Earlier this year, new guidelines issued by the European Medicines Agency (EMA) governing first-in-human clinical trials went into effect. The new guidance aims to further improve the safety of clinical trial participants, with a broader scope – going beyond first-in-human trials to also apply to all new chemical and biological investigational and medical products.
 
I led two discussions on this topic at DIA 2018 in Boston, and it was clear from those conversations that professionals in the clinical trial community are wondering how the new guidelines may impact trials conducted in the U.S. and Canada.
 
This new EMA guidance was issued in response to the 2016 Biotrial/Bial incident, in which one study participant died after receiving multiple doses of the drug. The corresponding guidance further focuses on dosing protocols and data supporting dosing criteria.
 
The new EMA guidelines place more emphasis on the notion of intrinsic uncertainty in early clinical development and the justification for the starting dose, dose escalation, and maximal dose (or exposure) to be evaluated in the trial. The guidance also focuses on the importance of pharmacokinetic (PK) and pharmacodynamic (PD) information in the selection of doses, and in the decision to proceed to the next cohort (interim PK analyses). Clear rationale and decision criteria are expected in integrated single ascending dose (SAD) and multiple ascending dose (MAD) protocols. The guidance also places more emphasis on a sentinel dosing approach for SAD and MAD cohorts, well-defined stopping rules, and precautions taken within and between cohorts.
 
At this time, it does not appear that either Health Canada or the U.S. Food and Drug Administration (FDA) have plans to implement guidelines similar to those issued by EMA. However, the Institutional Review Boards (IRBs), who review and approve research protocols to ensure the safety and well-being of human subjects, appear to be adapting to the new EMA guidelines in their review process.
 
Our Experience with IRB Feedback
In my work, I have recently seen a shift in the kind of feedback we may receive from an IRB seeking additional information regarding elements of the protocol that are not required in the U.S. or Canada but that are now required by the EMA. For example, if you’re not including sentinel data, you really need to provide data-driven justification in the protocol. (Sentinel dosing is where one subject receives the full dose of medication in advance of others in the study.) You also need to provide safety justification and rationale for dose escalation rates and overlap of study parts (e.g. SAD and MAD cohorts).
 
I’ve seen IRBs suggest that the safety review committee should have an independent third-party physician, which is something specified in the EMA guidelines. I’ve also received feedback that the maximum dose should be defined in the protocol and that the study should state that dosing will not continue beyond the maximum dose, even though that may be intuitive – both EMA guidelines. Furthermore, you now need to have a built-in plan to anticipate and medically manage adverse events, such as having a variety of rescue medication on site.  
 
Steps You Can Take in Future Trials
There are some protocol considerations you can take when designing your trial to anticipate IRB concerns. You need scientifically sound justifications with enough flexibility to change things as needed. Avoid being too vague. For example, avoid simply saying, “The maximum dose will be determined based on interim safety and PK results.” Provide information regarding the exposure that would be anticipated at the maximum dose, relative to the exposure that should be associated with therapeutic effects. Discuss the maximum exposure anticipated, relative to exposure associated with toxicity in animal studies.
 
When moving from single to multiple dosing, demonstrate that the dosing interval and dosing duration is based on PK, PD, non-clinical safety data and ALL data from single-dose cohorts. The expected exposure in multiple-dose cohorts should be covered by previous single-dose cohorts. With integrated protocols, the dose selection criteria should be established with flexibility to adapt design. Keep in mind that changes outside of the predefined criteria require a protocol amendment.
 
In recent experience, IRBs expect best practices and have demonstrated that they are taking the EMA guidelines into close consideration for first-in-human trials. Even though the new EMA rules are not reflected in current regulatory guidances in the U.S. and Canada, we need to be adaptive and consider them as the underlying trend in North America.