INTRODUCTION:

A clinical trial is a research study of new drug, new vaccine or any treatment on animal or any human death body. Developers of drugs, biological, and medical devices must ensure product safety, demonstrate medical benefit in people, and mass produce the product. Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison.

Clinical trials generate data on dosage, safety and efficacy. Clinical trial is better way to stop the side effect in treat or diagnose a disease. Research may include pharmacodynamics, pharmacokinetics, absorption, distribution, metabolism and excretion studies, and toxicity testing. After research of any new drug is enter into the pre-clinical test. In preclinical study the participant receives the drug by injections. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. Preclinical studies involve in test-tube or Laboratory studies and trials on animal populations. Preclinical studies in test-tube is known as vitro studies. Costs for clinical trials can range into the billions of dollars per approved drug. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Preclinical study design aims to ensure the scientific validity and reproducibility of the results. The four possible outcomes are: 1) the new treatment has a large beneficial effect and is superior to standard treatment; 2) the new treatment is equivalent to standard treatment. 3) The new treatment is neither clearly superior nor clearly inferior to standard treatment; or 4) a new treatment is inferior to standard treatment. The US Food and Drug Administration (FDA) role begins after preclinical evaluation for safety and effectiveness.^1,2

Phase of Preclinical Study:

Clinical Trials Phase:

The entire process of moving a drug from a design to clinical trials takes average 10-12 year.

Phase 0:

Pharmaceutical company performs phase 0 studies to decide which of their drug candidates has the best pharmacokinetics parameters in humans.

Phase 1:

The aim of phase 1 to give the more or highest amount of dose to human being without any side effect. Investigators see the patients very closely for any reaction body to after taking the dose during the phase 1. Preclinical research gives information about dose, but the reaction or effect of medication on human is unpredictable. For evaluation of safety dose, the best way is give the medication through orally and intravenously or tropically.³

There are different kinds of Phase I trials:

1. SAD:

Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until precalculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up at which point the drug is said to have reached the Maximum tolerated dose (MTD).

2. MAD:

Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug.

Phase 2:

The phase 2 design depends on the quality and adequacy of phase1 studies. Phase two trials also referred to as “Therapeutic exploratory” trials, are usually larger than phase 1 studies Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements, whereas Phase IIB is specifically designed to study Efficacy. Some trials combine Phase I and Phase II, and test both efficacy and toxicity.³

Phase 3:

Phase 3 trials also called as Therapeutic confirmatory. This stage of drug conduct in large amount of population in order to demonstrate to identify adverse effect. Phase III studies are randomized controlled multicenter trials on large patient and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration. Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase 3 trials cannot be required in all cases, typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies

(FDA (USA), TGA (Australia), EMEA (European Union), etc). Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines.³

Phase 4:

Phase IV trial is also known as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Efficacy and detection of rare or long-term adverse effects over a much larger patient population and longer time period are evaluated, healthcare costs and outcomes are determined, and pharmacogenetics are studied. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons. Pre-planned metaanalyses of a series of related trials and establishment of a national health data network to evaluate post-marketing surveillance independent of the FDA-approval process. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses. Example: Troglitazone (Rezulin)and rofecoxib (Vioxx).³

Types of Cinical Trial:

1. Treatment trials:

Test experimental treatments, new combinations of drugs, treatment of mentally disabled person, or new approaches to surgery or radiation therapy.⁵

2. Prevention trials:

It's specially use to prevent disorder come after take any medicine or return any disease. Look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.^4,5

3. Diagnostic trials:

It's refer to find out a particular disorder or health condition Conducted to find better tests or procedures for diagnosing a particular disease or condition.

4. Screening trials:

Test the best way to detect certain diseases or health conditions.⁵

5. Quality trials:

Trial (or Supportive Care trials) explores ways to improve comfort and the quality of life for individuals with a chronic illness.

SIGNIFICANCE:

Clinical trials are well-designed to benefit the participants or volunteers, investigators, sponsors and the entire medical community. These trials conducted in four phases by a team of doctors, nurses and medical or healthcare professionals play an important role in providing medical options to patients in the present and future. Clinical trials play a vital role in the development of intervention to treat or combat chronic degenerative diseases and improve the health of the world’s population. These trials provide invaluable and reliable information to doctors and patients on safety or benefits of existing therapies and help choose between alternative treatments. The large quantity and quality of clinical research conducted has increased the volume of devices, drugs and therapies under development. Clinical trials determine the safety and effectiveness of new drugs, treatments or diagnostic methods.

