FDA Sponsor Communications Best Practices
Transcript Of FDA Sponsor Communications Best Practices
December 29th, 2014
Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852
Re: Docket No. FDA–2014–N–1575: Best Practices for Communication Between the Food and Drug Administration and Investigational New Drug Sponsors During Drug Development; Request for Comments
Dear Sir/Madam:
The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on “Best Practices for Communication Between the Food and Drug Administration and Investigational New Drug Sponsors During Drug Development.” This docket represents an important step in identifying effective practices for communication during drug development, both through official meetings and less formal means of communication outside of established meetings. Modern drug development requires scientific collaboration by all parties in the innovation ecosystem, and promoting effective FDA-Sponsor communication is fundamental to our ability to translate scientific discoveries into safe and effective new therapies for patients.
BIO represents nearly 1,000 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture and a cleaner and safer environment.
I.
INTRODUCTION:
BIO strongly supports the Prescription Drug User Fee Act (PDUFA 5) program to enhance FDA-Sponsor communication, which is based on FDA’s stated philosophy that “timely interactive communication with Sponsors during drug development is a core activity to help achieve our mission to facilitate the conduct of efficient and effective drug development programs, which can enhance public health by making new safe and effective drugs available to the American public in a timely manner.” In recent public statements, FDA has noted that “Sponsors who avail themselves of the opportunity to meet with FDA early in development have substantially reduced the time from the start of human testing—when FDA first becomes involved—until
marketing approval.”1 For instance, companies that meet early with FDA have experienced a median product development time reduction of 1.4 years and upwards of 2.1 years for orphan drugs. Thus, increased communication during drug development ultimately will reduce time to market and speed the availability of important new therapies to patients.
There are currently a number of formal avenues for FDA-Sponsor communication. For example, current regulations (21 CFR 312.41(b)) require FDA to provide consultative advice during the investigational new drug (IND) phase.2 There are also existing Good Review Management Practices (GRMPs) that encourage communication with the Sponsor during the IND phase, as well as PDUFA mechanisms that allow for these communications (e.g., Type A, B, and C meetings and the Special Protocol Assessment (SPA) process). 3 Sponsors are encouraged to take advantage of milestone meetings utilizing these established meetings procedures.
Changes to a development program often need to be discussed and addressed by the Agency in a more expeditious fashion to help prevent or minimize delays in development and for the Agency to be perceived as a collaborator in drug development. Many of these time-sensitive communications can occur efficiently outside of formal meetings. While some Review Divisions should be commended for providing advice and working in a responsive and collaborative way, this is not the norm in all divisions. BIO members have noted that communications practices can be inconsistent both within and across Review Divisions.
Additionally, early communications on development do not always represent the entire Agency’s recommendations. For example, early communications for combination products from the Center for Drug Evaluation and Research (CDER) do not always include input from the Center for Devices and Radiological Health (CDRH), though such input could inform development programs.
BIO’s expectation is that the results of this docket will inform forthcoming FDA guidance on best practices for FDA-Sponsor interactions during drug development (expected in FY15), and to encourage greater timeliness, quality and consistency in communication across and within FDA Review Divisions through routine staff training and standard operating procedures.
1 FDA, Woodcock, Janet, Testimony before the House Energy and Commerce Committee, “21st Century Cures: Modernizing Clinical Trials and Incorporating Patient Perspective” (July 11, 2014) “For the 181 new drugs approved from 2008 - 2013 (for which a clinical development time could be calculated), the Sponsors of the 67 applications who met with FDA before submitting their Investigational New Drug (IND) applications had a median development time of only 6.6 years, compared to 8.0 years for applications for which such a meeting did not occur (a mean reduction of 1.4 years). The median drug development time for applications for which a meeting with FDA was held at the end of the Phase 1 (EOP1) milestone was 1.1 years shorter than for applications for which an EOP1 meeting did not take place. For orphan drugs, drug development was a median of 2.1 years shorter.”
2 (21 CFR 312.41(b)) “On the Sponsor's request, FDA will provide advice on specific matters relating to an IND. Examples of such advice may include advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.”
3 Good Review Practice: Good Review Management Principles and Practices for Effective IND Development and Review. http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualof policiesprocedures/ucm349907.pdf
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 2
II. BIO SURVEY ON EFFECTIVE FDA-SPONSOR COMMUNICATIONS
In support of the PDUFA V Enhanced Communications program, BIO initiated a multiyear survey initiative to better understand biotechnology company experiences during drug development and to identify best practices for FDA-Sponsor communication. The online survey was administered by a professional survey firm, Penn Schoen Berland (PSB), between June 18 and September 14, 2013 and received 102 unique responses from 91 BIO member companies. A preliminary analysis of the results is included in the slide deck prepared by PSB, which can be found in the appendix of these comments.
As discussed below, the initial survey demonstrated moderate improvement in certain communication practices in recent years, however, 40% of respondents reported that some FDA-Sponsor miscommunication contributed to one or more delays in product development.
BIO launched the second phase of this initiative in the summer of 2014. This phase includes collecting information on FDA and Sponsor interactions during drug development for over 190 individual clinical programs currently under development. PSB will complete the initial analysis in January 2015 and we look forward to sharing the results with FDA.
The 2013 survey demonstrated wide variability in the level of satisfaction in communication across different Review Divisions. Those divisions that communicated reasonably well did so across most avenues of communication— formal meetings, written letters, and informal communication—while those that were ranked lower communicated less effectively across all of those channels. BIO would like to partner with the Agency to identify the best practices from those divisions with the highest levels of satisfaction so that FDA can apply those practices to the other divisions to improve overall consistency.
