Inspections, Compliance, Enforcement, and Criminal Investigations
PART III - INSPECTIONAL
Inspections involve evaluation of the clinical investigator's or sponsor-investigator's practices and procedures to determine compliance with applicable regulations. When the inspection occurs as a result of FDA’s receipt of a marketing application/submission, it will include a comparison of the data submitted by the sponsor to FDA with source documents at the clinical investigator's site (i.e., where original source data are recorded; also known as supporting data) and case report forms (CRFs) in the clinical investigator's files. In such cases, the study will usually have been completed, possibly for a considerable time. If it is a “for cause” or surveillance inspection of an on-going study, data comparison will generally involve only source documents and case report forms, because there may not always be data supplied by the sponsor. Source documents may include office records, hospital records, laboratory reports, records of consultations, etc.
The following areas should be covered during all inspections.
- Clinical investigator inspections are product specific, i.e., human drugs and biologics, animal drugs, medical devices, or foods. Field investigators must apply the pertinent regulations to each clinical investigator inspection.
- Inspections under this program will be 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 clinical investigator or sponsor-investigator to unduly delay an inspection, by more than ten working days, without sufficient justification.
- Inspection Refusals
Refusal of entry
If a clinical investigator or the investigator's staff refuses to permit an inspection by FDA personnel, the field investigator should inform the clinical investigator about the regulatory requirements 5 permitting 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 supervisor, the District Compliance Officer, the assigning Center contact, and DFI (HFC-130) of this refusal.
- Refusal of Information
If at any time during the inspection, the clinical investigator or a staff member 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 clinical investigator or the staff member about the regulatory requirements 6 permitting this access. 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 DFI (HFC-130). The same procedure should be followed when it becomes evident that delays by the clinical investigator or his staff 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 DFI, 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).
- 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.
- The field investigator issues a 483 at the conclusion of the inspection when deviations from regulations are observed. 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. Such deviations may be discussed with the clinical investigator or sponsor-investigator during the exit interview, however, and reported in the EIR. The field investigator encourages the firm 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. Review of records should include a comparison of data in source documents with case report forms as well as with any sponsor-provided data tabulations that may be included with the 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 clinical investigator's practices and procedures comply with regulations. The field investigator should not attempt to scientifically evaluate the study data or protocol(s).
Full narrative reporting of any deviations from regulations should be thoroughly documented. For example, any records demonstrating discrepancies between source data, case report forms, and/or data submitted by the sponsor to FDA 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.
C. AUTHORITY and ADMINISTRATION for STUDIES INVOLVING HUMAN DRUGS, BIOLOGICS, and DEVICES
- If available at the clinical investigator’s site, compare the Statement of Investigator Form FDA-1572 (human drugs and biologics) or the Investigator’s Agreement (medical devices) with the information provided by the assigning Center. If they are different, or if the assigning Center did not provide one, obtain a copy.
- Obtain a list of all studies performed by the clinical investigator. This list should include available information such as:
- Protocol number;
- Protocol title, including the product name, and the research or marketing permit number, if available;
- Name of sponsor (including government agencies and commercial sponsors); and
- Study dates.
- For the assigned study, document in the narrative of the EIR:
- The addresses of all locations at which study subjects were seen;
- How the sponsor provided information to the clinical investigator about the test article, protocol, and the obligations of a clinical investigator (e.g., telephone, memo, meeting);
- Whether the authority for the conduct of the various aspects of the study was contracted and/or delegated properly so that the investigator retained control and knowledge of the study. Include a list of delegated tasks. If there are questions about appropriate delegation, obtain information (e.g., curriculum vitae, medical or other license) about the qualifications of the person performing the task.
- The following dates:
1. IRB approvals (human studies) including initial review of the protocol, all amendments, the informed consent document and all revised informed consent documents;
2. For human studies, when the Form FDA 1572 or Investigator Agreement was signed by the clinical investigator (when available);
3. When the first subject was screened;
4. When the first subject signed the informed consent document;
5. First administration of the test article; and
6. Last follow-up for any study subject.
- If the clinical investigator discontinued his/her participation in the study, describe the reason(s).
- List the name and address of the facility(ies) performing laboratory or diagnostic tests required by the protocol. Describe the clinical investigator's documentation of the laboratory or diagnostic testing facility's qualifications (e.g., certification under CLIA--Clinical Laboratory Improvements Act). If any laboratory testing was performed in the investigator's own facility, determine whether that facility is equipped to perform each test specified. List name(s) of individuals performing such tests and indicate their position. Consult with the Center if there are questions related to a facility's qualifications or necessary documentation.
