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The Medicines and Healthcare products Regulatory Agency (MHRA), sponsors and investigators came together for the Clinical Trials in the EU Workshop in Boston last month to discuss how pragmatic regulators, innovative study design and the harmonisation of clinical trials approvals across Europe can help drive early stage clinical programs forward and maximize information obtained.Summaries of presentations

Dr Ulrike LorchRichmond PharmacologyCombined adaptive protocolsfrom First Time in Human to Proof of ConceptEarly phase trials aim to explore safety and efficacy and to establish proof of concept in patients as soon as possible. Combined adaptive protocols can accelerate this by encompassing several conventional trials in one single protocol. Single ascending, multiple ascending, food effect, drug-drug-interaction and age/gender comparison parts can be combined. Elements to add value to a trial and to de-risk further drug development can be included. Value can be added by inclusion of Japanese participants, assessing safety, tolerability, pharmacokinetics and pharmacodynamics. Intensive cardiac safety assessments de-risk further drug development. The inclusion of biomarkers and the exploratory evaluation of efficacy in patients may do both, add value and de-risk.Combined adaptive protocols need to be detailed, clear and well-structured whilst allowing for flexibility and redirection of a trial as a result of the continuous review of evolving data. The layout of these protocols should facilitate ethical and regulatory review, study conduct, data analysis and reporting, setting the boundaries of maximum risk and inconvenience an authorised trial may entail. To simplify the protocol writing, we published a three-step approach to writing early phase adaptive protocols (1).

Using this approach, the protocol features that can be adapted, the limits of these adaptations and the mechanisms to control the decision making to progress through the various parts of a trial are described in a methodical way that is easy to follow for reviewers and researchers.Depending on the therapeutic indication and the number of patients required, early exploration of efficacy can be performed in a single centre, or if larger groups of patients are required, the patient part of a combined trial can be rolled out to a small number of pre-selected centres that are capable of handling protocols of greater complexity.Patients included in such trials may have common or rare diseases. They should be mobile enough to attend the trial visits. The Clinical Pharmacology Unit (CPU) needs to be able to adapt to patients’ needs. To enhance acceptability of a trial for patients and to allow the conduct of more complex trials in smaller sample sizes, clinical procedures and investigations should be carried out in a small number of locations, by the CPU and/or in direct collaboration between CPU and clinical specialists.Trials suited to make a combined, healthy and patient volunteer trial a success are – in our experience –

• Trials where the patient part can be run as a straight continuation from healthy volunteer parts, benefitting from the same highly standardised and efficient clinical pharmacology processes, i.e. the trial plan for patients and healthy volunteers should be largely the same;
• Trials that can be run in one to three pre-selected centres with similar setup run by established pan-European collaborators, to widen the recruitment area where necessary;
• Trials that lend themselves to a multidisciplinary collaboration of clinical pharmacology investigator(s) with a small number of enthusiastic clinical specialists;
• Trials that have close communication between investigator(s) and sponsor for competent and fast decision making

1Three steps to writing adaptive study protocols in the early phase clinical development of new medicines\ Ulrike Lorch1*, Martin O’Kane2 and Jorg Taubel1BMC Medical Research Methodology 2014, 14:84 doi:10.1186/1471-2288-14-841 Richmond Pharmacology, St George’s2 Medicines and Healthcare Products Regulatory Agency (MHRA)

Dr Jorg TaubelRichmond PharmacologyEfficient integration of cardiac safety and ethnic (Japanese) data in early Phase study programsFollowing on from Dr Lorch’s presentation, Dr Taubel further explored opportunities to include cardiac safety risk mitigation strategies and value adding strategies such as the addition of Japanese PK and PD data by incorporating sub-groups during early phase studies.Recent modifications of the ICH E14 guidelines allow sponsors to collect ECG data in non-dedicated intensive QT studies. Such assessments, which need to be as thorough as in a standard QT study, can be incorporated in SAD, MAD, DDI or Japanese PK bridging studies. Dr Taubel showed data from recently published studies, which were conducted in both Japanese and Caucasian volunteers, allowing comparisons of PK and ECG effects using concentration effect modelling (CEM) as the main analysis tool.He discussed the various challenges and limitations of these approaches but concluded that these can be resolved in most instances by carefully planning and integrating these assessments into a phase I umbrella protocol. This allows for sufficient flexibility to respond to unexpected findings during the first administration in humans.He presented data from his original research establishing the effect of a carbohydrate rich meal on the ECG. There now is a solid body of published evidence showing the magnitude and time-course of the effect, the relationship to blood glucose concentrations and the release of C-peptide by the pancreatic beta-cells.

The intra-individual and between subject variability is comparable or even better compared to the standard pharmacological control of 400mg of moxifloxacin. Given that trial participants have to be fed during a trial and given the ECG traces are usually available for the relevant 3 hour time-point from starting a meal, he concluded that it was almost ignorant not to verify the ECG quality by utilising data that is readily available.He strongly advocated the integration of Japanese cohorts to allow instantaneous assessments of potential PK differences.

He explained that in most instances (about 90%), no differences beyond the obvious body weight difference are found. In all these instances the seamless integration of the Japanese data into pooled analyses of PK, PD and safety will increase the sample size with the obvious benefits of doing so. The ability to demonstrate comparable PK in Japanese allows the inclusion of Japan in global studies and facilitates the identification of interested partners in those instances where sponsors wish to explore partnering opportunities in Japan.Given the relatively high cost of managing clinical studies, many early phase studies now seek to explore more than one single objective leading to an increasing number of combined protocols. Care must be taken when drafting these as they must be simple in structure and define strategies clearly (see Dr Lorch). The integration of ICH E5 compliant Japanese participants and the integration of precise and validated thorough ECG assessments are straight forward, relatively inexpensive and therefore truly value adding.

