Clinical Trial Phases – an epic journey of medicine

Posted On October 17, 2020October 17, 2020

What’s up guys! Welcome to pharmacistopinions.com/. Today, I am going to explain an intriguing topic – Clinical Trial Phases.

Overview of Clinical Trial Phases

Friends! We use the medicine for certain disease either it’s beneficial or harmful. But do you know what’s the journey behind of any single medicine?

It is not a simple process to launch any drug in the market. It takes a lot of patience, hard work, skills, knowledge, research, investment and time. Generally, the development of a new medicine takes at least 10 years and the huge investment of around 500-1000 million US$.

Whatever we have drugs now, only because of the highest success rate of clinical trials.

Clinical trials mean the testing or research of drug on human beings. But before going to the clinical trials, the drug is tested on animals which are known as Pre-clinical trials.

Clinical trials only happen when there is a demand for the drug. We need a solution if we have a problem or question.

For example, an emerging disease COVID-19 is addressing all around the world.     This pandemic is such a devastating for us. Our researchers are rigorously working on COVID’s medicine or vaccine in clinical trial phases. Sooner or later, we will get the vaccine.

Any medicine originates from basic biochemical research (laboratory and animal studies) then it reaches to clinical trials. Let’s we know the complete process in stepwise –

1. Discovery of a drug molecule

It is an initial and important step for drug development. The scientists discovered the new molecule from the various parts of the plant, animals, aquatic mammals, minerals, microbes and some from recombinant DNA technology.

Then they isolate the compound by various screening techniques like HPLC, gas chromatography, spectrophotometry etc. Depending upon the need (or study), they find the particular chemical constituent from the group of chemical constituents. This compound is known as a lead compound or target compound.

The lead compound should have a pharmacological activity (clinical therapeutic use). They may do some possible structural modification in existing drug or new lead compound which is called SAR (structure-activity relationship).

After that researcher transforming a drug into proper dosage form which is also an important milestone in the drug discovery phase. 

The whole process in this phase takes around 1-2 years.

2. Preclinical Trial

After getting the identified lead compound, it is tested on animals. It requires to determine the toxicity and pharmacological profile of the drug. It is an important step before starting a clinical trial. This preclinical trial takes around 2-4 years.

The researchers use large animals (monkey, chimpanzee, cat, dog) or small animals (mice, rat, guinea pig, rabbit, hamster) depending upon the study. They follow the standardised procedure by GLP (Good Laboratory Practices). They need to take permission from IAEC (Institutional of animal ethical committee), OECD (Organisation for Economic Co-operation and Development) guidelines.

In this preclinical trial, scientists determine the safety, efficacy and toxicity of drug by in-vivo and in-vitro studies. In-vivo, study occurs in a living organism such as a mouse, rat etc. and they analyse how the body responds to a drug.

In contrast to in-vitro, study happens with the animal sample within a controlled environment e.g. in test-tube, laboratory dish.

Toxicity studies –

This is such a crucial step to move forward in a clinical trial. The purpose of this study to determine the risk or safety of a drug. For this study, the researcher uses small animals like mice, rat, guinea pig etc.

They use the LD50 (lethal dose 50) method to determine the toxicity of the drug. LD50 describes that dose at which the 50% animal population dies. For example, if the researcher takes 10 animals and after giving the particular dose of a drug, 5 animals died that called LD50.

Researcher work on various toxicities like acute toxicity (single dose toxicity, 1-3 days), subacute toxicity (repeat dose toxicity – 28 days), chronic toxicity (long term toxicity – 6 to 12 months), carcinogenicity, mutagenicity, reproductive and teratogenicity.

Therapeutic or pharmacodynamic studies –

To determine the efficacy of a drug, the researcher need to induce disease to experimental animals. They use a large animal like a monkey, dog, cat etc.

Then they detect the specific activity of drug such as antihistaminic, anti-inflammatory, antidiabetic, antimicrobial, antiviral, anticancer etc.

They use the ED50 (Effective dose) method to find the efficacy of any drug. ED50 describes that dose at which the 50% animal disease population response from the drug. For example, if the researcher takes 10 animals and after giving the particular dose of a drug, 5 animal shows pharmacological activity that called ED50.

Pharmacokinetic studies –

For an ideal drug –

• It must be easily absorbed into the systemic circulation
• It must have proper distribution in a specific site of action
• It must efficiently metabolize
• It should be eliminated well from the body

Researcher keeps this thing in mind and works on pharmacokinetic parameters (absorption, distribution, metabolism and excretion) of the drug.

3. Clinical Trial

After getting the satisfactory result or data (minimum toxicity and maximum therapeutic effect) in the preclinical trial, they need permission for a clinical trial from a higher authority. It takes almost 3-6 months.

When the researcher gets the permission then they move towards clinical trials.

A clinical trial is a type of prospective intervention studies. In this trial, researchers test the drug on human beings and watch the outcomes of studies by long term follow up of volunteers.

