Perspective: Communications with the Food and Drug Administration on the Development Pathway for a Cell-Based Therapy: Why, What, When, and How?

Effective interaction between key stakeholders and the U.S. Food and Drug Administration (FDA) is central to successfully navigating the regulatory process and advancing new therapies into clinical trials. This article provides an overview of the types of interactions with the FDA that are available throughout the regulatory process, and it notes some common pitfalls to avoid.

Abstract

Effective interaction between key stakeholders and the U.S. Food and Drug Administration (FDA) is central to successfully navigating the regulatory process and advancing new therapies into clinical trials. This is especially true when developing cell-based therapies, which pose unique challenges to demonstrating safety and effectiveness. There are numerous opportunities for developers of a new cell therapy to interact with the regulatory agency, through both formal and informal processes. It is important to understand how to maximize the productivity of dialogue with the FDA and develop an effective regulatory strategy. This article provides an overview of the types of interactions with the FDA that are available throughout the regulatory process. This article also notes some common pitfalls to avoid and directs readers to additional references and resources to help inform cell therapy researchers and product developers and enable successful regulatory interactions.

Introduction

Successful navigation through the regulatory process relies on precise communication and meaningful interactions between stakeholders. These interactions are most frequently written, structured, and formatted into applications. Written communications often can be supplemented by meetings, in-person or by telephone. Some meetings are formal, whereas others are informal discussions; conversations can be confidential or can take place in open, public U.S. Food and Drug Administration (FDA) meetings.

A sponsor, as defined by the FDA, refers to the person or organization that takes on the responsibility for product development and initiates a clinical investigation [1]. Some interactions between sponsors and the FDA are required, such as an Investigational New Drug application (IND) to initiate a first-in-human clinical trial or a safety report of a serious adverse event. However, reasons to communicate with the Agency go beyond regulatory compliance and include defining a regulatory development path for novel therapies, learning from the FDA's experience with manufacturing challenges, preclinical and clinical development issues, and obtaining agreement from the FDA about the sponsor's plans.

Preparation for regulatory interactions is critical to an effective regulatory strategy and helps ensure productive interactions with the FDA. Good planning involves timing the communications so the sponsor's development efforts do not stop and wait for an FDA response or meeting, while simultaneously making sure there is adequate information or data available for the FDA to provide specific, meaningful feedback. Effective communication between the FDA and sponsors is most necessary in the case of novel and unique scientific challenges associated with cutting-edge technologies, such as regenerative medicine. Regenerative medicine encompasses a broad scope of products, including cell therapy, devices, and combination products. This paper focuses on cell therapy, but the broader scope of regenerative medicine may involve additional regulatory complexities, which are the responsibility of the Center for Biologics Evaluation and Research (CBER).

The regulatory process as applied to cell therapy products involves several key steps. Any clinical testing must be performed under an IND or Investigational Device Exemption [2]. The sponsor must submit an IND to the FDA so that the Agency can determine that the proposed study does not expose subjects to unreasonable risk and that the rights of subjects are protected. The FDA will assign an IND number and review the application within 30 days. If no deficiencies are identified, the IND will become active and the study may proceed.

However, if deficiencies are identified, the FDA can place the study on clinical hold until the sponsor's actions to address the issues are reviewed and addressed to the FDA's satisfaction in subsequent communications. The sponsor may also be placed on clinical hold after a study has begun if deficiencies or unanticipated safety issues are subsequently identified. FDA-regulated cell therapy products fall under the authority of the CBER, within the Office of Cellular, Tissue and Gene Therapies (OCTGT). If the cellular therapy is a combination product with a device, the Center for Devices and Radiological Health, FDA, may be consulted during the review process. A cell therapy proven to be safe and effective through clinical trials could subsequently receive market approval under a Biologics License Application (BLA) [3]. This article focuses on CBER-regulated cell therapies and does not address minimally manipulated or other human cells, tissues, and cellular-based products (HCT/Ps), which might not go through the IND pathway. (For information on HCT/Ps, the FDA has developed a webinar in the OCTGT Learn series on this topic [4].) Sponsors should communicate with the FDA regarding any question as to whether their cell therapy product is minimally manipulated as defined by Title 21, Part 1271 of the Code of Federal Regulations.

