Regulatory challenges for the next wave of cancer therapies

During the FIGON Dutch Medicines Days on October 1-2, the RSNN organized two regulatory science sessions around novel cancer treatments and the associated regulatory challenges. During the morning session, potential implications for regulators, companies and other stakeholders were discussed, using so-called Advanced Therapy Medicinal Products or ‘ATMP’ as an example. These products require innovative approaches to trial design, risk-benefit assessments, and market access.

Four presentations from different perspectives gave rise to a lively discussion about the interaction needed between the research, innovative industry, regulatory, patient, and prescriber communities present in the audience. It became clear that early stage cooperation between all these parties involved is critical for success in cancer treatment development. We look back at engaging presentations and discussions with a large, varied group of stakeholders.

Sjaak Bot (Janssen, RSNN Steering Committee) welcomed all attendees and introduced the topic. A wave of innovative oncology treatments is moving from bench to clinic, such as therapies based on tissue engineered products, gene therapies, and cell therapies using, for instance, CAR-T cells (Figure 1). These so-called Advanced Therapy Medicinal Products (ATMPs) have the potential to transform the future of oncological treatment, but require innovative approaches concerning risk-benefit assessment, trial design and market access. In the morning session, the focus was on the question of whether the regulatory landscape is ready to facilitate registration of this new generation of personalised cancer therapies. For example, immunotherapy that is based on collecting and modifying patients’ own immune cells to treat their cancer. What can we learn from the hurdles and barriers as experienced in recent innovative procedures?

Regulatory considerations for ATMP based cancer therapies

The first speaker was Dr Marcel Hoefnagel (CBG-MEB) who gave an excellent overview of the European Union (EU) regulatory framework and the manufacturing and clinical aspects specific to ATMPs. Every development phase and manufacturing step has its specific (ATMP) regulations.

In contrast with chemical products or biologicals, ATMPs are not standardised products. They are more personalised and targeted than traditional treatments and require us to find other ways for the evaluation of product safety, efficacy, and potency. As stated by Dr Hoefnagel: “the product is the process itself” (Figure 1). This is why a new risk-based approach has been introduced that enables the control and management of the risks related to the product and manufacturing process. This risk-based approach is, as Marcel Hoefnagel stated, nothing more than “formalized common sense”.

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Figure 1: CAR-T cell therapy: “The product is the process” © Novartis Pharmaceuticals

In the evaluation of complex products that are difficult to characterise, such as cell-based medicinal products, potency is a key parameter. These potency assays should reflect the clinical mechanism of action. A combination of multiple methods may be needed to define the potency of ATMPs.

Dr Hoefnagel emphasised that early dialogue between all stakeholders is important to ensure that the new regulatory processes that come with innovative and more personalised products are understood and shared. In this context he mentioned PRIME, a scheme launched by the European Medicines Agency (EMA) to enhance support for the development of medicines that target an unmet medical need. It is based on enhanced interaction and early dialogue with developers of promising medicines, to optimise development plans and speed up evaluation so that these medicines can reach patients earlier.

Planning for successful and efficient ATMP development

Then Dr Harm Hermsen (Xendo) took the audience on an ATMP-development journey guided by his ‘Integrated Development Roadmap’ (Figure 2). His main message was: start (the planning of) the regulatory process earlier and integrate this with the development process to maximise the likelihood of success for developers, patients, and society. So, the question is not: “Is the regulatory landscape ready for ATMPs?” It is the other way around: “Are the ATMP developers ready to interact with the current regulatory landscape?” As we had already heard from Dr Hoefnagel, the ATMP manufacturing process is complicated and diverse due to the characteristics of the product. Therefore, a strong emphasis on quality is important, and this along with safety and efficacy should be integrated in the development process in such a way that we – think Stephen Covey – ‘‘start with the end in mind”. This means that you should start with a clear understanding of your destination. Dr Hermsen explained the concept of this ‘backward planning’ step by step: from defining the Target Product Profile, based on the Mechanism of Action with the clinical trial in mind, to planning your Regulatory Strategy. He pointed out how this concept will also help to show potential investors that a company is carefully planning the development process and is willing to step over hurdles and create opportunities.

