Clinical Researcher—February 2022 (Volume 36, Issue 1)

PEER REVIEWED

Steven Eric Ceh, DPM

 

The terms “investigator,” “co-investigator,” “clinical investigator,” “principal investigator,” “co-principal investigator,” “study principal investigator,” and “sub-investigator” are often used loosely. This article clarifies the roles and responsibilities for each term according to U.S. regulations and international guidance, with the following factors in mind:

• The terms investigator, principal investigator, and clinical investigator are interrelated but not necessarily synonymous.
• Sub-investigators are individual members of the research team and are not equivalent to investigators.
• Co-investigator and co-principal investigator are uncommon, misunderstood terms.
• Clinical investigator, as described in 21 CFR Part 54 in the Code of Federal Regulations,{1} differs from the term used in 21 CFR Parts 312 and 812, which is a cause for confusion.

Detailed information and discussion follow, with a review of key references that will provide clarity for these terms.

How Are These Terms Defined?

21 CFR 312.3 states that “investigator” means “an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject).” Similarly, 21 CFR 812.3 states that “investigator” means “an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered to, or used involving, a subject …” Both of these definitions also specify: “In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team.” 21 CFR 312.53(a) states that investigators are “qualified by training and experience as appropriate experts to investigate the drug.”

The International Council for Harmonization E6(R2) Good Clinical Practice (ICH GCP) guideline{2} states in section 1.34 that an investigator is “a person responsible for the conduct of a clinical trial at a trial site.” It further states: “If a trial is conducted by a team of individuals at a site, the investigator…may be called the principal investigator.” Therefore, the term principal investigator is an appropriate term whenever there are one or more team individuals in addition to a single investigator. However, “investigator” is primarily used throughout the regulations. The term co-principal investigator is not defined, as it is not possible to have more than one outright leader and, therefore, should not be used. Also, study sponsors will sometimes designate an investigator in a multisite study to be the study principal investigator and team leader over the other site investigators.

ICH GCP 4.4.1 adds that an investigator “should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial and should meet all the qualifications specified by the applicable regulatory requirement(s) and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the [institutional review board/institutional ethics committee (IRB/IEC)] and/or the regulatory authority(ies).” ICH GCP 2.7 adds that “the medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.”

The U.S. Food and Drug Administration (FDA) Compliance Program Manual 7348.811 for the agency’s Bioresearch Monitoring (BIMO) Program utilizes the term “clinical investigator” and states{3}:

A clinical investigator is the individual who conducts the clinical investigation. The clinical investigator is responsible for overall conduct of the study at the clinical site, including directing the administration or dispensing of the investigational product to the subject and ensuring that data are collected and maintained in accordance with the protocol and applicable regulatory requirements. When the investigation is conducted by a team of individuals, the clinical investigator is the responsible leader of the team.

With that, the term clinical investigator encompasses “investigator” as stated in 21 CFR 312 and 812 and “principal investigator” as stated in ICH GCP 1.34.

The term “clinical investigator” is also used in a document on “Financial Disclosure by Clinical Investigators—Guidance for Clinical Investigators, Industry, and FDA Staff” from 2013.{4} Those individuals who would be clinical investigators under 21 CFR Part 54 are individuals listed on lines 1 and 6 of the Form FDA 1572 (Statement of Investigator) (drug study) and the investigator and all individuals designated by him/her as sub-investigators (device study). Therefore, one must be careful of the context when referring to an individual as a clinical investigator. How the terminology differs from that of 21 CFR Parts 312 and 812 is further discussed below.

In a 2010 document on “Frequently Asked Questions—Statement of Investigator (Form FDA 1572)—Guidance for Sponsors, Clinical Investigators, and IRBs,”{5} question 21 addresses the term co-investigator and states:

As commonly used, the term is meant to indicate that each co-investigator is fully responsible for fulfilling all the obligations of an investigator as identified in 21 CFR 312.60. Thus, under 21 CFR 312.3(b), each co-investigator is an investigator, and as such must sign a separate 1572.

Who Can be a Principal Investigator?

Section 505 of the Food, Drug, and Cosmetic (FD&C) Act{6} requires the FDA to ensure that the investigational drug will be provided only to investigators who are “experts qualified by training and experience to investigate a new drug.”

The FDA has the following to say about non-physicians as investigators:

While technically a non-physician can be an investigator, this requires that the non-physician be qualified to personally conduct or personally supervise all aspects of the study. In practice, we have found it rare that a non-physician can comply with this requirement. In general, where we have seen non-physicians on the Form FDA 1572 as an investigator, we usually would find an MD as a sub-investigator to perform those study functions requiring the appropriate level of medical expertise.

