11/09/2021

There are two recent warning letters relating to sponsor-investigators. (warning letter 1 HERE and warning letter 2 HERE). A sponsor-investigator both initiates and conducts a clinical trial, which is also known as an investigator initiated clinical trial (IIT). In both examples, the investigator used protocols internal to the institution but did not submit an Investigational New Drug (IND) application to the FDA. The drugs chosen for the protocols were approved and being used for on label use in the protocols. However, the protocols restricted what drug was being used and so could not be considered standard of care. Warning letter 1 protocols alternated the drug used in the emergency room by time period, assessed and documented the time until sedation, and compared different drugs in their ability to sedate. Warning letter 2 protocols removed alternative treatment options from ambulances. Because the clinical trial design restricted options to only certain drugs to collect comparison data on human subjects, these protocols are clinical investigations as defined under 21 CFR Part 50.3(c).

Also, the investigators claimed that the drugs were exempt from needing an IND per 21 CFR 312.2(b), but all five of the exemption criteria must be met. The criteria are:

The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use, and there is no intent to use the investigation to support any other significant change in the labeling of the drug.
In the case of a lawfully marketed prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
The investigation does not involve a route of administration, dosage level, use in a patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
The investigation is conducted in compliance with the requirements for institutional review set forth in 21 CFR part 56 and with the requirements for informed consent set forth in 21 CFR part 50.
The investigation is conducted in compliance with the requirements of 21 CFR 312.7.

The studies did not fulfill criteria three. Warning letter 1 protocols did not exclude subjects with liver or kidney dysfunction and subjects taking drugs with a known interaction with the investigational products, thus increasing risks to the subjects. A warning letter 2 protocol did not exclude subjects who were under the influence of intoxicants which would be hazardous with one of the protocol’s investigational products, and other protocols did not exclude vulnerable subjects for which the investigational products would be hazardous.

Both warning letters mention that the sponsor-investigators submitted an IND for a clinical trial very similar to one of each of their protocols, but there were serious issues with the inclusion and exclusion criteria. Warning letter 1’s IND clinical trial was placed on full clinical hold and warning letter 2’s investigator withdrew the IND amid deficiencies noted by the FDA. Both sponsor-investigators continued already existing clinical trials after learning of the FDA’s concerns about including subjects who may be at greater than acceptable risk for the protocols submitted for IND, including the ones that were very much like the IND submissions.

Another issue was that the request by emergency medical personnel for alternative treatments to be returned to the ambulance for those who could not be enrolled in the clinical trial was denied. They were told that it was a clinical trial period, and they would not enroll enough subjects otherwise. This is a violation of patients’ safety and rights.

These examples of sponsor-investigator violations of good clinical practice are more concerning than typical. There are times where a sponsor external to the investigator’s institution may rely on an IIT as a strategy to collect data for an approved product. The relationship arrangement between the sponsor and investigator for an IIT can vary depending on the needs of the specific clinical trial. Sponsor-investigators are usually experienced with conducting a clinical trial but are not as familiar with sponsor regulatory responsibilities, such as having an independent monitor. Adequate monitoring of the clinical trial is needed to meet sponsor regulatory requirements.

Unsure of what is needed to start or conduct an IIT? Clinical Pathways offers an eLearning course “Investigator Initiated Clinical Trials” to help you get started.

Adequate knowledge and training in advance of beginning a clinical trial would reduce the rate of violations, reduce risk to subjects, and increase the quality of and confidence in the data.

Understanding the importance of clearly identifying roles and ensuring clear expectations can support a successful trial outcome. Our interactive eLearning course offers:

Knowledge Checks
Post Assessment
Scenarios to apply your knowledge
Certificate of Completion

To sample an interactive demo or to purchase the full course, visit our store HERE.

IIT training can be purchased as a single license for limited individual use, as a SCORM package for use in your LMS, or can be fully customized to your organization's requirements. No LMS? We can host this course or a full curriculum to train your teams or site staff. Contact us at info@clinicalpathwaysresearch.com for more information.

- The Clinical Pathways Team

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