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PART III – INSPECTIONAL

1. General Instructions
1. All inspections of sponsors, CROs, and monitors are to be conducted without prior notification unless otherwise instructed by the assigning Center.
2. Each inspection will consist of a comparison of the practices and procedures of sponsors, CROs, and monitors to the commitments made in the application for investigational exemption (including 510(k)), and applicable regulations and guidelines as instructed by the report formats in the attachments. Use the firm's copy of the application to compare with actual practices.

DEVICES ONLY: Requests for inspections from CDRH normally involve Significant Risk (SR) devices that require full compliance with the Investigational Device Exemption (IDE) requirements. In addition to covering the identified SR device, the investigator should determine whether the sponsor/monitor is involved in clinical investigations of Non-significant Risk (NSR) devices, which require compliance with the abbreviated IDE requirements of 21 CFR 812.5, 812.7, 812.46, 812.140(b)(4) and (5), 812.150(b)(1) through (3) and (5) through (10). When appropriate, the investigator should choose at least one (1), but no more then three (3), NSR device investigations to determine the level of compliance with the abbreviated requirements.

Determine whether the sponsor/monitor is involved in any clinical studies involving the humanitarian use of a device described in 21 CFR Part 814 Subpart H. Determine whether the sponsor has submitted any Humanitarian Device Applications Exemptions. Review distribution records for humanitarian use devices at the sponsor site to ensure compliance with exemption criterion (<4000 patients/year), proper accountability, confirmation of institutional review board (IRB) approval prior to distribution, and prompt notification to CDRH’s Office of Device Evaluation of the withdrawal of approval by an IRB.

3. If significant violative practices are encountered, the assigning Center should be notified and will provide guidance on continuing the inspection.
4. If access to records or copying records is refused, or if actions by the inspected party take the form of a partial refusal, call attention to 301(e) and 505(k)(2) of the Act. If this does not resolve the issue, proceed with the inspection and at the earliest opportunity notify the Bioresearch Monitoring Program Coordinator (HFC-230) and the contact for the assigning Center. IOM Section 514 provides general guidance on dealing with refusal to permit inspection.
5. Issue a Form FDA 483, Inspectional Observations, at the conclusion of the inspection when deviations from regulations are observed. Deviations from guidance documents should not be listed on the FDA 483. However, they should be discussed with management and documented in the EIR.
1. Establishment Inspections
1. Organization and Personnel
1. Determine the overall organization of the clinical research activities and monitoring of the selected studies.
2. Obtain relevant organizational charts that document structure and responsibilities for all activities involving investigational products.
1. Identify all departments, functions, and key individuals responsible for areas of sponsor activities such as protocol development, selection of investigators, statistical analysis, clinical supplies, monitoring, and quality assurance.
2. Determine who has the authority to review and approve study reports and data listings.
3. Determine who is responsible for final evaluations and decisions in the review of adverse experiences.
3. Obtain a list of outside services and contractors (CROs, laboratories, IRBs) and document the services they provide and who is responsible for their selection and oversight.
1. When a sponsor transfers responsibility for their obligations to a CRO:
1. Determine if the transfer of responsibilities was submitted to the agency as required by 21 CFR 312.23(a)(1)(viii), 314.50(d)(5)(x), 511.1(b)(4)(vi), and 514.1(a)(8)(viii).
2. Document any instance where transfer of responsibilities was not reported to the agency.
3. Obtain a copy of any written agreement transferring responsibilities.
2. If a CRO is contracted to collect adverse experience reports from clinical investigators, determine who at the sponsoring firm is responsible for obtaining these reports and submitting them to FDA.
4. Obtain a list of all monitors (for the studies being inspected) along with their job descriptions and qualifications.
2. Selection and Monitoring of Clinical Investigators
1. Obtain a list of all investigators and determine if there is a FDA 1572 (21 CFR 312.53(c)(I)) or a signed investigator agreement (21 CFR 812.20(b)(4)&(5)) for each clinical investigator identified.
2. Regulations require that the sponsor select clinical investigators qualified by training and experience (21 CFR 312.53(a), 511.1(b)(7)(I), and 812.43(a)). Determine the sponsor’s criteria for selecting clinical investigators.
3. Determine if the sponsor provided the investigator all necessary information prior to initiation of the clinical trial. This may include clinical protocols or investigational plans, labeling, investigator brochures, previous study experience, etc.
4. Determine if the sponsor identified any clinical investigators who did not comply with FDA regulations. Did the sponsor secure prompt compliance? Obtain evidence of prompt correction or termination by the sponsor.
5. Identify any clinical investigators whose studies were terminated and the circumstances. Review monitoring reports for those clinical investigators and determine if those instances were promptly reported to FDA as required by 21 CFR 312.56(b) and 812.43(c)(3).

