Clinical Trials Administrative Start-Up Handbook

SECTION 10

PREPARING FOR FDA INSPECTIONS



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Why are FDA inspections done?

What is the regulatory basis of FDA inspections?

Enforcing FDA regulations for drugs and devices involves regulatory oversight. The FDA exercises its oversight by conducting clinical site inspections. In a clinical site inspection, FDA investigators compare your actual practices and procedures against the commitments and requirements contained in the regulations.

Federal law allows an FDA investigator who provides a written Notice of Inspections (Form FDA 482) and shows appropriate credentials to enter a regulated establishment. The FDA has broad - but not unlimited - authority to inspect equipment, materials, products, labeling, and certain records.

If you conduct research under your own IND or IDE, you are a "sponsor-investigator" and FDA inspection authority extends to you.

Does the FDA publish advice about its own inspections?

The FDA has issued a useful five-page Information Sheet, intended to provide guidance for clinical investigators about FDA inspections. For another comprehensive overview of the scope of an FDA inspection, you may want to review the FDA's Guidance Manual (click on "Program #7348.811"). This manual was written by the FDA, for its own (FDA) inspectors.

The FDA has a recommendation for recordkeeping. They call it “ALCOA.” If you follow the ALCOA recommendation, you are on your way to being well prepared for an FDA inspection. ALCOA stands for:

A ttributable - The record shows clearly who completed it. This will confirm that the appropriate person performed the study activity. (Refer to your Study Site Signature and Delegation of Responsibility Log.)

L egible - The FDA needs to be able to re-create what happened during the study, but they can't do it if events are recorded in illegible handwriting. If the original handwriting is illegible, cross it out (do not erase it!) and re-enter so it is legible. Never obscure original data.

C ontemporaneous - Enter the study data at the time the activity is performed. Do not wait until the end of the day. Memories fade. Failure to record data contemporaneously leads to simple mistakes, resulting in inaccurate data.

O riginal - You may have recorded the original data on a napkin or a yellow stickey, then later transferred the data to a study data collection form. Maintain the original data source with the study records - do not throw out the napkin!

A ccurate - Following the A-L-C-O recordkeeping recommendations above will result in the final "A," i.e., accurate data.

What types of inspections does the FDA conduct?

An inspection can be comprehensive, focused on a specific issue or set of issues - or it can be conducted in response to a reported problem. More than one clinical investigator may be involved. The most common types of inspections conducted by the FDA are:

How does the FDA notify clinical investigators about impending inspections?

Usually, the FDA will notify you by telephone. Unless there are serious reasons for concern, the FDA will notify you one or two weeks before an inspection to arrange a mutually acceptable time for the inspection. It's possible to negotiate a delay if you have a good reason for doing so. However, if the audit is "investigator-related," the lag between notification and inspection will be a short one. If the FDA has serious concerns about subject safety, there may be no advance notice at all. A site cannot refuse an FDA inspection.

  How long do FDA inspections last?

An FDA inspection is likely to take one or two weeks, although the length of the inspection will depend on the size of the study and the findings. Although the inspection may begin as "routine," if the FDA's on-site findings show that further investigation is required, the routine inspection may become a "for-cause" inspection.

How do I prepare for an FDA inspection?

Remember, the best preparation for an FDA inspection is to do it right in the first place! Several good self-assessment tools are available, including the University of Kentucky's Self Assessment Form and the Partners HealthCare System's Self-Assessment Checklist. By tailoring these excellent tools to the UW environment, then using them to assess your own study(ies), you'll have a clear picture of your preparedness for any compliance audit and, beyond audits, for assurance that you are conducting your study according to the highest standards.

Request information from the FDA. Talk with the FDA investigator who will conduct the inspection and request information about:

•  The nature and scope of the visit.
•  The number of FDA investigators to expect.
•  The inspection start date and its expected duration.
•  What study personnel should be available during the inspection. Note: As the principal investigator, you must be available.
•  What documents should be available.

Alert study stakeholders. Do this immediately. Alert:

•  All members of the study team.
•  The study sponsor.
•  UW Medicine Compliance (206-543-3098) and School of Medicine Compliance (206-685-7369). The compliance offices will help you by ensuring that all appropriate staff are notified. They will also help you with preparation, planning, and support.
 •  UWMC/HMC Investigational Drug Pharmacy (UWMC: 206-598-4901 - HMC: 206-731-5448).
•  UWMC Operating Room Business office (206-598-3751) and/or HMC Operating Room Director Don Millbauer (206-731-6577).
•  Laboratory.
•  Your School of Medicine department/division administration.
•  Human Subjects Division (206-543-0098).
•  Affiliated institutions (as applicable).