Key Points:
• 70% of respondents were generally satisfied with the state of FDA-Sponsor communication, up from 64% in the early stages of PDUFA 4.
• However, only 18% of Biologics License Applications (BLA) Sponsors found the quality of communication to be very good or excellent, compared to 35% of New Molecular Entities (NMEs). The quality of communication was deemed best for Breakthrough Therapy-designated products (52%) and Priority Review products (52%).
• Of the respondents reporting that FDA-Sponsor miscommunication contributed to one or more delays in product development, 44% of these delays were caused by an unexpected FDA reinterpretation of an existing agency policy.
• 78% of Special Protocol Assessments required multiple review cycles.
• Survey respondents reported wide variability in communication across different Review Divisions; Figure 1 shows the divisions that ranked highest and lowest for communication satisfaction. Figure 2 evaluates the level of
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 3
communication satisfaction across the Review Divisions with which BIO member companies most commonly interact. Figure 1: Satisfaction with Communication Varies Among Review Divisions
Figure 2: BIO Member Interactions with FDA by Review Division
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 4
III. IMPROVING SCIENTIFIC DIALOGUE AND ENABLING EFFECTIVE COMMUNICATION DURING DRUG DEVELOPMENT
Based on our survey and discussions with members, BIO identified four main areas where improvement in communications could enable a more effective development and review process:
A. Improving Scientific Dialogue B. Improving Effectiveness of Formal Meetings with FDA C. Improving Communications between FDA and Sponsors Regarding Emerging
and Evolving Science D. Improvements to Communication on FDA Website
Below we have noted several points for FDA to consider as it drafts guidance on this topic.
A. Improving Scientific Dialogue
Communications best practices should improve the ability for Sponsors and FDA to engage in scientific dialogue in a collaborative manner across all Review Divisions during drug development to ensure there is timely resolution of issues and prevent any unnecessary delays.
While there have been significant improvements in how FDA and Sponsors communicate during drug development over the past few years, there are still issues with consistent and transparent practices across Review Divisions. Given the resources needed to prepare for formal meetings, efficiencies for FDA and Sponsors could be gained if there were mechanisms for more frequent feedback from the Review Division outside of formal Type A, B and C meetings and consistency across Review Divisions. For example, under what circumstances is it more appropriate for a Sponsor to communicate with FDA via informal communications (email, telephone, etc…) and when should an issue be addressed through a formal PDUFA meeting? Additionally, we continue to note a lack of cohesive process for programs that involve multiple FDA Centers, specifically CDER and CDRH. We believe FDA’s best practices guidance should address combination products and diagnostics to ensure that interCenter communication and coordination are adequately addressed.
We recommend that any best practices training is structured for consistency across Review Divisions, but tailored to meet the specific needs of each Review Division. The training should provide both Sponsors and reviewers with examples of what types of issues could be addressed through informal communications.
Specifically, we would like any best practices guidance and training to address the following:
• Appropriateness of Types of Communication: FDA should clearly define the appropriate type of communication (i.e., email, teleconference, IND submission of request for comment/advice, formal meeting request, etc.) to be used to address various categories of questions. In the case where it is determined that the answer being sought requires formal vetting and documentation by FDA or review of data, preliminary communications can help to prevent multiple meetings or letters to obtain the appropriate answer.
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 5
• Facilitating Timely and Interactive Communications via Teleconference: Many Review Divisions currently provide an opportunity for a brief teleconference with Sponsors to allow subject matter experts to discuss specific technical or timesensitive issues, as needed. These teleconferences can be quickly scheduled, limited in scope and duration—for example for 15 or 30 minutes—to brief the Agency on time-critical issues, such as pre-approval use of a drug in development or safety-related issues. We recommend expanding this best practice across Review Divisions. The meeting request would include limited briefing information (e.g., 5 slides or 7-10 pages). The teleconference would include a limited number of participants from FDA and the Sponsor and standard documentation would be shared afterwards with all participants. For important development questions requiring Agency input, where some live discussion would be useful toward gaining agreement, a shorter meeting format with quick scheduling could be useful (e.g., addressing potential clinical hold questions or discussing data requirements for submission to support a new protocol under an existing IND). These types of interactions to help align on an issue more expeditiously could reduce the need for additional formal meeting requests or improve the efficiency of any follow-up meetings.
• Access to Agency Review Staff: BIO suggests establishing an Agency policy and process regarding scenarios where Sponsors may contact Agency staff (in addition to the Project Manager function). For certain issues that arise during development (e.g., changes being considered in endpoint assessments), the Sponsor would benefit from direct access to Agency staff within a specific functional area (e.g., Clinical, Chemistry, Manufacturing, and Controls (CMC)). Best practices should identify instances where direct communication with Agency staff may enhance speed with which questions and answers can be facilitated. Any guidance should address the type and frequency of communication that would allow FDA to receive questions, identify an answer and respond to the Sponsor. These processes should acknowledge the workload and time commitment that medical reviewers dedicate to the review of INDs, New Drug Applications (NDAs), and BLAs, and carefully balance that consideration with their capacity to respond to important IND-stage Sponsor inquiries.
