Clinical investigator inspection programs

The FDA carries out three distinct types of inspections: bioequivalence, study-orientated inspections, and investigator-orientated inspections.

Bioequivalence inspections

From 1993, the FDA established an inspectional program to inspect in vivo bioequivalence studies (clinical and analytical components)

supporting approval of marketing applications for generic drugs. The target of inspections are facilities new to FDA regulated research, high-volume facilities, facilities performing novel/non-conventional study procedures, and facilities with problems reported to the FDA.

Study-orientated inspections

FDA field offices conduct study-orientated inspections on the basis of assignments developed by headquarters staff. Assignments are based almost exclusively on studies that are important to product evaluation, such as new drug applications and product licence applications pending before the Agency. These assignments are based almost exclusively on studies that are important to product evaluation, new drug applications, and product licence applications pending before the FDA. Assignments may include pivotal clinical studies, studies where there have been an unusually high number of safety concerns or compliance issues raised by the sponsor, investigator, and/or the patient. Most FDA assignments are conducted on clinical investigators, whereas assignments on sponsors are relatively few. The FDA inspectional procedures and activities are described in the following FDA Compliance Programs: clinical investigators (CP 7348.811), sponsors (CP 7348.810), and institutional review boards (CP 7348.808).

The investigation consists of two basic parts. First, determining the facts surrounding the conduct of the study: who did what; the degree of delegation of authority; where specific aspects of the study were performed; how and where data were recorded; how test article accountability was maintained; how the monitor communicated with the clinical investigator; and how the monitor evaluated the study's progress.

Second, the study data are audited. The FDA investigator compares the data submitted to the Agency and/or the sponsor with all available records that might support the data. These records may come from the physician's office, hospital, nursing home, laboratories, and other sources. The FDA may also examine patient records that predate the study to determine whether the medical condition being studied was, in fact, properly diagnosed and whether a possibly interfering medication had been given before the study began. In addition, there may be a review of records covering a reasonable period after completion of the study to determine if there was proper follow up, and if all signs and symptoms reasonably attributable to the product's use had been reported.

Investigator-orientated inspections

An investigator-orientated inspection may be initiated because an investigator conducted a pivotal study that merits in-depth examination because of its singular importance in product approval or its effect on medical practice. An inspection may also be initiated because representatives of the sponsor have reported to the FDA that they are having difficulty getting case reports from the investigator, or that they have some other concern with the investigator's work. In addition, the FDA may initiate an inspection, if a subject in a study complains about protocol or subject rights violations. Investigator-orientated inspections may also be initiated because clinical investigators have participated in a large number of studies or have done work outside their specialty areas. Other reasons include safety or effectiveness findings that are inconsistent with those of other investigators studying the same test article; too many subjects claimed with a specific disease given the locale of the investigation; or laboratory results outside the range of expected biological variation.The FDA may institute an investigator-orientated inspection for the following suspicious conditions: attempts to delay inspection; attempts to limit access to documents; investigator did it all himself; consent signature similarities; sudden tragedies (the "Titanic Phenomena"); notations out of chronological order and squeezed in between lines; and no original charts only photocopies of charts, ECGs, lab results.

Once the Agency has determined that an investigator-orientated inspection should be conducted, the procedures are essentially the same as in the study-orientated inspection except that the data audit goes into greater depth, covers more case reports, and may cover more than one study. If the investigator has repeatedly or deliberately violated FDA regulations or has submitted false information to the sponsor in a required report, the FDA will initiate actions that may ultimately determine that the clinical investigator is not to receive investigational products in the future.

After the site inspection, FDA headquarters usually issues a letter to the clinical investigator. The letter is usually one of four types:

• A notice that no significant deviations from the regulations were observed. This letter does not require any response from the clinical investigator ("classification NAI").

• An informational letter that identifies deviations from regulations and good investigational practice. This letter may, or may not, require a response from the clinical investigator. If a response is requested, the letter will describe what is necessary and give a contact person for questions ("classification VAI").

• A "warning letter" identifying serious deviations from regulations requiring prompt correction by the clinical investigator ("classification OAI"). In these cases, the FDA may inform both the study sponsor and the reviewing IRB of the deficiencies. The recipient of a warning letter is required to respond to the FDA within 15 working days. The Agency may also inform the sponsor if the clinical investigator's procedural deficiencies indicate ineffective monitoring by the sponsor.

In addition to issuing these letters, the FDA may take other courses of action, that is regulatory and/or administrative sanctions, including;

• A "Notice Inspection, Disqualification, Proceeding, and Opportunity to Explain (NIDPOE) Letter" issued when the FDA believes that it has evidence that an investigator has repeatedly or deliberately failed to comply or has submitted false information to the FDA or sponsor as described in 21 CFR 312.70. The NIDPOE letter informs the recipient clinical

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