May 8, 2014
Division of Dockets Management (HFA–305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Re: Docket No. FDA-2013-D-0576, 2 July 2013, “Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”
Dear Dockets Manager:
AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries.
AABB appreciates the opportunity to provide comments on the draft guidance titled “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.” In developing these comments, AABB collected feedback from members with cellular therapy expertise, namely experts actively involved in the development, planning, and execution of clinical trials. In general, we commend the FDA on developing this guidance document which, when finalized, will be a useful resource. We also appreciate the format in which the guidance is presented (i.e., the recommendations common to cellular and gene therapy [CGT] products are compiled in one section, subsequently followed by separate sections for cellular therapy and gene therapy products, respectively) and feel that it is especially user friendly.
Listed below are specific areas that we feel would benefit from wording modification or additional clarification. Comments are arranged in the following format:
Section – language from draft guidance reprinted with page number and other identifying information.
Recommendation or Request for Clarification – recommendation or clarification request.
Background – rationale with information supporting the recommendation or clarification request.
Section – I. INTRODUCTION. Page 1, paragraph 2. The scope of this guidance is limited to products for which OCTGT has regulatory authority. CGT products within the scope of this guidance meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)). This guidance does not apply to those human cells, tissues, and cellular-and tissue-based products (HCT/Ps) regulated solely under section 361 of the PHS Act (42 U.S.C. 264), as described in Title 21 Code of Federal Regulations (CFR) Part 1271 (21 CFR Part 1271), to products regulated as medical devices under the Federal Food, Drug, and Cosmetic Act, or to therapeutic biological products for which the Center for Drug Evaluation and Research (CDER) has regulatory responsibility.
Recommendation – We recommend including the following sentence: “This guidance also applies to CGT products regulated as combination products (21 CFR 3.2) where one or more of the products is regulated as a “biological product” under section 351 of the PHS Act.”
Background – As noted in the guidance document, many CGT products will utilize novel delivery methods using medical devices that may not be FDA-cleared or approved. A statement identifying the applicability of this guidance for combination products as defined in 21 CFR 3.2 will strengthen the document.
Request for Clarification – We request clarification as to whether this guidance applies to therapeutic vaccines under the jurisdiction of OCGT.
Background – As CGT therapeutic vaccines are subject to the authority of the OCTGT, we believe including such language will clarify the scope of the guidance document.
Section – IV. CLINICAL TRIAL DESIGN. B. Choosing a Study Population. Page 7. Choice of the subjects to include in the trial depends on the expected risks and potential benefits, recognizing that there will be considerable uncertainty about those expectations in an early-phase trial. Expected risks may be estimated by the nonclinical data and any previous relevant human experience, but the clinical significance of those risks can depend on the population that receives the product. Similarly, the potential for benefit might depend on the choice of study population. In addition, the choice of study population may affect the ability to detect the product’s activity, either adverse or beneficial. For example, a biomarker that may be indicative of risk or benefit might be more sensitive, meaningful, or interpretable in one population versus another. Some populations may offer advantages (e.g., higher cell numbers or viability) as sources for autologous products. The objective is to select a trial population with an acceptable balance between the anticipated risks and potential benefits for the study subjects, while also achieving the study’s scientific objectives. As discussed below in Section IV.E.5 of this guidance, there are special considerations regarding selection of the study population for patient-specific products.
N.B. The subsections of Section IV.B are as follows:
B.1. Healthy Volunteers
B.2. Disease Stage or Severity
B.3. Lack of Other Treatment Options
B.4. Pediatric Subjects
Recommendation – We recommend adding a subsection titled “Geriatrics Subjects” which would be sequentially numbered “IV.B.5” to the list of considerations for patient-specific groups.
Background – Geriatric subjects, generally defined as individuals 60 years or older, often have co-morbidities and concomitant therapies that may interact with investigational CGT products. These age-associated issues may not be observed or extrapolated from the adult population. Therefore, from a patient safety perspective, we believe that considerations for this patient population should be included in this guidance document.
Section – IV.F. Monitoring and Follow-up. 3. Duration of Follow-up. Page 17, paragraph 2. Sponsors sometimes propose to have one protocol for a CGT study of safety or efficacy, and a separate protocol for long-term monitoring. However, long-term follow-up is sometimes necessary for the trial to have an acceptable balance of risks and benefits. In that case, long-term monitoring should be included as an integral part of the CGT trial, and not designed as a separate protocol.
Recommendation – We recommend this paragraph/recommendation be deleted from the guidance document.
Background – For academic centers or any other organization, federal funding will not allow carryover grant money to cover long-term follow-up. Additionally, there are logistical challenges with keeping a database open, especially if the clinical development of the CGT product will progress to phase 2 and 3 trials. On this basis, we urge FDA to remove this recommendation from the guidance document.
Section – IV.F.4. Stopping Rules. Page 17, paragraph 6. Stopping rules typically specify a number or frequency of events, such as serious adverse events or unexpected deaths, that will result in temporary suspension of enrollment and dosing until the situation can be assessed. Based on the assessment, the clinical protocol might be revised to mitigate the risk to subjects. Such revisions could include changes in the enrollment criteria, for example, to exclude individuals who might be at relatively high risk for developing particular adverse reactions. Revisions might also include dose reduction, some other change in product preparation or administration, or changes in the monitoring plan. Following the implementation of such changes in the protocol, it may be safe for the trial to resume. Therefore, stopping rules do not necessarily terminate a trial. Well-designed stopping rules allow sponsors to assess and address risks identified as the trial proceeds, and to assure that risks to subjects remain reasonable.
Recommendation – In addition to the examples provided, we recommend including a specific example of a stopping rule related to observing early adverse events.
Background – Generally, asessments of safety and tolerability are the primary objectives of early phase clinical trials. As such, we believe including an example of a stopping rule associated with adverse events will be useful to users of the guidance document and will help guide follow-up measures for clinical trial investigators.
Section – VI. GUIDANCE ON SUBMITTING AN IND. Page 19, paragraph 2. Sponsors also may find it prudent to develop an overall product development plan early in the course of development (prior to clinical trial initiation). Such a plan should be sufficiently flexible to accommodate adaptation based on data acquired through product development. One potential approach to planning development is known as a Target Product Profile (TPP). FDA has published a draft guidance for comment that discusses how this particular planning tool might be used (Ref. 14). When finalized, this guidance will represent our current thinking on this topic.
Recommendation –We recommend adding a new paragraph, which would be pargagraph 3 on page 20, after the above mentioned text with information on charging for an investigational product. We suggest that the paragraph reads: “You must obtain prior written authorization from FDA to charge for an investigational drug used under an IND(21 CFR 312.8(a)(3)). For clinical trials conducted under an IND, a request to charge may be included. The request must comply with the requirements set forth by 21 CFR 312.8, and include the amount to be charged and the documentation for the calculation of that amount.”
Background – We believe the additional subsection will inform sponsors naïve to the clinical trial and IND process of the regulations surrounding charging for an IND.
AABB appreciates the opportunity to comment on these draft recommendations. Should you have any questions regarding these comments or would like additional information, please contact Rafael Cassata by email (email@example.com) or telephone (301.215.6542).
Rafael Cassata, MS, RAC (US, EU)
Deputy Director, Regulatory Affairs
AABB Center for Cellular Therapies