• FDA Written Responses to Requests for Advice: Given the resources needed to prepare for Formal Meetings, efficiencies for FDA and Sponsors could be gained if there were a mechanism for more frequent written feedback from the review team outside of Formal Type A, B or C meetings, with consistency across Review Divisions. We suggest establishing target timing of 30-60 days from submission for request for advice (per 21 CFR 312.41) to respond to the Sponsor. Sponsors would benefit from having timely responses to requests for advice, as these requests are important to continuation of ongoing clinical programs but may not fall into a Type B meeting category. For example, requests for comments and feedback on study protocols outside of formal avenues are sometimes under review for extended periods of time. In this situation, it is difficult for the Sponsor to plan development timelines and budgets, to ensure that advice from other regulatory agencies will be aligned and coordinated with FDA comments, and to ensure that feedback from the Agency is implemented prior to study initiation. As current timelines for responding to requests for comments differ across Review Divisions, we encourage that any forthcoming guidance establish clear delineation of timelines for feedback. Other examples where timely feedback would be beneficial to the Sponsor and speed development times include function specific questions such as those for CMC or protocols related to
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 6
postmarketing requirements and commitments (PMRs/PMCs). The scope should also include requests for which the Review Division will need to request participation from other offices (e.g., Study Endpoints and Labeling Development (SEALD) for patient-reported outcomes (PRO); CDRH for companion diagnostics and human factors protocols).
• Creation of Standardization and Templates for Routine Communications: We encourage standardization for written and telephone communication methods across Review Divisions. We acknowledge the need to send official correspondence via post; however, as paper correspondence may take several days to arrive, we encourage the adoption of standard processes across Review Divisions that allows for the sending of copies of official correspondence as a PDF or similar file type via secure email. Additionally, we recognize the value of telephone correspondence. Given that voicemails may not be heard in a timely manner, we suggest the further adoptions of a standard process across Review Divisions that allows for the use of secure email for informal correspondence. Use of templates for letters such as "study may proceed" would improve consistency (covering key categories of information including the annual reporting period). This can reduce the call/email volume to project managers (PMs) for routine information. FDA should also respond in the same manner in which the Sponsor communicated with them (i.e., FDA should respond via email if the Sponsor initially communicated via email).
• Communication with Email Accounts: As a best practice, we suggest that Review Divisions should acknowledge receipt of Sponsors’ emails within one business day. Additionally, response times for communication with general/blind FDA email accounts are widely variable. While some will acknowledge receipt of communications within 24 hours, others will take up to a week or more.
• Staff Assignments: In addition to assigning main contacts for each program, both the Agency and the Sponsor should assign alternates. The Agency and the Sponsor should provide updates as they become available. This should be extended to include Supervisory PM and Division Director information. Such a practice will provide clarity regarding key contacts and key personnel changes (e.g., recent Division of Oncology Products 1 (DOP1) Division Director change) and help preserve continuity in the review when there is turnover during reviews.
• Improvements to the Enhanced Communications Office: The BIO survey found that while FDA has made the efforts to publicize the existence and availability of the Enhanced Communications Office, the office remains underutilized and often unknown to Sponsors. BIO would like to partner with the Agency to continue to raise awareness of the Enhanced Communication Office as a resource for Sponsors, for example through webinars or conferences.
B. Improving Effectiveness of Formal Meetings with FDA
Sponsors often do not take advantage of entitled meetings with FDA either due to perception that the value of these meetings is not high enough to allocate the resources and time required to participate in such meetings or a perception that any such conversations may lead to a higher regulatory burden than Sponsors would have otherwise. Best practices should provide information about how such discussions before, during and after would be valuable to Sponsors and serve to
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 7
identify and resolve key issues in the most effective manner possible. Below we provide a few specific examples of such improvements for your consideration.
General Considerations:
• Understanding “Regulatory Speak”: We request that FDA provide guidance and training that better clarifies—to both Sponsors and reviewers—how the Agency should communicate to Sponsors the limitations of what the Agency can or cannot say in the context of a regulatory communication and how the Sponsor should interpret the type of “regulatory speak.” For example, as a regulatory agency, FDA can provide guidance on acceptable and validated scientific methods, but the Agency cannot compel a Sponsor to take one approach to drug development over another. Based on the Agency’s past experience and perspectives across many confidential drug development programs, FDA may use terms such as “encourages,” “cautions,” or “advises” in a meeting to provide guidance to a Sponsor. In some instances, a Sponsor may not interpret FDA’s feedback as definitive or absolute and may continue a particular approach to drug development at risk, which can create issues at later stages of development or review. Consequently, Sponsors should recognize the weight and significance of these terms used by FDA in formal meetings and appreciate the limitations of what the Agency can communicate. An upfront understanding of the vocabulary that is used in regulatory communications, such as through a disclaimer at the start of each meeting or in the meeting minutes and utilization of these terms in in a more consistent manner would serve to minimize miscommunications between FDA and Sponsors. Additionally, consistency between spoken and written feedback is encouraged.
• Preliminary Comments: We understand that FDA typically aims to send written preliminary comments at least 48 hours in advance of a formal meeting, which should be viewed as a best practice in order for a productive meeting to occur. If the FDA is requesting a response from the Sponsor, the preliminary comments should be provided four business days prior to the meeting. In the experience of BIO’s members, there has been a trend for the Agency provide these preliminary comments very late (within 24 hours of the meeting or less); occasionally, comments are only received at the meeting, and are thus not “preliminary” at all. Providing comments so close to the scheduled meeting makes it very difficult for Sponsors to determine if a meeting should still be held (or changed to a teleconference) and it may have a considerable impact on travel plans. If the Sponsor decides to proceed with the meeting, it can be quite challenging to adequately prepare verbal or written responses if FDA’s comments are significant or FDA provided preliminary comments on matters beyond the scope of questions posed in the Briefing Document. Where comments are received only at the time of the meeting, it is difficult if not impossible for the Sponsor to respond substantively to any of the issues raised in those comments; however, by such point, the responses and time to prepare for and attend the meeting have already been expended.
