- General Instructions
- All inspections of sponsors, CROs, and monitors are to be conducted without
prior notification unless otherwise instructed by the assigning Center.
- 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 CDRHs Office of Device Evaluation of the withdrawal of approval by an IRB.
- If significant violative practices are encountered, the assigning Center should be
notified and will provide guidance on continuing the inspection.
- 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.
- 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.
- Establishment Inspections
- Organization and Personnel
- Determine
the overall organization of the clinical research activities and
monitoring of the selected studies.
- Obtain
relevant organizational charts that document structure and responsibilities
for all activities involving investigational products.
- 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.
- Determine
who has the authority to review and approve study reports and data
listings.
- Determine
who is responsible for final evaluations and decisions in the review of
adverse experiences.
- 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.
- When a sponsor transfers responsibility for their obligations to a CRO:
- 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).
- Document
any instance where transfer of responsibilities was not reported to the
agency.
- Obtain
a copy of any written agreement transferring responsibilities.
- 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.
- Obtain
a list of all monitors (for the studies being inspected) along with their job
descriptions and qualifications.
- Selection and Monitoring of Clinical Investigators
- 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.
- 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
sponsors criteria for selecting clinical investigators.
- 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.
- 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.
- 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).
- Identify any non-compliant clinical investigator not brought into compliance and not
terminated by the sponsor. Determine the reason they were not terminated.
- Selection of Monitors
- Review
the criteria for selecting monitors and determine if monitors meet
those criteria.
- 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.
- Monitoring Procedures and Activities
- Procedures
- 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.)
- Obtain
a copy of the sponsors 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.
- Activities
- Review
pre-trial and periodic site-visit reports.
- Determine
if the sponsor assured, through documentation, that the clinical
investigation was conducted in accordance with protocols submitted to FDA.
- 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).
- Review of Subject Records
- Compare
individual subject records, supporting documents and source documents with
case report forms (CRFs) prepared by the clinical investigator for submission to the
sponsor.
- Determine
if, when, and by whom CRFs are verified against supporting documents
(hospital records, office charts, laboratory reports, etc.) at the study site.
- Determine
if all CRFs are verified. If a representative sample was selected, determine
how the size and composition of the sample was selected.
- 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.
- Determine
how the sponsor assures that IRB approval is obtained prior to the
enrollment of subjects in the study.
- Determine
how the sponsor assures that informed consent is obtained from all
subjects in the study.
- 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 investigators participation in
the investigation and reported it to FDA.
- Determine
if the sponsor makes corrections to CRFs and if the sponsor obtains
confirmation or verification from the clinical investigator.
- If sponsor-generated, site-specific data tabulations are provided by the assigning
Center, compare the tabulations with CRFs and source documents.
- 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.
- Determine
if the firm conducts QA inspections and audits.
- Determine
how the QAU is organized and operates.
- Obtain
a copy of any written procedures (SOPs and guidelines) for QA audits and
operation of the QAU.
- Describe the separation of functions between the QAU and monitoring of clinical trials.
- 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 sponsors
records.
- Adverse Experience/Effects Reporting
- Regulations require that FDA be promptly notified of unanticipated adverse
experiences/effects with the use of investigational articles.
- 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.
- 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.
- Devices 812.150(b)(1) Within 10 working
days of unanticipated adverse device effects.
Determine if adverse experiences reported from clinical sites were relayed to FDA as
required by regulation.
Determine the sponsor's method or system for tracking adverse reactions and for
relaying information of adverse experiences to participating investigators.
Obtain copies of any notification to investigators relating to adverse experiences.
Data Collection and Handling
- Study Tabulations
- 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)).
- Obtain a list of all clinical studies contained in the application(s) referenced in
the inspection assignment.
- Identify any studies not included in the NDA/PMA and document the reason they
were not included.
- Investigator Tabulations
- 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)).
- Review all signed agreements submitted to the associated IND/IDE.
- Identify any clinical investigators with signed agreements not included in the
NDA/PMA and document the reason they were not included.
- Data Tabulations
- 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)).
- 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.
- Data Collection and Handling Procedures
- 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).
- Verify that the procedures were followed and document any deviations.
- Record Retention
- Refer to 21 CFR 312.57, 511.1(b)(7)(ii), and 812.140(d)
- Automated Entry of Clinical Data
In August 1997, the Agencys 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 firms 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.
- Software
- Who designed and developed the software?
- Can it be modified, or has it been modified? If so, by whom?
- If the clinical investigator can modify it, how would the sponsor be aware of any
changes?
- Has the software been validated? Who validated the software? What was the process used
to validate the software? How was the validation process documented?
- Are error logs maintained (for errors in software and systems) and do they identify
corrections made?
- Data Collection
- Who is authorized to access the system and enter data or change data?
- 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?
- Is there an audit trail to record:
- changes to electronic records,
- who made the change, and
- when the change was made?
- Are there edit checks and data logic checks for acceptable ranges of values?
- How are the data transmitted from the clinical investigator to the sponsor or CRO?
- Computerized System Security
- 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?
- What methods are used to access computerized systems, e.g., identification code/password
combinations, tokens, biometric signatures, electronic signatures, digital signatures?
- How are the data secured in case of disasters, e.g., power failure? Are there
contingency plans and backup files?
- Are there controls in place to prevent, detect, and mitigate effects of computer viruses
on study data and software?
- 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?
- Procedures
Are there written procedures for software validation, data collection, and computerized
system security?
- Test Article
- Integrity
- Describe the procedures the sponsor uses to ensure the integrity of the test article
from manufacturing to receipt by the clinical investigator:
- Determine if the test article met required release specifications by review of the
Certificate of Analysis.
- Determine where the test article was stored and if the conditions of storage were
appropriate.
- Determine how the sponsor verifies article integrity during shipment to the clinical
investigator.
- Determine if test article was properly labeled (See 312.6, 511.1(b)(1), and 812.5).
- Determine if the test article was recalled, withdrawn, or returned.
- Accountability
- Determine whether the sponsor maintains accounting records for use of the test
article including:
- 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).
- Shipment date(s), quantity, batch or code mark, or other identification number for test
article shipped. See regulations above.
- Final disposition of the test article. See 312.59, 511.1(b)(7)(ii), and 812.140(b)(2).
- 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.
- Determine whether the sponsors records are sufficient to reconcile test
article usage (compare the amount shipped to the investigators to the amount used and
returned or disposed of).
- 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.
- If the test article was not returned to the sponsor, describe the method of
disposition and determine if adequate records were maintained.
- Determine how the sponsor controls and monitors the use of devices that are not
single-use products, such as lithotripters or excimer lasers.
- Determine if the sponsor is charging for the test article and document the
fees charged.
- Sample Collection
- Samples may be obtained at the direction of the assigning Center.
- During the inspection, if collection appears warranted, contact the assigning Center for
further instructions.
- 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.
- Full Reporting
- A full report will be prepared and submitted in the following situations:
- The initial inspection of a firm.
- All inspections that may result in an OAI classification.
- Any assignment specifically requesting a full report.
- 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.
- Abbreviated Reporting
- 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.
- The report should include all the headings described in IOM section 593.1 and include:
- Reason for inspection
- Prior inspectional history
- Updated history of business
- Administrative procedures
- Persons interviewed and individual responsibilities
- Areas covered during the inspection
- Discussion with management
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