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FDA Institutional
Review Board Inspections
FDA Clinical
Investigator Inspections
Clinical
Investigator Regulatory Sanctions
Background
Since 1971, FDA regulations have required that studies involving investigational new drugs and biologics performed on human subjects in institutions (including hospitals, nursing homes, mental institutions, and prisons) receive review and approval by an Institutional Review Board (IRB). Medical devices have required IRB review since 1976.
FDA developed the Bioresearch Monitoring Program and began an expanded review of IRB operations in April 1977. The Bioresearch Monitoring Program, which encompasses not only IRBs, but also clinical investigators, research sponsors, monitors, and non-clinical (animal) laboratories, is primarily intended to ensure the quality and integrity of data submitted to FDA for regulatory decisions, as well as to protect human subjects of research. For this reason, the IRB regulations note that FDA may inspect IRBs and review and copy IRB records [21 CFR 56.115(b)].
IRB Review Program
Under the Bioresearch Monitoring Program, FDA conducts on-site procedural reviews of IRBs. These reviews are conducted to determine whether an IRB is operating in accordance with its own written procedures as well as in compliance with current FDA regulations affecting IRBs. These regulations include 21 CFR part 50 (Informed Consent), part 56 (Standards for IRBs), part 312 (Investigational New Drugs), and part 812 (Investigational Devices).
When an IRB is selected for a procedural review, an investigator from one of the Agency's District Offices will contact a responsible individual at the institution, usually the IRB chairperson, and arrange a mutually acceptable time for the visit. When the field investigators arrive at the institution, they will show FDA credentials (photo ID) and present a "Notice of Inspection" form to the responsible official. This is done simply to let those persons at the institution know that the investigators are duly authorized representatives of FDA conducting official business. The investigator will interview appropriate persons and obtain information about the IRB's policies and procedures. Then, using one or more studies which are subject to FDA regulations, the investigator will examine the IRB's performance by tracking these studies through the review process used by the IRB. The IRB procedures and membership rosters will be examined to see whether they conform to current Agency regulations. The FDA investigator may request copies of records of IRB membership, IRB procedures and guidelines, minutes of meetings at which the studies were reviewed and discussed, material on the studies submitted by the clinical investigator to the IRB, and any other materials pertaining to these studies. Copies of these materials become part of the field investigator's report to FDA Headquarters.
After the inspection has been completed, the investigator will conduct an "exit interview" with a responsible institutional representative and/or the IRB chairperson. At this interview, the investigator will review the findings, clarify any misunderstandings that might exist, describe any deviations from the current regulations, and may suggest corrective actions. A written Form FDA-483 (Notice of Observations) may be left with the institution.
After the investigator returns to the District Office, a written report is prepared. This report is forwarded to FDA Headquarters for evaluation. When the evaluation is completed, a letter may be sent to the IRB chairperson or other responsible institutional official. If the regulations have not been followed, the letter may suggest methods to achieve compliance and ask the IRB to correct its procedures. If serious deviations were observed, a written response assuring adequate correction is usually required. A follow-up inspection may be also conducted. FDA may take administrative actions against IRBs and/or their institutions for noncompliance with the regulations [21 CFR part 56 subpart E].
Additional Information
A copy of the FDA Compliance Program Guidance Manual for IRB Inspections (Program 7348.809) is available to the public by writing to:
Freedom of Information Staff (HFI-35)
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
Contact Person for Inspection Problems
If, during the course of an inspection, questions arise that the FDA field investigator has not answered, the Director of the District Office may be contacted. The name and telephone number of the District Director is available from the field investigator and is also on the Notice of Inspection (Form FDA-482).
Background
The FDA Bioresearch Monitoring Program involves site visits to clinical investigators, research sponsors, contract research organizations, Institutional Review Boards (IRBs), and nonclinical (animal) laboratories. All FDA product areas, i.e., drugs, biologics, medical devices, radiological products, foods, and veterinary drugs, are involved in the Bioresearch Monitoring Program. While program procedures differ slightly depending upon product type, all inspections have as their objective ensuring the quality and integrity of data and information submitted to FDA as well as the protection of human research subjects.
