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Early-access schemes aim to make medicines available to patients faster but the regulatory framework remains unclear especially for biologics that involve complex manufacturing.
Early access schemes are bringing in a new regulatory procedure for commercialization of innovative drugs in Europe-both at the national and European Union levels. The EU’s European Medicines Agency (EMA) has given the biggest impetus to accelerated access with its decision in 2016 to press ahead, after the completion of a pilot project, with an adaptive pathway (AP) programme. However, the position of the development of processes for the production of the new drugs within early-access systems remains unclear, especially for biologics whose manufacture is expensive and complex. This is particularly the case for advanced therapy medicinal products (ATMPs)-somatic-cell and gene therapies and tissue-engineered medicines.
The main focus of early access projects is on making medicines for unmet needs, such as rare diseases or conditions that have inadequate treatments on the market, available to patients faster than the normal approval timespan. Under AP, the new drugs are fast tracked through clinical trials to be given marketing authorization with the proviso that the approval will have to be confirmed by real-world data (RWD) once on the market-such as electronic health records, prescription databases, patient registries, claims databases, and patient surveys.
The APs programme being adopted by EMA emphasizes the pre-planning of the evidence generation in support of the new medicines-from the preclinical to the post-authorization stages. This planning is done at an early point in drug development, not just by the regulators but with the participation of other stakeholders, such as patient organizations, healthcare professionals groups, and health technology assessment (HTA) organizations that recommends newly approved drugs for reimbursement.
EMA, which is responsible for the EU’s centralized approval of medicines, stresses that the AP is not a new route to marketing authorization. Instead, it offers a new approach to product development and data gathering. Drugs going through the AP procedure will still be approved under existing early access regulations such as those for conditional authorization or compassionate use.
EMA has concluded that a two-year pilot project completed in 2016 had shown that the AP system can be an effective means of bringing different stakeholders together so that they can plan a product’s development in a way that ensures all the evidence needed are obtained. This can be achieved by using real-world data and evidence to complement information from randomized clinical trials (RCTs).
Although the use of APs is not suitable for all products, it is particularly appropriate for supporting the development of medicines in therapeutic areas where evidence generation is challenging, such as infectious diseases, Alzheimer’s disease, degenerative diseases, and rare cancers, according to EMA.
The AP system is based on an iterative approach to drug development. As more evidence is accumulated and more is learned about the benefits of a medicines, the regulator will approve broader applications. “The medicine will first be authorized in a patient population that is likely to benefit most from the medicine,” explained an EMA spokesman to PharmaceuticalTechnology Europe. “Then, additional evidence is gathered over time, which potentially results in changes to the marketing authorization-for example, through (process) variations-reflecting the expanded knowledge acquired.”
Nonetheless, AP and national early-access schemes pose difficulties for companies dealing with the high cost of developing processes for making new biological and other advanced medicines. Companies are expected to provide the drugs free when participating in early access schemes, usually after a Phase III, or even a Phase II, clinical trial. But at this stage, they cannot be sure what reimbursement price the medicine will be given. Furthermore, with some ATMPs especially, all the GMP standards or even regulations for new medicine technologies are still not in place.
“ATMPs can be seen as a type of products where an adaptive approach might be both beneficial and challenging,” the EMA spokesman commented. “In some cases, the acceleration of clinical development might be competing with the refinement of the data on chemistry, manufacturing, and controls (CMC).”
In a report (1) issued in 2016 on its AP pilot project, EMA acknowledges that CMC evolves continuously before and after authorization. “In the context of the lifecycle approach, certain validation and/or upscaling/change activities may be agreed to be conducted post-marketing with the use of appropriate regulatory tools available-e.g., post-approval change management protocols,” says the report (1). “The acceleration of development time presents challenges in delivering a product of appropriate quality for the conduct of clinical studies and reliable supply to the patient,” it continues. “The product used for the clinical trial needs to be representative of the product that will be submitted for approval.”
