March 6, 2000 FDA Gene Therapy Letter
Preclinical and Clinical Issues
On September 19, 1999, the first (and only) death attributed directly to the administration of a gene transfer product was reported to FDA and to the NIH/Office of Biotechnology Assessment (OBA). FDA undertook a series of steps intended to further investigate this event and to determine what additional actions might be undertaken to minimize the risks to subjects participating in clinical trials of gene transfer products. The investigation included, but was not limited to,
This report summarizes FDA’s review and assessment of the responses to items 6 and 7 of the letter. The requests for information posed in these two items were as follows:
http://www.ifpma.org/pdfifpma/e6.pdf. (Attachment D)
For further guidance regarding sponsors' responsibilities in a clinical trial, including monitoring, please refer to the ICH document on GCPs, which can be found on the Internet at
Categorization of Responses to the Item 6 of the March 6, 2000 letter and Administrative Actions
The March 6, 2000, letter was sent to approximately 150 sponsors holding 276 active INDs or Master Files. Responses to the March 6, 2000, letter, were submitted to 200 INDs as of March 8, 2001. In order to capture systematically the information received, a form for collection of the responses (Attachment F) was generated and the information entered into a database. In addition, review staff were encouraged to add comments, which were also captured in the FDA database. Since the information for the clinical monitoring program is protocol-specific, separate information on the monitoring program for each protocol within an IND was recorded.
FDA did not request information regarding the clinical monitoring programs for INDs where the sponsor stated that all clinical development of the product had concluded, no further studies were planned, and the response consisted of a request to inactivate or withdraw the IND. Sponsors were asked to identify each protocol, by title, conducted under the IND and to confirm that no patients were continuing to receive drug or active follow-up. For INDs investigating retroviral vectors, where life-long monitoring is currently required, the sponsor was allowed to inactivate but not withdraw the IND. The request for inactivation was acknowledged along with the reminder to submit long-term monitoring information annually and, in the event of a request for re-activation, to provide all the information requested in the March 6, 2000 letter.
FDA Assessment of the responses regarding clinical monitoring procedures
Monitoring and auditing are fundamental aspects of GCP. Although their purposes are similar (to assure appropriate trial conduct and data validity), the approaches differ. As stated in the ICH GCP document, monitoring is "the act of overseeing the progress of the clinical trial and ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, GCP, and applicable regulatory requirements." Medical monitors, usually employees of the sponsor, perform on site (and, if indicated, off site) evaluations of trial-related activities. The extent and frequency of monitoring should be appropriate for the length, complexity, and other particulars of the trial. Among the functions of the monitor is identification of deviations in protocol conduct and taking appropriate corrective steps, e.g., retraining investigators, closing out certain sites, etc.
Auditing is defined in the ICH CGP document as "the systematic and independent examination of trial-related activities and documents." The sponsor may conduct an audit at any time during the course of the trial, particularly if there is cause to suspect problems with certain sites/data. However, the study audit is usually at the conclusion of the trial. The sponsor is responsible for hiring the auditors, and auditors are required to document findings in a written report to the sponsor. FDA field inspectors also conduct independent study audits. Traditionally, the purpose of the FDA audits has been to verify the data submitted to FDA in support of a marketing application. FDA and the sponsor may conduct "for cause" audits at any stage of clinical investigation if there is reason to suspect a problem with trial conduct or data integrity.
Clinical Monitoring and Auditing Procedures
While larger commercial (industry) sponsors generally provided an adequate response to the initial letter, many smaller firms and academic sponsors misunderstood the intent of the letter, and provided a description of implementation or initiation of the study, but did not describe evaluation during or after the conduct of the study. In telephone conversations requesting further information of the monitoring program, comments such as "Isn’t this the responsibility of the FDA?" or "Monitoring is performed by the IRB." resulted in the generation of more detailed letter more clearly identifying our requests.
After receipt of telephone calls and/or letters from FDA specifying our request in greater detail, the majority of the sponsors submitted expanded responses. FDA’s review of these supplemental responses indicates that the monitoring program generally contain procedures to evaluate the conduct of the protocol and adherence to reporting requirements. The description of the auditing procedures was also generally acceptable and included the elements described in the ICH E6 document. There were, however, a small number of responses in which deficiencies in the standard operating procedures for the clinical monitoring and/or auditing programs were noted. This primarily included the absence of a specific procedure to ensure the following:
FDA comment: Some sponsors believe that the IRB forwards adverse event reports to FDA, others believe reports are sent to the Medwatch system for post-marketing reports, and others simply failed to identify FDA as one of the recipients of safety reports.