Clinical Investigator Inspection Programs
FDA carries out three distinct types of clinical investigator inspections: (1) study-oriented inspections; (2) investigator-oriented inspections; and (3) bioequivalence study inspections. Bioequivalence study inspections are conducted because one study may be the sole basis for a drug's marketing approval. The bioequivalence study inspection differs from the other inspections in that it requires participation by an FDA chemist or an investigator knowledgeable about analytical evaluations. The other two types of inspections are discussed in more detail below.
Study-oriented Inspections
FDA field offices conduct study-oriented 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 license applications pending before the Agency.
When a clinical investigator, who has participated in the study being examined, is selected for an inspection, the FDA investigator from the FDA District Office will contact the clinical investigator to arrange a mutually acceptable time for the visit. Upon arrival, the FDA investigator will show FDA credentials (photo ID) and present a "Notice of Inspection" form to the clinical investigator. FDA credentials let the clinical investigator know that the FDA investigator is a duly authorized FDA representative.
If, during the course of an FDA inspection, a clinical investigator has any questions that the FDA investigator has not answered, either the Director of the District Office or the Center that initiated the inspection may be contacted. The name and telephone number of the District Director and the specific Center contact person are available from the FDA investigator.
The investigation consists of two basic parts. First, determining the facts surrounding the conduct of the study:
Second, the study data is 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. 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. The FDA investigator may also review 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-oriented Inspections
An investigator-oriented 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 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 Agency may initiate an inspection, if a subject in a study complains about protocol or subject rights violations. Investigator-oriented 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 with a specific disease given the locale of the investigation are claimed; or laboratory results that are outside the range of expected biological variation.
Once the Agency has determined that a investigator-oriented inspection should be conducted, the procedures are essentially the same as in the study-oriented 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, FDA will initiate actions that may ultimately determine that the clinical investigator is not to receive investigational products in the future.
Inspection Findings
At the end of an inspection, the FDA investigator will conduct an "exit interview" with the clinical investigator. At this interview, the FDA investigator will discuss the findings from the inspection, clarify any misunderstandings that might exist, and may issue a written Form FDA-483 (Inspectional Observations) to the clinical investigator. Following the inspection, the FDA field investigator prepares a written report and submits it to headquarters for evaluation.
After the report has been evaluated, FDA headquarters usually issues a letter to the clinical investigator. The letter is usually one of three types:
(1) a notice that no significant deviations from the regulations were observed. This letter does not require any response from the clinical investigator.
(2) 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.
(3) a "Warning Letter" identifying serious deviations from regulations requiring prompt correction by the clinical investigator. The letter will give a contact person for questions. In these cases, FDA may inform both the study sponsor and the reviewing IRB of the deficiencies. 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, FDA may take other courses of action, i.e., regulatory and/or administrative sanctions.
Additional Information
A copy of the FDA Compliance Program Guidance Manual for Clinical Investigator Inspections (Program 7348.811), the document used by the FDA investigator to conduct the inspection, is available by writing to:
Freedom of Information Staff (HFI-35)
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857.
Also see this FDA Information Sheet
"Clinical
Investigator Regulatory Sanctions"
This information sheet focuses on the applicability of regulatory sanctions to clinical investigators participating in studies involving investigational new drugs, antibiotics, biologics, medical devices, medical foods or food additives. [Note: Although this information sheet refers to human subjects in the context of an Investigational New Drug Application (IND), analogous principles apply to animal subjects in an Investigational New Animal Drug Application (INAD).]
Regulations do not state that hearings will be held at FDA headquarters. Investigators may suggest another location. Hearings can be denied if investigators fail to submit any information that raises any question of fact.
