Cell and gene therapies (CGTs) might be showing amazing promise in tackling cancers that were previously thought almost-untreatable, but their novelty and complexity mean the industry is still working out how best to run trials for these therapies – which have some key differences from ‘traditional’ studies.
ICON was one of the first CROs of scale managing CGT trials, and Tamie Joeckel, the company’s global business lead for their cell & gene therapy center of excellence, says they have learnt from first-hand experience what does and does not work.
“When we first started working in the earliest CAR-T programmes, there was definitely an overall lack of awareness of how these trials are different from traditional studies,” she says. “We were literally learning alongside our sponsors.
She adds that there is not a “one size fits all” approach to these studies, and that working with clients on CGT programmes often present unique challenges, requiring detailed reviews of workflows, communication plans and strategies.
“In the past, very few companies seemed to grasp just how different CGT trials can be from standard trials,” adds Brandon Fletcher, cell and gene therapy principal at ICON. “Every trial, therapy, mechanism of action etc. is vastly different – therefore so are the processes, the skillsets, the knowledge and even the resources required.”
Nevertheless, Fletcher and Joeckel note that there are a few common challenges and best-practice solutions that apply to the majority of CGT studies.
“This is the most complex supply chain in medicine. When we come to the table to discuss requirements, we’re often talking to groups who don’t understand the nuances of working with ‘living therapies’. Cell therapies require ultra-cold temperatures, micro-managed timelines, rigorous quality standards and coordination of an extremely complex ecosystem that involves sites, service providers and the patients,” she explains.
“Chain of custody and chain of condition is of the utmost importance as shipments and storage are both time and temperature sensitive. In autologous programmes, the patient’s own cells are used to manufacture a batch of a single dose, so the chain of identity must be tracked from the point of cell collection through multiple handoffs from manufacturing to final dose administration.
“We spend a significant amount of time working with sites to integrate their specific procedures with the IP and sponsor’s cell therapy manuals and protocols. We routinely hold dry runs with mock shipments with each site to document and train site personnel.”
Joeckel says there is often competition for the most desirable sites.
“We also have to research and consider the CGT competitive programmes that can overlap,” she says. “Site selection requires robust feasibility with detailed patient population assessment. Strong site relationships and leveraging patient advocacy groups are key. ICON has made significant investments in building global site intelligence databases that allow us to ‘think outside the box’ to expand site selection when necessary.”
Likewise, Fletcher says that sponsors need to conduct deep due diligence regarding site resources.
“You also need to know your centres and their capacity. Don’t assume the key centres with the greatest experience will have the capacity for another trial, as CGT trials are exhaustive and drain the system.”
A related challenge is data management.
“Data in a CGT trial does not follow the standard linear curve as seen in standard trials, where data accumulations slowly build over time,” says Fletcher. “Roughly 80% of study data collected in CGT trials is in the first few weeks, from screening to post infusion. This significantly impacts the site entering the data, the clinical monitoring, and the risk of not obtaining expedient exposure of potential safety information – thereby compromising the ability to extrapolate critical information for forward protocol and safety decisions.
Fletcher says that sponsors and CROs need to optimise tools and techniques used to manage high volumes of data.
“This might include: Lab Sample Work Flow, which clarifies the optional paths of lab samples; Positive Lab Reconciliation, which provides seamless reconciliation with the specialty lab from the start; Data Cleaning Plans, which define review by role, thus eliminating gaps; or batch cleaning early and often to facilitate cleaning of bolus of data collected in the first six months of a trial.”
“The labelling of CGT therapies and any related products as genetically modified organisms adds multiple layers of reviews, considerations, red tape etc. They also require heavy involvement of institutional biosafety committees (IBCs), and often other oversight entities – which can, and often do, bog the study down.
“Meanwhile, aspects like extensive, mandated long term follow-up – sometimes up to 15 years – raise their own, entirely new sets of complications.
“We also have to account for unique and complex serious adverse events. Non-CGT trials do not typically require intense understanding of cell therapy related syndromes such as CRS, immune effector cell-associated neurotoxicity syndrome, etc.”
Fletcher therefore stresses the importance of managing long term follow up strategy early, having it in place before study launch, and also engaging early with the FDA and the CRO.
“Beyond the operational execution excellence that’s required, it’s also important to remember we’re dealing with patients and families who are frightened, who have probably failed standard treatments and are running out of options.
“While there are strict rules around informed consent that dictate how the risks are communicated to the patient and their caretakers, the often incomprehensible technical documents can be daunting. Having a clear, concise and coordinated communication plan that’s understandable and transparent about what to expect is critical.”
Once the patient journey begins, the coordination of concierge services such as travel planning and coordination is a huge value add to the process, says Joeckel.
Another factor is that there are often more eligible patients available than slots for manufacturing.
“Often there is only one drug, made specifically for one patient being made at a time – literally a batch of one,” Fletcher explains.
“Expansion of this scalability limitation is underway, and many modalities can now produce cell product volume, but this is not often the case, especially in the earlier, phase I and autologous arena.