Extent and Frequency of Monitoring and Auditing
With regard to the description of the extent and frequency of monitoring and auditing, the responses were highly variable in both the extent and frequency of either monitoring or auditing. In addition, sometimes only the extent or frequency was specified. For example, the description for some programs specified the proportion of subjects for whom records were reviewed (e.g., 10%, 100%, or "at least 50%") and in other programs, the intervals of assessment, from weekly to annual, was specified. There were instances described in which not all studies were continuously monitored but were subject to "spot checking" on a selected basis. The selection of a given study for monitoring in such programs most commonly occurred as a random selection among a proportion of active studies. In this situation, a portion of all the studies being conducted at the institution were considered in the pool for selection rather than a selected assessment of active patients within each study. This type of program raises the concern that any individual investigator study might not be monitored at all for a period of up to several years.
With regard to verification of data, in those programs where all patient information was not verified against source documents, the procedure for selection of records to be reviewed varied. The most common schemes were random selection or a combination of random selection plus review of records for patients in whom significant adverse events had been observed. Generally when a small number of patients were enrolled (e.g., 10 patients) at one site, auditing of all or part of each patients records was planned. However, some programs failed to clearly state if there were a minimum absolute number of patient records to be assessed. For example, the criteria that data from "at least 10% of patients" would be audited against source documents might be inadequate for a small, phase 1 study enrolling only 14 patients.
The extent of the records reviewed ranged from portions of clinical site patient charts to all records at the clinical study site plus all copies of outside physician notes and laboratory information.
Organizational structure; training and qualifications of staff
Even upon resubmission, the response to this portion of the March 6, 2000, letter was frequently not addressed. With regard to the description of the clinical monitoring staff, the following arrangements were noted:
The basis for qualifications of the monitoring staff under most INDs was not provided, however the staff generally consisted of individuals with degrees in health-related fields. Contract research organizations provided the greatest detail regarding specific training for monitoring staff, which occurred over weeks to three months.
In the review of the description of the clinical monitoring staff, three specific areas of concern were identified.
Categorization of Responses to the Item 7 of the March 6, 2000 letter and Administrative Actions
Responses to the March 6, 2000 letter have been submitted to 200 INDs and Master Files. In order to capture systematically the information received, a form for collection of the responses (Attachment F) was generated and the information entered into a database. In addition, review staff were encouraged to add comments, which were also captured in the FDA database. The responses for animal safety study were not considered to be protocol specific and responses are considered for the entire IND file.
The review of response to item 7 indicates that most sponsor are in compliance with the requirements to the extent they are capable. However a limited number of sponsors are unclear about the role of animal safety studies and appeared unaware of, or failed to recall, animal safety studies which existed in cross-referenced INDs or MFs in support of their clinical studies. There were also a few sponsors who stated that they had provided all required information but failed to note that they were currently on hold for failure to provide certain types of pre-clinical animal safety data requested by FDA.
The major concerns raised by the FDA staff reviewing these submissions was in regard to animal safety information that was contained in cross-referenced INDs and MFs held by a different sponsor. The first issue concerned sponsors who believed that animal safety data in a cross-referenced IND was being used to support their clinical studies. In a few cases, the IND/MF was known only to contain product and manufacturing information, whereas in others, the letter authorizing cross-reference did not indicate that animal safety studies were included in the scope of the cross-reference letter. FDA contacted such sponsors to obtain additional clarification on the location of animal safety studies or clarification of the correct cross-reference. In a larger number of INDs, sponsors asserted that all animal safety studies had been submitted to a cross-referenced file, however reviewers raised questions as to how sponsors could verify this, as they generally do not have access to the contents of cross-reference file. The FDA staff considered whether sponsors seeking cross-references to information contained in other files should obtain a commitment from the cross-referenced IND or MF-holders that all required animal and product data will be submitted per 21 CFR 312.32 and 33.