We often hear on the news that a new promising oncology treatment is developed but later on that it was not successful. What are the challenges in drug development in oncology therapeutic area? Why some drugs fail and how the optimal dose is determined? 

Drug development process and oncology

As we know after preclinical studies and approval for new compounds to be used in humans the drug development process start with phase 1 studies. Usually in phase 1 studies participate healthy volunteers, however in oncology studies usually these are cancer patients in late stage who have consented to participate. These early clinical trials are focused on toxicity and establishing the optimal therapeutic dose. In later phases (2 and 3) the focus is on efficacy. The main reasons early phase clinical trials to fail is unaccepted toxicity of the studied compound, while in later phases – the reason for failure is lack of efficacy. One of the biggest concerns in drug development is to find the right balance between safety and efficacy.

How do we determine efficacy in new therapeutic?

There are 2 main approaches: a) Efficacy could be evaluated based on modulation of the drug’s intended target (usually when the mechanism of action is unknown); and b) Efficacy could be determine based on achievement of therapeutic effect (for example, lower blood pressure). During the preclinical studies is established the dose at which undesired or unacceptable toxic effects are observed. So the drug therapeutic margin is the ratio of the effective blood plasma concentrations of the drug concentrations associated with the highest nontoxic dose. Ideally this therapeutic margin should be as large as possible and consistent across species – this predicts that the drug could be administrated in clinic at maximum therapeutic benefit with minimal risk. 

In the case of oncology drugs maximum therapeutic benefit is not possible to be achieved because of toxicity. One of the biggest challenges in this case to provide patients with dose that will have maximum therapeutic benefit and at the same time limit the unacceptable and sometimes life-threatening toxicity. 

What are the disease specific challenges in drug development?

Cancer cells have lost normal growth control and often have the ability to escape and populate other locations in the body (metastasis). Tumours are frequently heterogeneous and very unstable genetically, which allow them to mutate and this could cause drug resistance. Therefor it is almost impossible to create single specific molecular target that will be effective for different range of cancer cells. Because cancer cells are variation of the normal cells molecular targets are not specific to the cancer cell and that increases the risk of undesired side effects. This means that very effective therapies have very high potential for significant toxicity. 

Many anticancer drugs that are used today are cytotoxic agents. Because they are not selective to cancer cells only often they can attack other organs and systems which are involved in proliferation like bone marrow and gastrointestinal tract. This is why classic anticancer drugs are considered with unknown mechanism of action, high toxicity and very narrow therapeutic margin. 

Developing novel anticancer therapies is a complex process which explains why there are not many options on the market. The nature of the disease and efficacy – toxicity relations are significant concerns in oncology drug development.   

Source: Pharmacokinetic and Toxicology Issues in Cancer Drug Discovery and Development

Author: Olga Peycheva

Olga is a clinical research professional who has been working in clinical research since 2005. She has extensive experience in clinical research in Eastern and Western Europe. 

Originally published on 1 June 2017