The Disqualification Process
Informal Conference or Written Explanation
FDA may disqualify clinical investigators from receiving investigational drugs, biologics and devices only when the investigator has repeatedly or deliberately violated the Agency's regulations, or has submitted false information to the sponsor in a required report. The appropriate FDA Center will send the investigator a written notice describing the noncompliance or false submission and offer the investigator an opportunity to respond to the notice at an informal conference or in writing. The Agency will specify a time period within which the investigator must respond. While the conference is informal, a transcript may be made, and the investigator may have legal representation.
If the investigator offers a timely and satisfactory explanation for the noncompliance, and the Center accepts, the process is terminated and the investigator is so notified in writing. If, however, the investigator offers an explanation that the Center rejects, or if the investigator fails to respond within the specified time period, FDA will offer the investigator an opportunity for an informal regulatory "Part 16" hearing under the Agency's regulations [21 CFR part 16] to determine whether the investigator should remain eligible to receive investigational test articles.
Notice of an Opportunity for Hearing on Proposed Disqualifications
FDA initiates a Part 16 hearing when it sends the investigator a written Notice of Opportunity for Hearing. The Notice specifies the allegations and other relevant information that is the subject of the hearing. If the investigator does not respond within the time period specified in the letter, FDA considers the offer to have been refused, and no informal hearing will be held. The Commissioner will then consider the information available to FDA to determine whether the investigator should be disqualified.
If a hearing is requested, the Commissioner will designate a presiding officer from the Office of Health Affairs (OHA), and the hearing will take place at a mutually agreeable time at FDA headquarters. If agreement cannot be reached, however, the presiding officer will designate a hearing date acceptable to FDA.
Part 16 Hearing and Final Order on Disqualification
Before the hearing, FDA gives the investigator notice of the matters to be considered at the hearing which includes a comprehensive statement of the basis for the proposal to disqualify the investigator and a general summary of the information that the Center will present. The Center and the investigator exchange written notices of any published articles or written information to be presented or relied upon at the hearing. If it seems unreasonable to expect the other party to have, or to be able to obtain, a copy of a particular document, a copy of the document is provided. The investigator or the Center may each file a motion for summary decision.
Part 16 hearings are informal, and the rules of evidence do not apply. Any participant may comment upon or rebut all data, information, and views presented. The presiding officer conducts the hearing. The hearing begins with Center staff giving a complete statement of the action that is the subject of the hearing and describing the information and reasons supporting disqualification. They may present any oral or written information relevant to the hearing. The investigator, who may be represented by legal counsel, then may present any oral or written information relevant to the hearing.
After the hearing, the OHA presiding officer prepares a written report. This report includes a recommended decision and the reasons for the recommendation. The administrative record of the hearing includes all written material presented at the hearing and the hearing transcript. The parties are given the opportunity to review and comment on the presiding officer's report. The report and the comments of the parties are transmitted to the Commissioner who considers them along with the administrative record to determine whether the investigator should be disqualified. The Commissioner issues a written decision giving the basis for the action taken.
Actions Upon Disqualification
If the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the regulatory requirements, or has deliberately or repeatedly submitted false information to the sponsor in any required report, the Commissioner will:
(1) Notify the investigator and the sponsor(s) of any investigation(s) in which the investigator has participated that the investigator is not entitled to receive investigational drugs, biologics or devices. The notification will include a statement explaining the basis for this determination.
(2) Notify the sponsors of studies conducted under each IND, IDE or each approved application containing data reported by the investigator that the Agency will not accept the investigator's work in support of claims of safety and efficacy without validating information establishing that the study results were unaffected by the investigator's misconduct.
(3) After the investigator's data are eliminated from consideration, determine whether the data remaining can support a conclusion that studies under the IND or IDE may continue. If the Commissioner determines that the remaining data are inadequate, the sponsor will be notified and will have an opportunity for a regulatory hearing under 21 CFR part 16. If a danger to public health exists, however, the Commissioner will terminate the IND or IDE immediately and notify the sponsor of the determination. The sponsor will then have an opportunity for a Part 16 regulatory hearing to determine whether the IND or IDE should be reinstated.