The FDA has reported [5] that some of the reasons for placing cell therapy INDs on clinical hold include dose regimen and safety monitoring deficiencies; problems with the chemistry, manufacturing, and controls (CMC) aspect of the IND; and inadequate study design or criterion for objective assessment of outcomes (Table 1). The FDA has specifically and publicly stated that many INDs go on clinical hold because the sponsor does not listen to or heed the advice given by the FDA in sponsor-FDA communications. Regardless of the reason, the result is delay in development time and additional costs for the sponsor.

Table 1.

Common reasons for clinical hold of INDs submitted to OCTGT

Modified from Wonnacott et al. [5] with permission.

Abbreviations: IND, Investigational New Drug application; OCTGT, Office of Cellular, Tissue and Gene Therapies.

Thus, regenerative medicine and cell therapy product sponsors would greatly benefit from better communication with the FDA. Senior Agency officials agree and have publicly encouraged greater communication. Although improved communication does not guarantee that an IND will not be placed on clinical hold by the FDA, it reduces risks for sponsors, identifies issues to be addressed, and helps facilitate a smoother pathway to market.

This paper provides a framework of the why, what, when, and how of FDA interactions. The paper is meant to serve as a guideline for sponsors to improve their communication with the Agency, thereby facilitating advancement of regenerative medicine products through the regulatory process. To that end, we attempt to delineate common issues and problems that occur and how they could be addressed, mitigated, or avoided through improved interaction with the Agency.

Regenerative Medicine Challenges

Regenerative medicine is heterogeneous, involves new and novel science, and spans multiple regulatory agency jurisdictions at the FDA. This spectrum of issues poses particular challenges for sponsors trying to develop their products in a safe and fast way. Regenerative medicine spans a multitude of disciplines in the biomedical and physical sciences, including biology, biochemistry, chemistry, materials science, and physics, and a wide range of products, including HCT/Ps. The range of disciplines encompassed within regenerative medicine can yield products that might be classified as a biologic, device, drug, or combination product [6].

The development processes for drugs and biologics, including cell therapies, are similar, but there are many unique differences for HCT/Ps, posing complex challenges for the regulatory pathway. As a product class, HCT/Ps (a) are extremely heterogeneous; (b) lack industry consensus on standards for product characterization; (c) have unique manufacturing challenges related to human donor source (autologous vs. allogeneic related vs. allogeneic unrelated, “off the shelf”); (d) may contain multiple cell populations (in many products); (e) cannot be terminally sterilized; (f) as living cells, may be unstable as to differentiation and survival; and (g) may have novel routes of administration. The FDA regulations, guidance, and review approaches have evolved relatively recently and will continue to do so as the field matures.

The unique considerations for HCT/Ps underscore the importance of sponsor-FDA interactions. In addition, because there are limited precedents to learn from, it is challenging to anticipate the FDA's position and response on certain issues, emphasizing why dialogue with the FDA is critical for development success. Some of the unique considerations are as follows:

• CMC considerations: cell source, manufacturing and storage, shipping and administration.

• Preclinical: relevant in vitro and in vivo animal studies, proof of concept, safety, biological activity. OCTGT does not usually make sponsors do pharmacokinetics/pharmacodynamics.

• Clinical study design issues.

Similar to the U.S., Europe has recognized and formalized the need for sponsor-regulatory agency communication, including for Advanced Therapy Medicinal Products, a category that encompasses HCT/Ps in Europe. The Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) identified this issue in its Work Programme 2010–2015, which describes milestones for CAT to bridge communication gaps with sponsors [7].

What Sponsor-FDA Communications Are Available? When Should They Be Used in the Development Life Cycle?