- Determine the process used to recruit subjects. If any recruitment materials or phone recruitment scripts were employed, document their review and approval by the IRB, or note the absence of such approval (see E. 2. c. below). Also, document any instances in which the investigator utilized methods or distributed information that appeared to be coercive in nature 7 , distributed any promotional material or otherwise represented the test article as safe and effective for the purpose for which it is under investigation, or implied in any manner a favorable outcome or other benefits beyond what was outlined in the consent document and protocol.
- Obtain a copy of the site’s enrollment log.
D. PROTOCOL for HUMAN DRUG, BIOLOGIC, or DEVICE STUDY
- Compare the copy of the protocol provided with the assignment to the clinical investigator's copy of the protocol and amendments. If the protocols are different, or one was not provided, obtain a copy of the clinical investigator's protocol and amendments.
Become familiar with sections of the protocol, such as primary endpoint, eligibility criteria, scheduling of visits, test article accountability. Did the clinical investigator follow the protocol with respect to:
a. Subject selection (i.e., inclusion and exclusion criteria);
b. Number of subjects enrolled;
c. Randomization scheme (where applicable);
d. Required procedures and evaluations (e.g., blinding procedures);
e. Administration of the investigational product:
- for human drugs and biologics - dosage, route of administration, and frequency of dosage
- for devices – use according to manufacturer’s directions; proper surgical techniques (where applicable)
f. Frequency of observations and testing prescribed for subject follow up; and
g. Any other information specific to the study and/or the inspection assignment.
- Verify that the clinical investigator followed the study protocol approved by the IRB. The investigator is responsible for ensuring that an investigation is conducted according to the investigational plan. (21 CFR 312.60; 812.100) Review any changes to and deviations from the protocol.
Protocol changes/amendments. During the course of a study, a protocol may be formally changed by the sponsor. Such a change is usually prospectively planned and implemented in a systematic fashion through a protocol amendment. Protocol amendments must be reviewed and approved by the IRB, prior to implementation, and submitted to FDA.
Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical well-being of the subject (21 CFR 812.35(a)(2)), and generally communicated to FDA. “Protocol deviation” is also used to refer to any other, unplanned, instance(s) of protocol noncompliance. For example, situations in which the investigator failed to perform tests or examinations as required by the protocol or failures on the part of study subjects to complete scheduled visits as required by the protocol, would be considered protocol deviations. Determine whether changes to the protocol were:
- Documented by an amendment, dated, and maintained with the protocol;
- Reported to the sponsor (when initiated by the clinical investigator); and
- Approved by the IRB and FDA (if applicable) before implementation (except when necessary to eliminate apparent immediate hazard(s) to human subjects).
For device studies: determine whether deviations to the protocol were:
- Documented, showing dates of and reason for each deviation;
- Documented, with prior approval from the sponsor for deviations from the investigational plan, except if emergency use (see iv).
- Documented, with prior approval from the reviewing IRB and FDA for deviations from the investigational plan that may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, except if an emergency (see iv).
- If emergency use, documented notification of the sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well being of a subject. In addition, determine that this notice was given within 5 working days after the emergency occurred. (21 CFR 812.150(a)(4))
Collect correspondence or other documentation that supports adverse inspectional observations.
E. INSTITUTIONAL REVIEW BOARD (IRB) for HUMAN DRUG, BIOLOGIC, or DEVICE STUDY
- Identify the name, address, and chairperson of the IRB for the study.
- Determine and describe if the investigator obtained IRB approval of the items listed below before initiation of study-specific procedures on subjects:
- The protocol and any amendments;
- The informed consent documents; and
- Advertisements and other information provided to prospective study subjects.
- Describe the nature and frequency of communications with the IRB. Determine whether the investigator submitted information promptly to the IRB, in compliance with the protocol and applicable regulations, of all unanticipated problems involving risk to human subjects.
- If there is a question as to whether the correct consent document was used, obtain a copy of each version of the consent document approved by the IRB for the study(ies).
- Collect correspondence or other documentation that supports adverse inspectional observations.
F. HUMAN SUBJECTS' RECORDS
- Informed Consent
- Describe the informed consent process.