Dr Martin O’KaneMHRAStreamlining early phase clinical trial authorizations in the UK and across Europe, in the context of the new EU Clinical Trials Regulation from First Time in Human to Proof of ConceptFollowing Dr Taubel’s talk, Dr O’Kane provided an overview of the EU and UK clinical trial environment. Applications for trials of medicines in the UK have increased year-on-year for 6 years and 2015 saw an 11% increase compared with 2014. The UK takes a large share of the total EU clinical trial activity and MHRA encourages early stage development via provision of scientific and regulatory advice, including very early stage advice through the MHRA innovation office. MHRA takes a pragmatic approach to innovative protocol designs and has approved ‘adaptive design protocols’ for early phase research. In addition, phase 1 studies undergo an expedited initial assessment with an average turn-around of 14 days instead of the statutory 30 days. For higher risk first-in-human studies MHRA also has access to independent experts of the Commission on Human Medicines to provide expert advice when required.

Throughout Europe, initiatives are underway to streamline the assessment of multi-Member State clinical trials. The Clinical Trials Facilitation Group (CTFG) acts as a forum to agree on common principles and processes to be applied throughout the European medicines regulatory network. This group promotes harmonisation of clinical trial assessment decisions and administrative processes across the national competent authorities.

One of the CTFG initiatives to promote harmonisation is the Voluntary Harmonisation Procedure (VHP). In the VHP, a sponsor submits a single set of core documentation electronically to the VHP coordinator. One Member State takes the lead in assessing the submission with the other participating Member States providing input on the draft assessment report.

The lead Member State consolidates the feedback and the sponsor is provided with either a notice of approvability or a harmonised list of questions to address. If the questions have been satisfactorily addressed during the VHP, the sponsor must then submit nationally to each competent authority (since the VHP, being voluntary, has no statutory basis). This ‘formal’ approval will be expedited with a turnaround of 10 days maximum. Guidance for sponsors wishing to submit via VHP is available here.The new EU clinical trials Regulation (Regulation 536/2014) aims to increase the attractiveness of the EU for clinical research in providing a new simplified approvals procedure and addressing many of the concerns raised with the current legislation. Under this Regulation (expected to apply in 2018), sponsors will submit their application via a new EU IT portal and database and a coordinated review by the concerned Member States, led by a lead ‘Reporting Member State’ (proposed by the sponsor) will be carried out.

The Regulation lays out clear timelines for assessment and introduces the concept of tacit approval for concerned Members who do not meet the required deadlines. Another concept that has been introduced with the Regulation is that of a ‘low-intervention’ trial allowing a risk-based approach to be taken in the authorisation and management of a trial.

The Regulation also requires decisions to be made on a Member State basis rather than separate decisions by the competent authority and ethics committees as is currently the case. Information submitted to the portal and database will be publically available unless strict criteria have been met (eg protecting commercially confidential information).Currently on a national and EU level, Member States are working to prepare for implementation of Regulation 536/2014 through input to the development of IT systems and training and Guidance documents required to support its functioning.

Dr. Andreas Hüser -Charité Research Organisation GmbHKeith Berelowitz -Richmond Pharmacology Save time and money through a national single centre approach to clinical trial conduct Funnelling clinical trial participants via national recruitment into a single centre for the conduct of early phase patient trials affords sponsors the ability to

• conduct studies of greater complexity; and
• reduce participant numbers through production of more homogenous data

This approach requires a competent clinical trial unit (CTU) with;

• existing access to the required study population
• the ability to competently assess and contribute to the proposed study design and recruitment requirements
• robust systems capable of scaling recruitment to a national level whilst still channelling subjects to a single centre

These factors drive the decision which of three proven recruitment strategies to adopt in order to achieve recruitment goals, namely;

1. CTU led

Suitable for healthy volunteer and high incidence patient populations, benefiting studies from the perspective of rapid approval times and study conduct. Example described: FTIH study in n=92 RA patients with DAS28 ? 3.2 combining SAD i.v., SAD s.c. and MAD s.c. dosing. At its peak 20 subjects were recruited into the trial in just one month, with recruitment targets met per schedule through the study.

1. Investigator led

Used for studies of rare diseases or highly specialised populations. This approach benefits sponsors and investigators by allowing investigators to seek out more patients for enrolment than they would otherwise be able to enrol in an academic/purely clinical setting by working with a dedicated study team in a professional CTU.Example described: Pivotal phase III, enrolling genetically defined rare disease patients; CTU accommodates the clinical conduct of 10 patients to boost the academic centre’s recruitment to a joint total of 12.

1. Blended Approach

Target populations are accessible via investigator networks, a CTU’s database and extended reach programme. This benefits study conduct through the ability to initiate and conduct the early phase trials in just one centre, allowing for the conduct of complex study designs, reduced sample sizes and the production of more homogenous data.Example described: 24 Schizophrenic subjects included in a 28 day MAD study requiring MRI & PET. Recruitment and clinic conduct achieved within 6 months of site initiation ensuring sponsor’s follow-on studies start to time.European Early Development Closed NetworkTo achieve study objectives in a timely manner, some studies will benefit from the initiation of more than one centre to recruit large or rare patient populations. The national single centre model can still be utilized, through the conduct of such studies by a small network of European CTUs aligned in their setup and processes.The net result being complex studies can be conducted;

• producing high quality, more homogenous data; thereby
• utilising a smaller patient population funnelling into few centres
• at a lower cost than could be achieved if these studies were run over several unconnected centres
• within the timelines required due to the parallel recruitment activities of the CTUs in the network