Investigator's Roles and Responsibilities (28%-32%)

FDA considers medical records to be a part of:

Case histories

QA process in a clinical trial:

For clinical trial conduct at a clinical site, QA can be ensured through clinical site's internal reviews of current procedures, processes, and their documentations, such as standard operating procedures (SOPs), to find cause of issues or problems and a development and implementation of new procedures, processes, and SOPs to resolve them. This process can be called corrective and preventive actions (CAPA).

QC process in clinical trials:

For clinical trial conduct at a clinical site, QC is usually done through the monitoring of the clinical trial by the study monitor. However, investigator and clinical research coordinator (CRC) should not rely on the study monitor to detect issues or problems, but rather identify issues or problems and make corrections as needed.

FDA form used for medical device studies instead of 1572:

For medical device studies, an Investigator Agreement is used instead of FDA form 1572. An Investigator Agreement should contain similar wording of form 1572.

21 CFR 812.140(3)- Records:

Records of each subject's case history and exposure to the device. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes.

FDA form 1572 commitment from Investigator details:

1. Conduct the study(ies) following the current protocol(s) 2. Personally conduct or supervise the study(ies) 3. Obtain informed consent following 21 CFR 50 and 21 CFR 56 4. Report adverse event (AE) following 21 CFR 312.64 5. Properly train staff and employees 6. Maintain adequate and accurate records following 21 CFR 312.62 and 21 CFR 312.68 7. Ensure that an IRB that complies with 21 CFR 56 oversees the study(ies) 8. Comply with all other requirements in 21 CFR 312

Correct document errors by:

1. Draw a line through original entry 2. Write the correct entry next to the original 3. Initial and date next to the correction 4. Original and new entry should be clearly legible 5. Do not use white-out or use pen or pencil to completely cover or obliterate the error *Use black or blue pen (never use pencil or erasable ink)

Steps that can be taken to create a CAPA plan:

1. Identify the issue or problem and the root cause of that issue or problem. Identify the person(s) involved with the issue or problem 2. Determine the solution: -Create plans with measurable actions to resolve the issue or problem. -Describe the person(s) who will be involved 3. Set deadline for each action 4. Define how and at what time point(s) will the progress be monitored. 5. The details of the steps above should be compiled into a written document, a CAPA plan.

Primary responsibilities of the investigator:

1. Ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations 2. Protecting the rights, safety, and welfare of subjects under the investigator's care 3. Controlling the use of drugs under investigation

Common issues that FDA investigators found during site inspection include:

1. Failure to follow the investigational plan and signed investigator statement/agreement (e.g., failure to conduct or supervise the study in accordance with the relevant, current protocol(s)) 2. Protocol deviations (e.g., failure to appropriately document and report any medically necessary protocol deviations). 3. Inadequate record keeping. 4. Inadequate accountability for the investigational product. 5. Inadequate subject protection, including informed consent issues.

The role of investigator with regards to protocol(s):

1. For investigator initiated study, the investigator is responsible to develop the study protocol and its content. 2. The protocol developed by the investigator should contain the sections recommended by ICH GCP and commonly used in industry. 3. For sponsor initiated study, the investigator is generally provided with a protocol from the sponsor. 4. the investigator should conduct the trial in accordance with the protocol. 5. FDA form 1572 also requires that the protocol be reviewed and approved by a 21 CFR 312.62 complied IRB. Any changes in research should be reported to the IRB prior to implementation (except emergency situation to prevent immediate hazards to subjects).

Examples of Source documents:

1. Hospital records 2. Clinical and office charts 3. Laboratory notes 4. Memoranda 5. Subjects' diaries or evaluation checklists 6. Pharmacy dispensing records 7. Recorded data from automated instruments 8. Copies or transcriptions certified after verification as being accurate copies 9. Microfiches 10. Photographic negatives, microfilm, or magnetic media 11. X-rays 12. Subject files 13. Records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial.

Safety Reports (Investigator):

1. Investigator is required to report any serious adverse events 2. (SAEs), whether or not considered drug related, to sponsor immediately after discovery. This includes known SAEs that are listed in the Investigator Brochure or protocol. 3. SAE reporting to the reviewing IRB is also required promptly upon discovery. 4. Non-serious adverse events are to be recorded and reported to the sponsor following description in the protocol. 5. For device studies, the investigator must report any unanticipated adverse device effects to the sponsor and to the reviewing IRB as soon as possible, but no later than 10 working days after discovery.

Continuing Reviews (Investigator):

1. Investigator is required to submit progress reports to the sponsor. 2. The regulation does not specifically state the time and frequency needed for the progress report, however the sponsor is required to submit annual reports to FDA on the progress of the clinical study.

Informed Consent Documents and Recruiting Materials (Investigator):

1. Investigator should develop informed consent documents that contain the basic and additional elements of informed consent listed in 21 CFR 50.25. 2. Informed consent form and recruiting materials must be reviewed and approved by the IRB prior to use (21 CFR 56.109). 3. The investigator must also ensure that each new version of informed consent form and recruiting materials are reviewed and approved by the IRB prior to use.