For the study being inspected, include the following information:
- Who (investigator, nurse, study coordinator, etc.) explained the investigational study and consent document to prospective study subjects, and was it provided in a language understandable to each subject?
- How did the informed consent process take place? (e.g., was this explanation given orally, by video, through a translator, etc.)?
- Was consent obtained prior to enrollment in the study (i.e., prior to performance of any study related tests and administration of the test article)?
- After signing and dating the informed consent document, was each subject or the subject's legally authorized representative given a copy of the consent document?
- Was the appropriate IRB-approved version of the informed consent document used for all subjects?
- If the short form was used (per 21 CFR 50.27(b)(2)), was the informed consent process appropriately documented?
- Did the subject or the subject's representative sign the short form?
- Was a witness present, who signed the short form and the copy of the summary?
- Did the person actually obtaining the consent sign a copy of the summary?
- Is the case history documented to show whether a copy of the summary and the short form were given to the subject or the subject's representative?
- Review the IRB approval letter for the study. Did the IRB stipulate any conditions for the informed consent process and, if so, did the clinical investigator follow those instructions/stipulations?
- Review the informed consent documents signed by the subjects. If the number of subjects at the site is relatively small (e.g., 25 or fewer subjects), review 100% of the informed consent documents. For larger studies, a representative number of informed consent documents should be reviewed (for example, may be specified in a sampling plan provided with the assignment).
- Determine the following:
- Did the subject or the subject’s legally-authorized representative sign the informed consent document prior to entry into the study? If the subject did not sign the informed consent document, determine who signed it and that person’s relationship to the subject. Describe how the clinical investigator determined that the person signing the informed consent document was the subject's legally-authorized representative.
- Whether subjects signed the version of the informed consent document that was current at their time of entry into the study.
- For pediatric studies, was assent obtained from the subjects in addition to the permission of the parents?
- Whether the written consent document(s) or oral consent complies with the eight (8) required elements in 21 CFR 50.25(a).
If any problems are found (e.g., investigator failed to obtain consent from one or more subjects, consent was not obtained prior to enrollment in the study, investigator failed to use the correct informed consent document, etc.), the sample should be expanded to determine the extent of the problem. Collect documentation to support each observation. Report the total number of informed consent documents that were reviewed and the number of documents exhibiting the problem.
- Describe the informed consent process.
- Source Documents
- Describe the investigator's source documents in terms of their organization, condition, completeness, and legibility.
- Determine whether there is adequate documentation to ensure that all subjects were alive and available for the duration of their stated participation in the study.
- Determine whether the records contain:
- Observations, information, and data on the condition of the subject at the time of entry into the clinical study, as required by the protocol;
- Documentation of the subject's exposure to the test article, as required by the protocol;
- Observations and data on the condition of the subject throughout participation in the investigation, including results of lab tests, development of unrelated illness, and other factors which might alter the effects of the test article; and
- Identification of key personnel involved in collecting and analyzing data at the site.
- Case Report Forms (CRFs)
- Describe the process for obtaining and recording information in CRFs.
- Who obtained and recorded the information;
- The source of the information (e.g., were data transcribed from another document or were data recorded directly onto the CRF); and
- Whether corrections were made to the CRF data entries. If corrections were made, determine who made them, the reason(s) for the changes, and whether the clinical investigator was aware of these changes.
- Compare the source documents with the CRFs and any background information provided (e.g., data tabulations provided by the sponsor) per the assignment memorandum and sampling plan (if applicable). Determine whether:
- The study subjects met the eligibility criteria (inclusion/exclusion);
- Protocol-specified clinical laboratory testing (including EKGs, X-rays, eye exams, etc.) was documented by laboratory records;
- All adverse events were documented and appropriately reported;
- The clinical investigator assessed the severity of the adverse event and documented the relationship of the event to the test article, including any adverse event that was previously anticipated and documented by written information from the sponsor; and
- All concomitant therapies and/or inter-current illnesses were documented and reported.
- Determine whether the clinical investigator reported all dropouts and the reasons to the sponsor.
- Describe the process for obtaining and recording information in CRFs.
G. OTHER STUDY RECORDS
Study-related information may also be recorded in other documents. Determine if the clinical investigator maintains other records pertinent to the study, e.g., administrative study files, correspondence files, master subject list, appointment books, sign-in logs, screening lists, and MedWatch forms. Review these records to ensure that all pertinent information has been reported to the sponsor. Document any discrepancies found.