Many of these difficulties can be eased during the early stages of R&D when companies have the opportunity to discuss plans for a product’s development, including CMC, with the regulator and other stakeholders such as HTA agencies. “The impact of any manufacturing changes must be proactively explored,” EMA explains in the report. “This is particularly true for ATMPs, where initial development costs are high, and logistics complex. It is important to agree on a strategy that ensures that initial clinical data are not invalidated by subsequent manufacturing changes.”
Having to work out the course of CMC development as early as the preclinical phase, however, could push up the production costs of an innovative medicine even further. Some companies have been deterred from entering the United Kingdom’s Early Access to Medicines Scheme (EAMS) because of financial uncertainties stemming from high production costs, according to a review (2) of the two-year-old scheme by PricewaterhouseCoopers (PwC), the London-based professional services company.
The BioIndustry Association, London, representing UK biotechnology companies, has complained about the absence of public sector financial support for product development for projects like EAMS. “The lack of funding poses a barrier to many small biotech companies from engaging with (EAMS),” Steve Bates, BIA chief executive, told Pharmaceutical Technology Europe. “Other nations have funded early access schemes that allow companies to recover some of the costs of engagement.”
Companies which are reluctant to enter early access projects, tend to be SMEs, which have to tread carefully with the development of drugs with high production costs. Only a small proportion of the 18 products selected to participate in the EMA’s AP pilot scheme came from SMEs with those progressing to the final stages of the pilot being developed predominantly by multinationals.
Among the most problematical of new technologies for SMEs and start-ups created by universities and other academic research institutes are gene and cell therapies in which the development of production processes and logistics seems to be lagging behind the progress of the science. They are even proving to be difficult for multinational pharmaceutical manufacturers.
At a London conference on ATMPs development in December 2016, jointly organized by EMA and the Brussels-based trade association European Biopharmaceutical Enterprises (EBE), Steven Howe, head of process research at of the Cell and Gene Therapy Platform of GlaxoSmithKline (GSK), Stevenage, UK, listed several production challenges just in ex-vivo autologous gene therapies. These challenges include the scale-up and scale-out of vector production and ex-vivo cell processing, the approach to comparability in production change management, and logistics and supply chain issues.
A major dilemma facing the gene-therapy sector is whether to opt for centralized or decentralized models for the processing and transfer of cells to patients. A regional hub solution could involve not only manufacturing in hospitals but by the bedside of the patient.
“Close collaboration between industry, academia, and regulatory agencies is needed to bring these transformational medicines to a wider patient population,” Howe said. For smaller players in gene and cell therapy and other advanced medicines, there is, on the other hand, greater hope of receiving state funding. Governments are willing to give research grants not necessarily with the objective of helping to provide treatment of unmet needs but to progress development of novel technologies in a new area of medicine.
Several European countries are anxious to establish centres of excellence for gene and cell therapies in what is predicted to become a fast growing pharmaceutical sector. The UK now has 22 GMP-compliant manufacturing units for gene- and cell-therapy products, many of them in state-funded universities and National Health Service (NHS) facilities. In neighbouring Ireland, GE Health of the US is investing €150 million ($160 million) in an ATMP and biopharmaceuticals project in Cork with staff being trained with the help of the state-funded National Institute for Bioprocessing Research and Training (NIBRT), Dublin.
What role AP and early access procedures will play in the scientific and commercial progress of new advanced technologies remains uncertain. There is a lot of scepticism about AP in Europe among healthcare professionals, patient groups, and academics whose worries include increased risks to patients, doubts about the quality of RWD, and whether drug companies will honour their obligations to provide it and the reversibility of marketing approvals.
APs and other early access systems have a lot to prove-not only that they can work successfully on the regulatory front and can provide positive benefits to patients. They also have to win over a lot of doubters in key areas of healthcare.
1. European Medicines Agency, Final report on the adaptive pathways pilot. EMA/276376/2016 (London, July 28, 2016).
2. PricewaterhouseCoopers (PwC), The Early Access to Medicines Scheme (EAMS). An independent review (London, March, 2016).