Sponsor Meetings with the FDA

The FDA meets with sponsors and applicants who seek guidance relating to the development and review of INDs or the review of marketing applications. These meetings represent critical points in the development process, and there are efficient, consistent procedures for the timely and effective conduct of such meetings. Sponsors should understand that FDA senior management does not attend all these meetings but may attend as needed. The FDA will review only information that was submitted within the specified time frame prior to the meeting. New information provided by the sponsor at the meeting will not usually be reviewed at the meeting for the FDA to make a decision. Sponsors may share new data during the meeting, but the FDA needs time to review in further detail, so it is important that the pertinent data package be submitted during the time period requested before the meeting.

Table 2 provides a high-level overview of opportunities for communications/interactions between the sponsor and the FDA. It is provided as a reference tool and is not intended to be restrictive or to show the only opportunities for open dialogue and communication. There are three types of confidential meetings, associated with the major milestones in drug development. They are classified as types A, B, and C, referring to the urgency of conducting the meeting (Table 3). Any formal meeting with the FDA will fall under one of these three categories, and there are clear definitions of requirements for each of these meetings [8]. The milestones in the regulatory product development pathway (IND filing, End of Phase 1, End of Phase 2, Special Protocol Assessment, pre-BLA, post-action) determine the content of the meetings.

Table 2.

Development milestones and communication opportunities

Abbreviations: BLA, Biologics License Application; CMC, chemistry, manufacturing, and controls; FDA, U.S. Food and Drug Administration; IND, Investigational New Drug application; SPA, Special Protocol Assessment.

Table 3.

Types of FDA meetings

Abbreviations: BLA, Biologics License Application; EOP1, End of Phase 1; EOP2, End of Phase 2; FDA, U.S. Food and Drug Administration; IND, Investigational New Drug application; OCTGT, Office of Cellular, Tissue and Gene Therapies; OTC, over the counter.

Pre-Pre-IND Interaction

This is an informal discussion, focused primarily on preclinical issues, always handled by teleconference (not an in-person meeting), and not part of the formal meeting process (e.g., it is not a type A, B, or C meeting). There is no set time frame to schedule these interactions, and, like all pre-IND discussions, they are nonbinding for future regulatory decisions made by the FDA. This dialogue was created to offer general guidance to sponsors for their IND-enabling preclinical program. A pre-pre-IND teleconference does not replace the ability of a sponsor to request a pre-IND meeting with the FDA.

These discussions can be extremely useful for novel products such as HCT/Ps. For example, one significant challenge of early-stage HCT/P development is the relevance of the animal studies to support entry into clinical trials. This discussion can help a sponsor understand the FDA's views regarding whether the animal model(s) selected is relevant; however, this interaction is a lead-in to a pre-IND and is not intended to decide whether the animal data support an IND.

It is also useful to begin the interactions with the FDA using the target product profile (TPP) tool [9]. The TPP is a useful planning tool for preclinical, IND-enabling studies and clinical trials and for effective communications with the FDA. Successful product development begins with having the end in mind, and the TPP conveys the long-term aspirational product attributes and overall intent of the development program. The TPP identifies the following: the optimal (ideal) profile for the therapeutic candidate, the threshold profile (minimally acceptable to differentiate from current and future competing products), and specific metrics for those attributes to enable key decisions in the development process. It is a living document and will change over time as data accumulate. The pre-pre-IND dialogue can help ensure that the IND proceeds and mitigate the risk of a clinical hold; however, the focus of the pre-pre-IND is only preclinical and sometimes very preliminary CMC, and for this reason, a standard pre-IND is still highly recommended. Although the FDA office that regulates cell therapies, OCTGT, readily incorporates pre-pre-IND meetings as part of its interactions with sponsors, not all offices of the FDA do so. The FDA meeting guidance document does not preclude a pre-pre-IND meeting, a sponsor needs to make sure that the office is aware of the sponsor's development/regulatory plan, and granting a pre-pre-IND meeting will not preclude granting a type B pre-IND meeting later on.

