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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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PART III – INSPECTIONAL

Inspections involve evaluation of the sponsor’s/CRO’s/monitor’s practices and procedures to determine compliance with applicable regulations.

A. GENERAL

The following pertain to all inspections.

1. Sponsor, CRO, and monitor inspections are product type-specific, i.e., human drugs and biologics, animal drugs, medical devices, or foods. Field investigators must apply the pertinent regulations to each inspection.

2. Inspections under this program will be pre-announced unless otherwise instructed in the inspection assignment. The field investigator should keep the time span between initial contact and actual inspection as short as possible. The field investigator should immediately report to the Center contact any attempt by the sponsor/CRO/monitor to unduly delay an inspection, by more than ten working days, without sufficient justification.

3. Inspection Refusals

a. Refusal of entry

If a sponsor/CRO/monitor refuses to permit an inspection by FDA personnel, the field investigator should inform the sponsor/CRO/monitor of the agency’s legal authority 2 to conduct such inspections. If entry is still refused, the investigator should issue the completed Form FDA 482 (Notice of Inspection) to the most responsible person available and leave the premises. The investigator should immediately notify his/her supervisor, the District Compliance Officer, the assigning Center contact, and DDFI of this refusal.

b. Refusal of Information

If at any time during the inspection, the sponsor/CRO/monitor refuses to allow FDA personnel access to or copying of records to which FDA is entitled under the law and regulations, the field investigator should inform the sponsor/CRO/monitor about the agency’s legal authority 3 to access the information. If access to or copying is still refused, the field investigator should continue with the inspection and notify his/her supervisor, the District Compliance Officer, the assigning Center contact and DDFI. The same procedure should be followed when it becomes evident that delays by the sponsor/ CRO/monitor are such that they constitute a de facto (i.e., actual) refusal.

When a refusal of entry or refusal to supply necessary information cannot be resolved by the assigning Center contact or DDFI, and it is deemed necessary to pursue an inspection warrant, follow the procedures in the Regulatory Procedures Manual, Section 6-3, Inspection Warrants, and notify the Division of Compliance Management and Operations (DCMO, HFC-210).

4. Each inspection will consist of an evaluation of the practices and procedures of sponsors, CROs, and monitors in the particular study(s), using the investigational plan in the research or marketing application/submission, applicable regulations, and any specific directives in the inspection assignment.

5. Field investigators who observe or suspect deviations from the regulations that affect data integrity or endanger subject rights, safety, or welfare should immediately discuss their observations with their supervisor, District Compliance Officer, and the assigning Center contact and continue the inspection. The assigning Center will promptly determine if the inspection should be expanded or modified and provide direction on how to proceed in order to obtain appropriate documentation for the noted observations.

6. The field investigator issues a 483 at the conclusion of the inspection when deviations from regulations are observed. Inspectional observations listed on the 483 must be based on the regulations. Approaches that differ from those described in FDA's guidance documents should not be listed on the 483 unless they constitute deviations from the regulations. Observed deviations from guidance may be discussed with the sponsor/CRO/monitor during the exit interview, however, and reported in the EIR. The field investigator encourages the sponsor/ CRO/monitor to submit a prompt written response to the District Office and Center regarding any inspection observations listed on the 483.

B. INSPECTION PROCEDURES

The Center may provide background information and special instructions with the inspection assignment. The following outline provides only the minimum scope of the inspection, and each field investigator should expand the inspection as the circumstances warrant. Inspections should be sufficient in scope to cover special instructions in the assignment and to determine if the sponsor’s/CRO’s/monitor’s practices and procedures comply with the appropriate regulations. The field investigator should not attempt to scientifically evaluate the study data or protocol(s).

Any deviations from regulations should be thoroughly documented. For example, if the sponsor failed to review monitoring reports in a timely fashion and/or failed to bring non- compliant clinical investigators into compliance, monitoring reports, report review dates, and evidence of clinical investigator continued non-compliance should be documented and copied. Discuss potential violations involving fraud subject to Title 18 of the United States Code (18 U.S.C.) with your supervisor, District Compliance Officer, and assigning Center contact for appropriate referral to the Office of Criminal Investigations (OCI).

C. ORGANIZATION AND PERSONNEL

1. Determine the overall organization of the clinical research activities and monitoring of theselected studies.

2. Obtain relevant organizational charts that document structure and responsibilities for allactivities involving investigational products.

a. Identify all departments, functions, and key individuals responsible for areas ofsponsor activities such as protocol development, selection of investigators, statistical analysis, clinical supplies, monitoring, and quality assurance.

b. Determine who has the authority to review and approve study reports and datalistings.

c. Determine who is responsible for final evaluations and decisions in the reviewof adverse events and safety information.

