Audits/Inspections Be Prepared for Anything Practices, laboratories, institutions, and clinics that participate in clinical trials are subject to audits by a number of different entities. As a primary investigator, it is important for you to be prepared for these, sometimes unannounced, visits because the outcomes can have a significant impact on your site and the overall clinical study. This chapter will contain information on what entities may make a visit to your site, what the auditor or inspector will be looking for, and how to conduct yourself during the actual inspection. The authority to audit/inspect is under the jurisdiction of a number of agencies, organizations, and institutions. In the United States, oversight falls under the US Food and Drug Administration (FDA), whereas Canada relies on the Health Products and Food Branch Inspectorate (HPFBI); the European Medicines Agency (EMEA) Inspections Services Group is in Europe, and the Ministry of Health, Labor, and Welfare is in Japan. Other possible inspections may come from trial sponsors or the supervising institutional review board (IRB) or research ethics committee (REC). Sponsors The first audit of your clinic by the sponsor will occur before any contracts are signed to determine if your facilities are appropriate to meet the needs of the study; for example, if bone mineral density scans will be required, does your clinic have a dual energy x-ray absorptiometry (DEXA) machine? Once the study has started, it is the sponsor s responsibility to periodically monitor its investigators. Thus, the sponsor s monitors may visit your site frequently to ensure that you are following the protocol and all applicable regulations. During these periodic visits, the monitor will look at all of your records. They will review the data for accuracy and completeness. If the study is blinded, these monitors will remain blinded. In 1988, the FDA set out guidelines for sponsors regarding the monitoring of clinical investigations, and they have been more recently updated. Although these guidelines are not legal requirements, they establish a model standard of practice the FDA wants sponsors and monitors to follow. Institutional Review Boards Your IRB/REC may also conduct an audit of your clinic. They are similar to the ones conducted by the FDA. Meetings will be scheduled before the visit to examine your study-related records that they have on file. They will be checking to make sure you are following all policies and procedures of the institution, which may be more stringent than that of either the sponsor or the FDA. Governmental Authority The United States The FDA s Bioresearch Monitoring program (BIMO) oversees inspections both nationally and internationally if the data is critical to product approval in the United States. They inspect approximately 1% of all clinical trial sites each year. At their discretion, 2 types of inspections may occur at any facility at any time: routine and directed. Routine inspections are performed when a site is randomly selected with no specific reason to audit. Directed inspections, or for cause inspections, occur when a specific problem, such as a safety concern, complaint, or clinical investigator misconduct, is identified by the FDA. The purpose of an FDA routine inspection is to verify:
Who performed various aspects of the protocol (eg, who verified inclusion and exclusion criteria, who obtained informed consent, who collected adverse event data); The degree of delegation of authority (eg, how the clinical investigator supervised the conduct of the investigation); Where specific aspects of the investigation were performed; How and where data were recorded; Accountability for the investigational product; The monitor s communications with the clinical investigator; and The monitor s evaluations of the progress of the investigation. The FDA requires that all files be kept for a minimum of 2 years after the trial has been published or discontinued by the sponsor, unless specified otherwise. The FDA has the authority to view, copy, and verify any records or reports made by the clinical investigator regarding the disposition of the product and subject case histories. The FDA inspector may also audit the study data, comparing what is on file with the FDA or study sponsor with what is contained in the individual investigator s files. However, they will not attempt to interpret or evaluate the data. Material they may review includes the informed consent forms, correspondence between you and the sponsor and the IRB, and medical records (eg, physician notes, hospital charts), not only from the trial but also files that predate the study to determine that eligibility criteria were met and post-study files to determine if proper follow-up was performed. The FDA s access to medical records should be included in the confidentiality agreement with the subjects. The FDA inspection is limited to the conduct of the clinical trial. They will not be reviewing your regular clinic business or your skill as a physician. At the conclusion of the audit, the FDA inspector will conduct an exit interview with the clinical investigator to discuss the findings. A written Establishment Inspection Report (EIR) will also be submitted to the FDA. After review of the EIR, 1 of the 3 of the following types of letters will be sent out to the investigator. A letter stating nothing deviated from the regulations. Sometimes this type of letter is not sent. An informational or untitled letter that identifies deficiencies in meeting statues and regulations and for which voluntary corrective action is needed. A warning letter that identifies serious deviations from statutes and regulations. Prompt correction of the deficiencies and a written response to the FDA is required. The FDA also has the authority to disqualify clinical investigators from participating in future clinical trials if the investigator repeatedly or deliberately fails to comply with applicable statutory or regulatory requirements or has submitted false information to the sponsor or the FDA.
