– Drug development is an extensive process involving three main phases: pre-clinical research and development; clinical research and development; post-marketing phase.
– Extensive testing in efficacy, safety and pharmacokinetics is mandatory at each stage.
Introduction : Development of new drugs is perceived as a very long and difficult process.The process of bringing a medicine to the market may take up to 12 years after rigorous testing and over 90% of drug leads do not make it to the market, as shown in Fig.1.
Figure 1- A diagram showing that over 90%of drugs that have been developed do not make it to the market, due to the rigorous testing of the drug development process.
Image credited: Genome Research Limited
There are three major stages in drug development:
1. Pre-clinical research and development
2. Clinical research and development
3. After the compound is on the market, a possible post-marketing phase
Pre-clinical : The pre-clinical phase represents in vitro, where the study takes place in a test tube, culture dish, or elsewhere outside a living organism. Using the knowledge of the biology of a disease, scientists will discover potential targets that a drug could act on. Typically this can be achieved through innovative insights into a disease process, meticulous testing of many molecular compounds, existing treatments that have unanticipated effects or new technologies [1]. A prospective drug will then undergo animal testing. This is an extensive process testing the primary kinetics, toxicity of various dosages (by checking other side effects that might be harmful), efficacy and carcinogenicity. A drug that shows potential in vitro will undertake many laboratory and animal tests, before being given clinical trials authorisation.However it is important to note that many drugs that showed promising results in this stage do not work during animal testing. Even drugs that showed promising results in animals may not always work in humans. This may be due to differences between human and animal metabolism[2].
Clinical : The clinical research phaseis by far the longest portion of the drug development cycle, lasting from 2 to 10 years.There are three phases to the clinical trials: phase I, phase II and phase III. Phase I trials are conducted on relatively small groups (typically 10 to 30) of healthy volunteers – except for oncology drugs or potentially toxic compounds.The inpatient portion of the trials lasts from a day to a week and is followed up to assess the safety of a compound. The pharmacokinetics (Pk), which is the process by which a drug is absorbed, distributed, metabolised, and eliminated by the body, and the pharmacodynamics (Pd), which deals with the course of action, effect, and breakdown of drugs within the body, is also tested.A general side effect profile and the rough maximum tolerated dose is obtained. In Phase II trials typically 20 up to a few hundred patients that have an uncomplicated form of the diseaseare enrolled. These trials tend to last only a few weeks toa few months and involve pilot trials(IIa) to determine a dose range and then subsequent Phase II trials (IIb), which is aimed at clarifyingdoses, understanding drug-drug interactions, safety, best method for delivery and efficacy of the compound treating the disease. Phase III trials involve much larger groups of patients, from hundreds to thousands, and are randomized, double-blind, usually placebo-controlled – unless it would be unethical to use a placebo- and often involve an active comparator. The larger sample is more representative of the general population. In addition numerous additional special trials are usually demanded evaluating special populations, such as groups with renal insufficiency or pregnant women, and looking at the effects of other conditions, such as allergies or hormonal variations. The addiction potentialof the drug is also assessed [3][4]. Data from all of these phases is presented to the regulatory authorities. This is the MHRA or the EMA in the UK. If approved by these regulatory bodies, the medicine is licensed. After licensing, NICE and SMC appraise the new medicine for the NHS and will look at issues such as cost effectiveness of the new treatments.
Post marketing phase : After approval post-marketing trials, also called Phase IV trials, are conducted. These studies are important for obtaining information about the long-term effects, efficacy, safety, and cost effectiveness compared with another proven drug for the same indication. Rare side effects may only become apparent once a medicine is in general use and these are noted as well.
Branded vs generic : Branded drugs are more expensive because they are more innovative and are often for conditions that are hard to treat. The brand name is chosen so that it can be remembered by the public. It must not sound or look too much like any other drug name to avoid medical errors.However after some time the market value of these drugs begin to form as they are outcompeted by more ground-breaking drugs, hence becoming generic [5]. When patents for brand-name drugs expire, manufacturers can apply to the WHO to have generic versions.This process does not require the repetition of preclinical and clinical trials but the manufacturer must demonstrate that a generic drug contains the same active ingredients as the brand-name drug, be identical in strength, dosage form, and route of administration[6].
Conclusion : Overall the drug development cycle is one that is not only time-consuming but extremely expensive. This is a necessity so that adverse effects do not take place for those who take the drugs, such as the thalidomide scandal in the 1950s and 1960s. Having rigours preclinical test and three phases for the clinical trials, evaluating various age groups, ethnicities, people with other diseases and side-effects. This has led to minimising adverse effects from drugs that are currently being developed, ensuring patient safety at the foremost.
COPYRIGHT: This text is the property of We Communicate Science, a non-profit establishment co-founded by Dr. Detina Zalli and Dr. Argita Zalli. The article is written by Shanthavi Wijayakumar, King’s College London, UK.
References:
1.Science in the News. (2015). Science in the News. [online] Available at: http://sitn.hms.harvard.edu/flash/2011/where-does-medicine-come-from/.
2.MS Trust. (n.d.). Drug development process. [online] Available at: https://mstrust.org.uk/a-z/drug-development-process.
3.Office of the Commissioner (2019). Step 1: Discovery and Development. [online] U.S. Food and Drug Administration. Available at: https://www.fda.gov/patients/drug-development-process/step-1-discovery-and-development.
4.Tonkens, R. 2005, “An Overview of the Drug Development Process”, Physician Executive, vol. 31, no. 3, pp. 48-52.
5.Pfizer.com. (2018). Understanding the Value of a Brand | Pfizer. [online] Available at: https://www.pfizer.com/products/drug-development/process/value-of-a-brand.
6.Howland, R.H., M.D. 2008, “How Are Drugs Approved? Part 3. The Stages of Drug Development”, Journal of Psychosocial Nursing & Mental Health Services, vol. 46, no. 3, pp. 17-20.