The transformative potential of personalised medicine in improving health outcomes has been well documented.
What is less well known is how early-stage clinical research has had to adapt to facilitate the new wave of gene therapy studies. Narrowly targeted medicines have great potential, with significant opportunities across all therapy areas.
It is a shift away from a ‘one-sizefits-all’ approach to treatment to one which uses new approaches, such as identifying genetic and other clinical information, to tailor therapies that achieve the best outcomes in the management of a patient’s disease.
We are fortunate that, in the UK, the government and the NHS committed early to embedding a personalised medicine approach across the health system. This is being progressed through the NHS Genomic Medicine Service which builds on the work of Genomics England to routinely offer NHS patients access to molecular and genomic testing.
This investment in genomic technology and research, plus the genetics education programme for the NHS workforce will enable more and more patients to have their individual biological make-up analysed and then be given improved care as a result.
Progress is also being made in ensuring that personalised therapies developed by the pharmaceutical industry can be accurately assessed by healthcare regulators. For example, the UK health technology appraiser, NICE, is undergoing a review of its methodology to ensure that it can be more flexible in evaluating complex innovations such as personalised medicines.
The MHRA has also adapted its processes to support the rapid development and uptake of precision therapies. For instance, the recently established Innovative Licensing and Access Pathway (ILAP) provides a more integrated and systematic approach to bringing the latest medicines forward for regulatory approval.
The role of clinical research in facilitating personalised medicine development
Just as health regulators, policymakers and clinicians have had to adapt in response to the potential of personalised medicines, and the demand for it, so too has my industry, early-stage clinical research. More than this, we have been crucial to their development.
I’ve undertaken hundreds of clinical studies over 30 years. The processes and types of therapies trialled have evolved significantly during this period. At the start of my career, I frequently led trials that used small molecules which blocked receptor sites – often only easing symptoms, not curing the disease.
More recently, we have increasingly trialled monoclonal antibodies instructing the immune system to destroy the target, which is often a faulty protein.
New modes of therapy that have become mainstream based on this type of clinical research include immunotherapy, which has been used successfully across a wide range of cancer tumour types and is also being used to treat autoimmune and cardiac conditions, and biologic medicines, which now account for 15% of medicines prescribed in Japan and 30% in the USA (in 2018).
More recently still, trials are focusing on small interfering RNA (siRNA) that has the potential to stop a disease ‘at source’ by inhibiting the production of an offending protein. The first ever siRNA therapy was only approved by the US Food and Drug Administration (FDA) in 2018 – Patisiran for the treatment of the nerve disease (polyneuropathy) – and two further siRNA therapies have been approved since (Givosiran and Lumasiran).
As of 2021 there are seven therapies in phase 3 studies and many more at earlier stages. A recent Biochemical Pharmacology review highlighted that ‘siRNA drugs are on their way to becoming a standard modality of pharmacotherapy’ and we therefore expect the demand for studies to significantly increase as the technology is tested in more conditions and biomarkers.
Lastly, gene editing is a hugely promising area for new drug development in which DNA is inserted, deleted, modified or replaced in a genome. This type of technology is becoming a reality for diseases where a genetic defect is known and appropriate for editing, presenting the potential to cure a disease forever through the use of one injection.
Designing studies for gene therapies is not simply ‘business as usual’ for contract research organisations (CRO) and clinical investigators. Getting these protocols right can deliver significant value enhancement to the trial sponsor and, eventually, the patient population.
There are a number of adaptations that CROs and the wider healthcare industry must make to deliver on the promise of personalised medicines. One of these adaptations relates to patient enrolment. Whereas previously CROs were able to draw on a wide-ranging patient cohort for firstin-human studies, gene editing studies require a cohort with a certain condition and biomarker.
This means that CROs need more sophisticated networks with volunteers, patient groups and the NHS in order to guarantee they can source patients that fit the trial profile. We saw the demands of this last year during a first-in-human study focused on a therapy with the potential to halt and reverse heart failure by blocking crucial regulatory RNA.
This successful phase 1b study in collaboration with Cardior Pharmaceuticals was published in the European Heart Journal. Delivering trials directly to the target population can reduce drug development times significantly, saving considerable costs for the manufacturer and helping to ensure faster access to the technologies for patients.
Moreover, as an industry we need to ensure that we are equipping pharmacologists with the right skills to undertake gene therapy studies. Industry has already been doing exceptional work in this area.
For example, the Clinical Pharmacology Skills Alliance (CPSA) has pioneered a workforce agenda for clinical pharmacologists that ensures their training needs are prioritised as these changes take effect.
It is also worth highlighting the work of the Faculty of Pharmaceutical Medicine – a charity and professional membership body – that helps equip doctors to become accredited pharmaceutical physicians via the Pharmaceutical Medicine Specialty Training programme.
It is important that physicians seek to develop more advanced and specialist skills via such schemes to ensure the safety of patients in the development of new gene therapies and other emerging medicines. Equally important in facilitating this is clinical research facilities becoming Local Education Providers to support the supervision of physicians on these specialty training programmes.
I’m proud to personally be a recognised educational supervisor and strongly support initiatives to deliver higher medical training. In this industry, we must never stand still.
As the demands of the technologies change, our skills and workforce must continue to change as well. Lastly, the clinical trial regulatory environment has also adapted to ensure that UK CROs are not disadvantaged when trying to compete for the development of these groundbreaking studies.
The MHRA has shown a willingness to understand the unique nature of gene therapy studies and they have shown flexibility and speed when assessing new protocol designs. For example, it has engaged extensively to understand the priorities of patients in the development and deployment of personalised medicines through its patient group consultative forums.
Lessons learned and building on successful gene therapy studies
The development of early-phase precision medicine studies is a complex undertaking. Nevertheless, when successful, it accelerates the development of personalised therapies in order to deliver dramatic improvements in patients’ quality of life.
We are still in the early stages of defining best practice in this area, but it is important that, when looking for partners, pharmaceutical companies are: assured that trial leads have experience in treating the medical condition, have delivered gene therapy studies and have access to a hospital setting to manage any complications arising from co-morbidities, and are guaranteed timely access to the target patient population and that adaptive studies can be delivered rapidly.