Pre-IND and IND Meetings:
• Pre-IND Meetings: We have seen an increased number of pre-IND meeting requests default to written responses only (WRO), and in most cases when this occurs, there is often a need to follow up on the written comments with a request for a teleconference to clarify the comments. Therefore, as the pre-IND meeting
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 8
request is in many cases the first interaction between the Sponsor and the Agency, we strongly recommend that a pre-IND meeting request should be honored with a teleconference or face-to-face meeting. This is optimal to ensure mutual understanding of any outstanding items and path forward to IND submission.
• Initial IND Teleconference: BIO recommends establishing communication (teleconference) with Sponsors three to five days prior to the Day 30 communication to convey any final issues in instances where there are substantial concerns from FDA. Instituting a standard practice of scheduling a teleconference will ensure the Sponsor team and FDA have availability to discuss any critical issues, if needed, before the IND is in effect.
End of Phase 2:
• Establishment of a Mechanism for a Sponsor to Request a Debrief Meeting for End of Phase 2 (EOP2) Meetings: We recommend establishing a mechanism that allows a Sponsor to discuss with FDA revisions that the Sponsor has made to the development program following the EOP2 meeting prior to the start of Phase 3 trials. These meetings could be held four to six weeks after the EOP2 meeting completion and would ensure alignment on the feasibility of the registration objectives and design of registrational studies. Clear alignment between FDA and the Sponsor will contribute to more efficient development through the minimization of regulatory risks.
• Target Product Profile Feedback: We request that more divisions follow the Target Product Profile (TPP) guidance and provide specific feedback to Sponsors. It would be beneficial to Sponsors if FDA feedback is obtained earlier in development, such as at the EOP2 meeting or in conjunction with Phase 3 SPA review, so adjustments can be made by the Sponsor.
Documenting Meeting Outcomes:
• Rectifying Differing Interpretations of Meeting Outcomes: Review Divisions provide their minutes to the Sponsor and often indicate that the Sponsor should let them know if there are areas of disagreement; however, there is often no further follow-through or mechanism for updating the minutes or receive greater clarity. The best practices guidance should address this issue and outline a mechanism for the Sponsor and FDA to resolve these issues within 90 days, including alignment on actions that the Sponsor has taken to address the issue raised in the meeting minutes.
• Extending Meeting Times to Allow for Process Issues: Formal meetings in which live meeting minutes are taken by FDA and reviewed with the Sponsor should be extended to 90 minutes. Many Review Divisions now take live meeting minutes and review for agreement with the Sponsor during the meeting. While there are many advantages to the practice of reviewing minutes, it takes time away from discussion at the meeting, leaving insufficient time for some discussion topics. Extending the meeting time to 90 minutes and advising the Sponsor of the amount of time FDA is reserving for minute review allows time for the primary purpose of the meeting (discussion of Sponsor questions and FDA responses), as well as live review of minutes/agreement on discussion outcome.
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 9
C. Improving Communications between FDA and Sponsors Regarding Emerging and Evolving Science
For companies working on a cutting edge technology in an emerging scientific field, it is essential that they communicate with FDA frequently and effectively so that all parties fully understand the state of the underlying science and the regulatory pathway to approval. In some instances, FDA thinking may be actively evolving and guidance may not exist for emerging issues, which may lead Review Divisions to provide inconsistent recommendations to Sponsors. This in turn can make it difficult for Sponsors to apply learnings to subsequent development programs. FDA should seek to ensure that changes in their thinking regarding novel or emerging areas of science and medicine are communicated to Sponsors in an efficient manner.
• Inclusion of External Experts: For many evolving scientific fields, it may be beneficial to include leading external experts in FDA-Sponsor meetings in order to best evaluate the clinical development and review procedures. FDA should work with Sponsors in these cases to ensure that consultations with external experts occur at the appropriate times during the drug development and review processes in order to ensure an effective process based on the best available science.
• Staff Briefings with Sponsors: Some Review Divisions, such as the Division of Oncology Products, hold meetings where Sponsors are invited to discuss their development programs. These briefings provide a forum for scientific dialogue outside of specific program meetings. We recommend adopting this best practice across Review Divisions. We also suggest that other divisions more consistently hold Applicant Orientation Meetings (AOMs). These meetings allow Sponsors to provide a guided overview of the application to FDA staff and/or give summaries of key attributes in the submitted data to help the Agency make its risk-benefit assessment. All staff within a division are invited to attend these AOMs and ask any questions. These meetings provide FDA staff the opportunity to learn about many aspects an application and provide the Sponsor with some early insights into the types of questions that may be asked during NDA/Supplemental New Drug Application (sNDA) review.
• Responses Informed by Other Development Programs: It is valuable for a Sponsor to receive input from FDA for a development program based on knowledge and/or experience FDA has gained from other programs. While we understand that the Agency must adhere to limitations to ensure confidentiality, FDA should continue to provide generalized input from other development programs without disclosing confidential information. Where appropriate, FDA should acknowledge to the Sponsor that their generalized feedback is informed by experiences gained through other development programs.