There are two key players in clinical trial – sponsor and CRO (Contract research organisation). The sponsor may be an individual, pharmaceutical company and government agency. Whereas CRO provides services like clinical research, preclinical research, pharmacovigilance activities, clinical trial management, biopharmaceutical development etc.

The trial is conducted with a team which includes principal investigator, physician, nurses, pharmacist, volunteers or other healthcare members.

The clinical trial must be conducted in proper SOP (Standard Operating Procedures) and researchers need to follows the guidelines by ICH, GCP, USFDA, Schedule Y, WHO, ICMR. They also need ethical clearance from the local institutional ethical committee/Review board as per GCP.

In a clinical trial, informed consent form (ICF) is a crucial step. It is an official document which provides all details and information regarding clinical trial to participants. It includes the purpose, procedure, potential benefit and risk. The volunteers should be participated by self-willing. They have permission to withdraw at any stage of a clinical trial.

Clinical trial plays a critical role in drug development. This trial happens in five phases. The safety is emphasised in each clinical trial phases.

Let’s know what are the 4 phases of clinical trials.

Phase 0 – Micro-dosing study

It is a new idea or concept from USFDA. It is done to test the safety and toxicity of the drug. A drug may be considered safe if its benefit is more than associated risk. For example, anticancer drugs (chemotherapy) are higher side effects but it may save cancer patient lives.

It is a type of pilot study (very small study) which includes 10 to 15 healthy volunteers.

The researcher uses a very small dose of a drug to minimize the future risk for human in large studies. It is also known as human micro-dosing studies.

The main purpose of this study to reduce the cost and time in the drug development process.

Phase 1 – Human pharmacology and safety

In this phase, the researcher gradually increases the dose and assess the maximum tolerated dose. The well-qualified pharmacologist monitors all vital organs and determines the safety of the drug.

They also observe the pharmacokinetic effects.

The clinical team see the effects of the drug on a large number of healthy volunteers which includes 20 to 80 subjects. This is an open-label study where both participants and researcher aware of the test drug. 

The success rate of this phase is appro. 70%, where drug moves from phase 1 to phase 2.

Phase 2 – Efficacy and side effects

After achieving the maximum tolerated dose. The researcher conducts this phase with patients which involves 100-500 participants. It involves specific disease patients like if the trial is going on the antidiabetic drug then they will work on diabetes patient with according to inclusion and exclusion criteria.

It is mainly focused on the therapeutic efficacy of the drug with continuous monitoring of all possible side effects.

Here, the physician decides the dose range and ceiling effect of the drug. Ceiling effects means the dose does not give therapeutic effect beyond the maximum therapeutic effect.

This is controlled and randomised study. In this study, they compare the two groups – one group (test drug) or another group (no drug or placebo) in a randomised way. It can be blinded or open-label study. 

If the test drug shows promising anti-disease effect then it moves towards Phase 3. The success rate of this phase is appro. 33%.

Phase 3 – Therapeutic confirmation/comparison and monitoring of side effects

To determine the confirmation of the drug’s efficacy, researchers conduct the trial on a large number (500-3000) of patients. It takes a lot of resources, efforts and cost. They work on target disease.

The researcher wants to make sure of safety, tolerability and efficacy of the drug on a wider scale.

They conduct double-blinded RCT (Randomised control trial) or double-blinded randomized placebo-controlled study. This is the strongest study design and it is considered as “gold standard” study.

In this study, both researcher and patients don’t know about treatment. They compare the test drug with a standard drug (existing drug in the market). They randomly choose the volunteers and gives the test drug or placebo or existing drug.

This type of study helps to reduce bias while interpreting results.

After the confirmation of efficacy and least side effects. The researcher submits the NDA (New Drug Application) to licence authority (US-FDA or European commission). Once authority satisfied with all clinical data and results, then they provide marketing permission.

The success rate of phase around 25% then drug moves toward the last stage i.e. phase 4.

Phase 4 – Post-marketing surveillance 

After getting the approval from FDA. The drug is launched in the market. Now it is widely used in general patient population or special population like elderly, children, pregnant women, breastfeeding women, kidney or liver disease patient.

The drug is still kept under long term surveillance to monitor the side effects, efficacy and possible drug interaction with other drugs.

Pharmacovigilance plays a key big role here to monitor the side effects of the drug. If they receive a higher number of cases of life-threatening side effects or toxicities, the drug could be withdrawn from the market.

Conclusion

Clinical trial phases are a very important part of the drug development process. It helps to assess the safety and efficacy of the drug.

So, we have discussed phase 1, phase 2, phase 3 clinical trial design and phase 4 marketing surveillance.

I hope it would be informative. If you have any query regarding this post – clinical trial phases, please write in below comment box.

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References –

1. Guosheng Yin. Clinical Trial Design. Wiley series in probability and statistics. Wiley publication, New Jersey, 2012.
2. KD Tripathi. Essentials of Medical Pharmacology, 7^th edition. Aspects of Pharmacotherapy, Clinical Pharmacology and Drug Development, Chapter-5, Page-79, 2013.
3. Clinical Research https://www.fda.gov/patients/drug-development-process/step-3-clinical-research.

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