# Presentation: 873975

## The Role of the Investigator in Clinical Research

- Pat Beers Block
- Good Clinical Practice Program
- February 27, 2004

## Clinical Investigators

- As THE point of contact with study subjects, the Investigator is a critical control point
- The success of sponsors, IRBs and FDA in meeting their responsibilities depends on the investigator meeting his/her responsibilities
- FDA’s inspection program for clinical research has therefore focused most heavily on inspections of clinical investigators

## Definition of Clinical Investigator

- An individual who actually conducts a clinical investigation (i.e., under whose 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

- --21 CFR 312.3

## Definition of Clinical Investigator

- The definition is important because the clinical investigator assumes responsibility for the study site
- FDA can take administrative or even criminal action against a clinical investigator for repeated or deliberate violations of FDA regulations

## Subinvestigator(s)

- Other members of the team
- Should be directly involved with subjects in the study
- It is the investigator (and not the subinvestigator[s]) who is held responsible for the study site and subject to enforcement action for violations of FDA regulations

## The Form FDA “1572”

- For any IND study, the Clinical Investigator must complete and sign a Form FDA “1572” and provide this to the study sponsor
- Name and address of CI
- Name and code number of any protocol(s)
- Name and address of research facility and any clinical labs
- Name and address of the responsible IRB
- Names of subinvestigators
- Signed commitment by the investigator

## The “1572” Commitment

- The investigator is committing to follow all FDA regulations that relate to investigator responsibilities
- FDA assumes that in signing this commitment, the clinical investigator is familiar with and freely undertakes these regulatory responsibilities

## Medical Device Studies

- Key difference from FDA’s drug/biologics regulations:
- No FORM FDA 1572 for devices
- Instead, FDA device regulations require a signed investigator’s agreement

## Device Investigator’s Agreement (21 CFR 812.43(c))

- Still requires a signed statement of the investigator’s commitment to:
- Abide by the agreement, investigational plan, regulations, and IRB/FDA conditions of approval
- Supervise all testing involving human subjects
- Ensure informed consent
- Provide accurate financial disclosure information

## Clinical Investigator’s Responsibilities  -1-

***Personally*** conduct or supervise investigations
- Assure that all persons assisting in the conduct of the studies are informed of their obligations

## What FDA Looks For

- The extent of personal involvement by the clinical investigator
- Is there over-delegation ?
- Is there adequate personal training and supervision of staff ?
- Is the investigator devoting adequate time ?
- What are the limits:
- How many studies?  How many subjects?

## Clinical Investigator’s Responsibilities  -2-

- Ensure informed consent               (21 CFR Part 50) and IRB review, approval, and reporting requirements (21 CFR Part 56) are met

## What FDA Looks For

- Informed consent is more than a form -- it is a process
- How personally involved is the investigator in this process ?

## Clinical Investigator’s Responsibilities  -3-

- Read and understand the information in the Investigator’s Brochure, including the potential risks and side effects of the drug
- Note: FDA device regulations do not require an Investigator’s Brochure but rather a report of prior investigations of the device (in addition to a copy of the investigational plan)

## Clinical Investigator’s Responsibilities  -4-

- Conduct studies according to the relevant, current protocol
- Make changes in a protocol only after notifying the sponsor and the IRB
- Except where necessary to eliminate apparent, immediate hazards to the human subjects

## Clinical Investigator’s Responsibilities  -5-

- Maintain adequate and accurate records
- Records of the disposition of the drug including dates, quantity and use by subjects
- Case histories
- Case histories and supporting data

## What FDA Looks For

- Does the Investigator understand and apply the basic elements of data quality ?
- Attributable
- Legible
- Contemporaneous
- Original
- Accurate

## What FDA Looks For

- Can the investigator produce source data to corroborate the case report form ?
- FDA considers source data to be the first commitment of data to durable medium
- Generally where data are FIRST recorded

## Clinical Investigator’s Responsibilities  -6-

- Retention of Study Records
- For 2 years following date marketing application is approved for the drug for the indication it was investigated
- If no application is to be submitted or if the application is not approved for an indication until two years after the investigation is discontinued and FDA is notified

## Clinical Investigator’s Responsibilities  -7-

- Maintain control of the investigational product
- Administered under his/her personal supervision or under the supervision of a subinvestigator responsible to him/her

## What FDA Looks For

- Is the drug secure and properly stored ?  Does drug handling preserve “blinding” of the study ?
- Is drug administered only under the investigator’s personal supervision or under supervision of a subinvestigator responsible to the investigator ?