 

6. Identify any non-compliant clinical investigator not brought into compliance and not terminated by the sponsor. Determine the reason they were not terminated.
3. Selection of Monitors
1. Review the criteria for selecting monitors and determine if monitors meet those criteria.
2. Determine how the sponsor allocates responsibilities when more than one individual is responsible for monitoring functions, e.g., a medical monitor may have the responsibility for medical aspects of the study (and may be a physician) while other monitors may assess regulatory compliance.
4. Monitoring Procedures and Activities
1. Procedures
1. Review the procedures, frequency, scope, and process the sponsor uses to monitor the progress of the clinical investigations. (Device regulations (21 CFR 812.25(e)) require written monitoring procedures as part of the investigational plan.)
2. Obtain a copy of the sponsor’s written procedures (SOPs and guidelines) for monitoring and determine if the procedures were followed for the selected study. In the absence of written procedures, conduct interviews of the monitors as feasible and determine how monitoring was conducted.
2. Activities
1. Review pre-trial and periodic site-visit reports.
2. Determine if the sponsor assured, through documentation, that the clinical investigation was conducted in accordance with protocols submitted to FDA.
3. Determine if responsibilities of the clinical investigators were carried out according to the FDA regulatory requirements (21 CFR 312.60, 312.61, 312.62, 312.64, 312.66, 312.68, 812.46, 812.100, and 812.110).
3. Review of Subject Records
1. Compare individual subject records, supporting documents and source documents with case report forms (CRFs) prepared by the clinical investigator for submission to the sponsor.
2. Determine if, when, and by whom CRFs are verified against supporting documents (hospital records, office charts, laboratory reports, etc.) at the study site.
3. Determine if all CRFs are verified. If a representative sample was selected, determine how the size and composition of the sample was selected.
4. Determine if a form is used for data verification and obtain a copy. Obtain a copy of any written procedures (SOPs and guidelines) for data verification.
5. Determine how the sponsor assures that IRB approval is obtained prior to the enrollment of subjects in the study.
6. Determine how the sponsor assures that informed consent is obtained from all subjects in the study.
7. Determine how the sponsor handles serious deviations from the approved protocol or FDA regulations. If serious deviations occurred, obtain evidence that the sponsor obtained prompt compliance or terminated the clinical investigator’s participation in the investigation and reported it to FDA.
8. Determine if the sponsor makes corrections to CRFs and if the sponsor obtains confirmation or verification from the clinical investigator.
9. If sponsor-generated, site-specific data tabulations are provided by the assigning Center, compare the tabulations with CRFs and source documents.
4. Quality Assurance (QA)

Clinical trial quality assurance units (QAUs) are not required by regulation. However, many sponsors have clinical QAUs that perform independent audits/data verifications to determine compliance with clinical trial SOPs and FDA regulations. QAUs should be independent of, and separate from, routine monitoring or quality control functions.

Findings that are the product of a written program of QA will not be inspected without prior concurrence of the assigning FDA headquarters unit. Refer to Compliance Policy Guide 7151.02 for additional guidance in this matter.

1. Determine if the firm conducts QA inspections and audits.
2. Determine how the QAU is organized and operates.
3. Obtain a copy of any written procedures (SOPs and guidelines) for QA audits and operation of the QAU.
4. Describe the separation of functions between the QAU and monitoring of clinical trials.
5. Sponsors are required to submit a list of audited studies (21 CFR 314.50(d)(5)(xi)). If the assigning Center provides the list, compare the list with the sponsor’s records.
5. Adverse Experience/Effects Reporting
1. Regulations require that FDA be promptly notified of unanticipated adverse experiences/effects with the use of investigational articles.
1. Drugs/biologics 312.32(c) and (d) - Telephone within 7 calendar days if fatal or life threatening; written reports within 15 calendar days if both serious and unexpected.
2. Veterinary drugs 511.1(b)(8)(ii) - Promptly investigate and report any findings associated with use of the new animal drug that may suggest significant hazards.
3. Devices 812.150(b)(1) – Within 10 working days of unanticipated adverse device effects.
2. Determine if adverse experiences reported from clinical sites were relayed to FDA as required by regulation.
3. Determine the sponsor's method or system for tracking adverse reactions and for relaying information of adverse experiences to participating investigators.
4. Obtain copies of any notification to investigators relating to adverse experiences.

