Introduction
World Health Organization (WHO) defines a clinical trial as “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes”. These may be used for prevention, treatment, diagnosis, or for relieving symptoms of a disease. Without clinical trials, we cannot properly determine whether new medicines developed in the laboratory or by using animal models are effective or safe.
History
1025- First introduced in Avicenna’s “Canon of Medicine” describes the rule for the testing of the drug.
1573- Ambroise showed that treatment of wounds with Oil of rose + + turpentine + egg yolk heals better & less painful than traditional oil treatment.
1747- James Lind proves lemon juice as a cure for scurvy; it can be called as one of the 1st controlled clinical trials.
1944- Concept of multicentric studies. US Public health service Act passed.
1947- Nuremberg Code establishes 10 points for the protection of patients in clinical trials.
1962- Kefawver-Harris Drug Amendment in the U.S.A. Proof of efficacy in addition to safety, required for new drug approval.
1964- World Medical Association develops the Declaration of Helsinki- Amended 1975, 1983, 1989, 1996, 2000, 2001. (Ethical codes are given)
1986-89- EU sets GCP guidelines
1990- International Conference on Harmonization (ICH) Tri-parties guidelines.
2001- Declaration of Helsinki revised
Phases in Clinical Trials
There are mainly 4 phases in clinical trials.
Pre-clinical
- In vivo/ in vitro
- Wide-ranging doses tested for efficacy, toxicity, and pharmacokinetics
- Decide scientific merit of candidate drug
Phase O
- It is also called as ‘Human micro-dosing’ trials (US FDA recommended 2006)
- Check whether drug behaves in the same way in humans as in pre-clinical trials
- Single sub-therapeutic doses to a small number of subjects (10-15)
- Gather preliminary data on pharmacokinetics and pharmacodynamics
- Does not give data on efficacy and safety
- This step gives go or no go decision
- This step is being debated and mostly used in US regions only
Phase I
- This is the actual 1st stage human trial
- Healthy individuals about 20-80 participants are taken
- This step tests safety, tolerability, pharmacokinetics, and pharmacodynamics
- This step requires preferably in-patient clinic as participants/drug need to be observed until several half-lives of a drug
- Dose-ranging is also done to find an appropriate therapeutic dose
- Testing of a fraction of dose that causes harm an animal is also done
- Participants are paid proportionately to the time spent
- There are 2 types of Phase 1: SAD (Single Ascending Dose) and MAD (Multiple Ascending Dose)
Phase II
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- This is performed on a little larger group than Phase one (20-300 participants)
- This requires volunteers and patients
- Continue assessing the safety and toxic effects
- If the drug development process is to fail- it happens in this phase
- Sometimes divided into Phase IIA and Phase IIB
Phase III
- Randomized Control Trial, Multi- centric.
- Max number of participants required, about 300-3000
- Compare with earlier drugs
- Most expensive prolonged and difficult especially for chronic conditions
- Obtain additional safety data and support marketing claims
- Prepare comprehensive document and submit for approval
Phase IV
- This is a post-marketing surveillance trial
- This may be required by regulatory authorities or sponsor for competitive and testing interaction with other drugs or special group of the population
- It detects any long term or rare adverse effects
- Harmful effects entail the withdrawal of drugs
References
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/
- https://www.australianclinicaltrials.gov.au/what-clinical-trial
- Notes on Clinical trial by Maj. General Dr. V.W Tilak AVSM, VSM (Retd.)