In early 2020, the Cell and Gene Therapy Catapult (CGTC) reported that there were 127 ongoing trials in advanced therapy medicinal products (ATMP) in the UK. This represented 12 percent of trials globally, helping to position the UK as a hub in the development of advanced therapeutics. As with any treatment, approval of cell- and gene-based therapeutics relies on robust clinical studies. Here Shrinidh Joshi, freelance biotech consultant at Kolabtree, gives his tips for conducting trials.

In February 2021, researchers at the University of California San Diego launched a phase I trial of gene therapy for treating early Alzheimer’s disease and mild cognitive impairment. The team had previously carried out another phase I study that involved injecting nerve growth factor (NGF) into the brains of eight patients with mild Alzheimer’s and assessing whether the treatment had triggered cognitive improvement. The latest trial will explore the effects of using a different protein than the first study.

Research into autologous therapeutics has intensified and these methods are being used to treat various diseases. A few years ago, I was working on one trial where we took mesenchymal stem cells (MSC) from patients with Osteoarthritis, modified them so they can perform better, and observed a year later to see if symptoms had improved. There have also been developments in oncological studies. In a separate trial, we tried to modify the chimeric antigen receptors (CAR) in natural killer (NK) cells so that they could destroy cancer cells that had become invisible.

Research into the stem and stromal cell treatment continues to grow and these methods offer hope to patients with diabetes, cardiovascular problems, and other unmet illnesses. They can also treat osteoporosis by restoring stem cell functionality, enabling the cells to proliferate and differentiate into bone-forming cells. Like any biological treatment, clinical trials must be conducted on autologous therapies to establish their safety and effectiveness.

Staying focussed

Generally, biotech companies design trials around four phases. Phase I assesses the safety of a new treatment by testing it on small groups. Phase II uses a larger population made up of different demographics and tests effectiveness by introducing a placebo group. Then, phase III trials monitor the treatment’s impact on an even larger population. At this point, companies can apply for regulatory approval. Finally, phase IV post-market analyses establish the long-term effects, documenting any reported side effects.

While the phased approach is rigorous, it is difficult to control for every variable. All cell and gene therapy treatments are unique and have their own challenges. Common trial issues include defining the research question, achieving sample randomisation, and selecting control groups and target populations. These can all distract from the core research objectives.

When devising individual phases, biotech firms must establish clear, attainable targets. They can do this is by selecting primary endpoints that determine what is being measured, like the occurrence of a particular symptom. These can be established by combining several measurable outcomes into a single composite endpoint or by using surrogate markers that may not have a relationship with the real clinical endpoint.

Biotech companies can also maintain research focus by recruiting external specialists that can assist with trial design and regulatory compliance.

Seeking advice

When developing autologous therapeutics, one of the most important skills is knowing when to seek advice. Generally, biotech companies have two options — manufacture in-house or outsource. There are four main steps when developing a gene therapy: raw material preparation, upstreaming, downstreaming, and finally product completion. A company may design the treatment in-house but then approach an external consultant for assistance with combining the vector genome, AAV protein, and helper proteins into a capsid that houses the functioning gene, for instance.

If biotech companies don’t have the in-house skills required for a particular task, they can recruit freelance biotech consultants or specialist biologic contract manufacturing organisations (CMOs). Alternatively, they can collaborate with catapults like the Cell and Gene Therapy Catapult in London or the Centre for Commercialisation of New Medicines (CCRM) in Australia and Canada. Catapults offer technical facilities, expertise, and access to industry, Government, and bodies like the National Health Service (NHS).

Chemistry, manufacturing, and control (CMC) processes are essential during clinical trials and these may differ depending on whether the biotech company is compiling an investigational new drug (IND) application to the US Food and Drug Administration (FDA) or is applying to the European Medicines Agency (EMA).

Regulatory compliance is two-prong — quality assurance and quality control are both keys. Quality assurance requires supplying documentation, checklists, and certificates of verification to ensure there are no issues with the final treatment. On the other hand, quality control flags any defects with existing therapeutics. A freelance biotech consultant can help companies improve their CNC and compliance processes by conducting statistical reviews, writing clinical evaluation reports (CER) and coordinating feasibility studies.

With the UK representing at least 12 percent of the world’s ATMP trials, its biotech industry is heavily focused on researching the effects of gene and cell therapy treatments. When conducting trials, biotech firms should maintain the same objectives and endpoints throughout. They can also recruit external consultants, including freelancers, CMOs, and catapults, to assist with various tasks.

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