Common practices for investigational product accountability at site:

1. Maintain complete records (include dates, quantities, batch/serial numbers, expiration dates, unique code numbers) of: -Product's delivery to the trial site -Inventory at the site -Product dispense -Usage by each subject -Product returned to the sponsor -Unused product disposed. 2. Reconcile all investigational product(s) received from the sponsor 3. Train the correct use of the investigational product(s) to each subject 4. Check, at appropriate intervals, that each subject is following the instructions properly

Describe the maintenance of essential study related documents (investigator):

1. Maintain trial documents (as specified in Essential Documents for the Conduct of a Clinical Trial) as required by the applicable regulatory requirement(s). 2. Take measures to prevent accidental or premature destruction. 3. Maintenance of essential documents includes both paper version and electronic version.

When the source data is printed on thermal paper:

1. Make a photo copy of the source data onto regular paper 2. Write on the photo copy that it is an exact copy of the original information 3. Sign, initial, and date 4. Keep both the copy and the source data on thermal paper in the same place. Note: information on thermal paper may fade over time. Above procedure will ensure that information is retained on the photo copy.

Following 21 CFR 50.20 an investigator is responsible for:

1. Obtaining legally effective informed consent of the subject or the subject's legally authorized representative 2. Providing the prospective subject or the representative sufficient opportunity to decide 3. Minimizing the possibility of coercion or undue influence 4. Providing information in language understandable to the subject or the representative 5. Avoiding any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

Measures that can be taken to maintain essential documents (investigator):

1. Organize documents into appropriate sections. 2. File documents in chronological order (e.g. file the most recent documents on top). 3. Use file note to explain any missing documents or documents stored at another location. *Avoid duplicate filing. 4. Store essential documents in a secure central location with control access. 5. Electronic documents should be kept secured with limited access to only study personnel. 6. When archiving, document inventory of items to be archived.

During Subject Study Visits- what activities are commonly performed by the Investigator?

1. Perform or oversee trial related procedures according to study protocol 2. Provide medical decisions or ensure that a qualified physician (Co-PI or sub-investigator) is responsible for trial-related medical decisions 3. Assess subject compliance with the investigational treatment: -Evaluate subject's response to investigational treatment -Assess adverse events and provide appropriate medical care.

Main requirement for an investigator regarding source documents is to:

1. Prepare and maintain adequate and accurate case histories (e.g. case report forms, informed consent forms, source documents or medical records) [21 CFR 312.62 (b), 21 CFR 812.140 (a)] 2. Document informed consent [21 CFR 812.140 (3)(i)] 3. Record in case histories (e.g. source documents or medical records) that informed consent was obtained prior to participation in the study [21 CFR 312.62 (b), 21 CFR 812.140 (3)(i)] 4. Record all observations and other relevant data (e.g. adverse events, previous medical history, test results) [21 CFR 312.62 (b), 21 CFR 812.140 (3)(ii)] 5. Document treatment given to subjects [ 1 CFR 812.140 (3)(iii)]

21 CFR 312.64 requires an investigator to provide the following items to sponsor company:

1. Progress reports (e.g. annual report) 2. Safety reports (e.g. adverse events (AEs) and / or serious adverse events (SAEs) report) 3. Final report 4. Financial disclosure report (during the study and for 1 year after study completion)

Follow Up Care activities by the Investigator:

1. Provide or refer subject on medical care needed for any intercurrent illness(es) 2. Inform the subject's primary care physician as needed

Measures that an investigator can take to help increase subject retention during the trial:

1. Provide subjects with complete understanding about the treatment risks, procedures required 2. Treat each subject with respect 3. Provide appropriate incentives for study completion without causing undue coercion 4. Utilize tools to enhance trial experience: -Provide visit calendar and provide phone / e-mail reminder -Allow flexibility in appointment date and timing within the limits of protocol -Train staff in customer service skills

Items that should be documented when a subject is discontinued from a trial:

1. Source - whether the discontinuation / withdrawal resulted from a decision by the subject or by the investigator 2. Reason - the reasons for the discontinuation / withdrawal 3. Impact - whether the withdrawal was from all components of the research study or just the primary interventional component.

Method or approach that an investigator should take when abstracting and verifying information from source documents (e.g. medical records):

1. Start with a strategy. Identify the data needed. How and when to obtain the information. 2. Create and use standard procedure for abstracting and verifying information 3. Determine the quality of the source data prior to abstraction. Is it up to date and complete? What needs to be done? 4. Consider different methods (e.g. scanning and capturing, manual abstraction, etc.). 5. Explore ways to increase efficiency: *Example: Batching, perform similar task for multiple number of patients (e.g. abstract one measurement, such as heart rate, for multiple patients at a time). This may help increase efficiency and reduce error. 6. Verify information (e.g. 2nd review, double data entry).