3. Obtain a list of outside services and contractors (CROs, monitors, laboratories, IRBs) and document the services they provide and who is responsible for their selection and oversight. Also document the accurate location/address of these contracted parties.

a. When a sponsor transfers responsibility for their obligations to a CRO:

i. Obtain a copy of any written agreement transferringresponsibilities. If there is a separate transfer of regulatory obligations (TORO) document, obtain a copy of it as well.

ii. Determine if the transfer of responsibilities was submitted to theagency 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). (As noted above, device regulations (21 CFR Part 812) do not provide for the transfer of regulatory obligations to CROs. Device study sponsors are therefore held responsible for any regulatory noncompliance by a CRO.)

iii. Document any instance where transfer of responsibilities was notreported to the agency.

b. If a CRO is contracted to perform an obligation of the sponsor for managing adverse event/safety information (e.g., including activities such as collecting, evaluating, or reporting such information), obtain information that identifies the responsibilities of each party.

4. Obtain a list of all monitors (for the studies being inspected) along with their jobdescriptions and qualifications.


 

D. REGISTRATION OF STUDIES ON CLINICALTRIALS.GOV

ClinicalTrials.gov is a website maintained by the National Library of Medicine (NLM). Its establishment was mandated by the 1997 FDA Modernization Act (FDAMA) to provide a public resource for information on studies of drugs, including biological drug products. The FDA Amendments Act of 2007 (FDAAA) mandated expansion of this data bank and included enforcement provisions to help ensure compliance. FDAAA requires 4 the submission of expanded information about certain clinical trials, including trial results. It also requires that a certification form (Form FDA 3674) accompany certain human drug, biological, and device product applications made to FDA. (The certification requirement went into effect on December 26, 2007.) With submission of this form, sponsors and others certify to FDA that they have complied with the statutory requirements to submit clinical trial information for inclusion in ClinicalTrials.gov. As stated in the guidance regarding this certification form 5, Form FDA 3674 is recommended to accompany the following types of applications and submissions:

  • IND
  • New Clinical Protocol submitted to an IND
  • NDA
  • Efficacy Supplement to an approved NDA
  • BLA
  • Efficacy Supplement to an approved BLA
  • ANDA
  • PMA
  • PMA Panel Track Supplement
  • HDE.

Specifics regarding ClinicalTrials.gov registration requirements are available at http://prsinfo .clinicaltrials.gov/fdaaa.html. The general requirements under FDAAA, as summarized on this website, are that a "responsible party" (i.e., the sponsor or designated principal investigator) register and report results of certain “applicable clinical trials.” Generally, applicable clinical trials, as defined in FDAAA, are:

1. For drugs and biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation.

2. For devices: Controlled trials with health outcomes of a product subject to FDA regulation (other than small feasibility studies) and pediatric post-market surveillance studies.

Applicable clinical trials must be registered within 21 days of enrollment of the first subject.

1. Determine if the sponsor/CRO has SOPs for complying with the requirements associated withClinicalTrials.gov. If so, determine if they complied with these SOPs.

2. Determine if the submission/application submitted to FDA for the study or studies beinginspected is one of the types listed above.

3. If so, determine if the study/studies was/were registered on ClinicalTrials.gov.

4. If the study/studies were registered on ClinicalTrials.gov, determine who (the sponsor or a designated clinical investigator) registered the study/studies, and the date of registration.

5. Compare the date of registration to the date of the first subject’s enrollment in the study/studies.

6. Determine whether primary and secondary outcomes measures are listed on ClinicalTrials.govfor the study/studies. Determine if the outcome measures, if any, listed on ClinicalTrials.gov are generally consistent with the primary and secondary outcomes in the sponsor’s study protocol(s).

7. When examining informed consent documents related to an applicable clinical trial registered on ClinicalTrials.gov, determine if the appropriate required statement referencing ClinicalTrials.gov is included6. 21 CFR 50.25(c). The statement is:

‘‘A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.’’

E. SELECTION AND MONITORING OF CLINICAL INVESTIGATORS

1. Obtain a list of all investigators and determine if there is a Form FDA 1572 (21 CFR312.53(c)(l) or a signed investigator agreement (21 CFR 812.43(c)) for each clinical investigator identified.

2. Regulations require that the sponsor/CRO 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/CRO’s criteria for selecting clinical investigators.

3. Determine if the sponsor/CRO provided the investigators with all necessary information prior toinitiation of the clinical trial. This may include clinical protocols or investigational plans, labeling, investigator brochures, and previous study experience.

4. Determine how the sponsor/CRO handles serious deviations from the approved investigationalplan (which includes the study protocol) or FDA regulations.

5. Determine if the sponsor/CRO/monitor identified any clinical investigators who did not complywith the investigational plan or FDA regulations. If so, did the sponsor/CRO secure prompt compliance? (When there is a CRO, determine who has the responsibility to follow up on noncompliance and secure investigator compliance, the sponsor or the CRO.) When instances of continued clinical investigator noncompliance are identified, obtain evidence of prompt correction or termination of the investigator’s participation in the study.

6. Identify any clinical investigator sites where studies were terminated and the circumstancesinvolved. 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). [Since termination of an investigator’s participation in a device study would require return or disposal of the investigational device(s), a report is likewise required under 812.150(b)(6).]

7. Identify any non-compliant clinical investigators who were neither brought into compliance norremoved from the study (participation in the study terminated) by the sponsor as required by 21 CFR 312.56(b) and 812.46(a). Determine the reason their participation in the study was not terminated.