Pre-IND Meeting

For each new product or new indication, there is one pre-IND meeting available to sponsors. Sponsors should come to this meeting ready with their questions and the data the FDA would need to see to answer their questions. Since the sponsor files an IND with the FDA and the Agency has 30 days to respond, the IND submission needs to address all required information for the FDA to determine the adequacy of the IND. This is why it is critical that issues are raised, addressed, clarified, and resolved before the IND filing. The pre-IND discussion is a key venue to communicate with the Agency if the sponsor wants to avoid having its IND placed on clinical hold by the Agency.

The pre-IND meeting is best for the new or novel product (e.g., new type of product, new indication), or a new or inexperienced sponsor. The focus should be on preclinical studies, any key CMC issues, and the design of the initial clinical trial. A pre-IND meeting does not guarantee an IND will not be put on clinical hold, but it can reduce the likelihood by identifying and addressing key issues in advance. Pre-IND meetings can also include discussions on later strategies for overall development, again particularly so when it is a novel therapy or indication. The FDA will be unlikely to provide definitive answers regarding later stage development at this early point, but it is helpful to understand where the FDA stands on novel issues and where the sponsor can do more work to help the FDA in its review.

End of Phase 1 Meeting

The focus of an End of Phase 1 (EOP1) meeting is on safety; efficacy is not usually evaluated at this juncture, although with many phase 1 studies of cell therapies, phase 1 data provide some indication of biological activity of the product in subjects with the targeted disease. The EOP1 meeting is also the venue for reaching agreement, albeit nonbinding as differentiated from the agreement reached through a Special Protocol Assessment (see below), on a clinical study design that is capable of providing support for safety and efficacy in the phase 2 trial(s) [10]. Design features include the target patient population, criteria for inclusion and exclusion, dose and administration plan, primary and secondary endpoints, and the statistical plan. In terms of predicting a smooth pathway to the next clinical phase, the EOP1 and End of Phase 2 (described below) meetings are critically important to successful product development. EOP1 may be designated for fast-track products where phase 2 trials can be used to provide data on safety and effectiveness to support approval. Sponsors seeking an accelerated approval pathway depend on having a surrogate that is reasonably likely to predict an effect on a clinically meaningful endpoint. Sponsors need to think about this (and discuss it with the FDA) early in development, so that their clinical development program (including preclinical and phases 1, 2, and 3) is designed to gather the evidence necessary to support a conclusion that the specified surrogate is reasonably likely to predict an effect on a clinically meaningful endpoint.

It is not too early to consider a risk evaluation and mitigation strategy (REMS) and also to consider a plan for pediatrics. As with previous meetings, a TPP can be used to guide such discussion and agreement to help ensure that the proposed trial design(s) supports the labeling goals. The FDA focus at these milestone meetings is to help ensure that the quality of the scientific evaluation is adequate to permit an evaluation of the drug's effectiveness and safety. These may typically encompass multiple phase 2 studies, addressing issues of (a) product characterization, (b) determination of therapeutic dose (schedule, frequency, and course of administration) and/or route of administration, (c) patient selection criteria—what segment of disease stage/patient characteristics are best suited for the intervention, (d) evaluation of multiple clinical endpoints and further hypothesis generation, and (e) development of hypothesized mechanism of action/clinical efficacy, to help understand phase 3 study design, trial size, power, and statistical considerations.

End of Phase 2 Meeting

The purpose of an End of Phase 2 (EOP2) meeting is to determine the safety of proceeding to a phase 3 trial and evaluate the plans for design of the phase 3 effectiveness trials [11]. It is critical that the sponsor reaches agreement with the FDA at the conclusion of the EOP2 meeting on key design elements of the pivotal trials. The discussion can address issues such as (a) acceptable endpoints for licensure; (b) study design, power, α confidence interval, and other statistical considerations; (c) whether a single study is sufficient or whether two independent confirmatory studies are required; (d) the need for double-blind, placebo-controlled randomized trials; (e) the control (placebo, standard of care, or, if the standard of care is evolving, some active agent); (f) consideration for crossover trial design if placebo patients progress; (g) blinding/unblinding issues and impact on the statistical analysis; (h) CMC-related issues such as adequacy of the potency assay, product comparability assessment, product and process validation, simulation of normal operating range and maximal operating range considerations, and issues related to stability, shipment, and delivery.