Role of Pharmacists in clinical trials:

In the clinical trial pharmacist is a member of the investigator’s site team. We provide the necessary facilities required for proper storage of the investigational medicinal products (IMPs), either in the fridge or a controlled room temperature. Regular temperature monitoring is ensured and recorded. It is also the pharmacist’s duty to ensure there is constant supply of IMPs at all times, and that they are dispensed to patients accordingly. They are responsible for the management of investigational products includes medicines and biologicals, but it may also manage gene therapy and radiopharmaceutical. The pharmacist’s duty to ensure there is constant supply of IMPs at all times, and that they are dispensed to patients accordingly. Drug Utilization Evaluations (DUEs) are research projects that are commonly conducted by pharmacist pharmacists also conduct observational surveys that are aimed at investigating patients’ or physicians’ perspectives and attitudes towards medications. DUEs are sometimes considered as drug audits because pharmacists are ensuring the use of medication is appropriate.⁶

Roles and Responsibilities:

· Health service organization

· Governing body

· Chief executive officers

· Approving authorities

· Human Research ethics committee

· Clinical trial team

· Study coordinator

· Research governance officers

· Principal investigator

· Sponsor investigator

· Clinical trial pharmacist

· Data manager

· Biostatistician ⁽⁸⁾

	Preclinical Trial (Usually done on animals to determine the drug is safe enough for human testing.	Phase 1 Determine Pharmacological action and tolerability.	Phase 2 Evaluate efficacy and Safety.	Phase 3 evaluate effectiveness and risk benefit ratio.	Phase 4 monitored long termed effect and effectiveness.
Duration	3-6 year since the drug discovery	Months	Months-Year	Years	Ongoing following FDA approved
Sample Size	Not Specific	Small	Large	Larger	Impacting Larger beyond
Population	In vitro and in vivo animals	Healthy population / may be with targeted disease e.g. cancer, T.B. etc.	Population with target diseases.	Diverse population with target disease	Diverse population with target disease and new age groups, gender
Types of studies	Not specific	Unblinded and uncontrolled.	May be Placebo (inactive substance) and Active, Controlled.	Randomized and controlled.	Expended Safety comparison.
Factors to be indentified	Mechanism of action, efficacy(Ability of drug to act against pathogen diseases)	Pharmacodynamics and pharmacokinetics, tolerated dose.	Drug -Drug and Drug-Diseases interaction.	Dosage intervals, Risk-benefit information, Efficacy and safety for subgroups	Epidemiological data, Efficacy and safety within large diverse populations, Pharmacoeconomics.

Tolerability:

Represents the degree to which overt adverse effects can be tolerated by the patient.

Effectiveness:

The extent to which a drug achieves its intended effectiveness

REFERENCE:

1. Vicki. L. Mahan Clinical Trial Phases. International Journal of Clinical Medicine,

2. Shahin Akhondzadeh, Avicenna Journals of Biotechnology

3. Craig A. Umscheid, David J. Margolis and Craig E. Grossman, A reviw on “Key Concept of of Clinical Trials.

4. Graham A. Colditz and Philip R. Taylor. A review on “Prevention trials their place in how we understand the value of prevention strategies”

5. Different clinical trials on web site: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/types-of-clinical-trials

6. Luisetto M. A reviw on “Clinical Pharmacist active role in registrative clinical trials”

7. phase of preclinical trials fig. on site https://www.google.com/imgres?imgurl=https%3A%2F%2Fpharmaguidances.com%2Fwp-content%2Fuploads%2F2019%2F06%2Fa-18.png&imgrefurl=https%3A%2F%2Fpharmaguidances.com%2Fphases-clinical-trials%2F&tbnid=8MC0D5MP7w05zM&vet=12ahUKEwjq1_brka3yAhVfK7cAHbu3DYIQMygPegUIARDMAQ..i&docid=M5dDgRX7ISZFyM&w=625&h=411&q=%20phases%20of%20preclinical%20trial%20diagram%20view&hl=en-US&ved=2ahUKEwjq1_brka3yAhVfK7cAHbu3DYIQMygPegUIARDMAQ

8. Role and Responsibilities of clinical trials on web site: https://www.viccompcancerctr.org/what-we-do/research-development/clinical-trials-expansion/investigator-initiated-trials/roles-and-responsibilities/clinical-trials-team/

Received on 13.08.2021 Modified on 20.09.2021

Asian J. Pharm. Res. 2022; 12(1):84-87.

DOI: 10.52711/2231-5691.2022.00013