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US FDA guidance says volunteers for clinical evaluation should be free from abnormalities

Dr Arun Bhatt
Wednesday, January 3, 2024, 08:00 Hrs  [IST]

What is the regulatory perspective on the sponsor prospectively approving patients for a clinical trial?

Dr Deepak Wakade

The regulatory agencies e.g. the US FDA do not prohibit sponsors from being involved with the selection of subjects. The sponsor’s medical monitor can review of check list of selection criteria with the participant’s name redacted and assist the investigator making a decision about the selection of the participant. However, there are ethical issues when the sponsor team gets involved with recruitment activities, which might include contacting potential participant. In 1998, US FDA indicated that sponsor involvement in recruitment activities would require IRB review and approval.

In USA, the Secretary’s Advisory Committee on Human Research Protections (SACHRP) has issued recommendations related to this area (available at https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-b-new-challenges-sponsor-clinical-trial-site-subject.html). Some of the recommendations are:
  • Sponsor or third-party vendor involvement in recruitment activities should not place sponsor or vendor staff in the role of final determination of trial eligibility. These personnel may share and discuss study eligibility information and answer questions from prospective subjects regarding eligibility criteria. With appropriate consents and authorization, these personnel may also collect relevant clinical information relating to prospective subjects, in order to  share that information with site investigators, but should avoid acting in the role of the clinician-investigator who ultimately must make eligibility determinations based on their assessments of patients, their medical conditions and their verified medical records.
  • All sponsor and sponsor’s vendors’ interactions with subjects or prospective subjects must be planned and executed to respect applicable privacy obligations of sponsors and vendors, as well as the privacy obligations of patients’ and subjects’ health care providers and of research sites and investigators.
What would be regulatory expectations for placebo-controlled trial in paediatric population which may not include standard of care (SoC)?

Dr Durgesh Gondkar

There is no prospect of direct benefit for paediatric participants enrolled in a placebo arm. Consequently, the risks to the participants from exposure to placebo must be minimal risk or no more than a minor increase over minimal risk. Several factors should be considered when evaluating the risks to a participants in the placebo arm. These factors include exposure to the placebo itself, route of administration, frequency of administration, and duration of placebo exposure, and the risks from withdrawal of known therapy, including SoC treatments, if any are available. If SoC is withdrawn, scientific justification should be provided. The risks of withdrawal may be mitigated by continuing SoC treatment in the placebo arm of the trial and should be considered in this scenario.

For the pediatric participants randomized to the unapproved investigational drug, the multiple administrations of an investigational drug would exceed the minor increase over minimal risk threshold, such that the individual participant  should  be offered the prospect of direct benefit from the intervention, the risks must be justified by the benefits, and the anticipated benefit must be as favorable as alternatives. To ensure prospect of direct benefit, the dosing and duration of exposures to the intervention must result in a clinically meaningful benefit to the pediatric participants. Therefore, a cross-over arm of limited duration may be too short to offer a benefit to the participant, depending on the disease process and the number of doses required to result in a meaningful clinical change. In some cases, the risks associated with withdrawal of SoC may substantially increase the risks to the pediatric participants and consideration should be given to evaluating the investigational drug as an add-on to SoC.

For a study in healthy individuals, the protocol allows inclusion of participants with a medical condition unless the investigator feels that inclusion of the participation might interfere with the evaluation of the study objectives. How do we interpret this?

Dr  Christina Davies

The US FDA guidance on general considerations for clinical evaluation of drugs recommends that the volunteers should be free from abnormalities which would complicate the interpretation of the experiment, or which might increase the sensitivity of the subject to the toxic potential of the drug. Individuals with mild, but stable disease may be included in the initial study of a drug. However, the investigator should consider whether the medical condition and its treatment can impact interpretation of efficacy and safety outcomes, or the investigational drug is likely to increase safety risk of the participant.

Dr Arun Bhatt is a Consultant - Clinical Research & Development,
Mumbai. Readers can send their queries at:arun_dbhatt@hotmail.com


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