Decoding the Differences: Small Molecule vs Microbiome-Based Clinical Trials

Key differences in trial design and endpoints

Safety and tolerability: Safety and tolerability are fundamental aspects of any clinical trial, but microbiome-based trials approach these differently. Small molecule trials typically begin with healthy volunteers to determine baseline safety data on potential adverse reactions. In contrast, microbiome-based trials often start with patient populations. This strategy provides an early opportunity to assess efficacy alongside safety, which is crucial for attracting investors or making rapid go/no-go decisions. However, it also presents challenges, as adverse events must be carefully differentiated from symptoms of the underlying condition.

Efficacy assessments: Small molecule trials focus on measurable pharmacodynamic effects, such as biomarker changes or symptomatic relief. For microbiome-based products, endpoints are highly product-specific and often unique to this category of therapeutics. One major endpoint specific to microbiome-based products is engraftment, which measures how well the therapeutic microbiome integrates with or replaces the patient’s existing microbiome. While engraftment can signal efficacy, it also raises important safety questions regarding the short- and long-term impacts of microbiome-induced changes. Other endpoints may involve practical outcomes like improvements in stool consistency (measured by the Bristol Stool Chart), reduction in atopic dermatitis or decrease in tumor size when used as adjunctive cancer treatments.

Pharmacokinetics (PK): In small molecule trials, pharmacokinetics – how the body absorbs, distributes, metabolizes and excretes the drug – is a core endpoint, providing insight into dose-response relationships and bioavailability. This is less relevant for microbiome-based products, which are often not absorbed into the bloodstream. Instead, these products may replicate or proliferate at their site of application, such as in the gut or skin. Therefore, PK assessments often focus on quantifying microbial strains and metabolites at the site of action rather than within the blood, using methods like stool analysis, vaginal swabs, bronchoalveolar lavage (BAL) or skin assessments.

Dose-finding studies: Small molecule trials rely heavily on dose-finding studies to determine the optimal therapeutic dose. Microbiome-based trials, however, often use a single dose level, as increasing the dose mostly does not significantly enhance efficacy. In some cases, multiple doses may be tested to ensure safety, especially if the product involves commensal strains that already exist in the patient’s microbiome, to avoid potential risks associated with overdosing.

Placebo control: Placebo-controlled designs are standard in clinical trials, and this holds for microbiome-based products. Early phase microbiome trials may skip placebo controls to expedite data collection, focusing instead on demonstrating preliminary safety and efficacy. However, later phase trials typically include placebos to establish robust comparisons and meet regulatory requirements.

Conclusion

The development of small molecules and microbiome-based products differ substantially, especially in terms of regulatory guidelines. As the landscape of clinical trials with microbiome-based products is relatively sparse, learning from past trials and making decisions based on scientific advice is crucial. Biotech companies can benefit from partnering with a clinical research organization that can provide guidance through these unique challenges.

For further information, please contact:

Wim Verreth
Health Science - Head of Business Development and Support
t: +32 (0) 475 79 20 60