The regulatory bodies in the EU and US have set standards that are necessary for a clinical investigator to be compliant with when performing clinical studies. It is important establish what type of training your candidates have completed before making a final decision. Working with an investigator who has principal knowledge of the applicable regulations can help prevent future adverse events and save manufacturing costs.
In the US, clinical investigators are required to submit a financial disclosure to FDA to confirm whether or not the investigators have any investments in the company. An investment may include, but is not limited to, stocks, grants and equipment. If an investigator has made an investment, the investments and/or arrangements must be included in the disclosure, as well as steps taken to reduce the potential for bias. On the occasion that the applicant does not include such information, or at least explain why he/she was unable to disclose such information, FDA can refuse to file the application.
If an FDA-regulated product is undergoing an investigation, FDA will conduct on-site inspections of the clinical investigators that are involved. Should the findings of an inspection indicate any regulation violations, an FDA warning letter may be issued to the investigator. Reviewing FDA Warning Letters is highly suggested before selecting an investigator to help narrow down the possible candidates. If FDA discover that an investigator repeatedly or deliberately breached any of the applicable regulations, or submitted false information on purpose or on multiple occasions, they may initiate a clinical investigator disqualification proceeding.
When initiating a disqualification proceeding, the FDA will first present the investigator with a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). A consent agreement may also be issued with the NIDPOE allowing the investigator to either agree to be disqualified or agree to specific restrictions regarding investigational products. If an investigator fails to respond to the NIDPOE or the explanation is not accepted by FDA, a Notice of Opportunity for Hearing (NOOH) will be issued. Following the NOOH, the investigator can choose to partake in an informal regulatory hearing (Part 16 hearing). In the case that the investigator does not respond, the Commissioner will review the information and determine whether or not to disqualify the investigator. Any investigator that has been involved with a disqualification proceeding can be found in the FDA Clinical Investigator – Disqualification Proceedings Database.
In the UK, it is necessary for clinical investigators to be trained on Good Clinical Practices as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH GCP) before they can conduct a study with medical devices. Other countries in the EU require training with EN ISO 14155:2011, Clinical investigation of medical devices for human subjects – Good clinical practice. Both guidances protect the rights, safety and well-being of subjects in accordance with the Declaration of Helsinki, and define strategies to ensure the integrity of the data and the credibility of the results. However, ICH GCP is more relevant to clinical studies involving pharmaceuticals where EN ISO 14155:2011 focuses more on clinical studies involving medical devices. It is best to find an investigator who has prior training with both practices to avoid gaps.
As part of EN ISO 14155:2011 compliance, a Clinical Investigation Plan (CIP) is necessary if you are conducting a clinical study in the EU. Annex A of the standard defines what content needs to be included in a CIP, such as the informed consent process and the methods an investigator should follow when reporting adverse events. It is essential that the investigator you choose complies with the CIP and its procedures.
Similar to the US, clinical investigators in the EU are required to notify the Research Ethics Committee (REC) if they have any direct personal involvement in the organisations sponsoring or funding the study. An involvement may include, but is not limited to, financial, shareholding and personal relationship. If an investigator has direct involvement, details of the investments and/or arrangements must be included in the REC application, as well as steps taken to reduce the potential for bias. This information would then be transferred to the Research & Development (R&D) Department at each individual institution.
In the UK, you can assess the suitability of an Investigator/institution through the National Institute for Health Research (NIHR). This service can help you identify patient population, site/resource availability etc. You can also ‘run’ your study through this service which has the added element of being able to assist you in adding extra resource at the site (if required), and encouraging the sites to meet their recruitment targets.
If you plan to conduct your clinical study in Germany, it is best to verify whether or not an investigator has completed training on the Gesetz über Medizinprodukte (MPG) laws (also known as The Act on Medical Devices) as it is a requirement. The MPG laws regulate trade in medical devices to ensure the safety of the devices and of patients, users and other persons. This document outlines several regulations, such as medical device requirements, the involvement of notified bodies, clinical evaluations and investigations, performance evaluations and investigations, risk management and more.
Beyond selecting an authorized representative, study site and an investigator, there are other notable elements that should be examined. How the end results are planned to be used effects what steps need to be taken in preparation of a clinical study.
Please look for the final part in this series, Additional Information You Should Know Before Performing a Clinical Study.
If you missed the previous blog in this series, Things to Consider When Selecting a Clinical Investigator, you can view it here.