Synergy in Action


24 January 2011

To: Division of Dockets Management
Re: Docket # FDA-2010-D-0529

The International Society for CNS Clinical Trials and Methodology (ISCTM) commends the FDA for preparing a draft of the comprehensive Guidance for Industry, “Qualification Process for Drug Development Tools”.

The ISCTM is a multi-disciplinary independent organization, devoted to promoting advances that address strategic clinical, regulatory, methodological and policy challenges that arise in the development and use of CNS therapeutic agents. This work is accomplished through partnership with persons in academia, industry, government, policy-making and the public. Recognizing the importance of this document for our constituency, the ISCTM convened a
working group of its members to review and comment on the guidance.

Workgroup members included:
Chairs: Douglas Feltner, MD, Douglas E Feltner, LLC
              Michael Davidson, MD, Sheba Medical Center, Israel
Judith Abdalla MD, Quintiles, Inc.
Munaf Ali MD, Munaf Ali Consulting
Larry Alphs MD, PhD, Ortho-McNeill Janssen
Stacey Boyer, Pfizer, Inc.
Marc Cantillon MD, Critical Path Institute (C-Path)
Michael Detke MD, PhD , MedAvante
Richard Keefe PhD, Duke University Medical Center
Herbert Meltzer MD, Vanderbilt University
James Mundt PhD, Center for Psychological Consultation
Tanya Ramey MD, PhD, Pfizer, Inc.
Dennis Revicki PhD, United BioSource Corporation
Henry Riordan PhD, Worldwide Clinical Trials, Inc.
Gary Sachs MD, United BioSource Corporation
Stephen Sainati MD, PhD, Takeda Pharmaceuticals International, Inc.
Cate Stasio, Brain Plasticity Institute
Monica Vance, Santium Group Inc.

General Comments: The ISCTM believes that having a defined process for DDT developers to interact with the FDA to qualify new drug development tools will facilitate bringing new drugs to market. Comments on specific aspects of the draft guidance are below.

     1) Line 18: Currently, many PROs and rating scales, and a few biomarkers are used in drug development and are generally accepted by virtue of their use as being qualified for the purposes they are used for. It would be helpful for the guidance to say clearly that it is intended to describe a process for qualifying new drug development tools (those that do not already have regulatory acceptance for a certain use). The guidance should indicate that drug development tools that have a current use with prior regulatory acceptance are considered to be qualified.

     2) The ISCTM supports the use of one guidance for describing the qualification process for all classes of DDTs. The document was not clear, given the varying classes of drug development tools (DDTs) that could be covered by the guidance, where language used in the guidance applies to all classes of DDTs and where the language applies only to a specific DDT class. (Line 119, for example, refers only to PROs, and not other types of rating scales, and this should be indicated. In lines 179, and 191, for example, references to a single qualification for use in multiple clinical disorders would not apply to many PROs or rating scales, since these are typical qualified for an intended population.) Specific issues related to this general issue are raised below.
          a. Line 19, Line 112: The guidance needs to be more specific on the types of tools that are covered. In addition to new PROs and new biomarkers, the ISCTM believes that new clinician-administered rating scales, new rating scales administered through automated methods (interactive voice response, other computerized methods and devices), remote (e.g. teleconference and videoconference) clinician assessments, new diagnostic rating questionnaires, new safety questionnaires, and new tools for cognitive assessment should be covered by the guidance.
          b. Line 99, Section IIIB, Appendix 3 and Appendix 5: The distinctions between qualifying PROs, clinician-administered rating scales, and automated methods of rating scale administration are not well-made and would benefit from clarification. Alternatively, an additional section paralleling the content of section IIIB (PROs), and additions made to Appendices 3 and 5, could be added to more specifically discuss clinician administered rating scales, and automated methods of administration of rating scales and questionnaires.
          c. Lines 126, 144, 164, 200, 325: It would be helpful for the reader if the document were organized in such a way that a reader interested in a particular class of DDT can find that information without having to sort through information on other classes of DDTs that are not of interest. This can be done by adding information to the heading of each section to indicate whether it applies to all DDTs or only a particular subclass (where this has not already been done).

