Commentary on the EMA Guideline on strategies to identify and mitigate risks for first‐in‐human and early clinical trials with investigational medicinal products

The European Medicines Agency (EMA) published in July 2017 a guideline for first-in-human (FIH) drug studies 1. The purpose of this document is to assist investigators, pharmaceutical companies, ethics committees and other regulators and stakeholders with the design and performance of early clinical studies of new compounds in humans. The focus of the guideline is on risk mitigation and promotion of safety. The guideline is a revision of an earlier version dated 2007 and extends the existing EU guidance to address FIH and early phase clinical trials (CTs) with integrated protocols 2. The first edition of the EMA guideline on FIH studies followed the devastating events that occurred during the FIH study of TGN1412 in March 2006. The first administered dose of this CD28 superagonistic antibody caused a cytokine release syndrome in all healthy volunteers. The causes of these unexpected severe effects were carefully analysed by different authorities and experts in the field 3-5. This resulted in guidelines that put an increased emphasis on the relevance of animal models; a revision of strategies to determine the starting dose (including the concept of MABEL, the minimally active biological effect level in humans); and an adaptation of safety measures for FIH studies (e.g. ‘sentinel’ cohort and intensive care access). Further research of TGN1412 revealed interspecies differences between the biological function of CD28 and led to the development of a bioassay that was predictive for humans. As a result, in 2014, the compound could be reintroduced at much lower doses in human development 6. Ten years after its first publication the EMA guideline on FIH studies has now been revised. This revision followed a tragic event that happened in January 2016 during an FIH programme with BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor that enhances endogenous endocannabinoid concentrations being developed by BIAL 7. Although BIA 10-2474 had never been administered to humans, FAAH inhibitors had been examined in numerous clinical trials. Other compounds of the class had generally failed to show therapeutic effects in a number of indications, but no concerns had been raised for safety. The study – which included several parts under the same ‘umbrella’ protocol – had an apparently uncomplicated single ascending dose (SAD) part, on which several lower multiple ascending doses (MAD) cohorts had followed before the events unrolled. It was therefore quite unexpected that severe neurological symptoms occurred in the third cohort on the fifth day of administration, which caused the death of one of the volunteers and neurological toxicity in four others. The root cause analysis of these tragic outcomes has not yet been completed, largely because of the ongoing legal proceedings that impose limitations on sharing the data and the results. The French authorities have issued a report, which outlines a number of factors that may have been involved 8. Despite strong public appeal from both clinical researchers 9, 10 and regulators 11, the pharmacokinetic (PK), pharmacodynamic (PD) and clinical data obtained in the SAD and MAD studies have not been published, and many questions regarding the preclinical characteristics of the compound remain unanswered. Irrespective of the ongoing debate about transparency and access to the BIAL data, EMA amended its guidance dated 2007 considering the conclusions highlighted in the TSSC Report 8 and also – as stated in the concept paper published in 2016 – to bring it in line with current practices for FIH CTs and early clinical drug development. This commentary aims to put the new guideline 1, which will become effective in February 2018, into perspective by guiding the reader of the regulatory document through its chapters and expanding on how the revised guideline might impact practical aspects of FIH trials. The section headings in this commentary provide a direct hyperlink to the corresponding section of the guideline under discussion in a copy of the guideline that is available as Supporting Information to this article online (see Supp Mat). The introduction of the new guideline starts with the assertion that the purpose of FIH trials is to evaluate an investigational medicinal product (IMP) in humans for the first time, to study the human pharmacology, tolerability and safety of the IMP and to compare how effects seen in nonclinical studies translate into humans. The revised guideline further acknowledges the integration of PK, PD and safety information, not only from preclinical experiments but also from human data emerging during the trial itself. The emphasis on human pharmacology seems to be a change from the first edition of the guideline in 2007 12, where the term ‘pharmacology’ was mainly used in the context of ‘nonclinical safety’. The emphasis of both versions remains on safety, but the revision seems to recognise the importance of the compound's pharmacological characteristics more clearly. This is in line with current R&D and lead selection practices in pharmaceutical industry of developing highly targeted IMPs. The need for incorporating emerging data is also associated with a tendency to include several early human drug studies – called ‘study parts’ in the guideline – under the same integrated ‘master’ protocol, or to run them in parallel rather than consecutively. The obvious advantage from a drug development perspective is efficiency: Doses and study schedules can be adapted to concurrent findings from other study parts, and precious time and resources can be saved. However, the process is only efficient and safe if the right information is shared effectively among sponsors, contract research organisations (CROs) and investigators. Decisions that involve deviations from the predefined design and dosing schedule will also require efficient contacts with ethics committees, participants and sometimes regulators. To optimise data sharing and integration, it is encouraged that a totality of evidence approach – including analysis of emerging PK, PD and safety data – is applied. There is an interesting shift in the scope of the revised