H. FINANCIAL DISCLOSURE
- Ask the clinical investigator if and when he disclosed information about his financial interests to the sponsor and/or interests of any subinvestigators, spouse(s) and dependent children. (21 CFR 54.4(b))
- Ask the clinical investigator if and when he updated the information about such financial interests, to report changes that occurred in the value of the financial interests during the course of the clinical investigation or within one year following completion of the study. (21 CFR 54.4(b))
I. ELECTRONIC RECORDS AND ELECTRONIC SIGNATURES
Computerized systems are commonly used in clinical investigations to collect and preserve 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” (Part 11 Guidance) that only certain electronic records will be subject to 21 CFR 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, 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.
- Scope of Electronic Records/Electronic Signatures.
- Determine whether electronic records and/or electronic signatures are required by predicate rules, 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 “Scope and Application 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.
- Determine whether electronic data and data collection methods are defined in the study protocol. 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).
- Determine whether electronic records are available for inspection and have been retained for the required period of time.
- How does the firm determine which records are used for regulatory purposes (e.g., does the firm have and did it follow an SOP)?
- Does the firm have procedures and controls in place to create, modify, maintain, or transmit electronic records, e.g., operating instructions, access policies and procedures, training policies, or management controls?
- Were the individuals who develop, maintain or use the computerized systems given the education, training, and experience necessary to perform their assigned tasks?
- DATA COLLECTION
- Is the clinical investigator able to ensure accurate and complete electronic and human readable copies of electronic records, suitable for review and copying? (If you are unable to access records from the computerized system, contact the Center immediately.)
- Determine whether electronic records and data meet the requirements applicable to paper records. For example, are electronic records used to meet case history requirements attributable, legible, contemporaneous, original, and accurate (ALCOA)?
- Describe how data are transmitted to the sponsor or contract research organization.
- Determine whether original data entries and changes can be made by anyone other than the clinical investigator.
- Determine how the electronic data were reviewed during monitoring visits. Document unauthorized changes or modifications made to original data and by whom.
- Determine who is authorized to access the system.
- Describe how the computerized systems are accessed (e.g., password protected, access privileges, user identification).
- How is information captured related to the creation, modification, or deletion of electronic records (e.g., audit trails, date/time stamps)?
- Describe whether there is backup, disaster recovery, and/or contingency plans to protect against data loss. Were there any software upgrades, security or performance patches, or new instrumentation during the clinical trial? Could the data have been affected?
- Describe how error messages or system failures were reported to the sponsor, CRO, or study site and the corrective actions, if any, that were taken.
- How were the system and data handled during site closure?
J. TEST ARTICLE CONTROL
- Accountability [312.62(a), 511.1(b)(7)(ii), and 812.140(a)(2)]
- Determine who is authorized to administer or dispense the test article.
- Determine whether the test article was supplied to a person not authorized to receive it.
- Compare the amount of test article shipped, received, used, and returned or destroyed. Verify the following:
- Receipt date(s), quantity received, and the condition upon receipt;
- Date(s), subject number, and quantity dispensed; and
- Date(s) and quantity returned to sponsor. If not returned to sponsor, describe the disposition of the test article.
- Determine where the test article is stored, whether it was stored under appropriate conditions as specified in the study protocol, and who had access to it.
- If the test article is a controlled substance:
- Determine how it is secured; and
- Determine who had access.
- Inspect unused supplies and verify that the test article was appropriately labeled.
K. RECORDS CUSTODY AND RETENTION
Determine whether study records are retained according to the protocol and 21 CFR 312.62(c), 511.1(b)(7)(ii), and 812.140(d) and (e).
L. REPORTS TO SPONSOR
Determine if required reports (including case report forms) are submitted to the sponsor in accordance with the study protocol and 21 CFR 312.64, 511.1(b)(7)(iii), and 812.150.
- Determine if the sponsor monitored the progress of the study to assure that the investigator complied with the protocol and applicable regulations.
- Describe monitoring activities. Examples:
- Pre-study contacts with the clinical investigator (e.g., meetings, visits, correspondence);
- Frequency and nature of monitoring (e.g., on-site visits, telephone calls, facsimile, e-mail);
- Determine if the study records include a log of on-site monitoring visits, written reports or other communication provided to the clinical investigator. Obtain a copy of the log (if any) and examples of monitor reports and communications; and
- Follow up activities performed by the clinical investigator when the monitor(s) found deficiencies or recommended changes, for example, in the conduct of the study or records associated with the study.
