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The development of an anti-cancer agent
The launch of a new cancer therapy is a long process that can take more than 10 years to complete. This developmental process can be divided into a number of stages, with successful completion of each stage required to progress through to the next one.
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Discovery
The discovery or research stage of drug development involves close collaboration between biologists and chemists to produce new, sometimes novel, compounds with anti-cancer potential. These compounds must be able to demonstrate anti-cancer potential in both external experimental systems (in vitro systems) and in internal, animal model systems (in vivo systems). Only compounds with the best anti-cancer potential will progress through to development. This stage of drug development often takes between 2 and 4 years and will result in the production of compounds that can be patented.
Development
Compounds from the discovery process, showing potential anti-cancer activity, move to the development stage, which consists of pre-clinical and clinical stages followed eventually by a pre-registration phase.
Pre-clinical development
In pre-clinical development potential anti-cancer compounds will undergo further extensive in vitro and in vivo tests to assess their efficiency, toxicity and stability. The aim of these tests is to determine the most effective compounds (with the fewest side effects) establish suitable dose ranges and how best to administer the candidate compounds. Only a few out of hundreds of candidate compounds will make it through pre-clinical development and into clinical development.
Cinical development
Clinical development is the stage when potential new therapies are evaluated in humans. This is the longest stage of drug development, often taking 6 to 8 years, sometimes longer, to complete. All people who participate in these studies are patients with cancer who have given their consent (signed informed consent form).
These assessments are essential to: - Determine the optimal dosage
- Evaluate pharmacokinetics
- Identify any potential side effects or toxicity
- Determine the antitumoral efficacy (effectiveness)
- Establish the best schedules of administration
- Establish any interactions with other compounds
Clinical development of new therapies is divided into distinct phases: - Phase I clinical trials usually involve few patients (generally 20 to 80) who usually lack other treatment options. They are designed to establish the optimum dose, in terms of tolerability, of the candidate compound. These studies often include a dose escalation study, in which a range of doses is assessed to establish the maximum tolerated dose (MTD) of a given compound. They may also be designed to obtain early evidence of effectiveness.
- Phase II clinical trials are larger studies (no more then several hundred) aimed at evaluating efficacy on different tumor types and determining common short-term side effects and risks.
- Phase III clinical trials are multi-centre, randomized controlled trials conducted on large numbers of patients (several hundred to several thousand). Their objective is to compare the novel candidate therapy with established standard treatment, to determine if the new therapy is non-inferior to the existing standard. Phase III trials are expensive to conduct, involving substantial planning and organization to ensure correct execution and data collection. They are required to evaluate the overall benefit-risk profile of the investigational drug and provide the basis for physician labeling.
Clinical trials are strictly monitored and controlled by public health and licensing authorities. The FDA, for instance, does not monitor each clinical trial conducted in the US. That is the responsibility of the respective sponsor. The FDA does have oversight and enforcement authority over clinical trials. Results are collected and analyzed by biostatisticians and evaluated by leading scientific and medical experts. As a conclusion, the discovery and development of novel anticancer agents involves substantial time, effort and resources. The effective development of new cancer agents demands the close interaction between basic research scientists, clinical pharmacologists, clinical research nurses, data managers, clinical investigators and many other disciplines.
Pre-registration
Once a cancer therapy candidate has successfully passed through all of these development phases, the supporting data from all studies, together with formulation, manufacturing and stability details, are submitted to licensing authorities for evaluation in order to get a license granted. There is no worldwide drug licensing authority. Licenses are granted on a country (i.e. FDA) or regional basis (i.e. EMEA).
Manufacturing
During clinical development, a new therapy is only needed in relatively small quantities. Before a new therapy can be launched it must be available in sufficient quantities to supply thousands of potential patients all over the world. This requires the development of large scale, efficient, reliable and safe production of the new therapy on an industrial scale.
Launch
Once a new anti-cancer therapy has been approved by a licensing authority it can be marketed in that country/region for doctors to prescribe for the treatment of cancer patients. Studies on new therapies continue after launch (phase IV or post-launch observation). Then the succession of strategies used for the management of the product goes through its life cycle: Life Cycle Management (LCM). LCM studies are designed to: - Obtain safety and efficacy data in real-world patient populations
- Monitor for side effects
- Obtain new indications
- Pursue new directions for use, such as combination with other treatment
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