The development of a drug is an expensive and resource-intensive process and it is therefore important, from the beginning, to meticulously plan ahead for all necessary steps in the journey towards the new product. A well-structured process provides greater knowledge and reduces the risk of failure, both in terms of substance and medicinal effect.
The process of developing a drug can be illustrated as two parallel branches. One comprises the steps where the model systems are set up that are needed to develop and evaluate pharmacological and toxicological effects during the development phase, as well as making it accessible and follow-up during the market phase. The other describes the production of the pharmacological product. Some parts of the process are regulated based on set legal requirements.
The first step in the process towards the market is provision of the fundamental research and it’s results that is a prerequisite for starting the development of a new product. In this step, it is important to obtain knowledge regarding the disease to be treated, in order to understand what target structures should be focused upon in the treatment and to investigate what tools must be used in the development of the substance.
In the next phase, a mental step is taken stretching from the research required to the journey towards a commercial product. Here an hypothesis is built as to how to influence the target structure to achieve the desired effect, the so-called mode of action. Already in this step, a business plan should be set up that targets the end-goal, a financially sustainable product satisfying unmet medical need and providing increased patient benefit. A small start-up that might not have much internal expertise needs to obtain advice and help from experts when think about its business model early on, particularly with respect to both patient needs and to valorisation in a competitive market.
The pre-clinical phase can be of widely varying lengths, entirely dependent on approach, access to model systems and how complicated it is to develop a product with the desired therapeutic profile in terms of efficacy and safety. However, there are some generic steps that are often included.
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A series of screening paradigms and tests are initially used as a starting point to define molecules of interest. These are then refined and used to optimize performance requirements set for the molecule. This preclinical work encompasses various kinds of laboratory tests and experiments, including experiments in silico, in vitro, in vivo and on patient material.
Altogether, the preclinical work should provide knowledge on how the drug candidate affects its target structure, underlying molecular mechanisms emanating from this towards pharmacological and toxicological effects, and the links between dose and effect. The hope is that the drug candidate’s functional mechanism will be able to be confirmed in subsequent clinical trials, with a good margin to safety.
Proof of concept
All of this leads to what is called a proof of concept on how a molecule performs in a particular disease state. In this step, one should also prepare both a translational plan for the development of biomarkers for both effect and safety, as well a regulatory plan to plan for both activities and costs incurred towards market approval and launch.
Before clinical trials in humans can be performed, a safety evaluation is required, which utilizes both cell cultures and in live animals, with the aim of predicting possible toxic effects from the drug candidate against the positive effect on the disease. In this step, the initial human doses are rationalized by definition of a safe margin of exposure between a dose predicted to be therapeutic and one known to cause toxicity in the regulatory animal toxicity studies. All studies are performed to internationally harmonized, Good Laboratory Practice standards.
In order to conduct clinical trials, approval is required from the Swedish Medical Products Agency and the Swedish Ethical Review Authority. The clinical trials are often performed in three phases, where the first phase (Phase I) generally takes place on healthy individuals and where exposure, and tolerability are studied. In Phase II studies, the treatment effect is studied on a small number of patients and in Phase III studies, there are more extensive studies on a larger number of patients. In the Phase III studies, the earlier results are statistically verified.
In order for the new medical product to be registered, it is important that the clinical trials are structured so that they comprise all of the documentation required to obtain European Medicines Agency (EMA) approval. However, one must also plan a design that supports medical evaluation for subsidization and introduction into healthcare systems, which takes place in the next step.
Health economics evaluation
The medication’s product journey is not concluded at market approval; many steps are included in what is called market access, which among other things comprises possible subsidization of the medical product based on a health economics evaluation. Sometimes, an assurance is also required that the hospital system is available for both treatment with and follow-up of the medication. For some products, such as cell-, gene- and immuno-therapies, there may be requirements for follow-up in connection with treatment.
The final step is to consider the possibility of following up the medication in register studies or in register-based, randomized clinical trials (RRCT). Knowledge from such studies can be important in order to optimize treatment routines, but can also provide input to new pharmaceutical projects.
The manufacturing process
In parallel with the preclinical phase, where one builds evidence for the proposed functional mechanism, one must work with the development of the actual product (beige boxes). Here, there are many issues to be investigated, such as: Can the product be produced and formulated on an industrial scale? Is the proposed dose level reasonable? What is the development cost?
Development of test drugs must take place according to Good Manufacturing Practice (GMP). The basic principle is that one must use controlled procedures throughout production and that all steps must be documented and traceable.
But before one can begin production according to GMP, one must optimize the production processes, develop methods and protocols for formulation that suit the drug product in question and how it is to be administered, and check and test all ingredients and materials to be included in the process. Operators, premises and equipment must also be approved. All of this is done in the pre-GMP phase.
The requirements for GMP can be found in the Swedish Medical Products Agency regulations (LVFS 2004:6) on good manufacturing practice for medicines.
Important to understand the process
“It is important that small and medium-sized enterprises that conduct research on pharmaceutical substances understand what steps must be achieved along the way to an approved drug,” says Anna Ridderstad Wollberg, head of the New Therapies focus area at RISE.
She emphasizes that the content in the steps may vary depending on what kind of drug is involved, but highlights that the principle is still the same, meaning gradually building evidence for the functional mechanism and effect, reducing the risk of side-effects and that the drug cannot be produced.
“RISE is not a pharmaceutical company, but we have knowledge of the entire chain and can work in it and thereby support companies in the various steps,” says Anna Ridderstad Wollberg.
Safety evaluation is a key step
One of the key steps where many projects fail is the safety evaluation.
“The entire process is incredibly complex and it is necessary to engage experts with thorough knowledge of industry standards,” says Björn Glinghammar, specialist in toxicology and project manager at RISE.
It is a good idea to conduct an early evaluation of the toxicological risks in the project, both in terms of the proposed target structure and drug candidate.
“If you do things right from the beginning, you most often save time and money,” says Björn Glinghammar“, and this is something we can help with at RISE. To help us, we have several different databases and softwares, where we use artificial intelligence, or AI, to predict risks and opportunities in various pharmaceutical projects. Then, with our unique expertise, we can help the projects interpret results and adapt the project plan to avoid or resolve identified risks along the way.”
“In general, it’s important to do things right from the beginning and to understand what steps are most critical, in order to avoid landing in a dead-end. This reduces the risk of failure, both in terms of the production of the substance and of its effect,” says Anna Ridderstad Wollberg.