guideline, compared to the previous version. Ten years ago, the guideline was basically limited to nonclinical issues for consideration of doses and designs of FIH studies with a SAD design. The current revision covers a much broader scope and is essentially meant to provide guidance for the design and dose selection of all early human drug studies, with different dosing regimens in different populations. The new guideline is restricted to studies that provide ‘initial knowledge’ of a new compound, but the recommendations apply to a number of important clinical pharmacological questions that cover major parts of early drug development. These questions deal with the ways in which the body handles the drug and how the drug affects the body and typically also include the interactions with foods and other drugs, and the influence of demographic variables and (concomitant) disease. These issues are not limited to healthy young males typically used in most early human studies but are also relevant to other populations including patients. studies in populations will require an integration of all the relevant preclinical and emerging human data, clinical pharmacological and characteristics into The of the scope of the guideline also from the need to be in line with in The drug development that studies in is to an approach to – as clinical of and safety – and practices more data and from and of has the to a into therapeutic trials. However, this not at the of an increased risk to study of the and the limitations of and of the data from these to a safe of the trial and a of the and of data to also be with an increased of analysis and in of during the The first edition of the guideline only to the EU and its and which apply to the for of a clinical trial to parts of this have been in or in guidelines or new The new FIH guideline to a of clinical for different drug to and and preclinical which be an early human clinical Other are to as the of and This section of the guideline acknowledges the that are to of new to humans. These are to to the to the characteristics of study participants and to study The guideline that and mitigation strategies be during the design of aspects to are the of the IMP the available data the selection of the doses to be administered and measures during the of early drug studies more can be in most risk include a analysis of the of of the its (including to of biological pharmacological the and of effects and and characteristics of the study The analysis on preclinical previous with compounds and and will generally require the from different experts to that the trial can be It is not only of importance that the are but also that the right data is and analysed to or of these The of this integrated approach to early drug development may the risk of human studies, which is an important a in and is – for compounds where are As of the IMP is the of drug the of this section might be as the scope of the guideline and apply to other of drug development. but not consideration is that for trial a risk that is to deal with the and to be in and and as data the section has the previous it that of the IMP never be a of to humans. of the of drug development is of the IMP for its in clinical This to of the release during the but also the process or the drug or other a new it is that the of will during the development However, the guideline the need for an level of at It is important that the address risk an FIH dose from preclinical studies the that the drug which was used in the could and also to the drug that will be used in humans. This may influence the of the This be carefully during the of dosing schedules for FIH studies and SAD or MAD and the selection of the dose and The of the study drug can also the to or and which may all influence the and of and to doses (e.g. to the of dose further the of if to pharmaceutical are during early human development of the IMP if are in the of an this be in as a of increased The information from preclinical experiments that be obtained to the design of early human drug studies is largely in other guidelines (e.g. This current guideline, as most of the nonclinical regulatory the of animal – to regulatory – and the of in and in in of in animal studies a in drug development not the of the in with the other of and the guideline and animal study in to of of studies and for the The of an FIH a of preclinical studies, it to the outcomes of of by itself. preclinical can a different of the FIH and a of experts is typically involved in on safety pharmacological and and other aspects of the design. 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However, the revised guideline more emphasis on the ongoing of of the because this is a approach for compounds a more on PD will information about pharmacological and effects of the drug and to the of that can be used in clinical trials. These aspects are to be for a drug development programme The of time and in early clinical trials in the guideline may therefore be in where all included in the guidelines might not be for safety The of the document is that a approach to the study is seen as to the safe of the study The different of investigators, and committees during the of an early human development study will require regarding the of shared information, and many and sponsors, the practical are active regulators and ethics committees will also need to It also be that a much of the authorities in the regarding dosing and safety might impact legal as regulators and many the practical and of the FIH guideline for the different largely need to be in more and will be also to how the authorities will the The of the new guideline are and lead not only to but also to more early development These be used and by all the stakeholders the is or or if the by the multiple stakeholders involved is to the this can the of an FIH study the safety of The included are on pharmacological and biological of drug which be to the clinical The same also be in the guideline is to There are no to The in this article are the of the and may not be or as being on of or the of the EMA or one of its committees or Supp on strategies to and for first-in-human and early clinical trials with investigational medicinal The is not for the or of information by the than be to the corresponding for the