## Clinical Investigator’s Responsibilities  -8-

*Promptly* report adverse effects to the sponsor
- Any adverse event that may be reasonably regarded as caused by, or probably caused by the drug
- Ensure that any alarming adverse effects are *immediately* reported
- Serious and unexpected adverse events

## Clinical Investigator’s Responsibilities  -9-

*Promptly* report to the IRB all unanticipated risk to human subjects or others
- This language derives from the “Common Rule”  (applicable across U.S. federal agencies including and beyond FDA)
- For FDA-regulated research, “unanticipated risk” is most often interpreted as serious and unexpected AEs

## Clinical Investigator’s Responsibilities  -10-

- Timeframes for CI reporting are even more explicit in FDA device regulations
- Submit to the sponsor and IRB a report of *any* unanticipated device effect ASAP, but no later than 10 working days after CI learns of effect (21 CFR 812.150(a)(1))

## What FDA Looks For

- Are adverse events appropriately, accurately, and promptly identified, recorded and reported ?
- Is there immediate reporting of serious and unexpected AEs to facilitate sponsor reporting requirements ?
- Are CIs submitting reports to both sponsors and IRBs as required ?

## Clinical Investigator’s Responsibilities  -11-

- Required Reports to the Sponsor
- Progress Reports (to facilitate sponsor annual reporting requirements to FDA)
- Safety Reports (as above)
- Final Report
- “An adequate report shortly after completion of the investigator’s participation”
- Financial Disclosure Reports

## Financial Disclosure

- FDA regulations require that an applicant for a marketing application to FDA submit financial certification or disclosure information on each investigator or subinvestigator (including spouse/ dependent children) who is directly involved in the treatment or evaluation of subjects in covered studies
- FDA investigator regulations require that the sponsor be provided with sufficient accurate information to meet this requirement

## Clinical Investigator’s Responsibilities  -12-

- Make records available for FDA inspection (to copy and verify)
- Not required to divulge subject names unless records require more detailed study or unless there is reason to believe records do not represent actual case studies or results
- Agree to comply with all other requirements in FDA regulations

## Sponsor-Investigators

- FDA regulations allow an individual to be both study sponsor and clinical investigator
- This may include individuals who are studying an unapproved drug for academic purposes and not for commercial development of the drug
- For example, Physiology studies

## Sponsor-Investigators

- Sponsor-Investigators must comply with BOTH sponsor and clinical investigator regulations
- FDA is currently reviewing its approach to sponsor-investigators due to recent problems (including deaths of subjects) in two sponsor-investigator studies

## Who Can Be a Clinical Investigator

- Sponsors are responsible for choosing clinical investigators based on their having appropriate qualifications, training, and experience
- Usually a medical doctor, although dentists or other medical professionals may serve as clinical investigators if they are appropriately qualified to personally conduct or supervise the protocol

## Who Can Be a Clinical Investigator

- There is no U.S. government sponsored certification or training program for clinical investigators
- However, there are private training and certification programs for investigators in the U.S.
- The FDA does not endorse any particular program

## How Does FDA Identify Clinical Investigators

- FDA maintains a publicly available list of all clinical investigators who have been involved in a study under a U.S. IND
- Bioresearch Monitoring Information System (BMIS) File
- Accessible at www.fda.gov/oc/gcp  under “Related Web Sites”
- Includes all U.S. investigators as well as non-U.S. investigators who have been part of an IND study or submitted a “1572”

## How Does FDA Identify Clinical Investigators

- BMIS List
- Different from FDA’s list of inspected investigators and different from FDA’s list of disqualified or restricted investigators
- Being on this list does NOT imply anything about the clinical investigator’s qualifications or performance

## Challenges for FDA

- The list of clinical investigators continues to grow
- There are always new clinical investigators
- Many will participate in only a single trial
- The number of non-U.S. investigators on the list has grown 16-fold between 1991 and 1999
- Protocols are becoming more complex
- Education and training are the key to quality

## How to Reach Us

- Good Clinical Practice Programs
- 5600 Fishers Lane, Rm. 9C24
- Rockville, MD 20857
- 301-827-3340
- _[www.fda.gov/oc/gcp](http://www.fda.gov/oc/gcp)_
- _[Gcpquestions@oc.fda.gov](mailto:Gcpquestions@oc.fda.gov)_