F. SELECTION OF MONITORS

1. Review the criteria for selecting monitors and determine if monitors meet those criteria.

2. Determine how the sponsor/CRO allocates responsibilities when more than one individual isresponsible 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.

G. MONITORING PROCEDURES AND ACTIVITIES

With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive. Regulations do not prescribe a specific monitoring technique, simply stating that sponsors are required to select monitors qualified by training and experience to monitor the investigational study (21 CFR 312.53(d), 511.1(b)(8)(ii), and 812.43(d)). Reference the sponsor’s/CRO’s/monitor’s procedures (written SOPs or procedures or stated practices) for the following.

1. Procedures

a. Review the procedures, frequency, scope, and process thesponsor/CRO/monitor uses to monitor the progress of the clinical investigation. (Device regulations (21 CFR 812.25(e)) require written monitoring procedures as part of the investigational plan.)

b. Obtain a copy of the sponsor’s/CRO’s/monitor’s written procedures (SOPs andguidelines) 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/or otherwise determine how monitoring was conducted.

2. Activities

a. Review pre-trial and periodic site-visit (monitoring) reports. When reviewingmonitoring reports, determine when they were reviewed by the sponsor/CRO and, where clinical investigator noncompliance with the investigational plan or regulations was indicated, what follow-up was initiated and how quickly action was taken by the sponsor/CRO.

b. Determine if the sponsor/CRO/monitor assured, through documentation, that theclinical investigation was conducted in accordance with the investigational plan submitted to FDA.

c. Determine if there is documentation that the responsibilities of the clinicalinvestigators were carried out according to the FDA regulatory requirements (21 CFR 312.60. 312.61, 312.62, 312.64, 312.66, 312.68, (312.69 if the investigational product is a controlled substance), 812.100, 812.110, 812.140(a), (d), and (e), and 812.150(a)).

3. Review of Site Records

a. Determine if monitoring visits included a comparison of individual subject recordsand other source documents with case report forms (CRFs) submitted to the sponsor.

b. Determine if, when, and by whom CRFs are verified against supporting documents(hospital records, office charts, laboratory reports, etc.) at the study site.

c. Determine if all CRFs are verified during monitoring visits. If a representativesample was selected, determine how the size and composition of the sample were selected.

d. Determine if a form is used for data verification and obtain a copy. Obtain a copyof any written procedures (SOPs and guidelines) for data verification.

e. Determine if the sponsor/CRO/monitor, or a data management company contractedby the sponsor/CRO, makes corrections to CRFs and if confirmation or verification from the clinical investigator is obtained when such changes are made.

f. Determine how the sponsor/CRO assures that IRB approval is obtained prior to theenrollment of subjects in the study.

g. Determine how the sponsor/CRO assures that informed consent is obtained fromall subjects in the study.

h. If sponsor-generated, site-specific data tabulations are provided by the assigning Center, compare the tabulations with CRFs submitted by the clinical investigator.

H. QUALITY ASSURANCE (QA)

Clinical trial quality assurance units (QAUs) are not required by regulation. However, many sponsors obtain independent audits/data verifications to determine the sponsor’s compliance with clinical trial SOPs and FDA regulations. These audits/data verifications may be conducted with or without the existence of an actual QAU. All QAUs and/or auditing personnel should be independent of, and separate from, routine monitoring or quality control functions. Findings that are the product of a written QA program 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 sponsor/CRO conducts QA inspections and audits.

2. If the sponsor/CRO has a QAU, determine how it is organized and operates.

3. Obtain a copy of any written procedures (SOPs and guidelines) for QA audits and theoperation of any QAU.

4. Describe the separation of functions between QA auditing and monitoring of clinical trials.

5. Sponsors of drug studies 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.

I. SAFETY/ADVERSE EVENT REPORTING

1. A sponsor must notify FDA and participating investigators (in addition to reviewing IRBs for device studies) of the following types of information associated with the use of investigational articles.

a. Drugs/biologics 312.32(c) – IND safety reports of potential serious risks within 15 calendar days after the sponsor determines that the information qualifies for reporting; no later than 7 calendar days if unexpected fatal or life-threatening suspected adverse reaction; 312.32(d) follow-up reports as applicable. 7

b. Drugs in bioavailability and bioequivalence studies that are exempt from the IND requirements 320.31(d)(3) – Report any serious adverse event within 15 calendar days; if fatal or life-threatening, within 7 calendar days; follow-up reports as soon as information is available.

c. Animal drugs 511.1(b)(8)(ii) – Promptly investigate and report any findings associated with the use of the new animal drug that may suggest significant hazards.

d. Devices 812.150(b)(1) – Written report within 10 working days after the sponsor first receives notice of the unanticipated adverse device effect.

2. Determine if safety information/unanticipated adverse device effects were reported to FDAas required by regulations.

3. Determine if safety information/unanticipated adverse device effects were reported toparticipating investigators (and to reviewing IRBs for device studies) as required by the regulations.

