Patient medical treatments are seeing a paradigm shift towards one of cure from that of a traditional disease management approach. Advanced therapy medicinal products (ATMPs) are a group of medicines for human use that are based on genes, tissues or cells which hold promise as treatments for a variety of previously untreatable and high-burden diseases.
There are three main types of ATMP:
Somatic cell therapy products consist of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered.
Gene therapy medicinal products contain an active substance consisting of a recombinant nucleic acid used in, or administered to humans to regulate, repair, replace, add or delete a genetic sequence, with the therapeutic, prophylactic or diagnostic effect relating directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.
Tissue engineered products contain or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.
In addition, some ATMPs referred to as combined ATMPs may also contain one or more medical devices as an integral part of the medicine e.g. cells embedded in a biodegradable matrix or scaffold.
In the EU, ATMPs are primarily governed by Regulation 1394/2007 (“the ATMP Regulation”) which provides for classification and evaluation of these products by a specialised committee within the European Medicines Agency ("EMA"), the Committee for Advanced Therapies (“CAT”), who prepare a draft opinion before the Committee for Medicinal Products for Human Use ("CHMP") adopts a final opinion and a market authorisation ("MA") is granted by the EU Commission. The ATMP Regulation also empowers Member States to permit the use of advanced therapies that are not authorised by the EU Commission, subject to certain conditions being satisfied, the so-called "hospital exemption".
Obstacles getting to market
However, there are tremendous challenges to the commercialisation of these products, which require new and innovative approaches to ensure patient safety and efficacy of the products that is comparable to that of traditional pharmaceutical products. The success of ATMPs is dependent on the use of science and risk-based approaches to their development and manufacture. Over the next few years, the regulatory requirements and industry practices will continue to be significantly developed and become benchmarks.
At a development stage, recent research carried out by the Alliance for Regenerative Medicine (ARM) has highlighted that whereas the number of new ATMP clinical trials has increased significantly over a 4-year period on a global scale (+32% from Jan 2014 to June 2019), with notable growth in North America and Asia, this trend is not reflected in Europe. Within Europe, significant country-by-country variability in the number of clinical trials, speed of assessment, and time for approval of clinical trials has also been observed, with the UK, Spain, and France attracting the highest number of ATMP clinical trials during the same 4-year period (112, 102, and 101, respectively). Survey respondents also indicated that the most important criteria for selecting a clinical trial site and a host country are the availability of local clinical expertise and suitable healthcare facilities, followed by the speed of approval, the quality of review, and the expertise of local regulatory authorities. The authors also speculated that fragmentation of regulatory/ethical guidance and a lack of harmonisation on various other factors (e.g. donor testing requirements, patient information consent forms, contracting agreements, etc.) across European countries may also make for a less attractive environment for clinical trials. As a further example, a possible cause of the relatively low number of gene therapy clinical trials in Europe compared to North America was also traced back to the classification of some of these therapies as GMOs, requiring specific approval by different national authorities, a step that adds complexity to the clinical trial authorisation process and often extends the time required for approval.
From a commercial point of view, ATMPs present a different scenario to that of pharmaceutical medicines in that there is not a classic supply and demand model largely because ATMP therapies are more likely have a patient pull to fulfil an unmet medical need. In addition, the clinical development of ATMPs does not typically follow conventional clinical trial phases unlike traditional medicine. It is often the case with rare disease indications, that ATMP clinical programs are compressed into one or two clinical studies, followed by conditional approval with post-marketing commitments. To this end, ATMPs often utilise Early Access Programs, which allow for supply to patients prior to marketing approval.
Compliance with good manufacturing practice (GMP) is mandatory for ATMP products. New GMP guidelines on ATMPs from the European Commission (EC) came into force in 2018. These guidelines apply to ATMPs with market authorisation, investigational ATMPs and those administered to patients under Article 3(7) of Directive 2001/83/EC (the "hospital exemption").
The guidelines seek to reflect the rapid technological and medical advancements being made in the field and recognise the need for a certain degree of flexibility so that manufacturers can implement measures most appropriate to the specific characteristics of their product. As such, the guidelines allow for a risk-based approach, giving manufacturers more autonomy over the production process.
The Pharmaceutical Inspection Co-operation Scheme Committee (PIC/S) has expressed concerns about the impact of the new GMPs on public health and the safety of patients, suggesting that the new guidelines lower the GMP standards. The PIC/S produce their own GMP guidelines, which, until now, have been developed in parallel with EC guidelines. The development of stand-alone EC guidelines on ATMPs has therefore led to an internationally non-harmonised approach to GMP regulation.