(4) After the investigator's data are eliminated from consideration, determine whether the continued approval of the product is justified. If it is not, the Commissioner will move to withdraw approval in accordance with the applicable provisions of the Federal Food, Drug, and Cosmetic Act.
The action to be taken with regard to an ongoing clinical investigation conducted by a disqualified investigator is made on a case-by-case basis. FDA considers the nature of the clinical investigation, the number of subjects involved, the risks to the subjects from discontinuation of the study, and the need for involvement of an acceptable investigator. If another investigator accepts responsibility for the investigation, FDA may allow an investigation to continue. If not, further use of the test article is deferred until another investigator is identified. If this deferment could create a life-threatening situation, FDA may permit a subject to continue to receive or use a test article without a further written statement from the disqualified investigator. The investigator can bring such cases to the Agency's attention during the regulatory hearing, so that the Commissioner may consider this option.
Public Disclosure of Information Regarding Disqualification
A danger to the public health includes not only the subjects' safety in any study in question, but also the safety of subjects in other studies in which the investigator is involved.
The Notice of Opportunity for a Hearing letter is available under the Freedom of Information provisions but is not placed on public display. FDA will notify other government agencies of a proposed disqualification whenever the Agency deems such notification to be appropriate.
If the Agency notifies other parties of its preliminary findings prior to final disqualification, FDA will provide a description of these findings, state that the Agency has yet to reach a final decision on whether the investigator should be disqualified, and will not recommend that action be taken by the third party. If the disqualification proceeding does not result in a disqualification or a consent agreement, FDA will so advise those third parties that had been contacted. A copy of each notification will be sent to the investigator.
If the Agency gives notice of the disqualification of a specific investigator to a third party, FDA will provide a copy of the final disqualification order, explain its legal meaning, and state that FDA is not advising or recommending that the person notified take any action upon the matter. A copy of each notification will be sent to the investigator. The list of investigators who are ineligible to receive investigational new drugs, biologics and devices or who have agreed to some restriction of use of investigational drugs, biologics and devices (see below) is not considered to be a "notice" as discussed above.
Reinstatement of a Disqualified Investigator
Investigators who have been disqualified may be reinstated if the Commissioner determines that the investigators have presented adequate assurances that they will employ investigational drugs, biologics and devices in compliance with FDA regulations. The Agency's reinstatement guidelines, entitled "Procedures for Reinstating Eligibility of Disqualified Clinical Investigators to Receive Investigational Articles" are available by writing to the FOI Staff at the address given below.
Consent Agreements
In addition to an opportunity for an informal conference or to respond in writing to Center allegations, the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health offer investigators the opportunity to enter into a consent agreement whereby the investigator agrees to meet certain conditions mutually acceptable to both FDA and the investigator. This agreement obviates the need to proceed further with the disqualification process. Consent agreements generally take one of two forms: (1) the individual agrees to refrain from further studies with FDA regulated test articles or (2) the individual agrees to specific restrictions in the use of investigational products, such as oversight by an individual acceptable to both the investigator and to the Agency. The consent agreement option remains available to the clinical investigator at all stages of the disqualification process. Most actions have been settled by consent agreements.
Criminal Prosecutions
After a Part 16 proceeding, a final order or entry into a consent agreement constitutes final Agency administrative action. This, however, does not preclude institution of criminal proceedings against an investigator. Those investigators referred for criminal prosecution are generally clinical investigators who have knowingly or willingly submitted false information to a research sponsor.
Additional Information
FDA maintains a list of investigators who are ineligible to receive FDA regulated test articles or who have agreed to some restriction of use of FDA regulated test articles. This list is regularly updated and is not considered to be a "notice" of disqualification (see above). The list is available to the public by writing to the following FDA office.
Freedom of Information Staff (HFI-35)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857.
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