• Responses Where Broadly-Applied Policy Questions Arise: We recognize that in many instances during drug development, new policy questions may arise that apply more broadly to other products in development. In many cases, these questions are time-sensitive and a venue needs to be available where these questions are addressed in a timely and efficient manner that is transparent. We recommend FDA leverage their established committee framework (e.g., CDER Medical Policy Counsel,4 Pharmacology/Toxicology Coordinating Committee,5
4 CDER MAPP 4301.1, “Center for Drug Evaluation and Research Medical Policy Council”
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 10
Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852
Re: Docket No. FDA–2014–N–1575: Best Practices for Communication Between the Food and Drug Administration and Investigational New Drug Sponsors During Drug Development; Request for Comments
Dear Sir/Madam:
The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on “Best Practices for Communication Between the Food and Drug Administration and Investigational New Drug Sponsors During Drug Development.” This docket represents an important step in identifying effective practices for communication during drug development, both through official meetings and less formal means of communication outside of established meetings. Modern drug development requires scientific collaboration by all parties in the innovation ecosystem, and promoting effective FDA-Sponsor communication is fundamental to our ability to translate scientific discoveries into safe and effective new therapies for patients.
BIO represents nearly 1,000 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture and a cleaner and safer environment.
I.
INTRODUCTION:
BIO strongly supports the Prescription Drug User Fee Act (PDUFA 5) program to enhance FDA-Sponsor communication, which is based on FDA’s stated philosophy that “timely interactive communication with Sponsors during drug development is a core activity to help achieve our mission to facilitate the conduct of efficient and effective drug development programs, which can enhance public health by making new safe and effective drugs available to the American public in a timely manner.” In recent public statements, FDA has noted that “Sponsors who avail themselves of the opportunity to meet with FDA early in development have substantially reduced the time from the start of human testing—when FDA first becomes involved—until
marketing approval.”1 For instance, companies that meet early with FDA have experienced a median product development time reduction of 1.4 years and upwards of 2.1 years for orphan drugs. Thus, increased communication during drug development ultimately will reduce time to market and speed the availability of important new therapies to patients.
There are currently a number of formal avenues for FDA-Sponsor communication. For example, current regulations (21 CFR 312.41(b)) require FDA to provide consultative advice during the investigational new drug (IND) phase.2 There are also existing Good Review Management Practices (GRMPs) that encourage communication with the Sponsor during the IND phase, as well as PDUFA mechanisms that allow for these communications (e.g., Type A, B, and C meetings and the Special Protocol Assessment (SPA) process). 3 Sponsors are encouraged to take advantage of milestone meetings utilizing these established meetings procedures.
Changes to a development program often need to be discussed and addressed by the Agency in a more expeditious fashion to help prevent or minimize delays in development and for the Agency to be perceived as a collaborator in drug development. Many of these time-sensitive communications can occur efficiently outside of formal meetings. While some Review Divisions should be commended for providing advice and working in a responsive and collaborative way, this is not the norm in all divisions. BIO members have noted that communications practices can be inconsistent both within and across Review Divisions.
Additionally, early communications on development do not always represent the entire Agency’s recommendations. For example, early communications for combination products from the Center for Drug Evaluation and Research (CDER) do not always include input from the Center for Devices and Radiological Health (CDRH), though such input could inform development programs.
BIO’s expectation is that the results of this docket will inform forthcoming FDA guidance on best practices for FDA-Sponsor interactions during drug development (expected in FY15), and to encourage greater timeliness, quality and consistency in communication across and within FDA Review Divisions through routine staff training and standard operating procedures.
1 FDA, Woodcock, Janet, Testimony before the House Energy and Commerce Committee, “21st Century Cures: Modernizing Clinical Trials and Incorporating Patient Perspective” (July 11, 2014) “For the 181 new drugs approved from 2008 - 2013 (for which a clinical development time could be calculated), the Sponsors of the 67 applications who met with FDA before submitting their Investigational New Drug (IND) applications had a median development time of only 6.6 years, compared to 8.0 years for applications for which such a meeting did not occur (a mean reduction of 1.4 years). The median drug development time for applications for which a meeting with FDA was held at the end of the Phase 1 (EOP1) milestone was 1.1 years shorter than for applications for which an EOP1 meeting did not take place. For orphan drugs, drug development was a median of 2.1 years shorter.”
2 (21 CFR 312.41(b)) “On the Sponsor's request, FDA will provide advice on specific matters relating to an IND. Examples of such advice may include advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.”
3 Good Review Practice: Good Review Management Principles and Practices for Effective IND Development and Review. http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualof policiesprocedures/ucm349907.pdf
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 2
II. BIO SURVEY ON EFFECTIVE FDA-SPONSOR COMMUNICATIONS
In support of the PDUFA V Enhanced Communications program, BIO initiated a multiyear survey initiative to better understand biotechnology company experiences during drug development and to identify best practices for FDA-Sponsor communication. The online survey was administered by a professional survey firm, Penn Schoen Berland (PSB), between June 18 and September 14, 2013 and received 102 unique responses from 91 BIO member companies. A preliminary analysis of the results is included in the slide deck prepared by PSB, which can be found in the appendix of these comments.
As discussed below, the initial survey demonstrated moderate improvement in certain communication practices in recent years, however, 40% of respondents reported that some FDA-Sponsor miscommunication contributed to one or more delays in product development.
BIO launched the second phase of this initiative in the summer of 2014. This phase includes collecting information on FDA and Sponsor interactions during drug development for over 190 individual clinical programs currently under development. PSB will complete the initial analysis in January 2015 and we look forward to sharing the results with FDA.
The 2013 survey demonstrated wide variability in the level of satisfaction in communication across different Review Divisions. Those divisions that communicated reasonably well did so across most avenues of communication— formal meetings, written letters, and informal communication—while those that were ranked lower communicated less effectively across all of those channels. BIO would like to partner with the Agency to identify the best practices from those divisions with the highest levels of satisfaction so that FDA can apply those practices to the other divisions to improve overall consistency.
