Belgium is among the leading European countries for number of clinical trials, with 507 new applications in 2016 and a total of almost 1,400 studies reached (22% phase 1, 28% phase 2, 39% phase 3 and 11% phase 4; data pharma.be). Investments in the sector of research into new medicinal products reached € 2.89 billion in 2016. The emergence of new, innovative types of therapies, i.e. advanced therapies (ATMPs) such as CAR-T or immuno-oncology products, asks for an updating of the traditional way to plan, design and run clinical trials.
The many challenges of personalised medicines
Precision medicine approaches are focused on the identification of small sub-groups of patients more likely prone to successfully react to certain therapeutic treatments. To identify such sub-groups – i.e. to select patients to be included in a new study – a wide variety of diagnostic methodologies are used to characterise specific biomarkers, many of which at the level of the patients’ DNA.
The choice of the most appropriate molecular testing, its validation, the coverage of its costs and the timing for use is one of the first barriers to be faced, according to the Educational book published by the American Society of Clinical Oncology (ASCO).
A barrier that also requires a strict collaboration between the biopharmaceutical industry and the manufacturers of these diagnostic devices in order to optimise the development of the respective products. Many innovative medicines are coupled to specific administration-approved companion diagnostics (CDx) falling under the medical device regulatory category. This development strategy is the one preferred in recent years by many regulatory authorities, i.e. US Food and Drug Administration, as it allows for a better identification of the eligible patients compared to other test methods. But ASCO warns about the possible greater discordance with the results from liquid biopsies, and underlines the need for clinical trials directly assessing solid vs. liquid biopsies and their utility in the decision-making and monitoring processes. Furthermore, explains the paper by Talia Golan et al. published in the Journal of Experimental & Clinical Cancer Research (JECCR), clinical biopsies are different from research biopsies, as the former aim to diagnosis and monitoring markers of response to targeted therapy, while the latter are part of a clinical trial protocol designed to answer specific scientific questions.
Genetic counseling services may be associated to the results of molecular panel testing, as a way to improve life style and prevent the emergence of pathologies that might be linked to the somatic or germline genetic profile of the patient.
The quality and quantity of the tumor tissue specimens collected, and their conservation in appropriate and standardised repositories (better if centralised), is another issue requiring attention. Time and modalities of conservation (i.e fixation with formalin) may also impact on the possibility to re-test archived samples, while techniques based on liquid biopsies are not yet validated in broader settings. More relaxed tissue requirements – e.g. with just optional tumor biopsies – are suggested by ASCO in order to improve patients’ participation to the studies.
How to optimise the study design
The first problem is to identify targetable molecular alterations valid from the clinical perspective, that may differ from the ones interesting under a non-research perspective. “Actionable” alterations are usually well defined, and their choice can be supported by computerised tools. An example made by ASCO is the LCI Integrated Knowledge database developed by the Levine Cancer Institute, which provides an automated synopsis of molecular alterations observed in patients and potential clinical trial matches on the base of the testing results specific for each patient. It is the provider itself (in the US) that can then choose the clinical trial more suited for the single patient, sending an email notification to the study coordinator.
The new interpretation of toxicity data from early phase studies on ATMPs has been discussed in the JECCR paper. The complexity of many forms of cancers, often associated with more than a single mutation, has caused a shift of paradigm that overcome the highly selective molecular testing to focus on unbiased whole-genome/whole-transcriptome testing. This is reflected by an increase of the number of “adaptive” or “umbrella” study designs, which according to the authors allow to rapidly test multiple hypotheses, drugs, and biomarkers. The majority of phase 1 trials with immuno-oncology antibodies have not reached the dose-limiting toxicity (DLT) dose, thus the recommended phase 2 dose is usually based on maximum administered dose or PK data, explained Golan et al. Furthermore, being this kind of products generally linked to significant early efficacy signals, phase 1 studies are often based on expanded cohorts. This is a design requiring a strong infrastructural capacity to capture early toxicity signals, as ATMPs may also lead to very severe adverse effects.
