Ever increasing knowledge of the molecular basis of malignant disease has stimulated development of targeted agents. This often leads to small, molecularly defined study populations and thereby limitations to the evidence for approval and reimbursement decision-making. At the same time, broad patient participation in clinical trials, an acceptable safety profile and the external validity of the results need to be ensured. To address this forcefield, new ways to collect and analyze clinical data are needed.
For this purpose, and already for quite some time, alternatives to the standard randomized controlled and single arm trial design have been explored. These include the application of master protocols covering platform, umbrella and basket trials; incorporating external control arms and adaptive trial designs. However, having a good understanding of the viewpoint and the needs of the patient is vital, as this may impact several decisions on study design such as the choice of endpoints and test frequency. Also, regulators and reimbursement decision makers would need to consider these innovative ways to collect data as acceptable in order for the patients to actually get access to the new medicinal product.
This blog aims to shed light on one challenging aspect of clinical trials in oncology, in particular in targeted anti-cancer drug development: Navigating the evolving regulatory landscape.
For more insights into overcoming challenges associated with oncology trials, watch a replay of our recent webinar.
First, speed in addressing the unmet need, where unmet need in oncology can be due to a lack of reasonable therapeutic alternatives or by the need for products with an improved efficacy and safety profile. Second, the identification of patients who will benefit (most), with benefit defined in oncology as improved survival, prolongation of the time a patient is without progressive disease or even a durable shrinkage of the tumor expected to translate into true clinical benefit. These conditions should be accompanied by sufficient certainty on internal and external validity of the effect estimate, the results being clinically relevant for the target population with an adequate understanding of the safety profile, and the quality of the data allowing for relative effectiveness assessment. Important, though not specific for oncology, is to take note of the requirements for developing in-vitro diagnostics to identify the right patients, ensure product supply and reduce environmental impact of manufacture and use.
These aims are ensued in different ways and by several stakeholders. Again, let’s start at the beginning, with the common groups who contribute to goals for anti-cancer therapies.
Without research by academia and sponsors to increase the molecular understanding of disease, there would be no new high potential drugs, no new ways to assure targeted delivery of the product and no new novel biomarkers for predictive and/or prognostic purposes. Insight into the disease and how the product works will also contribute to benefit-risk decision making as it feeds into the understanding of the drug effect both in terms of efficacy as well as safety.
A different angle is patient empowerment by patient organizations and regulatory agencies. The first by, for instance, active participation in discussions aiming to include patient reported outcomes as part of regulatory decision-making. The second by developing structured benefit/risk decision making processes, such as multi-criteria decision analysis, in which the experience of patients with a particular (serious) adverse event is weighed into the benefit-risk assessment in a quantitative manner.
As always, rules determine policy and as such regulators have a strong voice in determining which, when, and where data are to be collected. In this respect, the topic of broad patient participation is addressed by regulators by allowing pragmatic trials (Food and Drug Administration (FDA)) or decentralized trials (FDA and European Medicines Agency (EMA)) and the FDA guidance on diversity. The representativeness of the study population and the external validity of data are definitely in focus by the requirement for multi-regional studies as set by the FDA or, as in Europe, requesting from the sponsor a justification for the relevance of clinical trial results for the European population when obtained outside the European Union (EU). Furthermore, to enhance the safe use of products, FDA explicitly emphasizes the need for adequate dose-selection and dose-optimization studies pre-/post approval. This is of particular relevance for small molecules, like kinase inhibitors, for which dose selection is often based on the paradigm used for chemotherapeutics, while the dose-response relationship for these types of products may very well be different. In the EU the situation is somewhat different where in case the benefit/risk has shown to be positive based on the available data, the posology as studied is accepted, with at this time little legal possibility to enforce further research in terms of dose-optimization. This may change though with the new EU pharmaceutical legislation.
Drug approval takes time and assessment tasks are often repeated between regulators. To decrease repetition and increase knowledge sharing, collaboration among regulators has been formalized by instigating platforms such as Project ORBIS, ACCESS, OPEN and joint FDA-EMA scientific advice. Additional measures to speed up the process are real-time oncology review by the FDA and the rolling review in the EU. It should be recognized though that such opportunities condense the workload for the agencies as well as for the sponsors involved, so should be used under well-controlled conditions to maintain good quality and consistent decision-making. A further efficiency directed measure is the intent to harmonize the Health Technology Assessment (HTA) review in the EU with the implementation of the HTA-Regulation, through which a joined scientific assessment will serve as an advice to national competent authorities to take the final decision.
The enhanced use of regulatory intelligence, i.e, knowing and understanding what has been done before, and the need for alternative data sources (such as observational, “real world” data) and defining their conditions for use, will feed into further innovation of trial design.
Lastly, to truly speed up and better control oncologic drug development, there is abundant space for support by artificial intelligence and machine-learning. The conditions for use will need to be defined though to let these sophisticated tools contribute to regulatory decision-making in a sustainable manner. As it has been difficult to escape, in various parts of the world, legislation and guidance has been or is being developed.
As in other tech- and science-based areas, it is important to have one’s eyes and mind open during product development to connect the dots between rules, requirements and patient needs. As such procedure-independent interactions with regulators, in the form of Innovation (EU) or Catalyst (FDA) meetings offer a great opportunity. Similarly, pilots of regulators, reflection and position papers, as well as qualification procedures, are signals for policy trends. Lastly, it is often inspiring to understand what the neighbors do, so white papers from consultancies and pharmaceutical company collectives, as well as webinars and blogs from law firms, e.g., released upon changes to Laws and Acts/Directives and Legislations, can be very insightful.
ProPharma's unwavering commitment to navigating the complex landscape of anti-cancer drug regulations stands as a beacon of hope for pharmaceutical companies aiming to bring life-saving treatments to patients worldwide. By providing tailored regulatory strategy support, our regulatory experts will not only streamline the path to approval but also champion the advancement of innovative therapies that hold the potential to redefine the future of cancer treatment. Partner with ProPharma today and accelerate your journey toward a cancer-free world.
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