In The FDA Spotlight: Investigators And Sponsors

By James Hamilton

The issuance of guidance from the Food & Drug Administration is a wake-up call for the biopharma industry and is a strong indication that the agency’s attention might be turning to a particular concern. In October of 2009, the Guidance for Industry, Investigator Responsibilities was published after more than 25 warning letters were issued between Jan. 1, 2009 and Sept. 30, 2009. Aimed at investigators, sponsors, and institutional review boards (IRBs), the guidance clearly spells out the FDA’s expectations for protecting the rights, safety, and welfare of study subjects.

The guidance was a collaborative effort of the FDA’s Office of the Commissioner, the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH). The offices’ representatives came together as the Investigator Responsibilities Working Group and were charged with the task of formalizing the FDA’s current thinking and recommendations on the topic.

For anyone who is conducting a clinical investigation of a drug, biological product, or medical device, the guidance spells out their duties and aims to help them meet their responsibilities to protect the human subjects and ensure the integrity of the data. Investigators and sponsors are able to clearly ascertain the FDA’s expectations for their responsibility:

1.  to supervise clinical studies when study tasks are delegated to employees or colleagues
2.  to ultimately protect the rights, safety, and welfare of the study subjects.

THE TRIGGER POINT: FDA WARNING LETTERS
Whether it was the number of warning letters issued in a short period of time or whether it was the number and scope of violations that were found, the FDA’s Investigator Responsibilities Working Group released the guidance to the industry. A review of the warning letters indicates that the violations were given investigational priority.

INVESTIGATOR RESPONSIBILITIES: GUIDANCE HIGHLIGHTS
Although, in drugs and biologics, the investigator responsibilities are different from the responsibilities of an investigator in medical device clinical trials, the general duties are fundamentally similar. The guidance is clear in stating the overall responsibilities and focus of the investigator and the review board:

• ensuring the 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.

The guidance outlines the investigator’s role in supervising the conduct of the clinical investigation and protecting the rights, safety, and welfare of participants in drug and medical device clinical trials. Tasks can be delegated, but the investigator is responsible for providing supervision of the third party to whom they have assigned the task and is accountable for any regulatory violations.

A. Supervision Of The Conduct Of A Clinical Investigation: Guidance Highlights

1.  Investigators are expected to commit themselves to personally conduct or supervise the investigation in drugs and biological products. In clinical investigations of medical devices, they commit to supervising all testing of the device involving human subjects.
2. Investigators are expected to ensure that in assigning tasks to third parties the assigned individual is qualified and well-trained to conduct the tasks, and adequate continuous supervision is available.
3. The investigator is responsible for making certain that the study is done according to FDA regulations.
4. An initial plan for the supervision and oversight of the clinical trial should be developed by the investigator. The plan should include a system for routine review meetings, procedures for timely corrections and documentation, protocol compliance, and a way of addressing medical and ethical issues.

B. Protecting The Rights, Safety, And Welfare Of Study Subjects: Guidance Highlights

1. The investigator should ensure that reasonable medical care for the study subject during the participation is available.
2. The investigator should adhere to the protocol so study subjects are not exposed to unreasonable risks.
3.  The subject’s primary physician should be informed by the investigator of the subject’s participation, if consent is given by the subject to inform the primary doctor.
4. The investigator should adhere to inclusion/exclusion criteria in order to qualify and protect subjects for the trial.
5. The investigator should ensure that each subject in the study has given informed consent and that the study is not begun until the FDA and the Investigational Review Board approvals have been obtained.
6. The investigator should supervise the use of an investigational device with subjects under the investigator’s charge and according to FDA regulations.
7. The investigator should maintain complete and current records relating to the investigator’s participation in an investigation. The protocol should be included along with any other records required by the FDA regulations.

While this specific guidance, as with other FDA guidance documents, does not describe legally enforceable regulations, it does accurately describe the agency’s current position on the topic. The guidance does explain recommendations that the agency deems important and that relate back to the regulations and statutes cited in the document.

NOW IS THE TIME FOR THE INDUSTRY TO FOCUS
It is evident that the FDA considered the types of violations found as major risks to study participants. The investigators’, sponsors’, and IRBs’ violations were found across the drugs, biologics, and medical device trials. The industrywide problems needed to be addressed in light of the possible consequences to the human subjects. Serious injury or even death must always be considered if protocol and regulations are not followed.

The industry must also consider that if violations by investigators, sponsors, and IRBs are found and are not properly addressed, and that while the data generated might be scientifically valid, it may not be acceptable for review by the FDA. If the study cannot be used, it may have to be repeated, costing additional monies, but more importantly, the loss of development time.

The main emphasis of the Guidance For Industry, Investigator Responsibilities was on investigators and sponsors, while the IRBs’ responsibilities were not as clearly defined. It is inferred that the IRBs must have complete information from the investigator or sponsor in order to complete their responsibilities of protecting human subjects. Although warning letters were sent to the IRBs, the guidelines do not address their responsibilities directly, in regards to having a quorum, having enough data, and assuring that the investigators have attained informed consent.

The guidance document also does not fully discuss deficiencies found with nonclinical laboratories. These deficiencies must be addressed by the sponsors utilizing these labs.

The FDA has addressed these issues with the guidance document, and they will be high priority in upcoming inspections this year. It is now up to the industry to update and revise their operational procedures to handle the anticipation of increased FDA scrutiny.

About The Author
A veteran of the FDA’s Compliance Office and of senior level positions in private industry, James Hamilton brings a deep and diverse expertise of industry, regulatory compliance, team building, technical, and leadership resources to his company’s (J.E. Hamilton & Associates) clients.