Retrieve medical records and other source documents so that all of them are on hand for the inspection. The FDA is likely to request medical records and study-related documents for only a sampling of subjects, but it is a good idea to have all subject documents on hand in case there are questions or problems. Review the records. If any of them are missing, obtain copies.

Locate a private room for the FDA investigator(s), with telephone, copier, and computer access.

Prepare a general overview of the study. If you have not already done so, list all personnel, responsibilities delegated to them, and their qualifications for handling their duties. The FDA investigator will be checking to see who did what.

Prepare a list of subjects. List all subjects enrolled, including names, contact information, dates enrolled and completed, and medical record numbers. List all subjects screened, and indicate whether they were included in the study.

Organize all of the following study documents and have them in one place, by chronological order.

Regulatory files:

•  Study protocol (all versions), plus amendments.
•  Investigator's Brochure (all versions).
•  Form FDA 1571 or 1572 (all versions).
•  Clinical principal investigator's CVs and CVs for others listed on the FDA Form 1571 or 1572 (for drug studies) or the Investigational Device Exemption (IDE) for devices.

IRB files:

•  IRB application and initial approval letter, including initial IRB-approved consent form.
•  IRB-approved amendments and consent forms.
•  All consent forms with original signatures of each study subject (including subjects who were screened and excluded).
•  IRB-approved continuing (renewal) reviews.
•  Adverse experience reports sent to the IRB.
•  IRB study termination notification, including final summary.

Communication:

•  Sponsor correspondence, including adverse experience reports sent to and received from the sponsor.
•  CRO correspondence (if applicable).
•  Monitoring log - the FDA investigator will check to see how frequently the monitor evaluated the study's progress and how this information was communicated to you. The FDA will look for evidence of a close working relationship between you and the sponsor.

Laboratory:

•  Laboratory certification and normal ranges.
•  CV of laboratory director.

Drug/device accountability:

•  Receipt records.
•  Dispensing records.
•  Disposition or return records.

Note: The FDA investigator may check equipment, such as refrigerators or freezers, daily temperature logs, standardization, cleanliness, or calibration. If your drug is kept by the UWMC/HMC Investigational Drug Pharmacy or in the UWMC/HMC Implant Room, they will have this information readily available.

Subject documents:

•  Source documents for each enrolled subject (labs/x-rays/scans, etc.).
•  Completed case report forms (CRFs) for each subject.

Review the data for each subject enrolled. This review is essential and will provide an important indicator of the success of the inspection because the FDA investigator's review of these same records will determine whether the site records substantiate the data that were submitted to the FDA. If you discover deficiencies or other issues during this review, be sure to discuss them with the rest of the study team. Subject data include:

•  The study inclusion/exclusion criteria as they apply to each subject, including documented reasons for excluded subjects.

•  Original, signed consent forms for each subject. Be sure that the correct version was signed.

•  The completed CRFs for each subject, along with source document verification. Verify that the source documents support the following:

What happens after the inspection?

After the inspection, the FDA investigator will meet with you to discuss the findings. At this meeting, you will hear whether the FDA investigator found any deficiencies at your site. It's possible that you can clear up misunderstandings at this point; however, if the findings included apparent deviations from applicable regulations, the FDA investigator will issue a Notice of Observations (FDA Form 483), on which the FDA will have listed the apparent deviations. Approximately 45% of domestic inspections conclude with a Form 483. The FDA investigator will review the Form 483 with you and may ask you to comment. You are also expected to respond promptly and in writing to the Form 483. For industry-sponsored clinical trials, it's likely that your study sponsor will want to help you write the response. Your timely, written response is important and can significantly affect whether the FDA takes further action after an inspection. As appropriate, include in your response a plan for corrective action.

Based on Form 483 (if one was issued), copies of materials collected during the inspection, and your Form 483 response, the FDA investigator will then prepare an Establishment Inspection Report (EIR) and will route the EIR through the appropriate FDA Center for further evaluation. Within several weeks of the inspection, you will receive a copy of the EIR. Note that it is possible for the EIR to include significant findings that were not listed on the Form 483. Then, depending on your EIR classification, you will receive one of the following types of letters:

•  No Action Indicated (NAI) - No significant deviations were found. No response is necessary.

•  Voluntary Action Indicated (VAI) - Identifies deviations from regulations. Voluntary action is sufficient. A VAI letter may or may not require a response.

•  Official Action Indicated (OAI) - Identifies serious deviations from regulations. These are also called “Warning Letters” and they require a prompt, formal, written response. OAI letters may result in other regulatory or administrative actions such as disqualification or restriction from conducting FDA-regulated clinical trials. In very rare and serious cases, the clinical investigator may even be prosecuted.

Check with the various stakeholders to determine whether they need copies of the FDA correspondence, including the completed Form 483, the EIR, and your response letters. Remember:

General advice for study staff: