Evidence Affirmative: Establishing Proof of Concept

For biotechnology companies bringing new therapeutic candidates through the development pipeline, establishing proof-of-concept is an essential early milestone. Achieving robust proof-of-concept requires evaluating whether an investigational drug demonstrates the expected biological activity and efficacy in treating a targeted disease or condition. Generating convincing proof of concept data provides the critical evidence to guide your ‘go/no-go’ decisions about investing significant resources into advancing a program through later stages of clinical development.

At its core, an effective proof-of-concept study needs to achieve several key objectives. First, it should confirm that the proposed therapeutic engages and modulates its intended biological target and mechanism of action as hypothesized. The study must also provide initial evidence suggesting potential clinical efficacy or benefit that can be linked back to that mechanism. It is important to define a therapeutic window by determining the dose levels and exposures that engage the target sufficiently for efficacy while avoiding exposures associated with unacceptable toxicity.

Additionally, exploring and validating strategies to enrich the study population with patients whose disease is more closely linked to the proposed mechanism of action is valuable for future study designs. Achieving this integrated package of mechanistic confirmation, preliminary efficacy signals, a viable therapeutic window, and patient selection strategies allows your program to advance with more confidence before larger clinical investments.

Integrated PK/PD/Safety Strategy

Achieving definitive proof of concept requires a comprehensive, integrated approach. This involves thoroughly evaluating safety by monitoring adverse events, lab results, and potential toxicity signals across multiple doses and regimens. Preferably, you should also conduct dedicated pharmacodynamic studies using appropriate biomarkers to confirm target engagement and modulation of the hypothesized mechanism of action.

As Dr. Laurie Smaldone Alsup, SVP Regulatory Science at NDA Group states, "Establishing proof of concept not only opens doors for further development but further investment and more considered regulatory interactions that lead to planning for pivotal trials. Biomarkers that are measured in early proof of concept studies can continue to be studied throughout development to better understand their relationship to clinical benefit. In some cases, certain POC biomarkers may eventually require validation as surrogates where there is a strong relationship to clinical outcome. Once validated, these surrogates could support accelerated approval pathways and bring important therapies to patients sooner."

By analyzing the pharmacokinetic, pharmacodynamic, and exposure-response data together, you can validate the proposed mechanism while defining an acceptable risk/benefit window that balances efficacy and safety. This integrated PK/PD/safety strategy allows you to de-risk development candidates by confirming mechanism, demonstrating initial tolerability, and informing optimal dose/regimen selection prior to advancing to larger, costly efficacy trials.

Designing Clinical POC Studies

Generating a comprehensive proof of concept package requires substantiating the proposed mechanism of action while also demonstrating potential clinical benefit. To maximize your chances of success, carefully consider the study population. Enriching with patients most likely to respond based on biomarker stratification is crucial. For certain targets, you may want to pursue opportunistic studies in rare disease cohorts where the pathway is highly relevant.

Whichever population you select, ensure the proof-of-concept study design aligns with your plans for future pivotal trials. The dosing regimen and other key aspects of your proof-of-concept study should match your intended approach moving forward. This cohesive strategy, linking proof of concept to registration-enabling studies, is essential for advancing promising drug candidates efficiently.

Conclusion

As a biotechnology company, you need to establish a robust proof-of-concept before significantly increasing investments in later-stage clinical development. This requires careful study design that incorporates relevant biomarkers, appropriate efficacy assessments, and strategies to enroll the intended patient population. Compiling a comprehensive proof-of-concept data package aligned with the proposed mechanism of action positions your program for efficient advancement and increases the likelihood of regulatory approval success.