As with previous meetings, a TPP can be used to guide such discussion and agreement. The proposed indication and dosing regimen in the TPP will help determine the appropriateness of trial design elements, including the primary endpoint(s), dose(s) selected for testing, and inclusion/exclusion criteria. In addition, the statistical analysis plan for the pivotal trials also needs FDA buy-in to reduce the risk of its becoming a BLA review issue later on. Statistical methods and analysis are often an important part of the discussion. Key statistical considerations include statistical methods, how to handle missing data/imputation method, potential multiplicity adjustment, and prespecified interim analysis. If agreements cannot be reached with the FDA at the EOP2 meeting, the sponsor must have follow-up discussions with the FDA to resolve any issues before initiating the pivotal studies.

Special Protocol Assessment

One optional type of interaction available to sponsors is to submit a Special Protocol Assessment (SPA) for pivotal phase 3 trials or other key studies, such as carcinogenicity or final product stability studies [12]. The SPA can be very helpful after adequate progress in the phase 2 studies to inform study design. Through the SPA process, the sponsor and the FDA negotiate the design of a clinical trial that will support an efficacy claim for licensure. The protocol intended for a SPA should be submitted to the FDA at least 90 days prior to the anticipated start of a study, accompanied by a cover letter including specific questions about the protocol design, scientific, or regulatory requirements to which the FDA can respond, leaving enough time to discuss and resolve any issues before the study begins. If an agreement is reached, the sponsor then has clarity in writing of the endpoints that must be achieved to support licensure. The SPA agreement can be binding; therefore, it is very important for the sponsor to plan well ahead and thoroughly evaluate the pros and cons of a SPA in its regulatory strategy and planning.

Pre-BLA Meeting

The communication at this milestone is essential to ensure an efficient BLA review process. Robust discussion of the application is expected, including discussion of all of the study results, problems in study outcomes and completion, how manufacturing issues are being addressed, the sponsor's plan to be ready for inspection, any plans for a REMS, seeking feedback on specific application needs such as data format and most importantly the size of the safety database, and any special analyses likely to be needed. These are working formal meetings. FDA concerns include whether the application will be complete and whether the sponsor is really ready to submit. The sponsor should be realistic; that is, sponsors should admit any problems and give an honest estimate of how long it will take to fix them.

Disagreements

Scientific and procedural disagreements between the sponsor and the FDA may arise during the product development process. As these disagreements can involve complex judgments and issues that are scientifically and commercially important, the Agency has procedures [13] in place that encourage open, prompt discussion of such disagreements at each step along the regulatory pathway. Sponsors should first seek resolution at the primary supervisory level; if not resolved at this level, there is a process through the supervisory chain of the Agency's chain of command.

How to Prepare, Conduct, and Follow Up on Sponsor-FDA Communications

The Request to Meet

The FDA's Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants states: “The meeting request, regardless of the method of submission, should include adequate information for the FDA to assess the potential utility of the meeting and to identify FDA staff necessary to discuss proposed agenda items” [14]. This guidance document, as well as the FDA Standard Operating Policies and Procedures on this topic [15], should be used to guide the sponsor when requesting a meeting. Meeting consideration by the FDA is a key step, and the sponsor needs to submit the request in writing, clearly identifying the submission as a meeting request. The sponsor should include relevant background in the request, including the purpose of the meeting, objective/expected outcome, draft questions (with a paragraph of explanation), and proposed sponsor attendees and requested FDA attendees.