Key Points:
• 70% of respondents were generally satisfied with the state of FDA-Sponsor communication, up from 64% in the early stages of PDUFA 4.
• However, only 18% of Biologics License Applications (BLA) Sponsors found the quality of communication to be very good or excellent, compared to 35% of New Molecular Entities (NMEs). The quality of communication was deemed best for Breakthrough Therapy-designated products (52%) and Priority Review products (52%).
• Of the respondents reporting that FDA-Sponsor miscommunication contributed to one or more delays in product development, 44% of these delays were caused by an unexpected FDA reinterpretation of an existing agency policy.
• 78% of Special Protocol Assessments required multiple review cycles.
• Survey respondents reported wide variability in communication across different Review Divisions; Figure 1 shows the divisions that ranked highest and lowest for communication satisfaction. Figure 2 evaluates the level of
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 3
communication satisfaction across the Review Divisions with which BIO member companies most commonly interact. Figure 1: Satisfaction with Communication Varies Among Review Divisions
Figure 2: BIO Member Interactions with FDA by Review Division
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 4
III. IMPROVING SCIENTIFIC DIALOGUE AND ENABLING EFFECTIVE COMMUNICATION DURING DRUG DEVELOPMENT
Based on our survey and discussions with members, BIO identified four main areas where improvement in communications could enable a more effective development and review process:
A. Improving Scientific Dialogue B. Improving Effectiveness of Formal Meetings with FDA C. Improving Communications between FDA and Sponsors Regarding Emerging
and Evolving Science D. Improvements to Communication on FDA Website
Below we have noted several points for FDA to consider as it drafts guidance on this topic.
A. Improving Scientific Dialogue
Communications best practices should improve the ability for Sponsors and FDA to engage in scientific dialogue in a collaborative manner across all Review Divisions during drug development to ensure there is timely resolution of issues and prevent any unnecessary delays.
While there have been significant improvements in how FDA and Sponsors communicate during drug development over the past few years, there are still issues with consistent and transparent practices across Review Divisions. Given the resources needed to prepare for formal meetings, efficiencies for FDA and Sponsors could be gained if there were mechanisms for more frequent feedback from the Review Division outside of formal Type A, B and C meetings and consistency across Review Divisions. For example, under what circumstances is it more appropriate for a Sponsor to communicate with FDA via informal communications (email, telephone, etc…) and when should an issue be addressed through a formal PDUFA meeting? Additionally, we continue to note a lack of cohesive process for programs that involve multiple FDA Centers, specifically CDER and CDRH. We believe FDA’s best practices guidance should address combination products and diagnostics to ensure that interCenter communication and coordination are adequately addressed.
We recommend that any best practices training is structured for consistency across Review Divisions, but tailored to meet the specific needs of each Review Division. The training should provide both Sponsors and reviewers with examples of what types of issues could be addressed through informal communications.
Specifically, we would like any best practices guidance and training to address the following:
• Appropriateness of Types of Communication: FDA should clearly define the appropriate type of communication (i.e., email, teleconference, IND submission of request for comment/advice, formal meeting request, etc.) to be used to address various categories of questions. In the case where it is determined that the answer being sought requires formal vetting and documentation by FDA or review of data, preliminary communications can help to prevent multiple meetings or letters to obtain the appropriate answer.
BIO Comments on Best Practices for FDA-Sponsor Communication Docket No. FDA–2014–N–1575, December 29, 2014, Page 5
• Facilitating Timely and Interactive Communications via Teleconference: Many Review Divisions currently provide an opportunity for a brief teleconference with Sponsors to allow subject matter experts to discuss specific technical or timesensitive issues, as needed. These teleconferences can be quickly scheduled, limited in scope and duration—for example for 15 or 30 minutes—to brief the Agency on time-critical issues, such as pre-approval use of a drug in development or safety-related issues. We recommend expanding this best practice across Review Divisions. The meeting request would include limited briefing information (e.g., 5 slides or 7-10 pages). The teleconference would include a limited number of participants from FDA and the Sponsor and standard documentation would be shared afterwards with all participants. For important development questions requiring Agency input, where some live discussion would be useful toward gaining agreement, a shorter meeting format with quick scheduling could be useful (e.g., addressing potential clinical hold questions or discussing data requirements for submission to support a new protocol under an existing IND). These types of interactions to help align on an issue more expeditiously could reduce the need for additional formal meeting requests or improve the efficiency of any follow-up meetings.
• Access to Agency Review Staff: BIO suggests establishing an Agency policy and process regarding scenarios where Sponsors may contact Agency staff (in addition to the Project Manager function). For certain issues that arise during development (e.g., changes being considered in endpoint assessments), the Sponsor would benefit from direct access to Agency staff within a specific functional area (e.g., Clinical, Chemistry, Manufacturing, and Controls (CMC)). Best practices should identify instances where direct communication with Agency staff may enhance speed with which questions and answers can be facilitated. Any guidance should address the type and frequency of communication that would allow FDA to receive questions, identify an answer and respond to the Sponsor. These processes should acknowledge the workload and time commitment that medical reviewers dedicate to the review of INDs, New Drug Applications (NDAs), and BLAs, and carefully balance that consideration with their capacity to respond to important IND-stage Sponsor inquiries.