Qualified individuals who are not (MDs/licensed physician) can participate in clinical trials as an investigator or sub-investigator provided that an MD, DO, DPM, or D.D.S. is listed in the [Investigational New Drug application] as an individual who will be responsible for diagnosis and treatment of disease, drug administration, and evaluation of safety.{7}

An FDA Office of Medical Policy communication has stated the following{8}:

Protocol-required tasks must be performed by the individuals specified in the protocol. For example, if the state [or jurisdiction] in which the study site is located permits a nurse practitioner or physician’s assistant to perform physical examinations under the supervision of a physician, but the protocol specifies that physical examinations must be done by a physician, then a physician must perform such exams.

As a result, a clinical psychologist could serve as investigator with an MD sub-investigator. Similarly, a Doctor of Pharmacy could serve as investigator of a pharmacological study with an MD sub-investigator. In theory, anyone qualified to conduct a clinical study who is not an MD or dentist could be an investigator, provided an MD or dentist handles the medical (or dental) decisions and care as sub-investigator or co-investigator.{7}

Nurse practitioners have full medical practice privileges in 22 states: Alaska, Arizona, Colorado, Connecticut, Hawaii, Idaho, Iowa, Maine, Maryland, Massachusetts, Minnesota, Montana, Nebraska, New Hampshire, New Mexico, North Dakota, Oregon, Rhode Island, South Dakota, Vermont, Washington, and Wyoming, as well as the District of Columbia.{9,10} In these states, nurse practitioners can be autonomous principal investigators; other similar emerging autonomous roles for nurses (e.g., advanced practice registered nurse [APRN]) are occurring in some states. However, that is currently not the case for physician assistants, who still work under the supervision of a physician, although there is currently legislation in several states to allow them to be independent practitioners.

Lastly, there can be instances where other healthcare practitioner/specialists can be an autonomous investigator based on their expertise, training, licensure, and the scope of the investigative study. Such an example would be an optometrist (OD) serving as the investigator on a study evaluating marketed pharmaceutical products or medical devices (e.g., contact lenses, lens care products, punctal plugs) where the inclusion of an MD on the 1572 or equivalent medical device form is not necessary.

Sponsors are responsible for selecting qualified investigators and often have the opportunity to discuss investigator qualifications with FDA prior to study implementation. The FDA’s acceptance of an investigator may vary with the FDA division, the indication, safety risk, study phase, and approval status, but this individual should always be an expert qualified by training and experience to investigate a new drug or device.

Who Must Make Financial Disclosures?

The aforementioned FDA guidance on “Financial Disclosure by Clinical Investigators” states the following{4}:

Section III A specifies the individuals for whom reporting under this regulation is required. Generally, these individuals are the investigators and sub-investigators taking responsibility for the study at a given study site. The sub-investigators are delineated in Section 6 of the Form FDA 1572 completed by the investigator. The definition also includes the spouse and dependent children of each investigator or sub-investigator.

For purposes of [21 CFR Part 54], “clinical investigator” means a “listed or identified investigator or sub-investigator who is directly involved in the treatment or evaluation of research subjects,” including the spouse and each dependent child of the investigator or sub-investigator. (See 21 CFR § 54.2(d).).

Therefore, this would be the investigator and all of the individuals designated by him/her as sub-investigators (i.e., other physicians, pharmacists, research fellows, residents, study coordinators, data coordinators, etc.).

Section IV D of this guidance discusses how the above definition differs and is otherwise not equivalent with investigators as defined in 21 CFR 312 and 812:

For drugs and biological products, an investigator under 21 CFR Part 312 is defined as “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.” This is the individual listed on line 1 of the Form FDA 1572 of a research site.

For medical devices, investigator is defined under 21 CFR Part 812 as “an individual under whose immediate direction the subject is treated and the investigational device is administered, including follow-up evaluations and treatments. Where an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. (21 CFR § 812.3(i).)” This is the individual listed as the investigator on the medical device study Investigator Agreement.

Who is a Sub-Investigator?

The aforementioned FDA resource on “Frequently Asked Questions—Statement of Investigator (Form FDA 1572),” under Question 31, discusses how investigators and sub-investigators are defined and documented in a clinical study{5}:

FDA regulation 21 CFR 312.3(b) states: “In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. ‘Sub-investigator’ includes any other individual member of that team.’ 21 CFR 312.53(c)(1)(viii) requires the investigator to provide ‘a list of the names of the sub-investigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s).’”

The purpose of Section #6 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether they are performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol and the collection of data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6.”

It is important to note that some sub-investigators will be licensed physicians/practitioners who were at one time an investigator for a study or have the qualifications to be one and thereby be appropriate for delegation of certain duties by the principal investigator. Further, sub-investigators have no automatic responsibilities—only those which are delegated to him/her by the investigator and which he/she is qualified to do.