Sponsors should identify questions before requesting the meeting and refrain from asking questions the FDA cannot answer. A sponsor should consider the following: why the sponsor needs this meeting and whether a meeting is the best method of communication. The sponsor may want to develop a draft package before submitting the meeting request, to help refine the questions, and align internal sponsor positions on each question. Scientific discussion and the science-regulatory interface are the best use of meeting time. FDA attendees should be identified on the basis of issues, and the sponsor should be realistic about asking for specific FDA attendees.

The biggest challenge to holding a meeting with the FDA is time. The sponsor wants the meeting to be convened quickly, whereas the FDA is juggling multiple requests with a finite amount of time and resources (e.g., the same people participating in a meeting are the ones doing the reviews). Many requests are submitted each year for meetings, and approximately 10% are denied. Note that the center director is unlikely to attend, but the office director or division directors may participate. The branch chiefs make the day-to-day decisions and have an important role in any interaction with a sponsor. The key is to plan for the meetings well in advance, incorporating meeting times into the development timeline.

The Preparation to Meet with the FDA

The background package submission is critical material, and the sponsor should provide this to the FDA in a timely manner, at least 30 days (at least 14 days for a type A meeting) prior to the scheduled meeting. The Agency's Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants provides the timing for when background packages are due for each type of meeting [14]. The background package should be organized by agenda topics/questions, grouped by technical discipline, and include pagination, table of contents, indices, appendices, cross-references, and tabs.

The background package content needs to support the intended objectives of the meeting and thus include the following: relevant summary product information, final list of questions to be addressed, supplementary information to address the specific issues and questions, and reference to any prior submission if data have already been submitted (the volume of the package should be managed). The FDA has welcomed the EMA's Committee for Medicinal Products for Human Use scientific advice packaging format, so in addition to general background and available data, under question, the sponsor can briefly describe the sponsor's position on the issue and proposed path forward with reference to supporting data in the later sections of the document.

What does the FDA do with the materials? The FDA holds an internal premeeting, ideally 2–7 days prior to the meeting with a sponsor. The FDA usually prepares draft/preliminary responses to the questions submitted in the background package and sends them to the sponsor 24–48 hours before the meeting. This increases the efficiency of the meeting by eliminating issues not requiring further discussion, highlighting areas needing more information for resolution, and alerting the sponsor to the FDA's issues of concern. The sponsor can choose to cancel the official meeting if the FDA's draft responses fully address all of the sponsor's questions.

If time allows, the sponsor can send in a brief submission to the premeeting response, indicating the items on which the sponsor agrees with the FDA so no further discussion is needed during the meeting, and the items that the sponsor would like to further discuss. Although it is not part of the guidance recommendations, it can be helpful to include additional data to support the sponsor's position on remaining questions. However, if providing new information that was not included in the background package, the sponsor must realize that the FDA will not assess this new information without having appropriate time to review and assess in response to the questions.

The Meeting

Sponsors must make the meeting with the FDA meaningful. We recommend using all the time allotted for discussion to hear the Agency's views. If a presentation is required, it should be kept short; the Agency should already have all the information needed to answer the questions in the background package. Sponsors should frame the issues for discussion and not hide concerns; instead, the topics at issue should be put “on the table” to stimulate discussion and propose solutions. It is also important to stay focused on the agenda and minimize surprises.

Prior to the meeting, the sponsor should conduct thorough research into precedents to understand the FDA's position on issues and be prepared for potential FDA responses. It is also important to have a realistic grasp of how likely the FDA is willing to be flexible. If the FDA has asked for responses to specific questions or made specific data requests, sponsors should be responsive to those questions. We recommend developing a message-driven, issue-oriented, data-supported agenda; testing presentations and questions on experts inside and outside the company or organization; practicing the tone of scientific advocacy; being prepared to listen; and doing a debrief for understanding. During the meeting, sponsors should not hesitate to ask for clarifications and the FDA's views.