• FDA Written Responses to Requests for Advice: Given the resources needed to prepare for Formal Meetings, efficiencies for FDA and Sponsors could be gained if there were a mechanism for more frequent written feedback from the review team outside of Formal Type A, B or C meetings, with consistency across Review Divisions. We suggest establishing target timing of 30-60 days from submission for request for advice (per 21 CFR 312.41) to respond to the Sponsor. Sponsors would benefit from having timely responses to requests for advice, as these requests are important to continuation of ongoing clinical programs but may not fall into a Type B meeting category. For example, requests for comments and feedback on study protocols outside of formal avenues are sometimes under review for extended periods of time. In this situation, it is difficult for the Sponsor to plan development timelines and budgets, to ensure that advice from other regulatory agencies will be aligned and coordinated with FDA comments, and to ensure that feedback from the Agency is implemented prior to study initiation. As current timelines for responding to requests for comments differ across Review Divisions, we encourage that any forthcoming guidance establish clear delineation of timelines for feedback. Other examples where timely feedback would be beneficial to the Sponsor and speed development times include function specific questions such as those for CMC or protocols related to
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postmarketing requirements and commitments (PMRs/PMCs). The scope should also include requests for which the Review Division will need to request participation from other offices (e.g., Study Endpoints and Labeling Development (SEALD) for patient-reported outcomes (PRO); CDRH for companion diagnostics and human factors protocols).
• Creation of Standardization and Templates for Routine Communications: We encourage standardization for written and telephone communication methods across Review Divisions. We acknowledge the need to send official correspondence via post; however, as paper correspondence may take several days to arrive, we encourage the adoption of standard processes across Review Divisions that allows for the sending of copies of official correspondence as a PDF or similar file type via secure email. Additionally, we recognize the value of telephone correspondence. Given that voicemails may not be heard in a timely manner, we suggest the further adoptions of a standard process across Review Divisions that allows for the use of secure email for informal correspondence. Use of templates for letters such as "study may proceed" would improve consistency (covering key categories of information including the annual reporting period). This can reduce the call/email volume to project managers (PMs) for routine information. FDA should also respond in the same manner in which the Sponsor communicated with them (i.e., FDA should respond via email if the Sponsor initially communicated via email).
• Communication with Email Accounts: As a best practice, we suggest that Review Divisions should acknowledge receipt of Sponsors’ emails within one business day. Additionally, response times for communication with general/blind FDA email accounts are widely variable. While some will acknowledge receipt of communications within 24 hours, others will take up to a week or more.
• Staff Assignments: In addition to assigning main contacts for each program, both the Agency and the Sponsor should assign alternates. The Agency and the Sponsor should provide updates as they become available. This should be extended to include Supervisory PM and Division Director information. Such a practice will provide clarity regarding key contacts and key personnel changes (e.g., recent Division of Oncology Products 1 (DOP1) Division Director change) and help preserve continuity in the review when there is turnover during reviews.
• Improvements to the Enhanced Communications Office: The BIO survey found that while FDA has made the efforts to publicize the existence and availability of the Enhanced Communications Office, the office remains underutilized and often unknown to Sponsors. BIO would like to partner with the Agency to continue to raise awareness of the Enhanced Communication Office as a resource for Sponsors, for example through webinars or conferences.
B. Improving Effectiveness of Formal Meetings with FDA
Sponsors often do not take advantage of entitled meetings with FDA either due to perception that the value of these meetings is not high enough to allocate the resources and time required to participate in such meetings or a perception that any such conversations may lead to a higher regulatory burden than Sponsors would have otherwise. Best practices should provide information about how such discussions before, during and after would be valuable to Sponsors and serve to
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identify and resolve key issues in the most effective manner possible. Below we provide a few specific examples of such improvements for your consideration.
General Considerations:
• Understanding “Regulatory Speak”: We request that FDA provide guidance and training that better clarifies—to both Sponsors and reviewers—how the Agency should communicate to Sponsors the limitations of what the Agency can or cannot say in the context of a regulatory communication and how the Sponsor should interpret the type of “regulatory speak.” For example, as a regulatory agency, FDA can provide guidance on acceptable and validated scientific methods, but the Agency cannot compel a Sponsor to take one approach to drug development over another. Based on the Agency’s past experience and perspectives across many confidential drug development programs, FDA may use terms such as “encourages,” “cautions,” or “advises” in a meeting to provide guidance to a Sponsor. In some instances, a Sponsor may not interpret FDA’s feedback as definitive or absolute and may continue a particular approach to drug development at risk, which can create issues at later stages of development or review. Consequently, Sponsors should recognize the weight and significance of these terms used by FDA in formal meetings and appreciate the limitations of what the Agency can communicate. An upfront understanding of the vocabulary that is used in regulatory communications, such as through a disclaimer at the start of each meeting or in the meeting minutes and utilization of these terms in in a more consistent manner would serve to minimize miscommunications between FDA and Sponsors. Additionally, consistency between spoken and written feedback is encouraged.
• Preliminary Comments: We understand that FDA typically aims to send written preliminary comments at least 48 hours in advance of a formal meeting, which should be viewed as a best practice in order for a productive meeting to occur. If the FDA is requesting a response from the Sponsor, the preliminary comments should be provided four business days prior to the meeting. In the experience of BIO’s members, there has been a trend for the Agency provide these preliminary comments very late (within 24 hours of the meeting or less); occasionally, comments are only received at the meeting, and are thus not “preliminary” at all. Providing comments so close to the scheduled meeting makes it very difficult for Sponsors to determine if a meeting should still be held (or changed to a teleconference) and it may have a considerable impact on travel plans. If the Sponsor decides to proceed with the meeting, it can be quite challenging to adequately prepare verbal or written responses if FDA’s comments are significant or FDA provided preliminary comments on matters beyond the scope of questions posed in the Briefing Document. Where comments are received only at the time of the meeting, it is difficult if not impossible for the Sponsor to respond substantively to any of the issues raised in those comments; however, by such point, the responses and time to prepare for and attend the meeting have already been expended.
