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Group recommends ways to improve and increase clinical research in new report.
"Further considerations should focus on biomarkers, modelling & simulation, and emerging clinical trials methodology." That is the stark conclusion from a new study conducted by the European Medicines Agency into how European drug innovation can be fostered.
The study was carried out by a self-styled think-tank group comprising agency staff and members of its scientific committees and working parties, with the aim of identifying scientific bottlenecks to the development of innovative medicines, both in industry R&D and in the academic environment.
The group did not operate in a vacuum. It took extensive soundings from individual pharmaceutical companies and academic groups or learned societies. And one of the key trends to emerge from the study is that the amount of pharmaceutical research carried out in Europe is decreasing.
In some cases, the study finds, this is despite the EU's longstanding attraction as a location for early clinical trials, particularly in terms of the many CROs with world-class clinical pharmacology capabilities, good academic centers with translational biology/experimental medicine strength, well-motivated volunteers, and regulatory authorities experienced in early phase guidance.
Phase Tweaks: Proposed Trial Models
Some companies signalled issues such as lack of treatment-naïve patients and underperformance of study centers as the aspects that may reduce the attractiveness of Europe as a key player in clinical research.
Contacts with European pharmaceutical companies revealed their wish for interaction and guidance on innovative statistical approaches and clinical study designs. The think-tank group recommends that the issues be addressed in the agency's efficacy working party, with a guideline on flexible design, and with the setting up of a specific subgroup to collate overall experience in adaptive or flexible designs. Everyone could benefit from sharing up-to-date scientific knowledge in this fast developing area, the report concludes.
In addition, the report recommends that a workshop should be held on the use of Bayesian methodology in confirmatory clinical trials. "There are advantages to including properly quantified existing knowledge in the design and analysis of future clinical trials," says the study, which suggests that Bayesian methods can provide a more natural framework for assessments of futility, selection of dose/patient population in trials with an adaptive design, and in quantifying efficacy and safety in small populations.
One of the topics spontaneously brought up by most companies and academic groups was the need for a more harmonized scientific evaluation of preclinical requirements and clinical protocols in clinical trials. The think-tank group's recommendations are that the agency might consider development of tailored guidelines for quality and nonclinical requirements for clinical trials, especially for certain types of innovative products, to harmonize the requirements within the EU. This should be complemented by appropriate training of assessors and the building up of further special assessor networks.
The think-tank noted that a harmonized EU position, taking into account ICH discussions, should be expressed soonest on nonclinical requirements to support clinical trials, as well as a recommendation on early clinical trials with low doses of pharmaceutical compounds. "This is of utmost importance for the selection of the most promising molecules and for speeding up drug development," the study remarks.
Most companies and academic groups also brought up the need for development of tailored scientific guidance for quality, nonclinical, and reporting requirements for clinical trials with investigational medicinal products. Lack of clear EU scientific position on these matters is perceived as a practical obstacle in conducting research and clinical development in Europe, particularly critical for certain types of products such as pediatric, orphan, and other innovative products. The think-tank group backed the idea firmly.
In addition, says the report, a common EU scientific position on nonclinical requirements prior to conducting early Phase I clinical trials with low doses of pharmaceutical compounds needs finalization and urgent implementation, and the scientific opinion should incorporate the final conclusions of the draft guidance on first-in-man trials with potential higher risk products.
Strong support was also evinced for scientific guidelines on the quality and nonclinical requirements for clinical trials with advanced therapy products. Companies involved in development of advanced cell and gene therapies welcomed the harmonization anticipated from the planned regulation for advanced therapies—which was agreed in principle by the EU during April—although industry emphasized the need for flexibility so that guidelines can cope with rapid developments in this field.
The think-tank group took the view that a common EU position should be developed as soon as possible on nonclinical requirements to support early Phase I clinical trials with doses in the low pharmacological range of pharmaceutical compounds. The position should take into consideration the ongoing preparation of guidance on first-in-man trials with "potential higher risk" products. "This is of utmost importance to allow companies to 'kill/fail fast' the nonoptimal molecules. Further, industry is encouraged to more proactively search for potential safety problems with new molecules." Realistically, the overall safety requirements will not become less stringent, but they might become more tailored, the report suggested.
It was also clear from the consultation that the importance of Phase II/exploratory data is appreciated by many companies. Certain methodological approaches, including the use of adaptive trial designs, decreased use of blinding, and continuous assessment of data might be permitted, even encouraged, in early phase, exploratory development. The think-tank group was not, however, in favor of a "provisional approval," with initial marketing authorization approval at the stage where a positive benefit/risk is not yet completely established, followed by later full approval: "This would not be compatible with the obligation for regulators to base the benefit-risk consideration on the best and sufficient safety data," it said. However, it recognized that the scientific principles of conditional marketing authorization (already positive benefit/risk) could be applied to cases of unmet medical need where there are exceptionally promising therapeutic results.
Some companies proposed a seamless and flexible approach to Phases II and III of drug development in preference to the current "Phased" approach. This would mean replacing the classical full drug development program, where the design features of a clinical trial (sample size, patient population, treatment arms) are fixed and the development phases are strictly separated. New approaches, using more efficient clinical trial designs, might shorten development times while maintaining the integrity of the data.
In particular, the so-called "seamless" Phase II/Phase III trials, where Phase III continues without a pause in recruitment following Phase II, could expedite drug development significantly and might increase the information available on dose response, the study concluded.
Much of the comment from academic groups and learned societies on methodological aspects of clinical trials mirrored the views of the pharmaceutical industry on use of adaptive trial designs and use of dynamic treatment allocation. They also felt that discussion with regulators and guidance on minimal clinically relevant differences would be useful. And they wanted systematic consultation of health care professionals on new agency guidelines.
In particular, they urged the creation of a European guideline for acceptance of large academic trials. The think-tank agreed that guidelines on the criteria for the scientific evaluation of results of large academic trials should be provided to increase awareness of the possible impact of those trials on the benefit/risk evaluation of medicines.
Building up European-wide clinical research networks would be very helpful, and any facilitation here by regulators would be appreciated, according to the academic input. They also suggested that in order to avoid repetition of studies unlikely to be useful, the publication of results from negative clinical trials should be made compulsory.
So much for the analysis. Change is needed—and, if the exercise is to have any merit at all, change is needed soon. So what are the next steps? Not very vigorous or imminent, to judge from the agency's own comments. "Prioritization within a following action plan will be done by the EMEA at a later stage," it says. And, it notes pointedly, the report quite deliberately "does not consider the impact of the recommendations on resources." European clinical trials regulation faces a familiar dilemma again: Everyone knows more or less what to do to improve the situation, but no one has the money to do it. It was ever thus in Europe—and unfortunately, it may ever be so.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.