The PIC/S are currently developing revisions to their own guidelines to account for the international developments in the regulation of ATMPs, with particular attention given to the EC guidelines, whilst also addressing any concerns related to patient safety and the proportionate regulation of ATMPs.
The challenge for manufacturers will now be to check whether their current established processes are in accordance with the new guidelines, including any revisions made to the PIC/S guidelines, or whether any changes or additional activities will be necessary.
The ATMP field is rapidly moving from pure science focus, led by small industry and universities, to a focus on how to commercialise such therapies. The high cost of ATMPs is predominantly driven by the small scale of manufacturing, the high degree of scientific testing required for the products and the need for ongoing patient monitoring testing which combined requires significant capital investment. Reimbursement of ATMPs is frequently mentioned as a major hurdle, both from a developer and health technology assessment (HTA) body point of view, as the manufacturing of ATMPs is considered more expensive by nature and is expected to pose pressure on healthcare budget. Combining the active ATMP pipelines with the prospect of healthcare budget constraints, sustainable ATMP reimbursement has become the next major challenge in this field.
Talking logistics: Supply chain challenges
One of the main barriers to commercial viability for ATMPs is the supply chain, which contributes significantly to the overall cost of goods and is limited by infrastructure, temperature requirements and, of course, the time frame for transportation taking into consideration cell viability. Poor co-ordination of supply and logistic conditions have the potential to negatively affect the quality of ATMPs.
Unlike traditional medicines, living cells have a short shelf life of between 1 to 3 days at ambient temperature conditions. Therefore, ATMPs require a quick delivery time from finished product to administration to a patient. Manufacturing constraints and the short shelf life of the product require the implementation of tight controls on logistical arrangements, which adhere to Good Manufacturing Practice (GMP), Good Distribution Practice (GDP) and ICH Q10 to ensure that patients receive these products safely at the correct time and within the shelf life.
Shipping logistics for example, require tailored temperature conditions, preservation techniques, and quality-control solutions. Due diligence must be performed to ensure that shipping companies have been evaluated to regulatory standards and that product quality oversight is a priority. Today, technology enables almost complete remote tracking of shipments while in transit be it with sophisticated geo-locating systems or sensors that automatically transmit while travelling with the product.
Clear traceability documentation is essential throughout the supply chain as is compliance with the trace-and-track regulations prescribed by GDP and the EU Falsified Medicine Directive to monitor and control the safety and supply of medicines for human use. For example, to minimise risk during transit, ATMP packaging labelling should indicate both the nature of the product and the special handling of product containers. It is also important that all customs paperwork and permissions are in order to ensure that the therapeutic agent is delivered to the correct clinical site, the correct patient and at the correct time.
As part of the journey to the patient, the therapy must be delivered from the manufacturer into the relevant country's facility where it will be stored until Qualified Person (QP) release. The QP should be familiar with sample collection, supply chain and manufacturing processes. Clinical sites should also provide appropriate facilities and licences for the storage and preparation of ATMPs. The absence of for example deep freezers, liquid nitrogen storage, cryopreservation, and GMO laboratories may restrict the use of clinical sites.
Traceability and control remains a consistent requirement throughout the supply chain. The challenge is that a therapy must not be administered to the wrong person; if that happens, the results could be catastrophic. Thus, a chain of custody is paramount, as the therapy changes hands among supply chain participants. The stakeholders of an ATMP supply chain are interdependent and must communicate and share data to provide transparency along the channel, while also assuring that sensitive patient data is appropriately protected. Manufacturers should outline a robust front-end supply chain and logistics planning strategy along with a thorough risk management assessment to help identify which factors in the chain might in turn influence manufacturing decisions.
As the shift from ‘one-size fits all’ towards personalized medicinal strategies for biological therapies continues apace, the regulatory landscape associated with the development and commercialisation of these treatments will continue to evolve. The challenges faced by manufacturers in adapting their processes and systems to ensure compliance with these requirements will also continue to change as new treatments and technologies are considered for scale-up and commercialisation. For the organisations that can navigate this shifting landscape however, the rewards associated with successfully delivering life-changing and often lifesaving treatments to patients are within reach.
Special thanks to Emily Lockey, trainee solicitor, for her contributions to this article.
This article originally appeared in The Life Sciences Lawyer magazine, Issue 3 2020
With special thanks to Emily Lockey, trainee solictior, for her contribution.
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