Thursday, November 11, 2010

Clinical trial Investigator Responsibilities Protecting the Rights Safety Welfare of Study Subjects

Clinical trial Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects

An overview of the responsibilities of a person who conducts a clinical investigation of a drug, biological product, or medical device (an investigator as defined in 21 CFR 312.3(b) and 21 CFR 812.3(i)).Investigators responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations
Investigator’s responsibility
(1) to supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator or other third parties
(2) to protect the rights, safety, and welfare of study subjects.

In conducting clinical investigations of drugs, including biological products, under 21 CFR part 312 and of medical devices under 21 CFR part 812, the investigator is responsible for:
Ensuring that a clinical investigation is conducted according to the signed investigator statement for clinical investigations of drugs, including biological products, or agreement for clinical investigations of medical devices, the investigational plan, and applicable regulations
Protecting the rights, safety, and welfare of subjects under the investigator’s care
Controlling drugs, biological products, and devices under investigation (21 CFR 312.60, 21 CFR 812.100)
Although specific investigator responsibilities in drug and biologics clinical trials are not identical to the investigator responsibilities in medical device clinical trials, the general responsibilities are essentially the same. This guidance discusses the general investigator responsibilities that are applicable to clinical trials of drugs, biologics, and medical devices.
An investigator’s responsibilities in conducting clinical investigations of drugs or biologics are provided in 21 CFR Part 312. Many of these responsibilities are included in the required investigator’s signed statement, Form FDA-1572  (hereinafter referred to as 1572). Note that although the 1572 specifically incorporates most of the requirements directed at investigators in part 312, not all requirements are listed in the 1572. Investigators and sponsors should refer to 21 CFR Parts 11, 50, 54, 56, and 312 for a more comprehensive listing of FDA's requirements for the conduct of drug and biologics studies.2
An investigator’s responsibilities in conducting clinical investigations of a medical device are provided in 21 CFR Part 812, including the requirement that there be a signed agreement between the investigator and sponsor (see 21 CFR 812.43(c)(4) and 812.100). The medical device regulations do not require use of a specific form for an investigator’s statement; and there are additional requirements not listed above (see Attachment B). Investigators and sponsors should refer to 21 CFR Parts 11, 50, 54, 56, and 812 for a more comprehensive listing of FDA's requirements for the conduct of device studies.

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.
During inspections of investigation sites,regulatory agency 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. 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, 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.

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