TABLE 2.
Comparison of considerations in designing, executing, and interpreting a clinical trial for probiotic food (PF), probiotic dietary supplements (PDS), medical foods/foods for specific medical purposes (MF/FSMP) and live biotherapeutics (LBPs) in oral applications.
| Trial type | Commonalities to note | ||||
| PF | PDS | MF/FSMP | LBPs | ||
| Acceptance of side effects | Very low | Very low | Very low | Yes | Managing informed consent |
| Tolerability of product | Good, but sometimes gastrointestinal discomfort is noted | Good, but sometimes gastrointestinal discomfort is noted | Good, but sometimes gastrointestinal discomfort is noted | Expected to be good, albeit exceptions can occur | Have a system in place to record adverse events |
| Incidence of side effects | Very low | Very low | Very low | Low | Have a system in place to record adverse events |
| Severity of side effects | Low to very high | Low to very high | Low to very high | Low to very high | |
| Average severity of AEs or SAEs | Minimal | Minimal | Minimal | Minimal | |
| Reporting of adverse events | Variable (but generally required) | Variable (but generally required) | Variable (but generally required) | Extensive and required | A requirement for all types of clinical studies |
| Expected efficacy | Modest | Modest | Major | Major | None |
| Actual efficacy (responders) | Modest | Modest | Modest-major | Modest-major | None |
| Response to efficacy | Variable | Variable | Variable to consistent | Variable to consistent | None |
| Target population | Typically healthy/at risk of a disease | Typically healthy/at risk of a disease | Typically diseased | Typically diseased | None |
| Study population | Heterogeneous | Heterogeneous | Relatively homogenous | Relatively homogenous | None |
| Preclinical data/baseline pilot data | Variable | Variable | Extensive | Extensive | None |
| What product is being studied in clinical trial?* | Not always finished product | Not always finished product | Finished product | Finished product | None |
| Size of study population** | Small/variable | Small/variable | Variable | Variable | Do power calculation |
| Study duration/follow-up** | Short/minimal | Short/minimal | Short/minimal | Variable | None |
| Trial registration/Data deposition | Yes/inconsistent | Yes/inconsistent | Yes/yes | Yes/yes | Required |
| Reporting results | Inconsistent | Inconsistent | Yes | Yes | Should be a requirement |
| Reproducibility | Variable | Variable | Variable | Variable | Required by some authorities |
| Statistical significance | Variable | Variable | Variable | Variable | Statistical plan should be developed and ‘locked’ before intervention start and completion |
| Health endpoint | Maintaining health, supporting normal bodily functions, reducing risk for a condition, reducing specific disease factors/biomarkers | Maintaining health, supporting normal bodily functions, reducing risk for a condition, reducing specific disease factors/biomarkers | Curing/mitigating disease | Curing/mitigating disease | Define upfront what is the primary outcome |
| Established health endpoint | No/not always | No/not always | Yes | Yes | None |
| Systemic function | Complex networks | Complex networks | Complex networks | Complex networks | None |
| Known mechanism of action | Not always known | Not always known | Generally better established than PF/PDS | Generally better established than PF/PDS | R&D challenges to justify and investigate the hypothesis within the available research budget |
| Biomarkers | Minimal established, more surrogates | Minimal established, more surrogates | Typically well established | Typically well established | None |
| Quality control | Dosing live microorganisms | Dosing live microorganisms | Dosing live microorganisms | Dosing live microorganisms | Live microbe counts |
| Administration | Non-systemic | Non-systemic | Non-systemic | Non-systemic | None |
The levels indicated assume that PF and PDS are indeed foods and supplements and as such should pose no risk to the general consumer and cannot claim effects on disease. MF and FSMP are also foods but are consumed by a specific patient population, the benefits in this population need to be documented. LBP’s are drugs that target a specific patient population, this requires thorough documentation. As the effect of LBP’s is expected to be bigger, side effects are also easier accepted. These comparisons between the product categories are intended to give an indication of hierarchy/rank/weight on the various elements, not as an empirical grading system. Many of these elements would be notoriously difficult to objectively quantify which is not within the scope of this article. *depends on product development plan/target product profile. **depends on the phase of randomized controlled trial/type of study, but in pharma for instance, minimal weight management trial duration is 6 months.