INSIGHT REPORT
Vol 8 #6 

2005

INSIGHT REPORT

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Insight Report Vol.  8-  No.6

FDA Inspection of Clinical Trial Sites

The pharmaceutical and biotechnology industry has long been acknowledged as one of the most profitable industries. However, the fact that it’s also one of the most heavily regulated ones is often under-reported. The Food and Drug Administration, as the regulator has been vested with the duty to ensure that any marketed or new drugs’ safety and efficacy is acceptable enough, in terms of its benefit to risk ratio, to be marketed in the United States.

FDA has a very thorough procedure in place to ensure the above and has very strict regulations concerning the conduct of laboratory and pre-clinical research (Good Laboratory Process, GLP), clinical studies (Good Clinical Practice, GCP) and drug manufacturing (Good Manufacturing Process, GMP). To supplement these, FDA conducts inspections at the concerned facilities to ensure that the above regulations are being adhered to. Inspection of clinical sites is a way that the FDA ensures that clinical studies have been done in accordance with GCP regulations and that the data so generated is authentic and reliable.

Clinical inspections are part of the FDA’s Bioresearch Monitoring Program and are conducted by the Office of Regulatory Affairs (ORA). Their main purpose is: to protect the rights and welfare of human subjects; assure quality and integrity of data and to ensure compliance with regulatory requirements. There are two types of inspections: “Routine” and “For Cause”. Routine inspections are the more common of the two, being 80% of all inspections, and are triggered as a result of the submission of a New Drug Application (NDA). For Cause inspections are conducted only when the agency suspects that something is amiss at a trial site, either with the records, the investigators or the way the trial was conducted.

If a drug’s trials are being conducted at multiple sites, FDA usually selects only a few out of them to visit. Some of the criteria the FDA uses to choose which sites to visit include: distribution of subjects – sites having high enrollment are usually always picked; history of investigators; inconsistent data from a site – increased efficacy, decreased incidence of adverse events; investigator conducting trial outside his area of expertise, complaint from a sponsor or subject etc. The sponsor can use the above criteria also to have a reasonable chance of guessing which sites would be chosen for inspections. Once the sponsor has established this, it can inform the site, which in turn, can then better prepare for the inspection.

Prior to coming, FDA usually informs the clinical site of their intent to inspect, though this may not always be the case. The FDA doesn’t notify the sponsor of their intent to visit a trial site, so it’s up to the investigators to inform the sponsor. Before commencing the inspection, the FDA inspector provides a Form FDA 482, which is also called a Notice of Inspection form.

Some of the key questions that the FDA addresses include: to what extent was the principle investigator involved with the study, whether adequate documentation exists to establish that patients existed and actually participated in the trial- medical records of patients – their progress reports etc., whether IRB approval was taken after any protocol changes, whether the inclusion criteria at the time of enrollment was followed, whether there is sufficient accountability of the test drug  (all the way from receiving from sponsors to administering it to patients to accounting for any left overs), whether informed consents were taken from all enrolled patients and how adverse events were handled. In addition, the inspector will audit the data. He will compare the data that was submitted to the agency with the source documents (medical charts, laboratory reports etc.) supporting the data.

In preparing for the inspection, it is advisable to get the following documents in order: Protocol, Investigator’s Brochure, Form 1572 with accompanying CV’s, documents detailing any correspondence with the IRB, Informed consent documents for each patient, drug accountability records – receipt, storage, administration and return of the investigational drug etc.

As mentioned before, an FDA inspection mostly takes place after the trial has been completed. Hence, corrections concerning previous activities are not possible. It is therefore important to have a good system in place so that while the trial is being conducted, personnel take necessary actions to ensure ongoing compliance. For example, it is important to acknowledge and document mistakes and initiate and document corrective plans for them. In addition, good file organization processes enable quick data and information retrieval when needed later on. 

The investigator has the authority to interview everyone and anyone associated with the trial. Thus, it is advisable to train all the staff appropriately. They should be aware of why the inspection is taking place and what the investigator is looking for. It goes without saying that they should be aware of their duties and also of their superiors and subordinates. In responding to questions, they should be advised to be very succinct and terse and refrain from speculating about anything they are not sure about. Going a step further, it is also advisable to identify and allocate responsibilities to staff members, like who would escort the investigator during the investigation, who would fetch documents the investigator needs, who would be in charge of follow up requirements etc. Standard Operating Procedures (SOPs) covering all these areas should be written and acted upon during the inspection. A mock self-audit or an audit by external consultants might be useful in highlighting any shortcomings or areas for improvement. All these steps will help smoothen the inspection process and create a professional image for the trial site.

However, often trial sites are negligent in some area or the other. Common problems encountered during inspections include: failure to follow the protocol (43%), record keeping errors (20%) and informed consent problems (25%), drug accountability issues (17%) and adverse event reporting issues (12%).  Some of the significant violations include: enrollment of ineligible subjects, protocol deviations affecting safety, inadequate oversight of study personnel, failure to communicate with the IRB and data integrity issues.

The investigator evaluates these violations to see if any of them affect the rights and safety of enrolled subjects, whether there is an impact on the integrity of the data and whether the violations point to bigger problems with the study.

Once the inspector completes his inspection, he meets with the investigator to discuss the findings. He issues a Form FDA 483 that lists any problems and deviations he found during his visit. Upon his return to the agency, the investigator writes an Establishment Inspection Report (EIR) and forwards it to headquarters for evaluation. When the evaluation is completed, FDA classifies the inspection and sends a letter to the site.  FDA could send one of these letters:
NAI – No action indicated.  Approximately 20% of inspections have this result.
VAI - Voluntary action indicated, it is the most common result, with 70% of cases being requested by the FDA.
OAI - Official action indicated. It is a warning to the company and approximately 10% of the inspections have this result. An immediate detailed response is required to explain how these violations would be corrected. Failure to sufficiently address this letter can result in the investigator/site being disqualified from conducting other studies, rejection of study data or worse, rejection of the marketing application and even criminal proceedings. For contract research organizations and small companies, any adverse inspection result might be a fatal blow. An example of a warning letter issued on the basis of a clinical site inspection can be found at http://www.fda.gov/cder/warn/2005/05-HFD-45-0601.pdf

Within four to six months, the EIR is available upon request to the investigator, sponsor and the general public via the Freedom of Information Act.

If the trial site follows GCP procedures, then the FDA inspection should not be a worry. By conducting the inspection, FDA is just ensuring that trial data is accurate and that the trial was conducted according to established regulations. By simply following required guidelines and maintaining good documentation, trial sites can easily pass the inspection. Closing on a positive note, in the 1960s and 1970s, FDA rejected data from around 20% of the sites inspected in the US; now this figure has reduced to 1% to 2%. This clearly shows that sites have understood what the FDA wants and that the general integrity and quality of clinical trials is of a high standard. However, for smaller companies and organizations that don’t have much experience conducting such trials, it might be beneficial to have outside advice on designing their procedures. Mock audits by consultants too would help them iron out their deficiencies, thereby ensuring a smooth FDA inspection later on.

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