 

6. Data Collection and Handling
1. Study Tabulations
1. Sponsors are required to submit in an NDA/PMA analyses of all clinical studies pertinent to the proposed drug/device use (21 CFR 314.50(d)(5)(ii-iv) and 814.20(b)(3)).
1. Obtain a list of all clinical studies contained in the application(s) referenced in the inspection assignment.
2. Identify any studies not included in the NDA/PMA and document the reason they were not included.
2. Investigator Tabulations
1. Sponsors are required to obtain from each clinical investigator a signed agreement (form FDA 1572 for human drugs and biologics and an investigator agreement for devices) prior to initiation of the clinical trial (21 CFR 312.60 and 812.43 (a)).
1. Review all signed agreements submitted to the associated IND/IDE.
2. Identify any clinical investigators with signed agreements not included in the NDA/PMA and document the reason they were not included.
3. Data Tabulations
1. FDA regulations require that sponsors submit data tabulations on each subject in each clinical trial in an NDA/PMA (21 CFR 314.50(f)(1) and 814.20(b)(6)(ii)).
1. Determine if the number of subjects in the studies performed under an IND/IDE is the same as the number reported in the NDA/PMA.
• Determine the number of subjects listed in each of the clinical trials and compare the number of subjects in the tabulations to the corresponding CRFs submitted to the sponsor.
• Document any subjects not included in the NDA/PMA and the reason they were not included.
2. Data Collection and Handling Procedures
1. Review the sponsor's written procedures (SOPs and guidelines) to assure the integrity of safety and efficacy data collected from clinical investigators (domestic and international).
2. Verify that the procedures were followed and document any deviations.
2. Record Retention
1. Refer to 21 CFR 312.57, 511.1(b)(7)(ii), and 812.140(d)
3. Automated Entry of Clinical Data

In August 1997, the Agency’s regulation on electronic signatures and electronic recordkeeping became effective. The Regulation, at 21 CFR Part 11, describes the technical and procedural requirements that must be met if a firm chooses to maintain records electronically and/or use electronic signatures. Part 11 works in conjunction with other FDA regulations and laws that require recordkeeping. Those regulations and laws ("predicate rules’) establish requirements for record content, signing, and retention.

Certain older electronic systems may not have been in full compliance with Part 11 by August 1997 and modification to these so called "legacy systems" may take more time. Part 11 does not grandfather legacy systems and FDA expects that firms using legacy systems are taking steps to achieve full compliance with Part 11.

If a firm is keeping electronic records or using electronic signatures, determine if they are in compliance with 21 CFR Part 11. Determine the depth of part 11 coverage on a case by case basis, in light of initial findings and program resources. At a minimum, ensure that: (1) the firm has prepared a corrective action plan for achieving full compliance with part 11 requirements, and is making progress toward completing that plan in a timely manner; (2) accurate and complete electronic and human readable copies of electronic records, suitable for review, are made available; and, (3) employees are held accountable and responsible for actions taken under their electronic signatures. If initial findings indicate the firm’s electronic records and/or electronic signatures may not be trustworthy and reliable, or when electronic recordkeeping systems inhibit meaningful FDA inspection, a more detailed evaluation may be warranted. Districts should consult with center compliance officers and the Office of Enforcement (HFC-240) in assessing the need for and potential in depth review of, more detailed part 11 coverage. When substantial and significant part 11 deviations exist, FDA will not accept use of electronic records and electronic signatures to meet the requirements of the applicable predicate rule. See Compliance Policy Guide (CPG), Sec. 160.850.

The following are basic questions to be evaluated during an inspection of electronic recordkeeping practices and the use of electronic signatures by sponsors, CROs, and monitors.

Primary raw data collection should be reviewed to determine when changes were made and by whom. Concentrate on any original data entries and changes that can be made by anyone other than the clinical investigator.

1. Software
1. Who designed and developed the software?
2. Can it be modified, or has it been modified? If so, by whom?
3. If the clinical investigator can modify it, how would the sponsor be aware of any changes?
4. Has the software been validated? Who validated the software? What was the process used to validate the software? How was the validation process documented?
5. Are error logs maintained (for errors in software and systems) and do they identify corrections made?

