Choosing a study population

Selection criteria for trial subjects depends on the expected risks and potential benefits, recognizing that there will be considerable uncertainty about those expectations in an early-phase trial. Expected risks may be estimated from the non-clinical data, an understanding of the biological mechanisms, and any previous relevant human experience, but the clinical significance of those risks can depend on the population that receives the product. Similarly, the potential for benefit might depend on the choice of study population. [1]

For rare diseases, limited sample size creates challenges around assessing feasibility, safety as well as interpreting the outcomes on bioactivity/efficacy. The objective is to select a trial population with an acceptable balance between the anticipated risks and potential benefits for the study subjects, while also achieving the study’s scientific objectives.

Choosing the appropriate study population is a critical aspect of trial design. The study population should reflect the target patient population for the gene therapy and align with the research objectives. Some rare diseases are more prevalent in low- and middle-income countries, where treatments are rarely tested. It’s important to ensure that whenever trials are being conducted, there is a good representation of the real-world demographics of the population that would benefit from the intervention. Because of this, some experts have begun advocating for clinical trials to operate in the countries most affected by the disease being studied.

Some considerations when selecting participants are listed below.

Healthy volunteers

Study of healthy volunteers may be reasonable for products with short duration of action with a well understood safety profile
The risks of most gene therapy products include the possibility of extended or permanent effects – the risk-benefit profile is therefore not acceptable for healthy volunteers

Disease stage or severity

Subjects with more severe or advanced disease may be more willing to accept the risks of an investigational gene therapy
In some cases, however, selection of subjects with less advanced or more moderate disease may be appropriate – subjects with minimal reserve of physiological function due to severe or advanced disease may be less able than subjects with less severe disease to tolerate additional loss, which could leave them with no function

Lack of Other Treatment Options

Early-phase studies of gene therapies typically have significant risks and an uncertain potential for benefits. Therefore, early-phase trials sometimes enroll only the subset of subjects who have not had an adequate response to available medical treatment or who have no acceptable treatment options
If a trial is designed to enroll only subjects for whom no other treatment options are available or acceptable, the trial should include procedures to ensure that each subject’s treatment options have been adequately evaluated, and it should be designed to capture the pertinent information regarding that evaluation

Other Considerations

For certain gene therapies, pre-existing antibodies to either the vector or the transgene may influence the safety or effectiveness of the product – the study might therefore exclude subjects with such antibodies
For products for indications (e.g., severe renal, hepatic, or cardiac disease) that might ultimately be amenable to organ transplantation, you should consider whether exposure to the investigational agent would cause sensitization that could compromise the prospect for future transplant success

Pediatric Subjects