5 Common Mistakes To Avoid Before The First Study In Man

Doing a study when it is not needed 

How embarrassing ! – I have seen unnecessary bioequivalence studies in several generic and hybrid generic dossiers, and also in some bibliographic applications where an unnecessary bridging PK study was submitted.  The alternative of a BCS-based biowaiver can be missed, or the requirements for locally administered, locally acting products not fully understood.  Alternatively, the design of the study is more complex than it has to be, perhaps because UK/EU and US requirements have been mixed up, or the intricacies of bioequivalence for generic modified release products are not understood. 

Thinking about the first study in isolation 

If I may be allowed just one Star Trek quote,  “Universal law is for lackeys. Context… is for kings” 

Before advancing to the first study, it is essential to understand how the study fits into an integrated regulatory and clinical development plan, the key objectives of the study, what a successful study would look like, and how the results will be used to inform subsequent development.    

As an example, a common mistake is to not  study a wide enough range of doses in the first study, which has effects later in clinical development when dose-selection for pivotal studies is considered.   

Not understanding the role of Agency scientific advice 

The process in the US is different, but in the UK and EU, it is not  mandatory to seek regulatory agency advice before the first study.  This is often seen as an unnecessary expense and source of delay.  However, the costs and delays can be modest compared to roadblocks with the clinical trial application, or the sub-optimal first study which does not provide a sound basis for further development, partnering opportunities, or further investment.   

Discounts, fee waivers or fee deferrals may be available for SME companies, but the SME designation has to be in place when scientific advice is requested, it is not retrospective.   

Scientific advice needs to be timed at the right moment in development.  Often,  I have seen premature requests for advice, or requests for advice where decisions have already been made and implanted.  Whilst there is a role for “broad scope” advice in some circumstances, going too early with hypothetical questions will only get you hypothetical answers.  In some circumstances, scientific advice is more an iterative process, and where there is a choice of agency, the selection can be critical. When working towards submission in the EU via the centralised procedure, it may be beneficial to first seek advice from one or more selected national EU Agencies.   

To maximise the value of advice, you need to ask the right questions and avoid questions which will result in unhelpful answers. It is important to understand the regulatory mindset, and be realistic about the limits of what is possible. 

Hopefully all this will convince you that you need a scientific advice strategy, not just to decide whether it is needed or not.  

Finally, there are  several traps to fall into during the actual scientific advice meeting.  It is very easy for a company to not use the time effectively, allow invited experts to ambush proceedings, confuse the scientific advice process with lobbying, or otherwise rile the Agency. Regulators have long memories and it is important to avoid an initial bad impression. 

Underestimating the costs and timelines  

Particularly with smaller and less experienced companies, there is a pattern of underestimating the cost and time to properly work up the formulation, bioanalytical methodology and non-clinical package, and also to underestimate  the documentation required for the clinical trial application.   

CRO selection 

There are multiple factors which go into CRO selection –  costs and timelines are the obvious ones, but it is important to consider if particular expertise or academic links are needed for your study, whether there are logistical challenges related to CRO location, and the local level of competition for the population you seek to recruit.  You must avoid “bait and switch” tactics where a highly experienced team is paraded before you, only to be replaced by a less impressive team in reality.  

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To gain practical insights into the strategic decisions that can help support a successful transition from preclinical development to first-in-human trials, and to find out how tranScrip can help you avoid these and other pitfalls, register for tranScrip‘s ‘Ask the Experts’ live Q&A webinar: Ask the Experts: From Preclinical to First-in-Human – Early Drug Development Strategy