4. Review the procedures (e.g., frequency, scope) the sponsor/CRO uses for the receipt,evaluation, and monitoring of safety information/unanticipated adverse device effects, as well as the process for updating the investigator brochure. If applicable, review the composition and function of the safety team/committee (for drugs and biologics).

Obtain copies of any notification to investigators relating to safety information/unanticipated adversedevice effects.

J. DATA COLLECTION AND HANDLING

1. Study Tabulations

a. Sponsors are required to submit analyses of all clinical studies pertinent to the proposed drug/device use in any marketing application/submission (NDA/NADA/BLA/ PMA/510(k)) that is supported by clinical data (21 CFR 314.50(d)(5)(ii-iv), 514.1(b)(8), 601.25(b)(3), 814.20(b)(3) and 807.92(b)).

i. Obtain a list of all clinical studies contained in theapplication(s)/submission(s) referenced in the inspection assignment.

ii. Identify any pertinent studies not included in the marketingapplication/submission and document the reason they were not included.

2. Investigator Tabulations

a. 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 312.53(c) and 812.43(c)).

i. Review all signed 1572s/agreements associated with the study(ies)specified in the assignment.

ii. Identify any clinical investigators with signed 1572s/agreementsnot included in the marketing application/submission and document the reason they were not included.

3. Data Tabulations

a. 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)).

i. Determine if the number of subjects in the studies performedunder an IND/IDE is the same as the number reported in the NDA/PMA.

a) Determine the number of subjects listed in each of theclinical trials and compare the number of subjects in the tabulations to the corresponding CRFs submitted to the sponsor.

b) Document any subjects not included in the NDA/PMAand the reason they were not included.

4. Data Collection and Handling Procedures

a. Review the sponsor’s written procedures (SOPs and guidelines) to assurethe integrity of safety and efficacy data collected from clinical investigators (domestic and international).

b. Verify that the procedures were followed and document any deviations.

K. RECORD RETENTION

Refer to 21 CFR 312.57(c), 511.1(b)(8)(i), and 812.140(d). Verify that the sponsor maintained required records (e.g., drug disposition, financial disclosure information from investigators) for the prescribed period of time.

L. FINANCIAL DISCLOSURE

1. Determine if the sponsor obtained financial disclosure information from each investigatorbefore his/her participation in the clinical trial, as required by 21 CFR Part 54 and 21 CFR 312.53(c)(4) and 812.2(b)(5) and 812.43(c)(5).

2. Determine if the sponsor received prompt updates regarding relevant changes in financialdisclosure information from investigators during the study and for one year after study completion.

3. Determine if the sponsor reported to FDA (on Form FDA 3454 and 3455, respectively), allpertinent investigator disclosures and certifications of financial information as required by 21 CFR 54.6.

4. Determine if the sponsor retained the documentation to support the certifications anddisclosures of investigators’ financial information that was reported to FDA.

M. ELECTRONIC RECORDS AND ELECTRONIC SIGNATURES

Computerized systems are commonly used in clinical investigations to create, modify, maintain, archive, retrieve, and/or transmit clinical data. Computerized systems range from isolated pieces of equipment that are used at a clinical site to collect/archive clinical data (e.g., a laptop) to complex integrated systems that consist of a variety of hardware, firmware, and software components that are located at multiple sites (e.g., a web-based system managed by an independent software vendor to which the sponsor and clinical sites have controlled access).

Regardless of the type of system used by the clinical site, an important principle to understand when evaluating clinical research data is that the regulatory requirements for the clinical data do not change whether clinical data are captured on paper, electronically, or using a hybrid approach. Data must be reliable and usable for evaluating the safety and/or effectiveness of FDA-regulated products.

Another important point is that the agency has stated in its guidance entitled, “Guidance for Industry Part 11, Electronic Records; Electronic Signatures – Scope and Application” (Part 11 Guidance) (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126953.pdf) that only certain electronic records will be subject to 21 CFR Part 11 (Part 11), and that the agency intends to exercise enforcement discretion with regard to specific Part 11 requirements. 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 is a companion regulation to other FDA regulations and laws. It is in these other regulations and laws, called "predicate rules," where specific requirements for issues such as recordkeeping, record content, signatures, and record retention are addressed.

Section III. B. 2 of the Part 11 Guidance states that Part 11 is applicable to the following electronic records and electronic signatures:

• Records that are required to be maintained under the predicate rules and that are maintained in electronic format in place of paper format.

• Records that are required to be maintained under the predicate rules, that are maintained in electronic format in addition to paper format, and are relied on to perform regulated activities.

• Records that are submitted to FDA, under predicate rules, and that are in electronic format.

• Electronic signatures that are intended to be the equivalent of handwritten signatures, initials or other general signings that are required by the predicate rules.

In Section III. C of the Part 11 Guidance, specific requirements for which the agency intends to exercise enforcement discretion include the:

  • Validation of computerized systems;
  • Use of computer-generated, time-stamped audit trails; 
  • Use of legacy systems;
  • Generation of copies of records;
  • Protection of records (i.e., record retention and availability)

The field investigator should consult with the Center contact for guidance on the depth to which Part 11 issues should be covered during an inspection. When assessing study compliance, any discrepancies should be documented under the appropriate predicate rule requirement. Questions should be referred to the Center contact.

1. Scope of electronic records/electronic signatures

a. Determine whether electronic records and/or electronic signatures are required by predicaterules, and/or are used in place of paper records (or relied upon to perform regulated activities) and handwritten signatures. If this is the case, requirements of Part 11, as interpreted by the Part 11 Guidance, apply. If this is not the case, Part 11 requirements do not apply, and the paper records should be evaluated for compliance with the applicable regulations.

b. Determine whether electronic data and data collection methods are defined in the studyprotocol. Describe any computerized system(s) used at the study site(s) to generate, collect, or analyze data (e.g., stand alone personal computer, web-based system, hand-held computers).

c. Determine how the sponsor/CRO has ensured that sites have access to their originalelectronic records and how this access is maintained for the required data retention period at a minimum.

2. Procedures

a. Determine how the sponsor/CRO determines which records are used for regulatory purposes(e.g., if there is an SOP and if it is followed).

b. Determine if the sponsor/CRO has established procedures to create, modify, maintain, ortransmit electronic records, e.g., user manuals, operating instructions, access policies and procedures, training policies, or management controls.

c. Determine if the sponsor/CRO has procedures to demonstrate that the computerized systemwas tested for its intended use (e.g., documentation of user acceptance testing).

d. Determine how the sponsor/CRO documents that there are sufficient personnel with thenecessary education, background, training, and experience to ensure that all protocol requirements that employ electronic systems are correctly performed.

e. Determine if the sponsor/CRO has procedures for identifying training needs to ensure that allpertinent personnel (e.g., individuals who develop, maintain, and/or utilize computerized systems, including staff at the clinical sites) are trained to adequately perform their assigned responsibilities.

f. Determine how the sponsor/CRO ensures that only authorized personnel have access to studydata – e.g., if there is a log of authorized users for each clinical site; if all users – at the sites, sponsor, CRO, data processing center – have appropriate user IDs, passwords, and access privileges..

3. Data collection:

a. Describe procedures for collection, retention, and transmission of data at each clinical site.That is, determine if there are file transfer protocols for electronic clinical data transmitted to and from the clinical site/sponsor/CRO/data processing center.

b. Determine whether original data entries and changes can be made by anyone other than theclinical investigators.

c. Determine how the electronic data were reviewed during monitoring visits. If any datamonitoring was accomplished remotely, determine what was covered and obtain copies of any SOPs and/or documentation of such reviews.

4. Security

a. Determine who is authorized to access the system.

b. Describe how the computerized systems are accessed (e.g., password protected, accessprivileges, user identification).

c. Determine how information is captured related to the creation, modification, or deletion of electronic records (e.g., audit trails, date/time stamps).

d. Describe whether there is backup, disaster recovery, and/or contingency plans to protectagainst data loss. Were there any software upgrades, security or performance patches, or new instrumentation during the clinical trial? Could the data have been affected?

e. Describe how error messages or system failures were reported to the sponsor, CRO, or studysite and the corrective actions, if any, which were taken.

f. Determine how the system and data were handled during site closure.

N. TEST ARTICLE

1. Integrity

Describe the sponsor’s procedures to ensure the integrity of the test article from manufacturing to receipt by the clinical investigator:

a. Determine if the test article met required release specifications. For drugs, review theCertificate of Analysis, if available. For biologics, review the Certificate of Analysis, where appropriate and available, and/or the lot release documentation.

b. Determine if the test article is not in its final form and requires preparation,manipulation, or processing by the clinical protocol and/or manufacturer’s instructions (e.g., mixing plasma with bone chips immediately before use or manipulation of a study subject’s cell or tissue specimen) prior to receipt by the subject.

c. Determine where the test article was stored and if the conditions of storage wereappropriate.

d. Determine how the sponsor verified test article integrity during shipment to theclinical study sites.

d. Determine if the test article was properly labeled (See 21 CFR 312.6, 511.1(b)(1), and812.5).

e. Determine if the test article was recalled, withdrawn, or returned.

2. Accountability

a. Determine whether the sponsor maintains accounting records for use of the test articleincluding:

i. Names and addresses of clinical investigators receiving test articles. See 21 CFR 312.57, 511.1(b)(3), and 812.140(b)(2).

ii. Shipment date(s), quantity, batch or code mark, or other identification number of test article shipped. See regulations above.

iii. Final disposition of the test article. See 21 CFR 312.59, 511.1(b)(7)(ii), and 812.140(b)(2).

iv. For animal drug products, final disposition of food-producing animals treated with the test article (21 CFR 511.1(b)(5)).

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

b. 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).

c. Determine whether the clinical investigator appropriately documented anymanipulation or processing of the test article and, if the investigator did manipulate or process the test article, verify that all relevant requirements set forth in the protocol were met and fully documented.

d. Determine whether all unused or reusable supplies of the test article were returned tothe sponsor when either the investigator(s) discontinued or completed participation in the clinical investigation, or the investigation was terminated.

e. If the test article was not returned to the sponsor, describe the method of disposition and determine if adequate records were maintained.

f. For device studies, determine how the sponsor controls and monitors the use of devices that are not single-use products, such as lithotripters or excimer lasers.

g. Determine if the sponsor is charging for the test article and document the feescharged.

O. DEVICES

1. Requests for inspections from the Center for Devices and Radiological Health (CDRH) generally involve Significant Risk (SR) device studies that require full compliance with the Investigational Device Exemption (IDE) regulations at 21 CFR 812. In addition to covering the identified SR device study, the investigator should determine whether the sponsor/CRO/monitor is involved in Non-significant Risk (NSR) device studies which require compliance with the abbreviated IDE requirements at 21 CFR 812.2(b). The abbreviated requirements address labeling, IRB approval, informed consent, monitoring, records, reports, and prohibition against promotion, including compliance with 21 CFR 812.5, 812.7, 812.46. 812.140(a)(3)(i), and (b)(4) and (5), 812.150(b)(1) through (3) and (5) through (10). NSR device studies do not have to have an IDE application approved by FDA. When appropriate, the investigator should choose at least one (1), but no more than three (3), NSR device investigations to determine the level of compliance with the abbreviated requirements.

2. Humanitarian Use Devices (HUDs) and Humanitarian Device Exemptions (HDEs) (see also the guidance document on the Humanitarian Device Exemption (HDE) Regulation: Questions and Answers, available at (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/u cm110194.htm)

As defined in 21 CFR 814.3(n), a HUD is a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. An HDE is an application similar to a premarket approval (PMA) application, but is exempt from the reasonable assurance of effectiveness standard. HDE approval is based, in part, on evidence that the device will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit from use of the device outweighs the risk of injury or illness. This decision must take into account the probable risk and benefits of currently available devices and alternative forms of treatment. FDA approval of an HDE authorizes an applicant to market a HUD, subject to certain profit and use restrictions. Specifically, HUDs cannot be sold for profit, except in narrow circumstances8, and they can only be used in a facility after an IRB has approved their use in that facility, except in certain emergencies.

There is a distinction between “use” of a HUD and “investigational use/clinical investigation” of a HUD.

a. Prior to approval of a HDE application, any studies using the device must be conducted in compliance with the applicable IDE regulations (21 CFR Part 812),. Determine if the sponsor is conducting any such studies. If so, verify that the study,if it is considered a significant risk device study, is conducted under an IDE – i.e., has IDE approval from FDA as well as IRB approval, or IRB approval with concurrence that it is a non-significant risk device study, or is exempt from IDE requirements under 21 CFR 812.2(c).

b. “Use” of a HUD that has an approved HDE, requires IRB approval before use in a facility, with the exception of emergency use (21 CFR 814.124). The HDE holder is responsible for maintaining records of the names and addresses of the facilities to which the HUD has been shipped, correspondence with the reviewing IRBs, and any other information required by the reviewing IRB or FDA (21 CFR 814.126(b)(2)). In addition, the HDE holder is subject to certain reporting requirements (21 CFR 814.126(b)(1)), including monitoring how many devices are distributed each year and periodically providing FDA with updated information, including information to demonstrate that the HUD designation is still valid. Determine if the sponsor holds any approved HDEs. If so, verify that there is documentation that all facilities using the HUD have the approval from an appropriate IRB; that required records are maintained, including those related to device distribution; and that periodic updates have been submitted to FDA.

c. An HDE holder may collect safety and effectiveness data in a clinical investigation for the HDE-approved indication(s) without an IDE. As long as the HUD is being studied in accordance with the approved indication(s) described in the labeling, the HUD is legally marketed and can be lawfully shipped without an IDE. IRB approval (21 CFR 56) and informed consent of the subjects (21 CFR 50) are still required for these studies. Determine if the sponsor is conducting such a clinical investigation. If so, verify that the study is being conducted in compliance with 21 CFR Parts 50 and 56.

d. Clinical investigations of a HUD for an indication different from the HDE-approved indication(s) must be conducted in compliance with the applicable IDE regulations (21 CFR 812), in addition to complying with the requirements for IRB approval and informed consent. If the study is a significant risk study, an FDA-approved IDE is required (21 CFR 812.2). Determine if the sponsor is conducting a study of a HUD for a different indication than the HDE-approved indication. If so, verify that the study is being conducted in compliance with 21 CFR Parts 812, 50, and 56.

P. EMERGENCY RESEARCH

1. Determine if the sponsor/CRO is conducting or has conducted any “emergency research”studies, i.e., studies described in 21 CFR 50.24, which specifies circumstances in which an IRB may approve an investigation without requiring that informed consent be obtained from research subjects. If so:

a. Determine if the sponsor consulted with representatives of the communities in which theinvestigation is conducted and from which subjects are drawn, as required by 21 CFR 50.24(a)(7)(i).

b. Determine if the sponsor provided public disclosure to the communities in which theinvestigation is conducted both prior to and following completion of the investigation, as required by 21 CFR 50.24(a)(7)(ii) and (iii).

c. Determine if the sponsor promptly submitted copies of the required public disclosures tothe Division of Dockets Management as required by 21 CFR 312.54(a) and 812.47(a).

d. Determine if the sponsor established an independent data monitoring committee toexercise oversight of the investigation, as required by 21 CFR 50.24(a)(7)(iv).

e. Determine if the sponsor received any determination from an IRB that the IRB couldnot approve an emergency research study under 21 CFR 50.24. If so, did the sponsor promptly provide this information in writing to FDA, the sponsor’s clinical investigators who are participating or asked to participate in the same or a substantially equivalent clinical investigation of the sponsor, and other IRBs that have been or are asked to review this or a substantially equivalent investigation by that sponsor (as required by 21 CFR 50.24(e))? (See 21 CFR 312.54(b) and 812.47(b).)

Q. INTERNATIONAL DATA – HUMAN DRUGS AND BIOLOGICS

Sponsors are not required to conduct non-U.S. clinical trials under an IND, but often submit data from international study sites to FDA in support of marketing or research applications. In 2008, FDA revised its criteria for accepting non-IND, non -U.S. clinical studies as support for an IND or a new drug application (NDA). See 21 CFR 312.120 (accessible from http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm). This revised section of the regulation became effective October 27, 2008.

FDA’s requirements for accepting such studies are as follows:

• The study must be conducted in accordance with Good Clinical Practice (GCP), which is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected.

GCP also includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of the subject (or the subject’s legally authorized representative if the subject is unable to provide consent) before initiating a study.

• FDA is able to validate the data from the study through an on-site inspection if the agency deems it necessary.

A sponsor or applicant is required to submit the following information for non-IND non-U.S. clinical trials to FDA that support an IND or application for marketing approval:

a. The investigator’s qualifications;

b. A description of the research facilities;

c. A detailed summary of the protocol and study results, and if we request them, case records or additional background data;

d. A description of the drug substance and drug product, including components, formulation, specifications, and, if available, the bioavailability of the drug product;

e. Information showing that the study is adequate and well-controlled (if the study is intended to support the effectiveness of the product);

f. The name and address of the independent ethics committee (IEC) that reviewed the study and a statement that the IEC meets the definition in 21 CFR 312.3;9

g. A summary of the IEC’s decision to approve or modify and approve the study or to provide a favorable opinion;

h. A description of how informed consent was obtained;

i. A description of what incentives, if any, were provided to subjects to participate;

j. A description of how the sponsors monitored the study and ensured that the study was consistent with the protocol; and

k. A description of how investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol, and a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained (any signed commitments must be maintained and available for agency review).

If the study identified for inspection includes non-IND, non-U.S. site(s), the sponsor should have records related to the information listed above. Consult with the Center contact about the need to review and/or obtain copies of these records.

R. NONCLINICAL LABORATORY STUDIES

ONE OR MORE OF THE FOLLOWING ARE ONLY APPLICABLE WHEN SPECIFICALLY REQUESTED IN THE INSPECTION ASSIGNMENT

1. Determine if the sponsor conducted or contracted for nonclinical studies related to theproduct that is the subject of the clinical study(ies) specified in the assignment – i.e., studies subject to 21 CFR Part 58, Good Laboratory Practice for Nonclinical Laboratory Studies. If so, collect copies of information documenting where and when the nonclinical studies wereconducted. For contracted studies, collect copies of the agreement with the contracted party.

2. Sponsors are required to provide a statement in applications/submissions to FDA that nonclinical studies were conducted in compliance with 21 CFR Part 58 or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for noncompliance. This statement must appear in the Notice of Claimed Investigational Exemption for New Animal Drug studies, IND and IDE applications, and marketing applications/submissions (for devices this statement must appear in a PMA) (21 CFR 312.23(a)(8)(iii), 314.50(d)(2)(v), 314.125(b)(15), 511.1(b)(4)(ii), 514.1(b)(12)(iii), 601.2(a), 812.27(b)(3), 814.20(b)(6)(i)). Collect copies of documentation used to support a sponsor’s statement that the studies were GLP compliant or the rationale as to why the studies were not conducted in compliance with the regulation.

3. Determine if the sponsor approved the nonclinical study protocol(s). Collect any availabledocumentation.

4. The regulation requires that specific information pertinent to test and control article characterization is available either before study initiation or concomitantly (21 CFR 58.105). This includes: stability testing; documentation for each batch of the identity, strength, purity, and composition or other characterization that defines the article; and documentation of methods of synthesis, fabrication, or derivation. Determine whether the sponsor or the test facility was responsible for meeting these requirements. Collect documentation regarding where and when the testing was conducted as well as copies of any resulting reports.

5. Determine where nonclinical studies data and records are retained and collect the name andaddress of that location. The test facility is required to retain, with a few specified exceptions, all raw data, protocols, final reports and specimens as specified in 21 CFR 58.195(b). If the test facility goes out of business during the required records retention period, the regulation requires that all data and records required to be retained be transferred to the sponsor’s archives and that FDA be informed of this transfer (21 CFR 58.195(h)). If such a transfer occurred, determine the location of the sponsor’s archives and collect documentation that FDA has been notified of the transfer.