The Nonscientific Considerations for the Meeting

The sponsor should stay professional, listen closely, and listen openly. Sponsors that ignore FDA advice make a critical and common error. Sponsors should consider the FDA's recommendations and ask for clarification if necessary. The meeting will entail discussion and reflection, not deals to be made. Sponsors should summarize what they heard, the outcomes, and any action items. Sponsors should confirm understanding of statements or recommendations from the FDA. Sponsors should know the audience (the reviewers are science-based and want to make data-driven decisions), listen, and understand what the FDA is telling them. Examples of the kinds of things that might be included in the FDA response to the sponsor's questions are that primary efficacy endpoint is not acceptable, more than one trial is necessary, or historical controls are not adequate. For instance, Agency responses may start with “In our letter of XYZ, we stated that …,” or “In our letter of X you were advised to …,” or “In our letter of Y we commented that …,” or, finally, “In a meeting on Z, you were again cautioned….” Successful regulatory communication should be message-driven, issue-oriented, data-supported, and audience-focused. It is essential for successful development to introduce critical concerns and issues; focus on target outcomes that lead to optimal indication, dosing, and safety; remember the FDA's role as regulators, not as codevelopers; and refer to a specific sponsor proposal.

After the Meeting

Official meeting minutes will be provided to the sponsor by the FDA within 30 days of the meeting. The FDA will summarize the following in bulleted form: important discussion points, decisions, recommendations, agreements/disagreements, issues for further discussion, and action items. Effective communication at this point will improve the sponsor path later. If, after receiving official minutes from the FDA, a sponsor or applicant needs additional clarification, the FDA project manager assigned to the meeting may be contacted for guidance or to arrange a follow-up teleconference. If the sponsor wishes to effect a change in the official minutes, a letter should be submitted to the FDA citing the recommendations and rationale. The sponsor's concern will be taken under consideration by the review division, and the project manager will issue an appropriate response in writing. If the FDA agrees to change the official minutes, such changes will be documented in an addendum to the official minutes. However, it is not OCTGT's policy to change meeting minutes. If sponsors are not satisfied with the response provided by the FDA, they may pursue the Agency's procedures for internal review and dispute resolution.

Conclusion

The FDA and sponsors do share some goals, most notably the desire to bring to market good products of value to patients. There is the value of perspective and experience, with the sponsor focusing on the product, whereas the FDA has a broader focus on the clinical, public health, and precedent issues. The FDA sees the full spectrum and must use that knowledge from competitor's plans, successes, and failures; it cannot typically share the details.

Meetings between the FDA and sponsors are valuable opportunities to discuss data and current and future study design and to address the development pathway to ensure that safe and effective products are brought to market in a timely manner. These meetings consist of informal discussions (pre-pre-IND, ad hoc teleconferences) and formal meetings (types A, B, and C), and for all of these interactions, it is important for the sponsor to have the pertinent list of questions and submit the right data package to enable an informed and productive discussion. Early dialogue with the FDA can help avoid major pitfalls in the development process. As described in this paper, there are many opportunities to interact with the FDA all along the product development continuum that should be fully taken advantage of, beginning at the pre-pre-IND stage. Milestone meetings are particularly important, especially after phase 1 or 2, and include key discussion of the final path to success; diligent and thoughtful preparation and conduct of meetings make a big difference to ensure productive discussions with the FDA and to identify key issues and challenges as early as possible.

Resources for Additional Information

Drugs@FDA website and CBER list of biologics: http://www.fda.gov; OCTGT Learn webinar series: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm; general information for OCTGT and related regulatory references: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/ucm094338.htm; OCTGT regulatory questions: CBEROCTGTRMS@fda.hhs.gov or Patrick.Riggins@fda.hhs.gov.

Author Contributions

E.G.F. and M.J.W.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.T., J.Z., and M.V.C.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript; K.J.W.: data analysis and interpretation, manuscript writing, final approval of manuscript.

Disclosure of Potential Conflicts of Interest

The authors indicate no potential conflicts of interest.