- For sponsor-investigators, determine if any monitoring was done for the study and, if so, describe. Obtain a copy of the monitoring SOP, if available.
N. ANIMAL CLINICAL STUDIES
The regulations for investigational new animal drugs are found at 21 CFR 511.1. In order to carry out studies involving investigational new animal drugs, the sponsor must submit a Notice of Claimed Investigational Exemption per 21 CFR 511.1(b)(4). The regulations pertaining to new animal drugs for investigational use differ from the requirements of the human drug regulations in several ways. For example, there is no requirement that the sponsor obtain a commitment from the investigator to comply with applicable regulations or use Forms FDA 1571 or 1572; there is no requirement that an approved protocol be used, or even that a protocol be submitted to FDA's Center for Veterinary Medicine (CVM).
For these reasons, inspections of animal clinical trials are extremely important as a means of verifying that the clinical investigator is complying/has complied with regulatory requirements for these studies.
In 2001, CVM adopted "Guidance for Industry, Good Clinical Practice, VICH GL9" (also known as CVM Guidance 85; see Part VI, Reference Section). This represents CVM's current thinking on acceptable clinical trial practices for veterinary medicinal products in the target species. Ask the clinical investigator if he is aware of (e.g., has a copy, has read) this guidance. If necessary, provide the clinical investigator with a copy of the guidance. Approaches that differ from those described in FDA's guidance document should not be listed on the 483 unless they constitute deviations from the regulations. Such deviations may be discussed with the clinical investigator or sponsor-investigator during the exit interview, however, and reported in the EIR.
- If the sponsor submitted a protocol, compare that protocol with the copy of the protocol used by the clinical investigator. Note any differences and document any deviations.
- Examine the facilities for compliance with the protocol (if available) and any written procedures. Describe any differences observed. If appropriate, take photographs of the research facilities for inclusion in the EIR.
- Report on the condition of the animals and adequacy of husbandry practices.
- Report the method used to identify study animals.
- Collect a copy of the clinical investigator's final report.
- Determine if multiple versions of data exist and which data are source data. Document discrepancies between versions, e.g., paper and electronic media or source data and the final report.
- Data may be collected on individual animals (e.g. weight) but other data may be collected on the “group” (e.g., feed consumption). To calculate feed conversion (i.e., weight of feed/weight of animal), individual body weights should be summed within a feed consumption group, in order to determine this measure. Determine whether scientific measurements are made on individual animals or on groups, i.e., herds, pens, or flocks. Determine whether the investigator maintains records on these groups.
- Determine the number of animals by age, weight, sex, and breed. Compare to the protocol and report any discrepancies.
- Determine whether this is the only study each test animal has participated in within a 30-day period prior to initiation or after completion of the study.
- Document the history of the test animals including any prior treatments or vaccinations.
- Determine the actual inclusion/exclusion procedure that was done compared to the procedures noted in the protocol. Describe any differences.
- Document any other drugs, vaccines, pesticides or other chemicals used on the animals during the study.
- Determine the scope and extent of the blinding procedures employed in the study and document any practices that may have compromised the blinding procedures.
- For studies involving drugs in animal feeds, review the drug mixing and feed allocation procedures. Determine if proper drug mixing procedures were followed. Reconcile the amount of feed allocated during the study against the amount of feed mixed for each treatment group.
- Determine whether the medicated feed is mixed on premises. (If not, report name and address of the mill utilized.)
- Determine the method used to identify each lot of drug or medicated feed, and the number of samples and types of assays run on the finished feed to verify dosage level. If available for sampling, check with the Center contact on the need to collect a sample.
- If the investigation involves food-producing animals, determine whether the investigator observed the time periods (withdrawal, withholding, or discard periods) required for authorization to use edible products from such animals.
- Determine if there is any evidence of unreported adverse reactions. Study-related information may also be recorded in other documents. Review the investigator's notes, observed clinical signs, clinical pathology, and diagnostic reports to ensure that all pertinent information has been reported to the sponsor. Document any discrepancies.
- Reconcile the number of animals allocated to the study with the number of animals that completed, were removed, or died during the study. Document and report any differences.
- Examine animal waste and carcass disposal records, and determine if the methods of disposal were consistent with any protocol requirements.
