FDA’s Compliance Program Manual provides Inspectors with instructions for evaluating industry compliance with regulations and Good Clinical Practice (GCP). Among other activities, the FDA Bioresearch Monitoring (BIMO) Program involves site visits to clinical investigators, sponsors, monitors, contract research organizations, nonclinical (animal) laboratories, and bioequivalence analytical laboratories. FDA developed the BIMO Program to help ensure the protection of the rights, safety, and welfare of human research subjects involved in FDA- regulated clinical trials, to verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications. Data collected in the clinical investigation and used for Investigational New Drug Application(IND)/ or Investigational Device Exemption (IDE) are frequently targeted by FDA. Important parameters of studies chosen are time lapse since initiation of the study and the nature of the medical product or medical product with a new intended use. An FDA Inspection usually occurs within 6 months of a regulatory submission (IND/IDE submission). On average, FDA will inspect 3 clinical investigation sites per study and the Inspector will stay 3-5 days at the site during routine business hours. Upon an inspection the FDA inspector will send a “Notice of Inspection” FDA 482 Form to the Clinical Investigator or appropriate study staff.
The FDA Inspection Process will follow applicable laws, regulations, and guidelines such as:
- Federal Food, Drug, and Cosmetic Act
- Code of Federal Regulations
- Title 21 – Food & Drugs Good Clinical Practice, Parts 11, 50, 54, 56, 803, 812, 814
- ICH E6-R2 Good Clinical Practice
- FDA Compliance Program Guidance Manuals
- Clinical Investigators CP 7348.811
The FDA inspection process largely consists of two activities:
- Review of documents
Inspectors are trained in interviewing techniques and may ask different staff members the same questions to determine if they receive conflicting answers.They will assess both verbal and non verbal (body language) communication to help evaluate the information provided by the interviewee. The Inspectors are generally non-accusatory and conversational in questions & answers and are focussed on fact finding. During For-Cause inspections the Inspector may use accusatory methods. The Inspection may be conducted by one or more FDA inspectors of varying experience and/or areas of expertise.
During the review of documents the inspectors will concentrate on:
- Policies and Standard Operative Procedures (SOP)
- Memos to File
- Adverse Event
- IRB/EC communication
- Source documents and medical records
- Good clinical documentation
The Investigator must provide access for the Inspector to access, copy and verify any records or reports made by the clinical investigator with regard to, among other records, the disposition of the investigational product and the subjects care history. In order to prepare a clinical investigation for an FDA inspection it is recommended to put focus on the following:
Documentation: What isn’t documented didn’t happen. Patient binder should tell the story of the subjects participation in the clinical investigation.
Signature/ delegation logs: Should identify that each site study staff member & their responsibilities are present. Should ensure that all study related tasks has been carried out by qualified individuals.
Established policies and procedures: Site has a Quality Management System (QMS) and SOP’s and hospital policies are followed as required .
Investigational site: Site is aware and fulfills its obligations associated with the conduct of Clinical Research and GCP.
Integrity and validity: Proof of the data collected can be demonstrated.
Screening/enrollment logs: Sequentially identifying each person screened for the study, their enrollment status and reason(s) for exclusion, if applicable. Screening procedures are followed as per protocol.
Review and preparation of the following study documents are recommended:
- Regulatory documents binder
- IRB/IEC submissions, approvals, reports
- Consent versions
- Investigational product accountability records
- Delegation of Authority
- Source Documentation and patient binder
- Records supporting eligibility criteria
- Key study activities
- Protocol deviations
- Demonstrate the PI was in control of the study
When a site is planning the FDA inspection the following dates are important:
- IRB/IEC approvals
- When the Investigator Agreement was signed
- First subject screened
- First subject signed the informed consent document
- First administration of investigational product
- Last follow-up for any study subject
Once the FDA inspector arrives at site he/she will want to know the address of all locations at which the study is performed. Inspector might ask Sponsor to provided the following documents:
Investigator Agreement: Signed before the study is initiated.
Financial Disclosure: Has the investigators disclosed information regarding his/hers financial interests to the Sponsor.
List of delegated tasks/delegation log: Determine if study responsibilities were properly delegated and study related tasks are performed by a delegated person on the log.
Qualifications and training: Check if individuals performing delegated tasks are trained and qualified.This can be done by verifying CV, Job descriptions, GCP certification with dated signatures and a training logs. CV’s and GCP certifications has to be updated every 2. year.
Clinical Investigation Protocol (CIP): Protocol changes, and approvals, determine whether changes were documented, dated, maintained, EC-approved and reported to sponsor.
Protocol deviations: Are protocol deviations documented and reported appropriately.
Subject Recruitment and Compliance: Recruitment materials used are reviewed and approved by the IRB/IEC. Screening procedure are followed as described in the CIP. Document that the subjects met the study enrollment criteria’s.
