Life Science Compliance Update

March 06, 2018

FDA Issues New Draft Guidance on Submitting Formal Meeting Requests

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A new draft guidance from FDA explains how sponsors can submit a formal request for a meeting, which can be face-to-face, teleconference/videoconference meetings or written responses only, what sponsors should include in that request, how FDA can respond, how long the agency can take to respond, and how the sponsor and FDA can go about conducting efficient, consistent, timely and effective meetings.

Meeting Types

FDA describes four types of meetings. Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue. Before submitting a Type A meeting request, requesters should contact the review division or office to discuss the appropriateness of the request.

Type B meetings include, but are not limited to: Pre-investigational new drug application (pre-IND) meetings; Pre-emergency use authorization meetings; and Pre-new drug application (pre-NDA)/pre-biologics license application (pre-BLA) meetings (21 CFR 312.47).

Type B (EOP) meetings are as follows: Certain end-of-phase 1 meetings (i.e., for products that will be considered for marketing approval under 21 CFR part 312, subpart E, or 21 CFR part 314, subpart H, or similar products) and end-of-phase 2 or pre-phase 3 meetings (21 CFR 312.47).

A Type C meeting is any meeting other than a Type A, Type B, or Type B (EOP) meeting regarding the development and review of a product, including meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.

Meeting Requests

According to the FDA’s guidance, before seeking a meeting, requesters should use the extensive sources of product development information that are publically available. To disseminate a broad range of information in a manner that can be easily and rapidly accessed by interested parties, the FDA develops and maintains web pages, portals, and databases, and participates in interactive media as a means of providing advice on scientific and regulatory issues that fall outside of established guidance, policy, and procedures.

To promote efficient meeting management, requesters should try to anticipate future needs and, to the extent practical, combine product development issues into the fewest possible meetings. When a meeting is needed, a written request must be submitted to the FDA via the respective center’s document room (paper submissions) or via the electronic gateway, as appropriate. Requests should be addressed to the appropriate review division or office and, if previously assigned, submitted to the application.

The meeting request should include the following information:

  • The application number (if previously assigned).
  • The product name.
  • The chemical name, established name, and/or structure.
  • The proposed regulatory pathway (e.g., 505(b)(1), 505(b)(2)).
  • The proposed indication(s) or context of product development.
  • The meeting type being requested.
  • Pediatric study plans, if applicable.
  • Human factors engineering plan, if applicable.
  • Combination product information (e.g., constituent parts, including details of the device constituent part, intended packaging, planned human factors studies), if applicable.
  • Suggested dates and times (e.g., morning or afternoon) for the meeting that are consistent with the appropriate scheduling time frame for the meeting type being requested. Dates and times when the requester is not available should also be included.
  • A list of proposed questions, grouped by FDA discipline. For each question there should be a brief explanation of the context and purpose of the question.

Request Granted or Denied

If a meeting request is denied, the FDA will notify the requester in writing. The FDA’s letter will include an explanation of the reason for the denial. Denials will be based on a substantive reason, not merely on the absence of a minor element of the meeting request or meeting package items. For example, a meeting can be denied because it is premature for the stage of product development or because the meeting package does not provide an adequate basis for the meeting discussion. Thus, the FDA will generally deny requests for Type A meetings and Type C meetings to discuss the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval that do not include an adequate meeting package in the original request. The FDA may also deny requests for meetings that do not have substantive required elements. A subsequent request to schedule the meeting will be considered as a new request.

If a meeting request is granted, the FDA will notify the requester in writing. For face-to-face and teleconference/videoconference meetings, the FDA’s letter will include the date, time, conferencing arrangements and/or location of the meeting, as well as expected FDA participants. For face-to-face and teleconference/videoconference meetings, the FDA will schedule the meeting on the next available date at which all expected FDA staff are available to attend; however, the meeting should be scheduled consistent with the type of meeting requested. If the requested date for any meeting type is greater than the specified time frame, the meeting date should be within 14 calendar days of the requested date.

Appendix

February 23, 2018

New Limitations on Guidance Documents Expected to Have Heavy Effect on Industry

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The Trump Administration recently adopted new limits on the use of “guidance documents” issued by federal agencies. Various industries use the applicable guidance documents to better understand the government’s interpretation of laws, and as such, this may have a sweeping effect on industry compliance measures.

The revised policy piggybacks off of a previous memo issued by Attorney General Jeff Sessions that prohibited the Agency from issuing guidance documents that effectively bind the public without undergoing the notice-and-comment rulemaking process. This means that the DOJ was unable to issue guidance documents that effectively created rights or obligations that were binding on those outside of the Executive Branch, or to create binding standards by which the DOJ determines compliance with already existing statutory or regulatory requirements.

Under the revised policy, issued by Rachel L. Brand at the Department of Justice (DOJ), the Agency will not “use its enforcement authority to effectively convert agency guidance documents into binding rules.” Guidance documents are not permitted to “create binding requirements that do not already exist by statute or regulation.” Additionally, DOJ lawyers representing the government in court “may not use noncompliance with guidance documents as a basis for proving violations of applicable law,” a common tactic previously used.

The guidance documents may be used for “proper purposes” in cases, such as by using them to explain or paraphrase legal mandates from existing statutes or regulations, or to use evidence that a party read such a guidance document to help prove that the party had requisite knowledge of the mandate.

Brand goes on to note that the DOJ “should not treat a party’s noncompliance with an agency guidance document as presumptively or conclusively establishing that the party violated the applicable statute or regulation.” Just because a party does not comply with the agency guidance that expands upon a statutory or regulatory requirement does not mean that the party violated those underlying legal requirements – agency guidance documents are not permitted to create any additional legal obligations.

This policy applies to future actions brought by the DOJ and – wherever practicable – to any matters pending as of January 25, 2018.

As such, defense attorneys seem to be pleased with this change, saying that it gives them a tool to help fend off wrongdoing allegations against their clients.

Benjamin C. Mizer, a former DOJ official, said that the new policy “may significant affect cases involving the health care and life science industries” because the Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS) heavily rely on guidance documents in court proceedings and other allegations of wrongdoing.

Lindsey E. Gabrielson, a lawyer in the Boston office of Foley & Lardner, stated that the government will now “face serious hurdles” in enforcement actions based on violations of health care guidance documents. Barry L. Goldstein, a lawyer based in Oakland, California, referred to the shift as “extraordinary.”

February 05, 2018

FDA Releases Guidance on IND Sponsors

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In December, the FDA issued a guidance describing best practices and procedures for timely, transparent, and effective communications between investigational new drug application (IND) sponsors and FDA at critical junctures in drug development, which may facilitate earlier availability of safe and effective drugs. The guidance applies to communications between IND sponsors and FDA during the IND phase of drug development, including biosimilar biological product development (BPD).

Guidance

Communications between FDA and industry are often opportunities to share information on clinical trials and for the agency to provide advice on trial design, dose selection, nonclinical study requirements, and manufacturing and facility issues. It is important that agency-industry interactions “be conducted efficiently and consistently, with clear, concise, and timely communication,” FDA says in announcing the guidance.

Pre-IND Meetings

Pre-IND meetings, which can prevent clinical hold issues, can be valuable for understanding proof of concept and initiating dialogue with the agency as the company develops a complete IND submission.

“FDA encourages sponsors to request a pre-IND meeting for the following: a drug not previously approved/licensed, a new molecular entity (NME), a planned marketing application intended to be submitted under the 505(b)(2) regulatory pathway, drugs for which it is critical to public health to have an effective and efficient drug development plan (e.g., counter-terrorism), drugs with substantial early development outside the United States, a planned human factors development program, and drugs with adequate and well-controlled trials to support a new indication,” FDA says.