- Determine whether the investigator informed the owner(s) of each animal that the test article is being used for research purposes and whether owner consent was documented. (Current regulations do not require written consent.)
- Reconcile the amount of investigational drug received, dispensed during the study, and returned to the sponsor or otherwise disposed of. Verify the dosing procedure was performed according to protocol requirements. Document and report any discrepancies.
- Confirm whether additional studies were conducted with the test article and obtain copies of final reports for these studies.
- Determine whether the clinical investigator has done/is doing any nonclinical animal studies (i.e., studies subject to FDA's Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies requirements at 21 CFR 58).
O. DEVICE STUDIES
The regulations for investigational devices are found in 21 CFR 812. They do not contain all the provisions of the drug regulations. For example, there is no requirement that Forms 1571 or 1572 be used but there is a requirement for a signed investigator agreement.
- Determine whether the clinical investigation poses a significant risk (IDE), non-significant risk (abbreviated requirements at 21 CFR 812.2(b)), or is IDE exempt (21 CFR 812.2(c)).
- Determine whether the clinical investigator has used the test article under the emergency use or expanded access 8 provisions.
- Determine if the clinical investigator is involved in any nonsignificant risk (NSR) studies and, if so, obtain a list of these studies from the clinical investigator and ascertain if they are being conducted in compliance with the regulations (Note: Unless FDA made an NSR determination for the study, there must be an NSR determination by an IRB. IRB approval is also required for NSR studies; see 812.2(2)(b)(1)(ii).)
- Determine if the clinical investigator has been involved in any use of a custom device. 9 If so, first make sure the device meets the definition of a custom device (21 CFR 812.3(b)) Contact the Center for further guidance.
- Determine if the clinical investigator has utilized a Humanitarian Use Device (HUD) 10 as provided by 21 CFR Part 814, Subpart H. If so, obtain the following:
- Name of the device;
- Documentation of IRB approval (see 21 CFR 814.124);
- Number of patients treated and the indications for which the HUD was used; and
- Document any emergency use.
P. 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 on-going study should be allowed to continue, either in its entirety or at the specific site. Therefore, the EIR must document all observations that could significantly impact the decision-making process.
- Standard Narrative Report
- A standard narrative report will be prepared and submitted in the following situations:
- The initial inspection of a firm;
- Any inspections for which the field recommends an Official Action Indicated (OAI) classification; and
- Any assignment specifically requesting a standard narrative report.
- 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.
- In addition to these, include the appropriate headings outlined in Part III of this Compliance Program (Sections III. C through O). The report must always include sufficient information and documentation to support the recommended classification.
- A standard narrative report will be prepared and submitted in the following situations:
- Summary of Findings Report
- A Summary of Findings Report may be submitted for non-violative inspections of clinical investigators 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. In addition, the EIR should be clearly identified as a Summary of Findings Report.
- The report should include information described in IOM 126.96.36.199, Narrative Reports for Non-Violative Establishments:
- Reason for inspection;
- Date, classification and findings of the previous inspection;
- The inclusive dates of the inspection;
- 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;
- Scope of the inspection, including:
- A definitive statement about the documents that were examined. For example, "The inspection package provided ten case report forms. I attempted to compare them with corresponding hospital charts."
- Protocol title, protocol number, name of the sponsor, and the FDA research (IND, IDE, INAD) or marketing (NDA, BLA, PMA, NADA) permit numbers;
- A list of the addresses of all locations at which study subjects were seen;
- Statement about who obtained informed consent and how it was obtained;
- Information regarding who monitored the trial, and when;
- Statement of test article accountability records that were reviewed;
- Statement whether there was evidence of under-reporting of adverse experiences/events; and
- Statement about protocol adherence;
- Significant observations, if any;
- Statement of the close-out discussion and the clinical investigator’s response(s) or correction(s);
- Discussion of inspectional observations, including observations noted on the 483;
- 483 observations should be referenced in the EIR; documentation of the observations should be included as exhibits;
- Firm’s response to the 483 observations. Attach any response to the EIR if provided by the clinical investigator prior to EIR submission to the Center;
- FDA investigator’s handwritten signature, and signature(s) of other members of the inspection team, if applicable.
