FDA Guidance Provides Clarity to Drug and Medical Device Companies

The Food and Drug Administration issued new guidance on two important topics for pharmaceutical and medical device companies: distributing written material on the unapproved uses of drugs and medical devices, and how to solicit feedback during the process for getting approval to market a medical device or permission to conduct a clinical trial of a medical device.

Earlier this month, the FDA weighed in on what types of written materials drug and medical device companies can circulate when they address unapproved uses of medical products and drugs. The area is a sensitive one for compliance, since charges of promoting off-label uses can lead to massive penalties under the False Claims Act.

GlaxoSmithKline, for example, paid a record $3 billion in July 2012 to settle criminal and civil charges that included allegations of unapproved off-label marketing and promotion of several of its drugs. Johnson & Johnson shelled out $2.2 billion to settle with the Justice Department charges that it illegally promoted the off-label use of certain drugs.

The draft guidance, which replaces final guidance published in January 2009, clarifies the types of journals that can be distributed and adds two new categories of materials that companies can safely circulate without concern that it could lead to charges of promoting off-label use of drugs or medical devices. 

“Consistent with longstanding FDA policy and practice, the upshot of this new draft guidance is that if manufacturers distribute such information as recommended, the FDA does not intend to use the distribution as evidence of the manufacturer's intent for the product to be used off-label,” says Colleen Heisey, a partner with law firm Jones Day.

In addition to scientific and medical journal articles, the revised draft guidance addresses the dissemination of two additional categories of materials—medical reference texts and clinical practice guidelines. Allowing the distribution of CPGs, in particular, is a welcome expansion from previous guidance, says Kathleen Sanzo, a partner with law firm Morgan Lewis. “CPGs, which generally represent the endorsement of relevant professional medical societies, carry significant weight with healthcare providers,” she says.

The latest draft guidance provides recommendations on the specific characteristics of scientific and medical publications that companies may opt to distribute. A scientific or medical journal article that is distributed should:

Be published by an organization that has an editorial board that uses independent experts who have demonstrated expertise in the subject of the article under review;

Be peer-reviewed and published in accordance with the peer-review procedures of the organization; and

Not be in the form of a special supplement or publication that has been funded, in whole or in part, by one or more of the manufacturers of the product that is the subject of the article.

The draft guidance recommends that the journal reprint or reference publication should be accompanied by a “prominently displayed and permanently affixed statement” disclosing that the uses described in the information have not been approved or cleared by the FDA.

“Medical device makers wanted the guidance, because they wanted to have greater predictability about the regulatory pathway to market for their devices.”

—Elizabeth Bierman,

Partner,

Morgan Lewis

The information also should disclose where the author of the article may have a financial interest in the drug or medical device maker, or where the author is receiving compensation from that drug or medical device maker. The FDA draft guidance also recommends that the drug or medical device maker disclose all significant risks or safety concerns associated with the unapproved uses. Public comment on the draft guidance is due by May 2.

Smoothing the Approval Process

The FDA also issued new guidance in February on how to obtain feedback from the FDA in response to questions a medical device company might have prior to submitting a proposed medical device application or conducting a clinical trial for a novel device.

Since it was created in July 2012, the pre-submission program has served as an important mechanism for companies in the industry. “Medical device makers wanted the guidance, because they wanted to have greater predictability about the regulatory pathway to market for their devices,” says Elizabeth Bierman, a partner in the FDA practice of law firm Morgan Lewis.

Among the issues the final guidance addresses are:

What specific types of feedback may be requested;

How to request a submission issue meeting with the FDA;

When submission issue meetings are appropriate to request; and

The FDA's timeframe for providing responses.

“The more interaction medical device makers can have with the agency, the more preliminary feedback they can incorporate into their final submissions,” says Allyson Mullen, who provides counsel to medical device makers for law firm Hyman, Phelps & McNamara. The idea is to reduce the overall time it takes to review applications by completing the submissions right on the first go-around.

The pre-submission program is not appropriate in all circumstances, the guidance states. Medical device makers should not use a pre-submission meeting for:

General questions on FDA policies or procedures;

Clarification questions that can be readily answered by a lead reviewer;

Requests for clarification on technical guidance documents; or

An interactive review of an already-active medical device submission.

Yarmela Pavlovic, a partner with law firm Hogan Lovells, says medical device makers should first decide whether it makes sense to have a pre-submission meeting with the FDA at all. “What are the questions you want answered by the agency? What are the goals for the meeting?”

The final guidance includes some important changes from the draft guidance. One of the most significant is the addition of a “refuse-to-accept checklist,” which the FDA uses to determine whether a submission includes sufficient information to provide feedback. “This seems to be a new trend for the FDA,” says Mullen. “They've now created these administrative ‘refuse to accept checklists' as part of the review process for many types of submissions.”

REQUESTS FOR FDA FEEDBACK

Below is an excerpt from the FDA's guidance on existing mechanisms for requesting FDA feedback.

This guidance provides information regarding existing mechanisms for requesting FDA feedback, and also establishes several new mechanisms, all of which will now fall within the same organizational “Q-Sub” structure for tracking purposes. The various types of Q-Subs addressed in this guidance and the timeframes within which FDA intends to provide the requested feedback are described in Table 1 below.

*As defined in MDUFA III Commitment Letter.

**21 days for urgent public health issues (see Section III.A.6.).

Source: FDA.

Bierman recommends that companies use the checklist prior to submission to ensure all of the required criteria are explicitly addressed. “They're going to have to try to ensure that anything they submit to the FDA meets the guidance requirements,” she says.

Then there is the issue of timing. The inclusion of the checklist could prolong the application process in situations where a medical device company has to go back and gather the required information and resubmit the application to the FDA, Bierman adds. From a practical standpoint, medical device companies will need to take into account this review time when entering into the pre-submission process, she says.

The FDA stated in the guidance that its timeline for providing feedback following a pre-submission filing is anywhere between 75 to 90 days. “If anything, the industry would like a quicker turnaround than what the pre-submission process usually entails, particularly if questions are fairly straightforward,” says John Smith, a partner with law firm Hogan Lovells.

According to the FDA, the agency's ability to hold timely meetings is contingent upon its limited resources. The FDA estimates that it receives roughly 2,544 pre-submission meeting requests annually, each of which involves roughly 137 hours of work per applicant.

The final guidance also addresses substantive changes to how the FDA handles meeting minutes. While the draft guidance directed meeting minutes to be submitted directly to the lead reviewer, the final guidance directs them to be submitted to the document control center, where those meeting minutes will then be logged as an amendment to the pre-submission. 

If a medical device company, after submitting its meeting minutes, wants to dispute any changes made by the FDA, it must now submit a meeting-minutes disagreement amendment. Otherwise, the FDA's edited version of the meeting minutes will become final.

From a practical standpoint, that means if a company issued a final submission to the FDA down the road based on feedback from pre-submission, “some ambiguity may remain on the outcome of the pre-sub meeting,” says Mullen.

The feedback provided on a pre-submission meeting will represent the FDA's best advice based on the information provided, “unless the circumstances sufficiently change, such that our advice is no longer applicable,” the guidance stated. An example of this would be if the intended use of a medical device is changed after the agency provides feedback, or if important new issues arise concerning the safety and effectiveness of a device.