III. Clarification of certain investigator responsibilities. FDA Guidance for Industry
This section of the guidance clarifies the investigator’s responsibility to supervise the conduct of the clinical investigation and to protect the rights, safety, and welfare of participants in drug and medical device clinical trials.
A. Supervision of the Conduct of a Clinical Investigation
As stated above, investigators who conduct clinical investigations of drugs, including biological products, under 21 CFR Part 312, commit themselves to personally conduct or supervise the investigation. Investigators who conduct clinical investigations of medical devices, under 21 CFR Part 812, commit themselves to supervise all testing of the device involving human subjects. It is common practice for investigators to delegate certain study-related tasks to employees, colleagues, or other third parties (individuals or entities not under the direct supervision of the investigator). When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. The investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the clinical study.
In assessing the adequacy of supervision by an investigator, FDA focuses on four major areas: (1) whether individuals who were delegated tasks were qualified to perform such tasks, (2) whether study staff received adequate training on how to conduct the delegated tasks and were provided with an adequate understanding of the study, (3) whether there was adequate supervision and involvement in the ongoing conduct of the study, and (4) whether there was adequate supervision or oversight of any third parties involved in the conduct of a study to the extent such supervision or oversight was reasonably possible.
1. What Is Appropriate Delegation of Study-Related Tasks?
The investigator should ensure 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. Appropriate delegation is primarily an issue for tasks considered to be clinical or medical in nature, such as evaluating study subjects to assess clinical response to an investigational therapy (e.g., global assessment scales, vital signs) or providing medical care to subjects during the course of the study. Most clinical/medical tasks require formal medical training and may also have licensing or certification requirements. Licensing requirements may vary by jurisdiction (e.g., states, countries). Investigators should take such qualifications/licensing requirements into account when considering delegation of specific tasks. In all cases, a qualified physician (or dentist) should be responsible for all trial-related medical (or dental) decisions and care (Guidance for industry, E6 Good Clinical Practice: Consolidated Guidance, section 4.3.1.).
During inspections of investigation sites, FDA has identified instances in which study tasks have been delegated to individuals lacking appropriate qualifications. Examples of tasks that have been inappropriately delegated include:
Screening evaluations, including obtaining medical histories and assessment of inclusion/exclusion criteria
- Physical examinations
- Evaluation of adverse events
- Assessments of primary study endpoints
- Obtaining informed consent
The investigator is responsible for conducting studies in accordance with the protocol (see 21 CFR 312.60, Form FDA-1572, 21 CFR 812.43 and 812.100). In some cases a protocol may specify the qualifications of the individuals who are to perform certain protocol-required tasks (e.g., physician, registered nurse), in which case the protocol must be followed even if state law permits individuals with different qualifications to perform the task (see 21 CFR 312.23(a)(6) and 312.40(a)(1)). For example, if the state 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, a physician must perform such exams.
The investigator should maintain a list of the appropriately qualified persons to whom significant trial-related duties have been delegated (Ibid, section 4.1.5.). This list should also describe the delegated tasks, identify the training that individuals have received that qualifies them to perform delegated tasks(e.g., can refer to an individual’s CV on file), and identify the dates of involvement in the study. An investigator should maintain separate lists for each study conducted by the investigator.
2. What Is Adequate Training?
The investigator should ensure that there is adequate training for all staff participating in the conduct of the study, including any new staff hired after the study has begun to meet unanticipated workload or to replace staff who have left. The investigator should ensure that staff:
- Are familiar with the purpose of the study and the protocol
- Have an adequate understanding of the specific details of the protocol and attributes of the investigational product needed to perform their assigned tasks
- Are aware of regulatory requirements and acceptable standards for the conduct of clinical trials and the protection of human subjects
- Are competent to perform or have been trained to perform the tasks they are delegated
- Are informed of any pertinent changes during the conduct of the trial and receive additional training as appropriate
If the sponsor provides training for investigators in the conduct of the study, the investigator should ensure that staff receive the sponsor’s training, or any information (e.g., training materials) from that training that is pertinent to the staff's role in the study.