S. 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.

T. ESTABLISHMENT INSPECTION REPORTS (EIRs)

If the inspection assignment resulted from FDA’s receipt of a marketing application/submission, information contained in the EIR may be used in support of marketing approval or denial. If the inspection was assigned “for cause” or as part of general surveillance, information contained in the EIR may be used to determine if the ongoing study should be allowed to continue, either in its entirety or at specific sites. Therefore, the EIR must document all findings that could significantly impact the decision-making process.

1. Standard Narrative Report

a. A standard narrative report will be prepared and submitted in the following situations:

i. The initial inspection of a firm;

ii. All inspections for which the field recommends an Official Action Indicated (OAI) classification; and

iii. Any assignment specifically requesting a standard narrative report.

b. Refer to IOM 5.10.4, Narrative Report. Individual sections that are relevant to a BIMO standard narrative report include: Summary; Administrative Data; History; Individual Responsibility and Persons Interviewed; Objectionable Conditions and Management’s Response; Supporting Evidence and Relevance; Discussion with Management; Refusals; General Discussion with Management; Additional Information; Voluntary Corrections; Exhibits Collected; Attachments; and Signature. See also, IOM 5.2.9: Interviewing Confidential Informants.

c. In addition to these, include the appropriate headings outlined in Part III of this Compliance Program (Sections III. C through Q). The report must include sufficient information and documentation to support the recommended classification.

2. Summary of Findings Report

a. A Summary of Findings Report may be submitted for non-violative inspections of sponsors/CROs/monitors who have previously been inspected. A full inspection must be conducted even if a Summary of Findings Report is appropriate, i.e., an abbreviated inspection is not justified. A Summary of Findings report must contain sufficient narrative and accompanying documentation to support the inspectional observations. The specific headings appearing under Part III. Inspection Procedures should be fully addressed during the inspection, as appropriate to the inspection assignment. In addition, the EIR should be clearly identified as a Summary of Findings Report.

b. The report should include all of the headings described in IOM section 5.10.4.1, Narrative Reports for Non-Violative Establishments:

i. Reason for inspection;

ii. Date, classification, and findings of the previous inspection;

iii. The inclusive dates of the inspection;

iv. Name of the person to whom credentials were shown and the Notice of Inspection was issued and the person’s authority to receive the Notice;

v. Scope of the inspection, including:

a) Updated history of business;

b) Administrative procedures;

c) Persons interviewed and individual responsibilities;

d) Protocol title, protocol number, and the FDA research (IND, IDE, INAD) or marketing (NDA, NADA, BLA, PMA, 510(k)) application numbers;

e) Areas covered during the inspection including but not limited to SOPs relevant to the study, test article accountability, monitoring reports, actions taken to secure site compliance when necessary, IRB approvals, adverse event reporting, special instructions or directives (if provided in the assignment);

vi. Significant observations, if any;

vii. Statement of the close-out discussion and the sponsor’s/CRO’s/monitor’s response(s) or correction(s)

a) Discussion of inspectional observations, including observations noted on the 483;

b) 483 observations should be referenced in the EIR; documentation of the observations should be included as exhibits;

c) Response to the 483 observations – attach any response to the EIR if provided by the sponsor/CRO/monitor prior to submission to the Center;

viii. FDA investigator’s handwritten signature, and signature(s) of other members of the inspection team, if applicable.


2 See Sections 301(f) and 704 of the Federal Food, Drug and Cosmetic Act (FFDCA), Sections 351(c), 360A(a), (b) & (f); 360B(a); and 361(a) of the Public Health Service (PHS) Act, and 21 CFR 312.68 and 812.145.
3 See Sections 301(f) and 704 of the FFDCA, section 351(c) of the PHS Act, and applicable regulations (e.g., 21 CFR 312.68, 812.145(c)).
4 See http://www.fda.gov/RegulatoryInformation/Legislation/Federal
FoodDrugandCosmeticActFDCAct/SignificantAmendments
t
otheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ucm095442.htm for specific FDAAA requirements.
5 Guidance on completion of the certification form is available at http://www.fda.gov/Regulatory
Information/Guidances/ucm125335.ht
m.
6 The rule is effective March 7, 2011, however, FDA has said that it intends to enforce this requirement only for informed consent documents and processes for clinical investigations that are initiated on or after March 7, 2012. See http://edocket.access.gpo.gov/2011/pdf/2010-33193.pdf.
Revised safety reporting regulations issued September 29, 2010, effective March 28, 2011, include new and revised definitions and new reporting requirements.
See http://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2010_
register&docid=fr29se10-3.pdf
and http://www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM227351.pd
f.
8 See Title III – Pediatric Medical Device Safety and Improvement Act of 2007 – in the medical device provisions of the Food and Drug Administration Amendments Act (FDAAA) of 2007 available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Overview/
MedicalDeviceUserFeeandMode
rnizationActMDUFMA/UCM109100.pdf.
9 21 CFR 312.3(b) defines "independent ethics committee" (IEC) as "a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An institutional review board (IRB), as defined in § 56.102(g) of this chapter and subject to the requirements of part 56 of this chapter, is one type of IEC."