include clinical practice guidelines and a company’s response to unsolicited requests for information about off-label uses.

Anne K. Walsh, an attorney with Hyman, Phelps & McNamara PC in Washington, told Bloomberg BNA the totality of evidence standard “it’s clear to me that FDA tried to avoid the notice and comment requirements of the APA,” Walsh said. Walsh said the petitioner’s APA argument “is certainly strong enough that they could have filed directly with the court and challenged it on an APA basis.”

Deborah M. Shelton, a partner in the FDA Practice Group of McCarter & English in Washington, told Bloomberg BNA the FDA “is saying [in the final rule] it’s not the knowledge in and of itself that would inform the ‘intended use,’ but that could be part of the equation and could go into the totality of evidence.”

“The petitioners have a very strong argument that this is actually a change in position from the proposed rule. To do that in the final rule without providing an opportunity for comment, is arguably violative of the APA,” Shelton said. Shelton noted that she felt it makes sense for the FDA to stay the final rule.

Public Citizen’s Health Research Group Disagrees

Michael Carome, director of Public Citizen’s Health Research Group, told Bloomberg BNA Feb. 13 that he doesn’t think the FDA violated the APA in making the change in the final rule. “We don’t think there’s anything unique there that’s inconsistent with the existing regulation or what was proposed in 2015,” Carome said.

The proposed rule struck the last sentence of the definition of “intended use,” which said “that if a manufacturer knows that a drug or device is being used for off-label uses such knowledge would require the manufacturer to update the labeling for that use,” Carome said.

February 10, 2017

FDA Finalizes Guidance on Assigning Non-Proprietary Names to Biologics and Biosimilars

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Recently, the Food and Drug Administration (FDA) finalized guidance detailing its approach to assigning non-proprietary names to biologics and biosimilars. The guidance, titled “Nonproprietary Naming of Biological Products,” finalizes an August 2015 draft of the same title. In the final guidance, the FDA says a biologic product’s nonproprietary name (“proper” name) will consist of two components: a “core name” and a distinguishing suffix (with no specific meaning) composed of four letters. The FDA, however, did not finalize an approach to the suffix format for interchangeable products.

Scope

The FDA intends to apply the naming convention to both newly licensed and previously licensed biological products. The FDA is also continuing to consider the process for implementation of the naming convention for previously licensed products but, for right now, intends to assign distinguishing suffixes to a limited group of these products and will accept submissions of prior approval labeling supplements that include proposed suffixes.

Core Name

FDA says the core name will be the name designated by the USAN Council for the originator biologic product, and that any related biological product, biosimilar product, or interchangeable product will have the same core name. The FDA notes in the guidance that “use of a shared core name will indicate a relationship among products.”

Distinguishing Suffix

For the second component of a product’s proper name, the FDA says “a distinguishing suffix that is devoid of meaning and composed of four lowercase letters will be attached with a hyphen to the core name of each originator biological product, related biological product, or biosimilar product.” The agency notes that its choice of using a suffix rather than a prefix will help products with the same core name being grouped “together in electronic databases to help health care providers locate and identify these products.”

Inadvertent Substitution

The finalized naming approach “should help prevent inadvertent substitution” which can lead to “unintended alternating or switching of biological products that are not determined by FDA to be interchangeable with each other,” the agency says. The FDA notes the distinguishing suffix should clear up potential confusion when related biological products are licensed for different indications, different routes of administration, or fewer than all indications for which the reference product is licensed.

The FDA also says the unique suffix should also prevent confusion among health care providers who, “based on their experience with small-molecule drugs and generic versions of those drugs, may incorrectly assume that FDA has determined biological products with the same proper name to be interchangeable.”

Interchangeability

In the guidance, the FDA says that it is continuing to consider the appropriate suffix format for interchangeable products. The FDA says it intends to apply a naming convention to interchangeable products that will feature a core name and a suffix included in the proper name; however, FDA is continuing to consider the appropriate format of the suffix for these products.

In addition, FDA requests that biologic and biosimilar applicants and application holders propose a suffix composed of four lowercase letters for use as the suffix included in the proper name.

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