“This complicates the patient experience and the ethical care of patients, as waiting for slots and manufacturing at a critical juncture in the patient’s journey must be central to design and care decisions.”
She says that sponsors should ensure they have clearly defined how patients will be managed around drug manufacturing constraints, and how that fits in with preconditioning, safety management and prophylaxis – especially where there are multiple cohorts in dose/cell load escalation and dose finding phases.
”There is no ‘one size fits all’ approach.
“You also need to be careful to not bite off more than you can chew,” she says. “Delays are costly and you can always expand as you go if necessary.”
She adds that sponsors should spend the time and money to fully vet the competitive landscape.
“Some indications are exploding with potential therapies and the competition is broader than just cell therapy trials, including many other targeted approaches such as antibody therapy, BiTES, oncolytics, viruses, vaccines etc.”
When preparing for any trial, Fletcher says that sponsors should ensure they have clearly vetted and defined the optimal end points, as well as the biomarkers for secondary or exploratory endpoints.
“For combination treatments, ensure you define whether to go sequential or parallel,” she adds.
Finally, Fletcher says that sponsors should be engaging with KOLs as much as possible.
“They add intelligence and credibility to the project.”
To navigate all of these potential challenges, from mapping out a strategic regulatory roadmap to fully understanding the manufacturing scale and constraints, Joeckel agrees that strategic planning is “vital”, and that it’s important to have a “keen focus” on documenting workflows and training – and having the tools and technology to provide ongoing re-training.
“Training isn’t a ‘one and done’ process in CGT trials,” she says.
Much progress has been made in finding the best ways to run trials while ensuring efficiency and keeping patients safe – but there are many factors that mean the space will continue to rapidly evolve, and companies will need to stay on their toes and continue to learn.
“Our increasing genome knowledge is likely to continually impact the CGT space,” says Fletcher. “We know the genome quite well now and this knowledge expands daily.
“Meanwhile, with roughly 1,000 companies developing in the regenerative medicine space, more brains are dedicated to the development of life altering, potentially curative modalities.
The success of existing CGTs is increasing confidence across the board, which means the pace of change will likely only increase.
“The data is pretty impressive, with some therapies showing 100% response rates, and the management of known toxicities is strongly improving,” says Fletcher.
“The CGT space is evolving every second.”
Within this context, Fletcher believes we will see more trials directed towards outpatient and early first line settings, especially in slow growing disease and multiple myeloma – as well as a predominance of solid tumour settings now that we can better understand the tumour microenvironment.
“I also expect to see more allogeneic, off-the shelf approaches and more combination therapy trials.”
She adds: “Soon we won’t need to just rely on the one patient, one patient-specific T cell therapy process. We now are experimenting with other cell types – even cells that we can manipulate to differentiate to anything we want, or can be produced in volume, ready and waiting on the pharmacy shelf.
And, of course, lessons from COVID-19 will be vital to improving research going forward.
“I need not remind anyone what we have seen and learned from streamlined and accelerated processes created, or leveraged, during COVID-19 drug development,” says Fletcher.
“I believe we have seen how we can cut the fat safely, and hopefully this will take hold more broadly, especially for these promising drugs for incurable diseases.”
One thing that won’t change is the clinical need that CGTs can help address – and Fletcher says that the sector’s current trajectory means that there are plenty of reasons to be optimistic about the future across therapeutic areas.
“We are guessing less, hoping less and are now leading with confidence. We are starting to get this down, and as a result we’re encountering fewer bumps in the road to slow us down.”
Brandon Fletcher, cell and gene therapy principal, ICON
Brandon is a biochemist and cancer immunologist with roughly 30 years of research experience, specialising in haematology-oncology, rare disease and infectious disease. She has held roles in broad immune-oncology and cell and gene therapy research within academia and industry. Brandon is a collaborator with NCI’s origination of cancer CGTs and co-founded a global immune-oncology research training and support organisation.
Tamie Joeckel, cell and gene therapy global business lead, ICON
Tamie has over 25 years of experience in commercialising specialty biologics and has worked in cell and gene therapies for the last 8 years in global cryologistics and operations. As a former senior executive at one of the largest drug distributors, she specialised in commercialisation, patient hub services and reimbursement support for plasma derived drugs and therapies for oncology and rare diseases. At ICON, she is a member of the Cell and Gene Therapy Centre of Excellence and supports ongoing strategy and innovation across therapeutic areas and is very active in industry groups focused on developing standards for the regenerative medicine sector.
ICON is a global provider of consulting, and outsourced development and commercialisation services to pharmaceutical, biotechnology, medical device and government and public health organisations. ICON’s focuses on the factors that are critical to clients – reducing time to market, reducing cost and increasing quality – and its global team of experts has extensive experience in a broad range of therapeutic areas. ICON has been recognised as one of the world’s leading Contract Research Organisations through a number of high-profile industry awards. With headquarters in Dublin, Ireland, ICON employs approximately 15,250 employees in 94 locations in 40 countries. Further information is available at www.iconplc.com.