     3) Several issues related to the Qualification Review Team (QRT) and the qualification decision-making process should be clarified:
          a. Line 261-264: The functional roles (clinician, statistician, technology expert, biomarker expert, PRO expert, etc) that will generally be expected to compose the FDA, QRT should be identified. The leadership of the QRT should be clarified. The composition of the QRT may differ, depending on the type of DDT being developed. . It would be helpful to have the proposed composition of the QRT communicated to the DDT development consortium and to allow the DDT development consortium to suggest functional roles that it believes should be included on particular DDT.
          b. Lines 266 and 359: It would be helpful for the guidance to specifically identify a primary point of contact at the FDA to deal with communications with external tool developers. The primary point of contact could differ, depending on the DDT class and the stage of tool development.
          c. Line 261, Lines 320-322: The administrative entity (office, division, etc) that constitutes the QRT and that provides the final decision on whether qualification has occurred should be indicated in the guidance. If this differs for different classes of DDTs, that should be indicated.

     4) Lines 320-322: The guidance should indicate whether FDA decisions on qualification of DDTs can be appealed by the DDT developer prior to issuance of the particular draft qualification guidance, the time-frame, and how to do so.

     5) Line 200, Section V: It would be helpful for the guidance to provide standard or anticipated amounts of time for the FDA to respond to and provide advice on the DDT Letter of Intent; to respond to the briefing package and hold the briefing package meeting; to provide subsequent advice during stage 1; to review, respond to, and complete the Stage 2 review for a qualification decision following submission of the formal qualification package.

     6) Section V, VI: It would be helpful to add an overall flow diagram showing the various stages of the process in a pictorial format.

     7) The guidance is envisioned to provide a degree of generalizability of use of a tool “across multiple clinical disorders, multiple drugs, or drug classes.” (p 5, ll 178-180) The guidance also specifies that the qualification of a DDT is limited to a clearly defined “context of use” (p 4, ll 134-135). Prior FDA guidance on the use of PROs to support labeling claims indicates PROs must be validated separately in each patient population, a position reinforced by the definition provided for “Context of Use.” (p 18, ll 657-658) It is suggested that the qualified context of use may be modified, expanded, or even withdrawn as additional data are collected submitted and analyzed (p 6, ll 233-236), the process and procedures for accomplishing such are unclear.
          a. Lines 134-135, 178-180,657-658, and biomarkers sections and biomarker appendices: The ISCTM believes that the generalizability of a DDT may depend in part on the class of DDT. Safety biomarkers, for example, might be more readily generalizable across populations than PROs and clinician rating instruments. Clarifying comments in the document on DDT generalizability across disorders and populations with respect to which class of DDT is being referred to is needed.
          b. Lines 233-234: The guidance should clarify whether review and re-qualification processes for expanding the applicability of a DDT that has been qualified though this process will be assigned to the same QRT that conducted the initial review, or whether a different QRT would or might be constituted. Will all qualification expansions need to re-start at the beginning of the process and complete the entire process, or might certain steps of the process might be skipped when adding new uses to a drug development tool previously qualified by this process?
          c. Line 235-236: The guidance should clarify the process for DDT qualification withdrawal. The withdrawal of a qualified DTT could have a substantial impact on ongoing drug development programs or on approved labeling and as such there should be an opportunity in the process for public involvement and an indication of how the FDA will work with impacted sponsors.

     8) Lines 200-207: The ISCTM believes that coordinating this qualification process with other major ex-US regulatory agencies could be useful, so that separate, sequential qualification processes are not required for each major region or country. The guidance could indicate whether this is considered a possibility . In general, regulatory experience that is public would be extremely helpful to reference. The renal biomarkers that have completed qualification and the ongoing PRO processes handled by Critical Path Institute, as well as the ongoing DDT in Coalition Against Major Diseases (CAMD), are useful examples.

     9) Lines 227-231; Line 315: The process should include the opportunity for full public comment prior to the final qualification decision. While many drug development tool consortia may have very broad expertise and be very inclusive, others may not. The engagement of an expert panel or advisory committee-like body may also be useful.

     10) Section V and VI: Can the FDA address whether a fee will be charged for initiating the process and whether paying the fee would result in guaranteed FDA response times for each of the stages of the qualification process, along the lines of the IND/NDA process?

     11) On page 6, footnote 8, a link to information on the VXDS would be useful.

     12) Line 95: change “quantitative predictions” to “quantifiable predictions”

     13) line 97: the FDA’s guidance on pharmacogenetic tests ( could be referenced here as one example of the types of information that are needed for qualification of one type of biomarker.