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European inspectors are doing a better job of implementing ICH GCP guidelines than their American counterparts at FDA. Here are 10 ways U.S. inspectors could improve their inspection process.
FDA inspectors are responsible for identifying substandard data and good clinical practice violations at clinical and data management facilities.1,2 Doing less jeopardizes public health.
Under the arm of the Division of Scientific Investigation (DSI), members of the Bioresearch Monitoring (BIMO) program are responsible for carrying out these inspections. But the public has insufficient indication as to the quality of the BIMO program inspection process. Neither in publications nor in public forums have we been given any indication of how successful the inspection process has been. The only information released for public consumption has been the frequency of clinical site inspections, the frequency of different kinds of citations, and the actions following inspections. Warning letters are published on the FDAs Web site. Criticism regarding specific inspections occasionally surfaces in newspaper articles that contain interviews with investigators. Firms and individuals regulated by the agency are reluctant to publicly discuss problems with, as well as improvements to, the inspection process.
At the present time, sponsors are scrambling to assemble computer systems that are 21 CFR Part 11 compliant. There are, and always will be, hot issues that divert attention from a fundamental clinical trial functionaccurate documentation of clinical data at investigational sites, and the ability of the data and the collection process to withstand outside scrutiny, that is, an FDA inspection. If the data are not valid, then the data in databases and data that are used for statistical analyses in support of new drug applications are also invalid. Equally important, if subject safety and ethical concerns are not met, the data might just as well be invalid. Only independent, outside auditing can make these determinations to the satisfaction of the greater scientific community.3
The purpose of this paper is to stimulate discussion about changing FDA inspection documentation, communication, and behavior to strengthen GCP compliance and the quality of studies. Ten improvements are described. These suggested improvements have been distilled from conversations with sponsor medical and clinical directors, project managers, auditors, monitors, investigators, study coordinators, and FDA inspectors.
1. More inspections
Typically, an investigational site has less than a 1% chance of being inspected by the FDA. Contract research organizations (CROs) or sponsor companies have even fewer chances of being inspected. The degree of compliance and subsequent quality of data being submitted to the FDA could be substantially improved if more inspections were conducted. More institutional review board (IRB) and overseas inspections also need to be conducted.
One of the reasons that so few inspections are conducted is because the FDA simply does not have enough trained inspectors. Those that are available are spread way too thin. More inspectors with direct clinical experience need to be hired and retained.Additionally, the FDA should initiate a program (with industrys assistance) to certify and deputize private consultants experienced in GCP auditing to perform some GCP inspections.
Other federal regulatory agencies, such as the Securities and Exchange Commission, the Federal Deposit Insurance Corporation, the National Highway Transportation and Safety Administration, and the Federal Aviation Administration make extensive use of expert private consultants to conduct agency inspections and investigations.
This latter suggestion is bound to meet with skepticism and resistance within the Agency. One way to overcome these objections is by developing a collaborative program between the FDA and industry. After being certified by the FDA, private consultants should co-inspect several sites with FDA employees prior to conducting inspections on their own.Another way to increase the number of inspections is for inspectors to be more efficient. Efficiency would be improved if inspectors spent a dedicated amount of consecutive, full working days on site instead of their current practice of being on site, for example, for four hours for a given day and then disappearing and returning for multiple broken-up short days. Travel time eats away at productivity and, in the aggregate, reduces the number of inspections.
2. Incorporate ICH guidelines into GCP inspections
The International Conference on Harmonisations (ICH) E6, Good Clinical Practice: Consolidated Guideline has been in existence for five years. The guideline has been debated, published, used in training, and most importantly, put into practice in Europe. European Agency for the Evaluation of Medicinal Products (EMEA) inspectors issue citations based on E6. Yet the FDA, while supporting the concept of global harmonization, still issues no citations for failure to comply with E6 guidelines that do not match FDA regulations. FDA, EMEA, and Japanese inspectors should be working from the same set of rules.
Could it be that the FDA does not believe in, or support, ICH efforts? Thats how its beginning to look. This situation should be rectified immediately. FDA inspectors should be trained on ICH E6 and begin to issue citations based on this set of rules.
3. Provide one set of GCP standards and guidelines for all studies
Standards are not currently the same for drugs, biologics, diagnostics, vaccines, and devices. For example, serious adverse events are defined differently for Class 3 devices than they are for the first four categories of products. The FDA should push for a uniform set of standards for compounds to which patients are exposed, including those instilled during surgery. The FDA should also consider making Phase 4 standards the same as those for Phases 1, 2, and 3, although most individuals in industry do not believe that Phase 4 marketing studies warrant the same attention to detail as Phase 4 new indication studies.
4. Reorganize and expand the content of 483s
FDA 483s only contain citations, that is, listing of discrepancies and problems identified by inspectors at sites and with investigators. Most are not logically organized or grouped into standardized sections. In contrast, most GCP audit reports prepared by industry are well organized into distinct sections, and the relative importance (for example, of regulatory risk) of various findings are explained. Establishment inspection reports (EIRs) more closely resemble industry audit reports, but EIRs are not intended for investigator, sponsor, or public consumption.
FDA inspectors should prepare 483s that are organized as follows:
This change in perspective might begin to alleviate some of the tension and adversarial conditions that investigators, their staff, and inspectors experience during the site inspection process.
