By Glenda Guest, vice president, Norwich Clinical Research Associates (NCRA)
While the title of the new guidance from FDA is ‘Investigator Responsibilities’, in reality sponsors also have obligations since securing investigator compliance with applicable regulations is one of their legal obligations.
“While these concepts are not new, FDA’s current thinking on these subjects may come as a surprise to investigators and sponsors alike. And while the overall focus is on investigator responsibilities, sponsors have a regulatory obligation to secure investigator compliance with applicable regulations, and therefore need to be prepared to evaluate investigator performance in some of the key areas discussed below.”
Clinical trial data is costly to obtain and there are risks to everyone involved in clinical research. Ethical researchers strive to minimize the risks involved and maximize the benefits available. However, in the real life conduct of clinical research, when investigator responsibilities are not met, events take place that may result in valuable data being excluded from the study analyses. This occurrence benefits no one and carries ethical implications in addition to financial losses and delays in obtaining all the data necessary for study analysis.
New guidance from the US FDA, released in October 2009, identifies some key areas where non-compliance could create just such an unfortunate outcome1. The guidance, ‘Investigator Responsibilities – Protecting the Rights, Safety and Welfare of Study Subjects’ is aimed at assisting clinical investigators to better meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations. Specifically, it is intended to clarify for investigators and sponsors FDA’s expectations in two main areas concerning the 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 and (2) to protect the rights, safety and welfare of study subjects. The focus of this article is on the first of these.
While these concepts are not new, FDA’s current thinking on these subjects may come as a surprise to investigators and sponsors alike. And while the overall focus is on investigator responsibilities, sponsors have a regulatory obligation to secure investigator compliance with applicable regulations, and therefore need to be prepared to evaluate investigator performance in some of the key areas discussed below.
Are your current processes robust enough to ensure that the investigators participating in your clinical research studies are meeting their obligations as FDA expects? Are your monitors and regulatory staff currently trained to be able to make the assessments recommended in this guidance? Sponsors and investigators alike need to review the current FDA thinking on these topics and evaluate the procedures they currently follow to ensure that they are prepared to meet these expectations.
Supervision of the conduct of a clinical investigation
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. As noted above, the sponsor also has obligations to ensure that investigators are complying with applicable regulations, and securing compliance if non-compliance is detected.
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.
FDA will request documentation from the investigator for any study-related task not personally performed. This includes documenting to whom the task was assigned and the start and end dates of that assignment. In this guidance FDA clarifies that they expect investigators to maintain separate documentation of these assignments for each study they are conducting.
In addition to the commonly accepted practice of documenting delegation to individuals qualified by education, training and experience (and state licensure where required), there are some more challenging and less frequently available documentation requirements identified within this guidance. Investigators need to be able to document that their delegates are aware of regulatory requirements related to the research study, are familiar with the purpose of the study protocol and have an adequate understanding of the protocol and attributes of the investigational product needed to perform their assigned tasks. This is required for all staff participating in the conduct of the study, including any new staff hired or assigned after the study has begun.
How will you demonstrate to FDA an awareness of regulatory requirements and an adequate understanding? What is required to demonstrate awareness of the acceptable standards of human subject protection? What documentation will be necessary to support that staff have been informed of any pertinent changes during the conduct of the trial and have received additional training as appropriate? Clearly the expectations are high and meeting them will be a challenge.
Adequate supervision is more clearly defined within the guidance. 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.
FDA recommends that investigators develop a plan and procedures for the supervision and oversight of the clinical trial including for individuals who are highly qualified and experienced. Consideration of the elements listed below (additional elements noted in guidance document) is recommended, and documentation would be expected. Other than routine meetings with the sponsor’s monitors, the majority of investigators do not currently have such plans in place and will find it difficult to 1) develop such plans and 2) follow such plans.
- Routine meetings with the sponsor’s monitors
- Routine meetings with staff to review trial progress, adverse events, and update staff on any changes to the protocol or other procedures
- Procedures 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
- Additional procedures as noted in the guidance document
FDA has clearly set their expectation that each investigator is responsible for supervising the study tasks performed by the staff, even though they are not in his/her direct employ during the conduct of the study. 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.
Additionally, when the investigator retains the services of an external facility to perform study assessments requiring special equipment or expertise that can’t be obtained at their site, the investigator should take steps to ensure that the facility is adequate; e.g., has the required certification or licenses. These 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.
There are clearly areas where new expectations have been spelled out and individuals engaged in clinical research can better meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations by carefully reviewing the guidance document.
1 Although FDA guidance documents do not establish legally enforceable responsibilities, they describe the agency’s current thinking on a topic and should be viewed as recommendations.