An opinion by Dr Ioannis Papasotiriou.

This article is sponsored by RGCC International.

How is a new drug developed in oncology?

While this may seem like a simple question, it is important to recognise that the process is far more complex than it initially appears.

The development of a new drug, especially in oncology, is a complex and multifaceted process. When we talk about a ‘drug’, it’s important to note that it refers to more than just the common pill or injection. Drugs are typically substances (often chemical) designed to target and combat disease mechanisms, but in oncology, the challenge is far more complex.

In cancer treatment, the drug must target mechanisms that are not only present in cancer cells but also in normal, healthy cells. Additionally, cancer cells are known for their ability to adapt to treatments over time, which complicates the development of effective therapies. Moreover, cancer is not a single disease, but it has many subgroups that behave differently across various tumours and even within different areas of the same tumour. This diversity underscores the need for precision and personalised approaches in oncology.

To effectively treat cancer, advanced therapies are required. These involve genetically engineered products, modified cellular products, or specially trained cells designed to fight cancer more precisely.

No matter what the new drug or advanced therapy may be, the process of drug development follows specific steps. The first step involves gaining a deeper understanding of the essential mechanism that drives disease progression. This step is called target identification. To do this, we rely on data obtained from patient samples or through cellular models developed in the lab, referred to as tumoroids. When we observe the same mechanism appearing consistently in the same type of cancer at a specific stage of the disease, we may have then identified a potential target.

The next step is to verify the importance of the target. Typically, the target is an overexpressed or mutated protein. In this step, we validate the target’s role in disease progression, often through experiments such as ‘knockdowns’. Additional techniques, like cloning in cell models, may also be employed. Afterward, we focus on developing a comprehensive understanding of the target protein’s features, including its structure and function. Based on these characteristics, including its location and role in the disease, we determine whether to develop a chemical molecule, a biomolecule, or a cellular product to target this protein.

If the protein’s structure allows it, we may proceed to drug discovery by developing small organic molecules that can inhibit the protein’s function. If the protein has antigenic potential, we may consider developing a monoclonal antibody to target it. For proteins with more complex functions, we may explore the development of genetically engineered products or cellular therapies.

At this stage, we should have a lead compound or candidate drug. These candidates are then assessed for efficacy and toxicity in cell cultures and animal models. The data collected from these tests are compiled into a technical dossier, which supports the drug’s clinical potential and safety. If the data justifies clinical benefit and safety, we decide whether to move forward with human trials. In Europe, the decision to initiate human trials is made by either the national competent authorities or by the European Medicines Agency (EMA) as long as the application follows a centralised procedure. At this stage, the drug is referred to as an Investigational Medicinal Product (IMP).

What is the legal frame and the procedure for licensing a drug?

In order for a drug to become available to the public, it must undergo specific procedures and approvals from relevant authorities. In the European Union, the responsible authority is the European Medicines Agency (EMA), while in the United States, it is the Food and Drug Administration (FDA). There is a mutual recognition agreement between various regulatory bodies such as the EMA, FDA, SwissMedic, the UK’s MHRA, and the relevant Canadian authorities. Additionally, there is an attempt to harmonise these processes under the framework of the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) which are referred to as the Good Clinical Practice (GCP) Guidelines.

Focusing on the European context, there are two main pathways for licensing most novel drugs (chemical or biomolecular). The first option is the centralised application procedure, where the Investigational Medicinal Product (IMP) is submitted to the EMA, which then oversees the next steps, including human clinical trials. The second option involves applying to a national competent authority (NCA), which governs the clinical trial stages 1-3 and issues the marketing authorisation license (also known as the marketing authorisation holder’s license). If a company chooses the second option, it can later seek mutual recognition across other EU member states, which is a relatively simplified process.

However, Advanced Therapy Medicinal Products (ATMPs), cannot be processed by a national competent authority. ATMPs require a centralised application procedure for marketing authorisation. ATMPs are governed by Regulation 1394/2007 in the EMA, and all member states are required to fully adopt this directive. Additionally, there are other relevant guidelines, such as Directive 23/2004, which mainly governs non-ATMPs, such as organ, tissue, and cell transplants. Specifically, it sets the standards for the quality and safety of the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells. All EU member states must integrate these directives and regulations into their local legislation. Unfortunately, this process has led to discrepancies and challenges in regulatory alignment across member states.