FDA further says it “encourages sponsors to request pre-NDA/BLA meetings for all planned marketing applications, particularly applications to be reviewed under the PDUFA V Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs.”

Interaction with FDA

The review division regulatory project manager (RPM), who has comprehensive knowledge of the drug and its regulatory history, is the primary point of contact for communications between IND sponsors and FDA during the life cycle of drug development. The RPM is the contact for facilitating the timely resolution of technical, scientific, and regulatory questions, conflicts, or communication challenges between the sponsor and the review team, FDA says.

Other project managers can include:

  • CDER’s Office of Pharmaceutical Quality regulatory business project managers, who manage meeting requests, regulatory submissions, and other inquiries related to chemistry, manufacturing, and controls, including facility and product quality issues;
  • CDER’s Office of Surveillance and Epidemiology safety regulatory project managers, who manage sponsor requests for proprietary name review; and
  • CDER’s Formal Dispute Resolution Project Manager, who manages sponsor requests for resolving scientific and/or medical disputes that cannot be resolved at the division level.

Types of Advice

During the life cycle of drug development, sponsors routinely solicit feedback from FDA on both scientific and regulatory issues. The breadth and frequency of advice sought can vary according to the experience of the sponsor, as well as the novelty and development stage of the proposed drug. During the IND phase of drug development, sponsors often solicit advice at critical junctures in their development programs. These topics include, but are not limited to the following:

  • Regulatory (e.g., plans for submission of proprietary name requests, plans to defer or waive specific studies, development plans with other FDA centers (e.g., the Center for Devices and Radiological Health) for combination products), applicability of an expedited program;
  • Clinical/statistical (e.g., planned clinical trials to support effectiveness, validity of outcomes and endpoints, trial size, enrichment designs);
  • Safety (e.g., safety issues identified in nonclinical studies and early clinical trials, size of the overall safety database, concerns related to particular populations, post-approval pharmacovigilance plans, risk evaluation and mitigation strategies, plans for human factors studies, issues related to evaluation of abuse potential);
  • Clinical pharmacology and pharmacokinetics (e.g., dose selection, use in specific populations, drug-drug interactions);
  • Nonclinical pharmacology, pharmacokinetics, and toxicology (e.g., genetic toxicology, reproductive and developmental toxicology, carcinogenicity, mechanism of action); and
  • Product quality (e.g., proposed shelf life and stability studies, delivery systems, characterization of drug substance/product, facility compliance with good manufacturing practices, comparability of lots used in clinical trials and commercial lots); and
  • The proposed pediatric development plan and dosing.

Complex questions that involve interpretation of regulations and statutes, or the application of existing FDA policy to novel circumstances, can demand additional vetting and response time, FDA says.

More on Communication

FDA notes that the guidance does not apply to communications or inquiries from industry trade organizations, consumer or patient advocacy organizations, other government agencies or other stakeholders not pursuing an IND development program.

Regarding companies that fail to respond, FDA notes that later drug development can be negatively affected by sponsors’ delay or failure to respond to FDA, though the timing of FDA’s response may also be negatively affected if the review team experiences “an unexpected shift in work priorities or team staffing. In these cases, the FDA project manager will try to keep sponsors apprised of changes to the estimated response timeline.”

Regarding delays in obtaining FDA response, FDA advises the sponsor to contact:

  • The appropriate FDA project manager, typically the review division RPM, for a status update after the expected amount of time (e.g., the timelines described in a MAPP) for a FDA response that has passed;
  • The appropriate FDA project manager, typically the review division RPM, for a status update after the estimated response time has passed (i.e., the estimated FDA-response date communicated to the sponsor previously);
  • The appropriate FDA project manager’s next level supervisor for assistance in eliciting a response from the project manager; and
  • The appropriate division or office management officials for assistance in eliciting a response from the project manager; or
  • CDER’s or CBER’s Ombudsman for assistance in eliciting a response from the project manager.

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