Questions 32 and 33 offer clarification as to whether hospital staff, nurses, residents, fellows, office staff, pharmacists, or research coordinators should be listed on the 1572:

It is a matter of judgment, dependent upon the contribution that the individual makes to the study. For example, a research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution. Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a sub-investigator in Section #6, but he/she should be listed in the investigator’s study records.

Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.

However, according to an informal response from FDA,{11} the Center for Devices and Radiologic Health would not consider research study coordinators to be sub-investigators unless they had the required expertise/training to also perform study-related procedures and this was noted on the study delegation log.

Sub-Investigators and the Assessment of Adverse Events

Just because someone is listed in the aforementioned Section #6 of Form FDA 1572 as a sub-investigator who will be assisting the investigator in the conduct of the investigation(s) does not mean they are qualified to be an investigator, can perform an investigator’s tasks, or bear an investigator’s responsibilities.

Per formal communication{8} with the Office of Medical Policy:

Listing someone [in Section #6] does not equate them to an investigator. In addition, the investigator is responsible for ensuring that any individual to whom a task is delegated is ‘qualified by education, training, and experience (and state licensure where relevant) to perform the delegated task’—and is not assumed to be qualified only on the basis of belonging to a particular category of healthcare professional nor only from having been included [in Section #6] of Form FDA 1572. Per 21 CFR 312.3, sub-investigator means any other individual member of that (clinical) team.

The FDA also indicates “a sub-investigator role in the clinical investigation is more limited.”{5} A specific case in point is registered nurses performing causality assessments under the guise of being considered clinical investigators when included in Section #6 of Form FDA 1572 or clinical investigators per the financial disclosure regulation.

The following formal communications and references{12} offer clarity:

• “While the investigator can delegate tasks to others in a study, it appears the investigator should assess Adverse Event (AE) causality and severity and report his/her findings to the sponsor. The investigator is required to report serious [AEs] to the sponsor and must include an assessment on whether there is a reasonable possibility that the drug caused the event (21 CFR 312.64). The sponsor is required to report serious and unexpected suspected adverse reactions to FDA and all participating investigators (21 CFR 312.32(c)(1). That said, much of this depends upon who is required by the study protocol to make the AE causality and severity decision. If the sponsor specifically wants it to be made by the clinical investigator, then the investigator would be incorrect in delegating this responsibility and it would be considered a protocol deviation to do so.”
• “Assessment of causality when evaluating [AEs] by the investigator is a complex clinical determination that requires an understanding of the risks of the investigational agent and an assessment of the totality of clinical factors related to the event, and such assessments are done typically by a licensed physician, whose qualifications are captured in Section 2 (of the Form FDA 1572).”
• The FDA Compliance Program 7348.811 Manual further implies that a clinical investigator should be performing safety AE evaluations and determined as such by the FDA Field Inspector when conducting a site inspection so, having someone other than a clinical investigator perform the assessment would pose an audit risk. The Field Inspector is to: “Compare the source documents with [case report forms] and any background information provided (e.g., data tabulations provided by the sponsor) per the assignment memorandum and sampling plan (if applicable) and…Determine: The clinical investigator assessed the severity of the [AE] and documented the relationship of the event to the test article, including any [AE] that was previously anticipated and documented by written information from the sponsor.Determine: The clinical investigator assessed safety monitoring, including documentation of [AEs] (or other treatment-related safety concerns), assessment of the severity of the [AE] and relationship of the [AE] to the investigational product, and any changes to the subject’s participation on the study related to the [AEs] (e.g., study discontinuation/termination).”

The rules above for assessing AE causation also apply to signing lab reports and any other responsibility that requires the expertise of a physician or dentist.

Responsibilities Listed On the Form FDA 1572

Form FDA 1572 does not list all investigator responsibilities. Per the 2009 guidance for industry on “Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects,”{13} a more comprehensive listing of FDA’s requirements for the conduct of device, drug and biologics studies by investigators is found in 21 CFR Parts 11, 50, 54, 56, and 312/812.

Obtaining Informed Consent

In many states, the investigator has a specific role in or related to the informed consent process that cannot necessarily be delegated. The following are some examples:

Pennsylvania. A Pennsylvania Supreme Court ruling in the case of Shinal v. Toms, M.D. stated that a physician must obtain informed consent.{14}

Indiana. A patient who has given informed consent for administration of experimental treatment in a clinical trial can only receive the treatment if a licensed physician has personally examined the subject and agreed to treat them. Mental health patients must be informed of the investigator’s credentials.{15}

Minnesota. Subjects in state hospitals require the investigator to provide certification that the subject is competent to consent.{16}

Montana. If a subject is a resident of a mental health facility, the investigator must send a notice of intent to enroll to the subject, their next of kin, and their attorney.{17}

California. An investigator who negligently allows or willfully fails to obtain a subject’s consent is liable for fines to be paid to the subject per California Health and Safety Code §24176.{18} The state also requires all subjects be given a copy of California’s Experimental Subject Bill of Rights (California Health and Safety Code §24172).{19}

Other states in which the investigator has specifications or requirements for certain types of subjects include Delaware, Illinois, Maine, Missouri, Nevada, New Hampshire, New York, North Carolina, Oregon, Texas, Utah, and Wisconsin. Please note, each state’s rules vary and a complete analysis is beyond the scope of the current article.