Figure 2: Integrated Development Roadmap, presented by Dr Harm Hermsen

Access to innovative cancer therapies: patients’ view

In the Netherlands, 19 individual patient organisations, focused on different forms of cancer, are connected via the Dutch Federation of Cancer Patient Organisations (NFK, https://nfk.nl/). The next speaker, Dr Pauline Evers, who is a senior policy officer at the NFK, explained that the Federation represents the interests of all cancer patients. The main goal of the NFK is to achieve a better quality of life and a better quality of care for all cancer and ex-cancer patients and their relatives.

Patients with cancer and patients who have had cancer have an experience-based, holistic knowledge of their disease, and thus can contribute to the development process of new cancer therapies. It is in their interests that ATMPs are safe, effective and become available as soon as possible. A recent presentation from the EMA however showed that executing over 500 clinical trials using ATMPs only resulted in nine licensed products so far, three of which are on cancer. Apparently, the development of and regulatory requirements for ATMPs are complex. There is a clear regulatory framework but ATMP developers need more support before, during, and after Marketing Authorisation Application.

In the Netherlands there are additional requirements after obtaining marketing authorisation. Before CAR-T cell therapies like tisagenlecleucel and axicabtagene ciloleucel can enter the reimbursement system, the National Health Care Institute (ZIN, Zorginstituut Nederland) executes a Health Technology Assessment (HTA) looking at therapeutic added value, cost effectiveness, and budget impact. Subsequently, the Ministry of Health will start price negotiations.

With respect to safety, Dr Evers mentioned the side effects of CAR-T cell treatment, such as cytokine release syndrome and neurological toxicities. The authorities require special training and certification of hospital staff. Furthermore, hospitals must have additional certificates relating to GMP, handling of genetically modified organisms (GMO’s), and a license as ‘tissue or cell facility’ before they can start using the commercial CAR-T cell products. Specific patient information is needed regarding adverse events, safety, and the need for patients to stay near the hospital after treatment to enable rapid intervention if necessary. All these additional steps can easily take up to nine months before patients really have access. Dr Evers therefore called for (cautious) action, stating that all involved should “hurry up” as patients with cancer are hoping for new therapies, but at the same time, “stakeholders should also be careful in their communication to patients and the general public to avoid unrealistic expectations”.

Challenges in European commercial ATMP development

The last speaker of the morning session was Renske ten Ham (Utrecht University). She shared the results of a recent survey (2017) and several interviews with ATMP developers in the EU (See Accepted Manuscript). The aim was to examine factors associated with successful ATMP development and commercialisation. In the EU, 65% of ATMP developers are SMEs (small and medium sized entrepreneurs); 35% are large developers. The majority of their projects are in the early clinical stage (Phase I-II). In managing these projects, they mainly face regulatory (34%) or technical challenges (30%) (Figure 3). This is in line with a prominent message given by the previous speakers: “ATMP developers have difficulty with the regulatory requirements”. SMEs especially do not have the resources to address the country-specific requirements caused by, for instance, different national interpretations of the EU regulation. Again, it was concluded that early-stage cooperation between developers, regulators, and HTA bodies, as well as “start with the end in mind” are critical success factors throughout the ATMP development process.

Figure 3: Survey results, presented by Renske ten Ham

Panel discussion

During the following panel discussion, the necessary interaction between academia, innovative industry, regulatory, patients, and prescriber professionals was further discussed. For regulators it is important to provide guidance while maintaining flexibility in order to allow for new scientific innovations. For products such as ATMPs that are very different from traditional ones, you cannot make a ‘cook book’ that will suit everyone. That triggered Dr Hermsen to state that scientific advice is helpful, but indeed you cannot ask regulators to tell us how ‘to cook’. Again, he emphasised that companies should do their homework first in the sense of: “I want to make this recipe, and this is how I planned to cook it, and this is why I think it is a delicious dish”. If companies present their plans in this way, regulators will be able to give feedback and advice. During the lively interaction with the audience, Prof van Gerven (CCMO) stressed the importance of having a validated potency assay in submissions, the lack of which is the main cause of the 25% rejection of applications by the CCMO. Prof Leufkens (UU) said that there is still a big knowledge gap and need for more training opportunities. Finally, Christine Gispen-de Wied (CBG-MEB) asked Renske ten Ham whether she had ever considered performing a similar survey among regulators; her response was “a brilliant idea”.