3. What Is Adequate Supervision of the Conduct of an Ongoing Clinical Trial?
For each study site, there should be a distinct individual identified as an investigator who has supervisory responsibility for the site. Where there is a subinvestigator at a site, that individual should report directly to the investigator for the site (i.e., the investigator should have clear responsibility for evaluating the subinvestigator’s performance and the authority to terminate the subinvestigator’s involvement with the study) and the subinvestigator should not be delegated the primary supervisory responsibility for the site. The investigator should have sufficient time to properly conduct and supervise the clinical trial. The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population. In FDA’s experience, the following factors may affect the ability of an investigator to provide adequate supervision of the conduct of an ongoing clinical trial at the investigator’s site:
- Inexperienced study staff
- Demanding workload for study staff
- Complex clinical trials (e.g., many observations, large amounts of data collected)
- Large number of subjects enrolled at a site
- A subject population that is seriously ill
- Conducting multiple studies concurrently
- Conducting a study from a remote (e.g., off-site) location
- Conducting a study at multiple sites under the oversight of a single investigator, particularly where those sites are not in close proximity
The investigator should develop a plan for the supervision and oversight of the clinical trial at the site. Supervision and oversight should be provided even for individuals who are highly qualified and experienced. A plan might include the following elements, to the extent they apply to a particular trial:
- Routine meetings with staff to review trial progress, adverse events, and update staff on any changes to the protocol or other procedures
- Routine meetings with the sponsor’s monitors
- A procedure for the timely correction and documentation of problems identified by study personnel, outside monitors or auditors, or other parties involved in the conduct of a study
- A procedure for documenting or reviewing the performance of delegated tasks in a satisfactory and timely manner (e.g., observation of the performance of selected assessments or independent verification by repeating selected assessments)
- A procedure for ensuring that the consent process is being conducted in accordance with 21 CFR Part 50 and that study subjects understand the nature of their participation and the risks
- A procedure for ensuring that source data are accurate, contemporaneous, and original
- A procedure for ensuring that information in source documents is accurately captured on the case report forms (CRFs)
- A procedure for dealing with data queries and discrepancies identified by the study monitor
- Procedures for ensuring study staff comply with the protocol and adverse event assessment and reporting requirements
- A procedure for addressing medical and ethical issues that arise during the course of the study in a timely manner
4. What Are an Investigator’s Responsibilities for Oversight of Other Parties Involved in the Conduct of a Clinical Trial?
a. Study Staff Not in the Direct Employ of the Investigator
Staff involved directly in the conduct of a clinical investigation may include individuals who are not in the direct employ of the investigator. For example, a site management organization (SMO) may hire an investigator to conduct a study and provide the investigator with a study coordinator or nursing staff employed by the SMO. In this situation, the investigator should take steps to ensure that the staff not under his/her direct employ are qualified to perform delegated tasks (see section III.A.1) and have received adequate training on carrying out the delegated tasks and on the nature of the study (see section III.A.2), or the investigator should provide such training. The investigator should be particularly cautious where documentation needed to comply with the investigator’s regulatory responsibilities is developed and maintained by SMO staff (e.g., source documents, CRFs, drug storage and accountability records, institutional review board correspondence). A sponsor who retains an SMO shares responsibility for the quality of the work performed by the SMO. The investigator is responsible for supervising the study tasks performed by this staff, even though they are not in his/her direct employ during the conduct of the study (see section III.A.3). This responsibility exists regardless of the qualifications and experience of staff members. In the event that the staff’s performance of study-related tasks is not adequate and cannot be made satisfactory by the investigator, the investigator should document the observed deficiencies in writing to the staff member’s supervisor(s) and inform the sponsor. Depending on the severity of the deficiencies, the clinical trial may need to be voluntarily suspended until personnel can be replaced.
b. Parties Other than Study Staff
There are often critical aspects of a study performed by parties not involved directly in patient care or contact and not under the direct control of the clinical investigator. For example, clinical chemistry testing, radiologic assessments, and electrocardiograms are commonly done by a central independent facility retained by the sponsor. Under these arrangements, the central facility usually provides the test results directly to the sponsor and to the investigator. Because the activities of these parties are critical to the outcome of the study and because the sponsor retains the services of the facility, the sponsor is responsible for ensuring that these parties are competent to fulfill and are fulfilling their responsibilities to the study.
Less frequently, a study may require that investigators arrange to obtain information critical to the study that cannot be obtained at the investigator’s site. For example, if the study protocol requires testing with special equipment or expertise not available at the investigator’s site, the investigator might make arrangements for an outside facility to perform the test. In this case, the results are usually provided directly to the investigator, who then submits the information to the sponsor. If the investigator retains the services of a facility to perform study assessments, the investigator should take steps to ensure that the facility is adequate (e.g., has the required certification or licenses). The investigator may also institute procedures to ensure the integrity of data and records obtained from the facility providing the information (e.g., a process to ensure that records identified as coming from the facility are authentic and accurate). Procedures are particularly important when assessments are crucial to the evaluation of the efficacy or safety of an intervention or to the decision to include or exclude subjects who would be exposed to unreasonable risk.