Conclusion

After evaluating all of the definitions and clarifications of misconceptions, we could expect that the investigator for a clinical trial will be a licensed physician identified as an investigator (or clinical investigator) in initial submissions or protocol amendments under an Investigational New Drug/Investigational Device Exemption whose name is listed in Section 1, qualifications (by training and experience as an appropriate expert to investigate the drug) are captured in Section 2, and who completes and signs the Form FDA 1572 (Statement of Investigator), assumes the responsibilities denoted on it including those outlined in 21 CFR Parts 11, 50, 54, 56, and 312/812, and completes a financial disclosure form. When the investigation is conducted by a team of individuals, the clinical investigator is the responsible leader of the team and is called the principal investigator.

In a small number of cases, an investigator can be an autonomous practitioner/specialist such as a nurse practitioner who meets the education, training, and experience requirements noted in 22 states and the District of Columbia.

Although very uncommon, there are scenarios where an investigator need not be a licensed physician, provided that a licensed physician(s) be included on the Form FDA 1572 as a sub-investigator to handle patient assessments, make medical decisions, provide care, and perform some or all safety review including AE severity and causality assessments. Responsibilities listed on the Form FDA 1572 and 21 CFR Parts 11, 50, 54, 56, and 312/812 therefore need to be handled by multiple personnel, including at least one licensed physician.

Equally uncommon is the use of co-investigators at a clinical site, both of whom would separately sign a Form FDA 1572. This would include at least one licensed physician/practitioner whose shared responsibility and leadership with another investigator would not necessarily be equal, but would include all obligations required of an investigator.

References

1. Title 21 of the Code of Federal Regulations at https://www.ecfr.gov/current/title-21.
2. ICH Good Clinical Practice E6(R2) at https://www.ich.org/page/efficacy-guidelines.
3. The FDA BIMO Compliance Program Manual 7348.811 at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-program-manual/bioresearch-monitoring-program-bimo-compliance-programs.
4. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/financial-disclosure-clinical-investigators
5. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/frequently-asked-questions-statement-investigator-form-fda-1572
6. See information on Section 505 of the FD&C Act at https://biotech.law.lsu.edu/blaw/fda/fdcact5a.htm. FD&C Act Chapter 5 on Drugs and Devices can be viewed at https://www.fda.gov/regulatory-information/federal-food-drug-and-cosmetic-act-fdc-act/fdc-act-chapter-v-drugs-and-devices.
7. Barnett International. GCP: A Question & Answer Reference Guide, Section 2: Investigators/Sites. (Outdated edition)
8. Per communication between the author and the FDA Office of Medical Policy (October 2019). https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-medical-policy
9. See information from American Association of Nurse Practitioners on “State Practice Environment” at https://www.aanp.org/advocacy/state/state-practice-environment.
10. Japsen B. 2017. More States Lift Patient Hurdles to Nurse Practitioners. Forbes. https://www.forbes.com/sites/brucejapsen/2017/02/24/another-state-lifts-patient-hurdles-to-nurse-practitioners/?sh=3b44ec6d5fc8
11. GCP Q&A: Focus on Subinvestigators, 2021. Journal of Clinical Research Best Practices 17(5).
12. U.S. Office of Good Clinical Practice. Communications regarding adverse events from March 2013, September 2014, and October 2019. https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/replies-inquiries-fda-good-clinical-practice
13. Guidance for Industry Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, Procedural October 2009, Section II. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigator-responsibilities-protecting-rights-safety-and-welfare-study-subjects
14. See information on Shinal v. Toms, M.D., 162 A.3d 429 (2017) at https://law.justia.com/cases/pennsylvania/supreme-court/2017/31-map-2016.html.
15. https://www.indianapolis-medical-malpractice-lawyer.com/medical-malpractice/informed-consent/
16. https://www.revisor.mn.gov/statutes/cite/253B.04
17. https://dphhs.mt.gov/assets/amdd/MSH/volumeii/patientrights/InformedConsentForTreatment.pdf
18. https://codes.findlaw.com/ca/health-and-safety-code/hsc-sect-24176.html
19. https://codes.findlaw.com/ca/health-and-safety-code/hsc-sect-24172.html

Steven Eric Ceh, DPM, (sec_consulting@sbcglobal.net) is a Consultant with SEC Clinical Consulting, Ltd. In Westerville, Ohio.