5. Publish 483s, warning letters, responses, and actions on the Web
Warning letters are currently published on the Web, but 483s are not. Freedom of Information is cumbersome and an inefficient way to learn about investigator performance. Using the agencys database and an efficient search engine, a Web inquirer should be able to search by investigator, by site location, or by study and to learn about the outcome of each inspection. It is important to find out which investigators have had uneventful inspections so that more studies can be assigned to these investigators.
6. Admit inspection mistakes
FDA inspectors make mistakes, sometimes glaring ones. For example, a 483 might state that a physical exam was not performed for a specific subject visit. The inspector, it turns out, failed to find the source notation that the study coordinator located after the inspection visit (it was buried in the five-volume medical record which was available to the inspector). Some inspectors unfortunately do not have enough clinical experience to adequately read and understand medical records. FDA staff who conduct site audits need to be specialists in clinical research, not generalists who do some GCP work along with conducting other types of inspections, such as food plants and dairy farms.
Clinical investigators should and do respond to 483 errors. However, their responses are sometimes not as thorough or as direct as they should be because of the investigators (and sponsors) reluctance or fear of antagonizing the FDA.
In the spirit of collaboration, when investigators show that inspectors have made mistakes, the Agency should document and admit where it has failed in the inspection process.
7. Conduct a more thorough review of consent content
Although most consents have sections that correspond to mandatory elements, their content is sometimes misleading and/or inadequate. For example, consents sometimes do not identify who will pay for medical injury, the benefits and risks of alternative therapies, and the purpose of the study as identified in the protocol. Risks of the experimental drug may not match risks identified in the investigator brochure. Field inspectors may not have the medical background to properly evaluate all aspects of the consent. In these cases, the consent could be brought back to the field office for review by more qualified staff. Inspectors should cite content deficiencies on 483s.Since the content of the consent is ultimately the responsibility of the clinical investigator (and not the approving IRB), the FDA should be just as involved in evaluating this document as it is in evaluating other study components.
8. Improve terminology and guidance documents
Physicians who lead studies at clinical sites are called investigators by the FDA and are called principal investigators in NIH grants. FDA recognizes only one lead investigator, whereas NIH permits co-principal investigators. The FDA recognizes sub-investigators; NIH does not use this term. FDA inspectors who visit and examine these clinical sites are also called investigators. How confusing. This and other FDAGCP terminology, such as the different kinds of inspections, are outdated.
FDA documents of GCP rules are disorganized and difficult to follow. There is little continuity. The documents read like Internal Revenue Service instructions for the alternative minimum tax or for capital gains. The FDAs GCP documents are nowhere nearly as well organized as the ICHGCP Guideline and related guidelines. They do not have to continue, in this age of information technology and hyperlinking, to be so incomprehensible and user-unfriendly.
9. Provide more public forums for exposure to FDA thinking and to field inspectors
Field inspectors seem to be invisible except when they appear at clinical sites. Industry needs more opportunities for dialogue with inspectors so that mutual concerns can be discussed and insight gained into the fine points of GCP compliance. While its nice to see the top guns of the Parklawn office once a year at the annual Drug Information Association (DIA) meeting, that is not sufficient.
FDA and industry need to jointly develop a venue or forum so that sponsors, clinical staff, and FDA meet together on a regular basis, at least semi-annually, so that they all hear the same information. Possibly an association of representatives of these entities could be developed, with a focus on understanding the new medical product approval process, as well as ICHGCP.
In addition, for midmanagement FDA officials at smaller, more intimate meetings, an oral disclaimer by the presenting inspector would be sufficient to protect the agency from worries about misinterpretations in policy or rules that might occur during the session.
10. Prepare better documentation
Currently there appears to be, at least for public consumption, no systematic inspection of the data trail from source documents to final data listings in the analytic database and to output tables in study reports. Sometimes inspectors bring data listings to sites and perform a two-way comparison between source documents and data listings.
Alternatively, after performing a two-way comparison between source documents and case report forms (CRFs) at a site, inspectors can perform a two-way comparison between CRFs and data listings at a data management center. Such a center is usually located at the contract research organization (CRO) or at sponsor headquarters. The CRF and data listing comparison can also be performed at FDA regional offices.
Regardless of where these examinations are performed, integrated reports should be prepared that determine the validity of study data from source documents to final data listings and to clinical study report tables, and that comment on the quality of processes and procedures applied to these data. More inspections need to be conducted of the processes and procedures used to prepare and analyze clinical data.4
1. M. Bruckheimer, FDAs Inspections of Clinical Investigators, Drug Information Journal, 27 (1) 21316 (1993).
2. Charles Curran, Preparing a Clinical Site for a Clinical Investigator Inspection by the FDA, Drug Information Journal, 33 (1) 2539 (1999).
3. Douglas R. Mackintosh and Vernette J. Molloy, Guarding the Pharmaceutical Chicken Coop: The Case for External Clinical Auditors, Good Clinical Practice Journal, 5 (3) 812 (1998).
4. Douglas R. Mackintosh, Quality Assurance of Data Management and Statistical Analysis, Applied Clinical Trials, June 1994, 4050.