Pharmaceutical Market Europe • October 2021 • 18-19
GENE-BASED THERAPIES
The future of new medicine development and first-in-human studies
Assessment of new gene-based therapies is radically reshaping the way
first-in-human clinical studies are delivered and the UK is leading the way
By Jorg Taubel
First-in-human (FIH) studies are the foundation of therapeutic development and new medicines discovery, yet despite the UK’s leading global position in delivering phase 1 trials, it is a discipline that can be poorly understood and is often overlooked in policy discourse and the media.
The primary aim of FIH studies is to test an investigational medicinal product (IMP) in humans for a safe dose range and potential side effects, how a medicine is metabolised and whether it might work in patients. This early-phase research is an essential stepping stone, leading to more detailed phase 2 and phase 3 patient studies and eventually medicines approved by regulators for mainstream use.
Recent research by the Association of the British Pharmaceutical Industry (ABPI) demonstrates that the UK is the leading location for phase 1 studies in Europe, with as much as a quarter of first-in-human studies during the past five years being undertaken in the UK.
I would identify several factors that foster such an attractive environment, including: first-class links between academia, the NHS and industry – this was how my organisation began 20 years ago and how many continue to innovate in the industry. Secondly, that regulators such as the Medicines and Healthcare products Regulatory Agency (MHRA) and NHS Health Research Authority (HRA) are genuinely responsive to Contract Research Organisations (CRO) and patient feedback and strive to remove barriers to progress and innovation. Finally, this all stems from having a government who understands the value of clinical research and is investing in improving the environment in which we operate, and I am impressed with the five key themes set out by the Department for Health & Social Care in its recent future of UK clinical research strategy paper.
Best practice in delivering phase 1 studies
There are specific considerations and challenges associated with FIH clinical studies. It is important to reiterate that there is potential risk in administering IMPs in humans for the first time and therefore vigorous design of phase 1 clinical trials is critical to ensuring participant safety. Robust toolkits exist for healthy volunteer trials, and it is of paramount importance that these processes are adapted for patients as closely as possible.
It is essential to be clear on the trial protocol and to have the study concept reviewed and approved by an ethics committee. Volunteer selection is also of paramount importance both in healthy volunteers and in patients with a specific condition. Indeed, CROs may screen hundreds of volunteers before settling on the correct cohort for a study. Improved data collection and analysis once a study is underway also means that fewer patients can be required to get to the desired result which reduces unnecessary testing and the risks associated with this.
The breathtaking speed by which the COVID-19 vaccine has been approved has increased expectations of the life sciences sector that treatments for other priority therapy areas can be developed and brought to market rapidly.
Early phase clinical research institutions are working to accelerate the process. Adaptive trial protocols are increasingly being used across all stages of clinical research and can deliver efficiencies in phase 1 studies. The key advantage that adaptive trials bring is the ability to operate flexibly, enabling the modification of a trial’s course in accordance with pre-specified rules in the protocol.
What this means in practice is that analysis of data is allowed while the trial is ongoing rather than having to reach a predefined end point. This agile approach saves time and resource through, for example, refining the patient sample size, improved understanding into which patients are responding and an earlier indication of whether to halt a study.
The MHRA has facilitated the use of adaptive protocol designs in the UK, and it is now possible to run an entire phase 1 programme as part of one protocol and following a single regulatory and ethical approval.
‘The new wave of advanced therapies based on gene editing is presenting additional challenges and opportunities in FIH studies’
How FIH studies facilitate the new wave of genomic medicines
The new wave of advanced therapies based on gene editing is presenting additional challenges and opportunities in FIH studies.
A series of precision medicines based on genomic technology have been approved for the treatment of cancers in recent years and this is now extending into trials in numerous conditions where there is significant need – for example in cardiology, neurological conditions and rare genetic conditions such as transthyretin amyloidosis.
Clinical research is experiencing a step change, having to design trials in different ways to successfully test new genomic therapies. Volunteer enrolment is one of the biggest reforms. Whereas previously, FIH studies demanded a selection of healthy participants, genomic medicine trials require patients with the relevant condition and often the genetic biomarker that the therapy will target. This presents greater challenges in sourcing and correctly managing the right type of patient. However, CROs such as Richmond Pharmacology have refined recruitment tools over years of conducting patient studies and are well equipped to fill these cohorts.
The demand for these types of FIH studies is growing and soon will become standard practice. The changes that I have implemented to deliver for sponsors and volunteers involves creating phase 1 units and protocols that are adapted for the needs of different patient types. This includes more comfortable facilities for patients, a hospital setting which can support complex conditions and comorbidities, specialist training for staff, additional safety processes and an understanding of their medical conditions which make it desirable for patients to take part in trials.
The bigger picture is that there are significant efficiencies to be made when trialling gene editing therapies and this should result in accelerated approval of new medicines. For example, traditionally there is a need to conduct a phase 1b study – to test on a patient cohort – after the initial assessment that the IMP is safe in healthy volunteers. The requirement of gene editing therapies to be tested immediately on the patient group in question removes this need, saving the pharmaceutical industry time and money.
To conclude, CROs, such as Richmond Pharmacology, which specialises in delivering FIH studies testing advanced therapies and other cutting-edge treatments in patients are transforming the way trials are delivered and data is analysed. The result is substantial time and resource savings for sponsors which facilitates faster progress to phase 3 studies and eventually approved medicines reaching the patients who need them.