Investigators should carefully review the reports from these external sources for results that are inconsistent with clinical presentation. To the extent feasible, and considering the specifics of study design, investigators should evaluate whether results appear reasonable, individually, and in aggregate, and they should document the evaluation. If investigators detect possible errors or suspect that results from a central laboratory or testing facility might be questionable, the investigator should contact the sponsor immediately.
c.Special Considerations for Medical Device Studies
Field clinical engineers (device sponsor employees) have traditionally played a role in some investigational device procedures (e.g., cardiology, orthopedics, and ophthalmology) by providing technical assistance to the device investigator. The field clinical engineer should be supervised by the investigator because the field clinical engineer’s presence or activities may have the potential to bias the outcome of studies, may affect the quality of research data, and/or may compromise the rights and welfare of human subjects. The field clinical engineer’s activities should be described in the protocol. If the field engineer has face-to-face contact with subjects or if the activities of the field engineer directly affect the subject, those activities should also be described in the informed consent.
B. Protecting the Rights, Safety, and Welfare of Study Subjects
- Investigators are responsible for protecting the rights, safety, and welfare of subjects under their care during a clinical trial (21 CFR 312.60 and 812.100). This responsibility should include:
- Providing reasonable medical care for study subjects for medical problems arising during participation in the trial that are, or could be, related to the study intervention
- Providing reasonable access to needed medical care, either by the investigator or by another identified, qualified individual (e.g., when the investigator is unavailable, when specialized care is needed)
- Adhering to the protocol so that study subjects are not exposed to unreasonable risks
The investigator should inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and the subject agrees to the primary physician being informed.
1. Reasonable Medical Care Necessitated by Participation in a Clinical Trial
During a subject's participation in a trial, the investigator (or designated subinvestigator) should ensure that reasonable medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial participation. If the investigator does not possess the expertise necessary to provide the type of medical care needed by a subject, the investigator should make sure that the subject is able to obtain the necessary care from a qualified practitioner. For example, if the study involves placement of a carotid stent by an interventional neuroradiologist and the subject suffers a cerebral stroke, the neuroradiologist should assess the clinical status of the subject and arrange for further care of the subject by a neurologist. Subjects should receive appropriate medical evaluation and treatment until resolution of any emergent condition related to the study intervention that develops during or after the course of their participation in a study, even if the follow-up period extends beyond the end of the study at the investigative site. The investigator should also inform a subject when medical care is needed for conditions or illnesses unrelated to the study intervention or the disease or condition under study when such condition or illness is readily apparent or identified through the screening procedures and eligibility criteria for the study. For example, if the investigator determines that the subject has had an exacerbation of an existing condition unrelated to the investigational product or the disease or condition under study, the investigator should inform the subject. The subject should also be advised to seek appropriate care from the physician who was treating the illness prior to the study, if there is one, or assist the subject in obtaining needed medical care.
2. Reasonable Access to Medical Care
Investigators should be available to subjects during the conduct of the trial for medical care related to participation in the study. Availability is particularly important when subjects are receiving a drug that has significant toxicity or abuse potential. For example, if a study drug has potentially fatal toxicity, the investigator should be readily available by phone or other electronic communication 24 hours a day and in reasonably close proximity to study subjects (e.g., not in another state or on prolonged travel). Study subjects should be clearly educated on the possible need for such contact and on precisely how to obtain it, generally by providing pertinent phone numbers, e-mail addresses, and other contact information, in writing. Prior to undertaking the conduct of a study, prospective investigators should consider whether they can be available to the extent needed given the nature of the trial. During any period of unavailability, the investigator should delegate responsibility for medical care of study subjects to a specific qualified physician who will be readily available to subjects during that time (in the manner a physician would delegate responsibility for care in clinical practice). If the investigator is a non-physician, the investigator should make adequate provision for any necessary medical care that the investigator is not qualified to provide.
3. Protocol Violations that Present Unreasonable Risks
There are occasions when a failure to comply with the protocol may be considered a failure to protect the rights, safety, and welfare of subjects because the non-compliance exposes subjects to unreasonable risks. For example, failure to adhere to inclusion/exclusion criteria that are specifically intended to exclude subjects for whom the study drug or device poses unreasonable risks (e.g., enrolling a subject with decreased renal function in a trial in which decreased function is exclusionary because the drug may be nephrotoxic) may be considered failure to protect the rights, safety, and welfare of the enrolled subject. Similarly, failure to perform safety assessments intended to detect drug toxicity within protocol-specified time frames (e.g., CBC for an oncology therapy that causes neutropenia) may be considered failure to protect the rights, safety, and welfare of the enrolled subject.
Investigators should seek to minimize such risks by adhering closely to the study protocol.
ATTACHMENT A: COPY OF FORM 1572
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