The Lindner Hotel, Antwerp, Belgium was the venue for clinical research organisation SGS’s 6th Biopharma Day,which was held on October 4 this year,and attendees heard fromspeakers and roundtable moderators from a number of leading drug development services and pharmaceutical sponsor companies on how the clinical trial paradigm is changing to result in successful early phase clinical trials.Themes throughout the day included the need for greater emphasis on the design of more practical protocols to ensure that the drug products needed to meet the demands of modern health care can be developed more quickly and easily, with a much reduced risk of failure and full regulatory compliance during the clinical development process.
Lectures and roundtables
The event was structured around a series of lectures and roundtable discussions covering a number of subject areas,ranging from how to choose the correctearly-phase clinical study design, to empowering early-phase R&D with human challenge trial solutions. First to speak was Dr.MikailRaghoebar, Senior Director and Head of Janssen’s Clinical Pharmacology Unit, with his presentation“Exploratory Phase 1 studies: From proof-of-pharmacokinetics to proof-of-relevance.” This presentation wasfollowed by that of Dr. Katrien Lemmens of SGS Life Sciences, “Biomarkers to assess benefit-risk for improved clinical trials.”
Dr.Raghoebar has more than 30 years of experience in pharmaceutical development, and has particular expertise in clinical, strategic and project management, having helda number of senior positions in leading international organisations including Solvay, Organon, Semaia Pharmaceuticals, NBPI International, Yamanouchi and FOCUS Clinical Drug Development.
Dr. Lemmens, who graduated with a Medical Degree from the University of Antwerp in 2000 and obtained a PhD in Medical Science (Pharmacology) in 2006, started her industrial career as Medical Director and Principal Investigator at the Phase I Clinical Pharmacology Unit of Janssen R&D. An Assistant Professor in Pharmacology at the University of Antwerp, she is now Medical Director Early Phase at SGS Life Science.
A new paradigm of early-phase pharmaceutical development
These two presentations showed how new R&D challenges have generated a new paradigm of early-phase pharmaceutical development in which the goals and objectives of phase 1 trials have moved beyond traditional dose and toxicity testing. In his presentation, Dr.Raghoebarobserved that when starting first-in-human(FIH) trials, only preclinical data are available, meaning that the study still has a strong focus on safety.However,the current practice is thatit has become important to look for early information that may indicate the potential usefulness of a drug by investigating the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug candidate. The presentation by Dr. Lemmens demonstrated how, in this context, new strategies such as the implementation of new biomarker technologieshave emerged.It was also shown how trial design has changed, with combined protocols with food effect or drug interactions being taken into consideration, orpatient or special population cohorts sometimes being included in the trial protocol. This is a marked change from how FIH studies have traditionally been performed, with them using healthy volunteers only. The result of these changes is that early-phase clinical studies now often have far more complex designs than before, requiring increased expertise on the part of the clinical researchers.
Roundtables A and B: reportable studies and study feasibility
These first two lectures were followed by the morning roundtable session, in which two parallel sessions were held:Roundtable A, “How to achieve reportable FIH study by bridging design, data analysis and results interpretation;” and Roundtable B, “How to ensure the operational execution feasibility of a, scientifically-speaking, perfect study design.”
Roundtable A considered how to justify the decisions that are made when designing a clinical trial protocol, bearing in mind that FIH trials are exploratory and aimed at obtaining sufficient and reliable information on safety, tolerability, PK and PD, but need to maintain their scientific validity. The number of subjects, the number of tested dose groups, the decision-making factors for dose escalation, the duration of PK sampling, and many other factors need to be discussed during the development of a study design, in order to justify the protocol design decisions and correctly interpret the results presented in the FIH clinical trial report. The workshop addressed these issues through the presentation of case situations from FIH studies, and a discussion between workshop participants around making the best choices to be made under different circumstances.It came to the following conclusions:
- It is important to keep in mind that FIH studies are exploratory and so one should “expect the unexpected,”however, it is also beneficial to anticipate, predict and be prepared for any outcome;
- The development of the trial design, synopsis, clinical trial protocol (CTP) and clinical study report (CSR) are related to each other and need input from different parties;
- The synopsis, CTP and CSR are not just submission documents, but scientific documents which require as much clarity and exactitude as possible;
- The lack in design development or synopsis/CTP writing may produce unreportable results.