What is the situation in EU countries regarding adherence to the legislation mandated by the EMA?

The situation regarding the adoption of EMA-mandated legislation by individual EU countries is complex. Some countries are leading the way in drug development and the licensing of novel medications. These are generally the countries that already have the necessary legislation in place, extensive experience in conducting clinical trials, and local authorities familiar with the processes. Unfortunately, many newer EU member states, particularly those from Eastern Europe, face significant gaps and discrepancies in their legislation. For example, some countries have either failed to adopt the necessary legislation or have interpreted it in ways that diverge from EMA guidelines. One such instance is the misclassification of transplantation units as pharmaceutical production units, resulting from confusion between Regulation 1394/2007 and Directive 23/2004.

Additionally, some countries have incorrectly processed ATMPs through their national competent authorities, when the process must follow the centralised application procedure through EMA. This directly violates EMA directives. Additionally, in these same countries, there are ongoing global advertisement activities for medical services – even from university hospitals – promoting ATMP products without regulatory oversight or licensing for such products. In other cases, some countries have licensed very few, if any, of the ATMPs approved by EMA, simply because they lack a local legal framework for distribution and pricing. Moreover, national competent authorities in some countries take an extraordinarily long time to adopt centrally recognised and licensed products from EMA. For instance, out of 28 or 29 products recognised by EMA, some countries have adopted none, or at most one, after 900 days or more. Even when a product is adopted, it may not be available to patients due to the absence of a pricing policy in the country. This reflects a lack of proper procedures, such as Health Technology Assessment (HTA), in some EU countries. A typical example of this situation can be found in many countries in Eastern Europe, as well as those in Southern and the Balkan regions.

These are just a few examples of the existing discrepancies between EMA and the national competent authorities in many EU member states. As a result, many novel drugs that are already licensed and available in other countries may not reach patients in all EU countries due to delays in local availability and the lack of appropriate legislation for novel therapies. Unfortunately, responsibility for this situation also falls to the EMA, as it has not taken sufficient action against national authorities to expedite the process of making new drugs available across all EU countries simultaneously. It is clear that many national authorities lack the experience and harmonisation required with EMA directives.

Moreover, there is considerable confusion in some countries regarding the legislation governing biobanking and human-origin substances versus ATMPs. This confusion has led to serious issues in the standards of cell biobanking and transplantation practices. It is crucial that stricter measures are implemented to harmonise the regulations across all EU member states. Without these measures, patients in different EU countries will continue to face inequality in access to treatments and medications.

EMA has made an attempt to address these issues by introducing Regulation 1938/2024, which is scheduled to come into effect in August 2027. However, delays in adapting this regulation have already been noticed, and there are concerns that the gap may widen as many countries lack the will or capacity to fully harmonise with the new rules. Meanwhile, the significant gap in the regulation of advanced therapies and biobanking within the EU has reached a point of concern, one that could even be considered a scandal that may result in relevant legal action on different levels.

About the author:

Dr Ioannis Papasotiriou was born in Munich, Germany, and graduated from the Medical School of Thessaloniki University, Greece. He specialised in both human genetics (University of Zurich) and haematology oncology (MLU/UKH/Halle/Saale). He earned a Master’s degree in Molecular Biology in Medicine from Westminster University and a second Master’s degree in Oncology from the University of Nottingham. He completed his doctoral degree (MD, PhD) at MLU University, focusing on TKIs in human cancer cell lines. Between 2001 and 2004, he founded and served as the director of Arzt Genetik Zentrum in Thessaloniki. In May 2004, Dr Papasotiriou established RGCC International GmbH, a company specialising in molecular oncology, with a focus on cancer stem cells and circulating tumour cells (CTCs). Since 2015, Dr Papasotiriou is a certified Cytometrist from ISAC. He received the Qualified Person certification in the pharmaceutical industry in Germany. Additionally, he has been a certified ICH-GCP for Clinical Research and Regulatory Affairs (CRRA) since 2018.

About RGCC International:

RGCC was launched in 2004 by Dr Ioannis Papasotiriou who believes that the key to effectively treating cancer lies in personalised medicine. Today, RGCC is a leading innovator in the field of oncology diagnostics. Using world-leading technology, equipment, and innovative techniques, our team of scientists has developed a range of liquid biopsies that help physicians track cancer progression and tailor treatment plans based on individual patient profiles.