When making corrections, what 4 items should be visible:

1. The old value / text 2. The new value / text 3. The date that the correction was made 4. The name or initial of the person making the correction *If the reason for the change is not apparent, an explanation can also be written

Recruitment and Screening (Investigator):

A fair procedure for subject selection should be used in recruiting and screening for subjects by an investigator. Any material used in the recruiting of potential subject (flyers, advertisements, and phone scripts for screening, etc.) should be approved by the IRB prior to being used (21 CFR 56.109)

FDA form 1572:

A signed declaration of the investigator that he or she will comply with FDA regulations on clinical trial conduct.

21 CFR 50.25 (a) (8):

Allows a subject to discontinue / withdraw participation in clinical trial at any time without penalty or loss of benefits. The regulation also allows for an investigator to discontinue / withdraw the subject's participation in clinical trial

Section 1.51 of IHC GCP guideline defines source data as:

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

Quality Assurance (QA) definition:

All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).

Investigator definition:

An individual who actually conducts a clinical investigation (i.e. , under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.

21 CFR 312.62(b)- Case Histories:

An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

Responsibilities of investigators:

An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this chapter.

21 CFR 312.61 describes the responsibility of an investigator for investigational product use and access in drug trials:

An investigator shall administer the drug only to subjects under the investigator's personal supervision or under the supervision of a subinvestigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized under this part to receive it.

21 CFR 312.62 (c) describes record retention requirement for an investigator as:

An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified (i.e. 2 years after FDA approval or 2 years after study end). Records should be kept for the above period due to the possibility of audit or FDA inspection

21 CFR 312.68:

An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to 312.62. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained.

Investigator's responsibility in obtaining informed consent of each subject:

An investigator shall, in accordance with the provisions of part 50 of this chapter (21 CFR 312.60), obtain the informed consent of each human subject to whom the drug is administered

ALCOA* stands for:

Attributable: who wrote it? Legible: can it be read? Contemporaneous: is the information being recorded at the time of the event? Is it written in the correct time frame? Is there a correction? If so, when and by whom? Original: is it the first place information was recorded? Is it a copy? Has it been altered? Accurate: is it accurate? Are there conflicting data elsewhere?

When Can Case Report Forms (CRFs) Be Used As Source Documents?

Case report forms (CRFs) may be used as source documents if the first recording of information was done on the CRFs. To be considered as a source document, the original CRF must be signed, initialed, and dated by the person recording the information. Note: additional source documentation may be needed to support CRFs considered as source documents (e.g. SAE reporting form may be used as source document, however, medical records, notations, lab results, etc. may be needed to support the SAE reporting).

Section 4.11 Source Documentation / Case Report Forms, section 4.9 of ICH GCP guideline:

Describes the expectation for information that are recorded onto CRF from source documents.

21 CFR 312.62 (a) requires investigator to keep records for:

Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 312.59.

Essential documents for the conduct of clinical trial (section 8 ICH GCP guideline):

Documents that permit evaluation of the conduct of a trial and the quality of the data produced. Essential documents are usually requested during an audit by the sponsor and inspected by the regulatory authority(ies). An investigator should ensure that essential documents are kept and available for any inspection. Protocol(s) and Protocol Related Document(s) are included in the essential documents list

The primary responsibility of an investigator during subject study visits:

Ensure that protocol procedures are followed and that subject's medical care are provided.

21 CFR 50.27 (a) requires documentation of informed consent as:

Except as provided in 56.109(c), informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject's legally authorized representative at the time of consent. A copy shall be given to the person signing the form.

21 CFR 812.140 (a) (4) requires:

Investigator must keep records on study protocol with documents showing the dates of and reasons for each deviation from the protocol. Although the documents listed above are required separately for drug and medical device, investigator should still maintain the above documents as part of best practices.

IRB reporting of discontinuation / withdrawal:

May be needed for research involving more than minimal risk. Overseeing IRB should clearly state its requirements on discontinuation / withdrawal reporting. Although not specifically stated on FDA regulation, discontinuation / withdrawal of subjects based on adverse events (AEs) and / or serious adverse events (SAEs) should be reported to FDA and other appropriate parties

Source documents are defined in section 1.52 of ICH GCP guideline to include:

Original documents, data, and records.

Controlled substance Act, 21 CFR 312.69:

Requires that investigational product be kept in secure location with control access: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.

Section 2.13 of the ICH GCP guideline recommends that:

Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Quality Control (QC) definition:

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

21 CFR 812.110 (c) also has similar wording for medical device trials:

The regulations require that an investigator administer the investigational product or supervise appropriate staff who will be administering.

How an investigator should approach case report forms (CRFs) completion:

With regards to source documentation and CRFs, an investigator is to: 1. Ensure the accuracy, completeness, legibility, and timeliness of the data in the CRFs. 2. Confirm that data copied on the CRF from source documents match with the original entry in source documents. Any discrepancies should be explained. 3. Make sure that any change or correction to a CRF be dated, initialed, and explained (if necessary) and should not obscure the original entry. 4. The investigator should retain records of the changes and corrections.