Roundtable B looked at the conditions required for a scientifically well-designed FIH study to be feasible from a practical point of view in phase 1 conditions.These included the choice of study population, Investigational Medicinal Product (IMP) preparation steps, the use of sentinel dosing groups, sample-handling processes, as well as the frequency and types of measurements necessary. Additionally, any implications and details of in-house stays and the natureof follow-ups should be included at an early stage in study design discussions.It also considered how to implement such an approach to avoid developing so-called ‘perfect protocols’ that are in fact completely impractical or impossible to execute. The discussion came to the following conclusions:
- A “perfect protocol” is a protocol written to be executed in real life to gain as much scientific insight as possible;
- While the “perfect protocol” exists on paper, operational execution of it might be a challenge;
- Clear communication on the content of a protocol and its operational feasibility is key to avoid issues;
- No protocol can be final before operational review.
Following networking over lunch, the seminar programme resumed with lecture session 2, “Empowering early-phase R&D with human trial challenge solutions,”presented by Stephan Chalon, VP R&D, Experimental Medicine & Clinical Pharmacology at Medicines for Malaria Ventures (MMV),and Adrian Wildfire, Project Director, Infectious Diseases & Viral Challenge Unit at SGS Life Sciences. The presentationsconsidered how the accelerated uptake of controlled human infection models, including the controlled human malarial infection model can be used to provide early efficacy data in healthy volunteers.
Stephan Chalon has drug development expertise in a number of therapeutic areas, including neuroscience, cardio-metabolism, immunological/inflammatory diseases, and infectious diseases/tropical medicine, specifically in candidate selection up to proof-of-concept/phase 2a studies and in developing clinical packages supporting submission. He joined MMV in 2014 after a 20-year career in early development, translational medicine and clinical pharmacology, that included 14 years working for large pharmaceutical companies in Europe and the US, with positions at Lilly Research Laboratories, Wyeth/Pfizer Global R&D, Roche Pharma and Shire Pharmaceuticals.
Adrian Wildfire is a Fellow in Medical Microbiology and holds a Masters in Parasitology. Having trained at the Wolfson Institute and the London School of Hygiene and Tropical Medicine, he has more than 30 years of experience working in the area of communicable diseases and is the author/co-author of a number of scientific papers in the area of infectious diseases including tuberculosis, HIV and influenza.
The two presentations showed how the retention of wild-type characteristics in pathogens manufactured to cause disease may allow for better translation from the clinic to the field, because in many cases attenuated strains are not effective enough. For example, malarial and upper respiratory tract infections can be effectively modelled in controlled environments as they are well-understood, being widely distributed diseases with known routes of transmission. The talks demonstrated how, as more agents that emulate naturally-circulating viral or bacterial strains are developed, a body of data will be created that will enable improved mapping of host-pathogen interactions and the identification of potentially new targets for therapeutic intervention. It was noted that to ensure such targets are effectively translated into drugs and vaccines, it remains essential that strong challenge agents with little attenuation from the wild-type pathogen are used in clinical trials, and that the manufacturing of challenge agents is better regulated in order to ensure their safety, purity and consistency.
Roundtables C and D: the ethics of challenge and pipeline development
As with the morning session, the two lectures were followed by two parallel roundtable discussions. Roundtable C, “The ethics of challenge – primum non nocere? A regulator view,”covered the hurdles that need to be overcome in selecting patient populations and discussed how far the challenge model can be successful, while Roundtable D, “Challenge models and pipeline development,” considered the applicability of efficacy versus effectiveness data in candidate selection and asked whether human clinical trials should be mandatory for certain disease states.
The conclusions and take-home messages from the roundtables were:
- Human challenge trials (HCTs) have to be carefully evaluated from an ethical standpoint, and good communication and supply of information to subjects is crucial, including the potential risks to both the subject and wider community in case of withdrawal from a study;
- Good Clinical Practice guidelines need to be evolved to also include societal risks and related obligations that might be laid upon subjects to mitigate;
- Safety is, and must remain, the primary driver in HCT trials;
- Western regulators may not approve study data produced in certain countries.
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