Inspections of U.S. Clinical Investigators by Foreign Health Authorities
Health authorities from European Union (EU) or other countries (e.g., Japan's Pharmaceutical and Medical Devices Agency [PMDA], Health Canada) may conduct inspections of clinical investigator sites in the U.S. In addition to complying with U.S. regulations, clinical investigator sites may be required to comply with non-U.S. requirements that are potentially more stringent (in some areas) than U.S. requirements.
If the field investigator becomes aware that a U.S. clinical investigator site has had an inspection by a non-U.S. inspectorate, this should be noted in the EIR (which inspectorate and the dates of the inspection).
Inspections of Non-U.S. Clinical Investigators – Human Drugs and Biologics
Sponsors are not required to conduct non-U.S. clinical trials under IND, but often submit data from such trials to FDA in support of marketing or research applications.
FDA recently 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 (http://www.fda.gov/oc/gcp/regulations.html). These regulations are 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 onsite inspection if the agency deems it necessary.
- The investigator’s qualifications;
- A description of the research facilities;
- A detailed summary of the protocol and study results, and if we request them, case records or additional background data;
- A description of the drug substance and drug product, including components, formulation, specifications, and, if available, the bioavailability of the drug product;
- Information showing that the study is adequate and well controlled (if the study is intended to support the effectiveness of the product);
- 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; 11
- A summary of the IEC’s decision to approve or modify and approve the study or to provide a favorable opinion;
- A description of how informed consent was obtained;
- A description of what incentives, if any, were provided to subjects to participate;
- A description of how the sponsors monitored the study and ensured that the study was consistent with the protocol; and
- 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 inspection involves a non-U.S. study that is not conducted under an IND, the documentation listed above may need to be verified on-site during the inspection. Consult with the Center contact about the need to verify such documentation.
- International Inspections - Devices
In general, according to 21 CFR 814.15, FDA will accept research in support of a PMA, but which has not been conducted under an IDE, provided that the data are valid and the studies are conducted in conformance with the "Declaration of Helsinki," 12 or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects.
Field investigators may be asked to conduct inspections of non-U.S. device studies, and to collect documentation as to the standards under which the study was conducted.
R. SAMPLE COLLECTION
Collect samples of the investigational product only upon specific instructions by the Center. For example, if irregularities in the product are suspected (e.g., if, in an investigational drug study, there is a noticeable difference in color, size, shape, dosage form, route of administration, etc., between the investigational drug and the placebo or control), the Center may request that investigational samples (1 package) of each be collected. Contact your supervisor and Center contact prior to collecting an investigational sample. [See Part IV - Analytical.]
5 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 or 812.145.
6 See Section 301(f) of the FFDCA, applicable sections of the PHS Act, and applicable regulations (e.g., 21 CFR 312.68, 812.145(c)).
7 FDA's Information Sheet Guidance on Payments to Research Subjects states, "While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable to FDA, providing that such incentive is not coercive. The IRB should determine that the amount paid as a bonus for completion is reasonable and not so large as to unduly induce subjects to stay in the study when they would otherwise have withdrawn. All information concerning payment, including the amount and schedule of payment(s), should be set forth in the informed consent document." [http://www.fda.gov/oc/ohrt/irbs/toc4.html]
8 See "Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs Improving Human Subject Protection" at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf.
9 Expanded access mechanisms for unapproved devices include emergency use and compassionate use. Emergency use is available when there is a serious disease or condition, no alternative, and no time to obtain FDA approval. Generally, FDA has considered this to be applicable when a patient is at risk for loss of life, limb or eyesight. Compassionate use is available for a single patient or group of patients that do not meet the study inclusion criteria where there is a serious disease or condition, and no alternative. Patient protection measures are the same for both: informed consent, IRB/chairperson’s approval; independent assessment; and institutional clearance. Compassionate use of a device under an approved IDE requires submission of an IDE supplement requesting approval of a deviation from the study protocol. 21 CFR 812.35(a).
10 A custom device is a device that has been custom developed for use by an individual patient under the order of a physician or dentist; or is intended to meet the needs of a physician or dentist in the course of professional practice. See 21 CFR 812.3(b) for a complete definition of custom device.
11 A Humanitarian Use Device (HUD) is a 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. (21 CFR 814.3(n))
12 21 CFR 312.120 defines "independent ethics committee" 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."
13 21 CFR 814 refers to the Declaration of Helsinki as revised in 1983. There have been subsequent revisions of the Declaration, but FDA has not officially adopted subsequent versions.