Canada Canadian regulation falls under the jurisdiction of the HPFBI. Their Compliance and Enforcement Policy provides the guiding principles for the fair, consistent and uniform application and enforcement of the Act and Regulations (Health Product and Food Branch Inspectorate 2008). The European Union European oversight falls to the Good Clinical Practice Inspection Services Group of the EMEA. Their inspectors use the Joint Audit Programme to ensure conformity among nations throughout the inspection process, and to make sure trials stay in accordance with mutual recognition agreements among European countries. In Great Britain specifically, the Medicines and Healthcare products Regulatory Agency works in conjunction with the EMEA to safeguard public health. Japan In Japan, the Ministry of Health, Labor, and Welfare is the authority on medical research. The Pharmaceutical Affairs Law was enacted with the basic goal of regulating the efficacy, quality, and safety of pharmaceuticals, medical devices, and cosmetics. This law promotes harmony with similar mandates of the United States, European Union, and other countries. Preparing for an Audit Preparing for an inspection should be started as soon as you agree to be involved in a study and should continue even after the study is completed. One of the easiest and most important things you can do is keep all of your paperwork regarding the conduct of the study, including protocols, patientspecific information, and reports well organized and easy to access. All of your staff involved in the study should be familiar with the protocol and applicable institution, sponsor, and governmental regulations, and one person should be assigned to assist the inspector throughout the day. It is also important that you alert the study sponsor of any government visits or audit requests, so they can be prepared to provide additional information as needed. Strategies for Success During a Regulatory Agency Inspection Although the prospect of a regulatory agency inspection is daunting, you can help it go smoothly by following these tips. Remember that first impressions are important, so be available and assume a cooperative attitude. When the inspection agent arrives, regardless of whether he or she represents the government, the sponsor, or the IRB, the first thing to do is ask for credentials to ensure that confidential files are not being seen by unauthorized persons. Once you have verified that the person is truly an authorized inspector, give him or her access to any study-related materials requested. When asked a question, confirm that you understand what is being asked before answering, and be brief and factual with your responses. Take immediate corrective action, if possible, and correct any misinformation, as appropriate. Make sure you are also readily available to the inspector at any time in case he or she needs clarification or is unable to locate important documents. Following the inspection, you may receive a written report of the findings. Respond promptly and factually to whatever requests are made. Do not volunteer any information without being asked; do not guess or offer opinions, be argumentative, delay responses to requests, entertain hypothetical questions, or answer questions outside your expertise. For additional suggestions, please see Table 1.
If you are well organized, pay attention to detail, and run the trial ethically, you should be able to avoid the common deficiencies listed below. Common Inspection Findings Informed consent inadequacies Example, old draft used to obtain consent Protocol nonadherence Example, drug stored at the wrong temperature Inadequate/inaccurate records Example, wrong units used for evaluation parameter Records not available Example, missing hard-copy informed consent forms Inadequate investigational article accountability Example, missing investigational compound for 2 patients for final dosing Inaccurate case histories Example, missing initial blood pressure data Unapproved concomitant therapy Example, subject took aspirin for a temporary headache when prohibited by protocol IRB not informed of protocol changes Example, sponsor changes the machine used in bone density evaluation Subinvestigators not listed Example, colleague doing initial subject evaluations not reported to IRB Failure to report serious adverse events (SAEs) Example, heart attack not recorded because subject dropped out of the trial Inappropriate follow-up of AEs Example, subject sent to hospital, with subsequent transfer of care Subjects enrolled into simultaneous investigations Example, subject in a trial of topical acne medication and another for a blood pressure drug Submission of false information Example, data transferred from one date to another date Inappropriate delegation of duties Example, clinical trial coordinator is evaluating lesions Conclusions Although they are intimidating, audits should not be looked at as a negative but rather a positive opportunity to improve your clinical trial methods. Becoming familiar with those regulations related to clinical trials will not only help you be prepared for an audit, but will also allow you to better run your clinic. The key to getting through an audit is organization and preparation, things that are applicable to all aspects of your practice. Table 1: Strategies for Success During a Regulatory Agency Inspection Contact from the Regulatory Agency Planning for the Regulatory Agency Visit Ensure that Obtain the inspector s name, office location and telephone number. Confirm the studies to be evaluated. Verify the intended dates for the inspection. Ask is sponsor personnel can be present during the inspections. Provide the sponsor with the above information. All study staff, including the pharmacy and support laboratories, are informed of the dates of the Regulatory Agency visit and the studies to be review. A room free of other sponsors study information is booked for the inspector to work in.