Site’s enrollment log: List of all enrolled subjects
Screening failures: List of all screening failures
Subject Records: Subject records/patient binders should be Attributable Legible Complete Original Accurate (ALCOA). Compare source documents to CRFs: medical history, eligibility criteria, lab testing, adverse experiences, concomitant therapy, concurrent illness.
Informed Consent of Human Subjects: Was the correct consent used?, Was the right version used?, Verify that subject consented prior to study procedures, description of the consent administration process (Who, How, When) and document the consent process.
IRB/IEC documentation: Approval of the protocol and any amendments. Approval of Informed consent documents. Approval of advertisements and other information provided to prospective study subjects. All approvals must be in place before initiation of study-specific procedures on subjects and that has to be documented.
(S)AE reporting: (S)AE has been reported according to the CIP, local law and GCP.
Investigational Product accountability: Provide evidence of control of the investigational device used for the clinical study. Provide a detailed log of device shipment, use, return, or disposal, storage areas and conditions.
Record retention: Determine who maintains custody of records, means of prompt access, verify proper length of document retention.
Electronic records and signatures: (Verify 21 CFR Part 11 Complian, computer systems and security, installation, training, computer access, maintenance, upgrades, problems, data entry –who & how, data corrections, Audit trails, data submission.
Adapted from – FDA-Guidance for Industry- computerized systems used in Clinical Trials: http://www.fda.gov/downloade/ICECI/EnforcementActions/BioresearchMonitoring/UCM133749.pdf
The FDA inspector also may audit the study data by comparing the data filed with the FDA in the IND/IDE application, with records related to the clinical investigation at site. Those records may include the case report forms and supporting source documentation including signed and dated consent forms and medical records. This also include the physicians progress note/physical examination, the subject’s hospital chart(s), and the nurses’ notes. These records should be in hard copy and electronical format. The FDA inspector may also examine subjects’ medical records that are part of the clinical investigation and predate the study to verify whether the condition under study was in fact diagnosed, the study eligibility criteria were met, and whether the subject received any potential interfering medication prohibited by the protocol.
If a clinical investigator conducts a study under an IND/IDE, the clinical investigation is subject to FDA regulations, including applicable provisions in 21 CFR parts 50, 56 and 312. FDA will validate the authenticity and accuracy of data and confirms compliance during an inspection, which is listed above. The FDA inspector may also request documentation as to whether the study was conducted under local laws and regulations and the Declaration of Helsinki.
So what happens after an Inspection?
At the end of an inspection a close out meeting will take place with the investigator or his/hers representative. The FDA inspector will review and discuss the findings from the inspection and, if deficiencies were found, issue a written Form FDA 483 (Inspectional Observations; 483) to the clinical Investigator. Following the inspection the FDA inspector prepares a written Establishment Inspection Report (EIR). The EIR are forwarded to the appropriate FDA Center for further evaluation and final classification of the inspection outcome. After this review , one of the following letters is typically sent from the appropriate FDA Center to the Investigator:
1. A letter that generally states that FDA observes basic compliance with pertinent regulations.
2. An Informed or Untiled Letter that identifies deviations from status and regulations that do not meet the threshold of regulatory significance for a Warning Letter. Generally such letter may request a written response from the clinical investigator.
3. A Warning Letter that identifies serious deviations from applicable status and regulations. A Warning Letter is issued for violations of regulatory significance. Significance violations are those that may lead to enforcement action if not promptly and adequately corrected.
4. A Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). FDA may initiate a process to disqualify the clinical investigation, if the investigator has repeatedly or deliberately failed to comply with applicable requirements or has deliberately or repeatedly submitted false information to the Sponsor or FDA in any required report. The NIDPOE provides the investigator with an opportunity to explain the matter at an informal conference or in writing. If the investigator provides an explanation that is accepted by the agency and the disqualification is not warranted, alternative such as a corrective action plan may be considered. If the investigator explanation is not accepted by the agency, the agency may issue a Notice Opportunity for Hearing (NOOH).
Following a final classification of the inspection by the FDA Center, the inspection results are shared with the FDA division assigned to review the marketing submission (IND/IDE). The assigned review division considers the results of the inspection during its review of the Sponsor’s marketing submission. If the inspection revealed serious violation the review division may reject the affected data as unreliable. All inspection classifications will posted on the FDA website: http://www.fda.gov/ICECI/ComplianceManuals/RegulatoryProceduresMaunal/ucm176870.htm
How can Qmed help?
In the past several years FDA has been more aggressive and active in conduction FDA Inspections on clinical investigations. FDA’s inspection of clinical investigators is not limited to the United States (U.S.). In order to provide your investigational site from receiving Warning Letters the processes of conducting a clinical investigation should always be prioritized and in focus. At Qmed Consulting we can work with the investigator and site on a daily basis to make sure that your clinical investigation is always ready for an FDA inspection. We have the capability to identify any findings that need to be solved prior to an FDA inspection and to train investigator and site in FDA readiness.
FDA compliance program manual for CDRH can be found here: https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/MedicalDeviceQualityandCompliance/ucm248922.htm