 

2. Data Collection
1. Who is authorized to access the system and enter data or change data?
2. Are original data entered directly into an electronic record at the time of collection or are data transcribed from paper records into an electronic record?
3. Is there an audit trail to record:
1. changes to electronic records,
2. who made the change, and
3. when the change was made?
4. Are there edit checks and data logic checks for acceptable ranges of values?
5. How are the data transmitted from the clinical investigator to the sponsor or CRO?
3. Computerized System Security
1. How is system access managed, e.g., access privileges, authorization/deauthorization procedures, physical access controls? Are there records describing the names of authorized personnel, their titles, and a description of their access privileges?
2. What methods are used to access computerized systems, e.g., identification code/password combinations, tokens, biometric signatures, electronic signatures, digital signatures?
3. How are the data secured in case of disasters, e.g., power failure? Are there contingency plans and backup files?

 

4. Are there controls in place to prevent, detect, and mitigate effects of computer viruses on study data and software?
5. Are controls in place to prevent data from being altered, browsed, queried, or reported via external software applications that do not enter through the protective system software?
4. Procedures

Are there written procedures for software validation, data collection, and computerized system security?

4. Test Article
1. Integrity
1. Describe the procedures the sponsor uses to ensure the integrity of the test article from manufacturing to receipt by the clinical investigator:
1. Determine if the test article met required release specifications by review of the Certificate of Analysis.
2. Determine where the test article was stored and if the conditions of storage were appropriate.
3. Determine how the sponsor verifies article integrity during shipment to the clinical investigator.
2. Determine if test article was properly labeled (See 312.6, 511.1(b)(1), and 812.5).
3. Determine if the test article was recalled, withdrawn, or returned.

 

2. Accountability
1. Determine whether the sponsor maintains accounting records for use of the test article including:
1. Names and addresses of clinical investigators receiving test articles (report names and addresses). See 312.57, 511.1(b)(3), and 812.140(b)(2).
2. Shipment date(s), quantity, batch or code mark, or other identification number for test article shipped. See regulations above.
3. Final disposition of the test article. See 312.59, 511.1(b)(7)(ii), and 812.140(b)(2).
4. Final disposition of food-producing animals treated with the test article (511.1(b)(5).

A detailed audit should be performed when serious violations are suspected.

2. Determine whether the sponsor’s records are sufficient to reconcile test article usage (compare the amount shipped to the investigators to the amount used and returned or disposed of).
3. Determine whether all unused or reusable supplies of the test article were returned to the sponsor when either the investigator(s) discontinued or completed participation in the clinical investigation, or the investigation was terminated.
4. If the test article was not returned to the sponsor, describe the method of disposition and determine if adequate records were maintained.
5. Determine how the sponsor controls and monitors the use of devices that are not single-use products, such as lithotripters or excimer lasers.
6. Determine if the sponsor is charging for the test article and document the fees charged.

 

5. Sample Collection
1. Samples may be obtained at the direction of the assigning Center.
2. During the inspection, if collection appears warranted, contact the assigning Center for further instructions.
6. Establishment Inspection Reports (EIRs)

Information contained in EIRs may be used in support of approval or denial of a pre-marketing application. The EIR must document all findings that could significantly impact the decision-making process.

1. Full Reporting
1. A full report will be prepared and submitted in the following situations:
1. The initial inspection of a firm.
2. All inspections that may result in an OAI classification.
3. Any assignment specifically requesting a full report.
2. The EIR should contain the headings described in IOM 593.3, in addition to the headings outlined in Part III, B. The report must always include sufficient information and documentation to support the recommended classification.
2. Abbreviated Reporting
1. An abbreviated report may be submitted in all but the above situations. An abbreviated report does not mean that an abbreviated inspection can be conducted. Abbreviated reports must contain sufficient narrative and accompanying documentation to support the inspectional findings. The specific headings appearing under Part III, Inspection Procedures should be fully addressed during the inspection. The EIR should be clearly identified as an abbreviated report.

 

2. The report should include all the headings described in IOM section 593.1 and include:
1. Reason for inspection
2. Prior inspectional history
3. Updated history of business
4. Administrative procedures
5. Persons interviewed and individual responsibilities
6. Areas covered during the inspection
7. Discussion with management

 

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