Someone is assigned to assist the inspector this may be all day if the inspector is not familiar with the clinical studies or the therapeutic area. Arrangements are made for all study staff to meet the inspector on the first day, at the opening meeting. All versions of the original signed informed consent forms are available All medical records pertaining to eligibility and the study period are available. If your site uses electronic medical records, review your local institutions policies on access methods for inspectors. All case report forms and queries are available and legible. If your site uses and electronic data capture (EDC) system in place of paper case report forms, contact the sponsor for guidance on how to make this information available to the inspectors. The regulatory binder is available and complete. The subjects results for central laboratory analyses are available. Preparing for the Regulatory Agency Visit Refresh your memory about During the Inspection Do s During the Inspection Don ts Meetings and training sessions about the protocol and amendments. Each subject s progress through the study- pay special attention to serious adverse events. Protocol deviations and what procedural changes were implemented to prevent future occurrences. Drug management issues. Inform all study staff, including the pharmacy and support laboratories of the dates of the Regulatory Agency visit and the study to be reviewed. First impressions are important be available. Examine the credentials of the inspector, and establish the purpose of the inspection. Assume a cooperative attitude. Work out a rough schedule for the visit so that key personnel can be made available. Make sure you understand the questions before responding. Answer questions directly, do not volunteer information. Give honest, complete and accurate answers. Take complete notes as you go along. Take immediate corrective or remedial action, if appropriate. Call the sponsor is information is needed to support a response. When making copies for the inspector, make one extra set for you. Solicit opinions. Discuss your personal opinions about the study. Respond to questions outside your expertise. Volunteer information. Guess what the response to a question should be. Entertain hypothetical questions. Read, sign or listen to affidavits. Delay in providing requested records or copies.
Resources Food and Drug Administration. Compliance Program Guidance Manual. Available at: www.fda.gov. Published September 2, 1998. Accessed May 20, 2008 Marcarelli M, Device Clinical Trials Regulatory Considerations. SoCRA SOURCE. May 2003; 13-16. Available at: www.socra.org. Accessed May 20, 2008. Health Product and Food Branch Inspectorate. Summary report of the inspections of clinical trials conducted in 2003/2004. Available at: www.hc-sc.gc.ca. Published December 14, 2004. Accessed May 21, 2008. NHS Research and Development Forum. How to prepare for an inspection for Good Clinical Practice by the Medicines and Healthcare products Regulatory Agency (MHRA): a guide for NHS organizations that sponsor or host clinical trials of medicinal products. Available at: http://www.sth-research. group.shef.ac.uk. Published November 6, 2007. Accessed May 21, 2008. Food and Drug Administration. Information sheet guidance for IRBs, clinical investigators, and sponsors. Available at: www.fda.gov. Published January 2006. Accessed May 21, 2008. European Medicines Agency. Joint Audit Programme for EEA GMP Inspectors. Available at: www. emea.europa.eu. Published September 19, 2006. Accessed May 20, 2008. Health Products and Food Branch Inspectorate. Health Canada website. Available at: www.hc-sc.gc.ca Accessed May 20, 2008. Neckers K. Harmonization of drug and medical device development in the US and Japan: movement towards international cooperation in the postgenomic Era. New England International and Comparative Law Annual 2006;12:65-96.