The choice of the cohort size should take into consideration the needed statistical power, the data already available on the product and clinical precedents, the eventual delay in effect, the choice of the primary endpoints (progression-free survival-PFS vs. overall survival-OS). From the ethical point of view, the setting up of the study design should also take into consideration the need to run research biopsies, suggests the JECCR paper.
The financial impact
The costs to access precision medicine therapies might be relevant, and unaffordable by many patients. From the industrial point of view, explains the JECCR paper, risk-based monitoring (RBM) models require quite big investments to validate the integrity of the clinical trial process according to the requirement of the FDA. The adaptive options indicated by the agency to simplify the process – e.g. centralised data collection and monitoring – are yet not so much frequently adopted both by experimental sites and sponsors. The Golan paper also provide a discussion of the budget definition for a study, which is based upon the general principle of fair value and varies with respect to the geographical location of the sites involved. External budget has also to cover all the costs included in the internal budget. All budgets are then negotiated with the industrial sponsor on the base of a justification approach.
The suggestion to community practices coming from ASCO is to use umbrella research protocols, in which data are shared allowing for a reduction of the costs for testing. But this approach needs to close partnership agreements with the company providing the service, something that can be difficult for smaller practices. These may also experiment issues in preparing business plans, or in the setting up of the infrastructure to support precision clinical trials. On the other hand, benefits include the possibility to administer highly innovative treatments to patients and an improved quality of care.
Emerging countries such as Brazil are increasingly proposing themselves as a location to run clinical trials on precision medicines, says the Golan paper, on the base of the high population, mainly “trial naïve”, and the support of an increasingly robust regulatory framework compliant to ICH GCP guidelines. The lack of cancer patients registries, the frequent uncertainty on the respect of regulatory timelines and logistical and cultural issues are factors limiting this opportunity.
A strong network of partnerships
The correct functioning of the supply chain for precision medicine (and its rapid evolution) requires a strong collaboration among all stakeholder, including the regulatory authorities, and dedicated shared resources, personnel and access to facilities, both at a national and international level.
The wide implementation of companion diagnostics and therapeutics tools is limited, according to the JECCR paper, by the availability of adequate and accessible laboratories and their close interaction with the clinicians, the access to drugs and the establishment of multicenter networks or collaborative groups.
A multi-disciplinary leadership team is suggested by ASCO in order to keep always update the precision medicine programme and its development. The availability of Molecular Tumor Boards (MTB) may also facilitate the correct interpretation of the testing results by less experienced community practices, and can provide support to identify the optimal time to start treatment, or options available to patients not wishing to participate to clinical trials.
The Belgian hub for clinical R&D
Quite one third (29.1%) of the R&D run in Belgian hospitals and research centres is targeted to the development of new anti-cancer medicines, followed by research on nervous system diseases (9%) and virus diseases (7,2%). This year will see the termination of the ‘Pact of the Future’ signed in 2015 between the local government and the pharmaceutical sector in order to attract more R&D investments in the country, included clinical trials. A Pact that has also led to the promulgation in 2017 of the new Belgian Law on Clinical trials, supporting ultra-fast approval procedures, particularly for phase 1 trials (just 15 days). All applications are scrutinised by a national College to provide harmonised assessment, under the central coordination by the competent authorities and designated ethics committees.
Patient recruitment efficiency, the quality of research centres and a dense medical infrastructure are the main features pharmaceutical companies are looking for while planning for a new clinical study, according to a survey run by pharma.be among 45 innovative pharma companies. With its over 70 top quality hospitals, Belgium was one of the first European countries to launch in 2018 pilot projects to prepare for the entry into force of the new EU regulation on Clinical trials (EU 536/2014), coupled with the creation in 2017 of the new National Innovation Office, the central access point for scientific and technical/regulatory questions.