Pre-IND and IND Meetings:
• Pre-IND Meetings: We have seen an increased number of pre-IND meeting requests default to written responses only (WRO), and in most cases when this occurs, there is often a need to follow up on the written comments with a request for a teleconference to clarify the comments. Therefore, as the pre-IND meeting
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request is in many cases the first interaction between the Sponsor and the Agency, we strongly recommend that a pre-IND meeting request should be honored with a teleconference or face-to-face meeting. This is optimal to ensure mutual understanding of any outstanding items and path forward to IND submission.
• Initial IND Teleconference: BIO recommends establishing communication (teleconference) with Sponsors three to five days prior to the Day 30 communication to convey any final issues in instances where there are substantial concerns from FDA. Instituting a standard practice of scheduling a teleconference will ensure the Sponsor team and FDA have availability to discuss any critical issues, if needed, before the IND is in effect.
End of Phase 2:
• Establishment of a Mechanism for a Sponsor to Request a Debrief Meeting for End of Phase 2 (EOP2) Meetings: We recommend establishing a mechanism that allows a Sponsor to discuss with FDA revisions that the Sponsor has made to the development program following the EOP2 meeting prior to the start of Phase 3 trials. These meetings could be held four to six weeks after the EOP2 meeting completion and would ensure alignment on the feasibility of the registration objectives and design of registrational studies. Clear alignment between FDA and the Sponsor will contribute to more efficient development through the minimization of regulatory risks.
• Target Product Profile Feedback: We request that more divisions follow the Target Product Profile (TPP) guidance and provide specific feedback to Sponsors. It would be beneficial to Sponsors if FDA feedback is obtained earlier in development, such as at the EOP2 meeting or in conjunction with Phase 3 SPA review, so adjustments can be made by the Sponsor.
Documenting Meeting Outcomes:
• Rectifying Differing Interpretations of Meeting Outcomes: Review Divisions provide their minutes to the Sponsor and often indicate that the Sponsor should let them know if there are areas of disagreement; however, there is often no further follow-through or mechanism for updating the minutes or receive greater clarity. The best practices guidance should address this issue and outline a mechanism for the Sponsor and FDA to resolve these issues within 90 days, including alignment on actions that the Sponsor has taken to address the issue raised in the meeting minutes.
• Extending Meeting Times to Allow for Process Issues: Formal meetings in which live meeting minutes are taken by FDA and reviewed with the Sponsor should be extended to 90 minutes. Many Review Divisions now take live meeting minutes and review for agreement with the Sponsor during the meeting. While there are many advantages to the practice of reviewing minutes, it takes time away from discussion at the meeting, leaving insufficient time for some discussion topics. Extending the meeting time to 90 minutes and advising the Sponsor of the amount of time FDA is reserving for minute review allows time for the primary purpose of the meeting (discussion of Sponsor questions and FDA responses), as well as live review of minutes/agreement on discussion outcome.
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C. Improving Communications between FDA and Sponsors Regarding Emerging and Evolving Science
For companies working on a cutting edge technology in an emerging scientific field, it is essential that they communicate with FDA frequently and effectively so that all parties fully understand the state of the underlying science and the regulatory pathway to approval. In some instances, FDA thinking may be actively evolving and guidance may not exist for emerging issues, which may lead Review Divisions to provide inconsistent recommendations to Sponsors. This in turn can make it difficult for Sponsors to apply learnings to subsequent development programs. FDA should seek to ensure that changes in their thinking regarding novel or emerging areas of science and medicine are communicated to Sponsors in an efficient manner.
• Inclusion of External Experts: For many evolving scientific fields, it may be beneficial to include leading external experts in FDA-Sponsor meetings in order to best evaluate the clinical development and review procedures. FDA should work with Sponsors in these cases to ensure that consultations with external experts occur at the appropriate times during the drug development and review processes in order to ensure an effective process based on the best available science.
• Staff Briefings with Sponsors: Some Review Divisions, such as the Division of Oncology Products, hold meetings where Sponsors are invited to discuss their development programs. These briefings provide a forum for scientific dialogue outside of specific program meetings. We recommend adopting this best practice across Review Divisions. We also suggest that other divisions more consistently hold Applicant Orientation Meetings (AOMs). These meetings allow Sponsors to provide a guided overview of the application to FDA staff and/or give summaries of key attributes in the submitted data to help the Agency make its risk-benefit assessment. All staff within a division are invited to attend these AOMs and ask any questions. These meetings provide FDA staff the opportunity to learn about many aspects an application and provide the Sponsor with some early insights into the types of questions that may be asked during NDA/Supplemental New Drug Application (sNDA) review.
• Responses Informed by Other Development Programs: It is valuable for a Sponsor to receive input from FDA for a development program based on knowledge and/or experience FDA has gained from other programs. While we understand that the Agency must adhere to limitations to ensure confidentiality, FDA should continue to provide generalized input from other development programs without disclosing confidential information. Where appropriate, FDA should acknowledge to the Sponsor that their generalized feedback is informed by experiences gained through other development programs.
• Responses Where Broadly-Applied Policy Questions Arise: We recognize that in many instances during drug development, new policy questions may arise that apply more broadly to other products in development. In many cases, these questions are time-sensitive and a venue needs to be available where these questions are addressed in a timely and efficient manner that is transparent. We recommend FDA leverage their established committee framework (e.g., CDER Medical Policy Counsel,4 Pharmacology/Toxicology Coordinating Committee,5
4 CDER MAPP 4301.1, “Center for Drug Evaluation and Research Medical Policy Council”
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