Companies preparing for an early phase study must deal with an array of challenges and decisions for biometrics, pharmacovigilance and regulatory activities.

Some Facts

Early phase studies, ranging from ‘First-in-human’ (FIH) to phase I/II adaptive studies, to focused studies such as food-effect, drug-drug interaction, bioavailability/bioequivalence, and renal or hepatic impairment constitute a sizable portion of clinical studies registered with clinical.trials.gov. The FDA reports that about 70% of phase 1 studies, about 33% of phase 2, and about 25-30% of phase 3 studies go to the next level.  

HOW TO INCREASE THE LIKELIHOOD THAT YOUR STUDY GOES TO THE NEXT LEVEL

Study Design

The primary goal of phase 1 studies is to find the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) as well as assessing dose limiting toxicities (DLT) for safety.  However, the process of selecting a dose has grown more complex. Where the 3+3 rule-based design was once common, now studies increasingly use model-based/model-assisted designs such as adaptive, Bayesian models continual reassessment methods (CRM) and other simulation-based models.  The new approaches can be cost-effective in limiting the number of patients needed in a study and identifying the ‘true’ MTD, but technical resources and statistical expertise to implement and operationalize these designs are needed.  The 3+3 design is easily understood, implemented and accepted among clinicians, making it a favored approach in many studies but not as effective in dose determination.  Understanding the pros and cons of these different approaches can help with the decision on which method is right for your trial.

Operational Considerations:  Safety

The risk, especially in FIH studies, is that the drug will not meet tolerability or safety standards.  Since safety is the primary focus for early phase studies, monitoring patients, collecting, cleaning and timely reporting the data is very important.  A well-defined safety management plan ensures appropriate handling and management of safety data. Also, it is critical that precise causality assessment is completed for each SAE by PV experts/physicians and sponsor which can suggest accurate safety profiles in context to any new potential risks or causal association of the study drug that is judged to be of sufficient likelihood and is under investigation or validated.

Approaches that foster data-based medical review in establishing a causal relationship between adverse events and the treatment under investigation need to be employed.  These approaches may come from pharmacovigilance and data management, using risk-based management plans and techniques, and from statistics, using quantitative methods.

Collaboration between stakeholders (client and vendor) is needed.  The planning and execution of safety activities with a team that is experienced in the needs of the trial and in good clinical practice methods is essential. 

Operational Considerations:  Coordination of Activities and Resources

Activities from various disciplines include pharmacovigilance services, pharmacokinetic collection and reporting, data management, statistics and programming and medical writing are needed.  Is an outside Data Monitoring Committee needed?  Or will an internal safety committee be best?  Setting up a structure to address needs, define an operational plan(s) and coordinate the activities of the various functions is a major need and a challenge. Is this a challenge that will be taken up within the company?  Do activities need to be outsourced?  Or is there a preference to supplement skilled personnel within-house using an FSP model?

Veranex has deep experience in over 1000 early phase studies. If you would like to learn more, please contact us!

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