A Roadmap to Clinical Trial Efficiency

Ketan Zota
Zota Healthcare

This article will discuss the process and roadmap needed for optimizing clinical study and trial and review why and how are the Trials being performed.

Clinical study is a research which involves human volunteers, also called as participants, with an intention to add to the medical knowledge.

Mainly there a two types of clinical studies, namely: Clinical Trial (aka Interventional Study) and Observational Study.

Clinical studies are the experimental studies to determine a better treatment of a particular disease. They are designed to answer specific scientific questions like:

• What side effects do the drug have?
• Does it reverses or stops the disease for which it is designed to heal?
• Are the outcomes effective than existing treatments?
• Can it be given along with the drug which is already being given for the same disease?

The answer to every question above must come in the form of scientific data and not in the form of opinions or the impressions of the scientists, doctors or patients involved with the studies.

The results can be enclosed by many factors and can be affected by bias. It is to be made sure this does not happen.

What is a clinical trial?

Clinical trials are clinical studies for exploring a medical strategy, device or a treatment, which is safe as well as effective for humans.

Also called as interventional study, clinical trial is a clinical study where participants are assigned to receive one or more inventions or sometimes no inventions at all, for the researchers to evaluate intervention’s effect on health related outcomes. For certain illness in humans or a particular group of people, these studies help to find out which medical approach will work better for their cure.

What is a clinical trial intended for?

The main purpose of performing a clinical trial is nothing but a research and so strict scientific standards are followed mandatorily. These standards are required to be maintained for the protection of patients and generate study results which are reliable.

How are the clinical trials approved?

Before starting a clinical trial, the protocol or the plan of the trial is approved by an independent and unbiased group of researchers who are not going to be involved in the trials, which is called an independent scientific review.

The trial protocol is reviewed by National Research Ethics Service, which is a Research Ethics Committee. The aim is to be concerned with the rights, safety, dignity and well-being of the patients taking part in trials. This committee is made up of 7 and 18 volunteers.

The researchers are bound with the protocol they proposed at the beginning of the trial. They cannot change the protocol without approval from ethics committee. They have to report to the ethics committee in case of any happening of serious side effects in-between trial. The committee receive reports at the end of clinical trial.

How is the clinical trial performed?

The process of a clinical trial begins in the laboratory. The scientists develop and test the ideas regarding the tests. Clinical trials are performed as a part of one of the final stages of a lengthy and carefully performed research procedure.
If the basic idea of clinical research is worth promising, animal testing is performed as the next step.

• Why are animals used for clinical testing?

Using animals for clinical tests is because there is a need to find out what happens to a living body. Replacing animals with any other alternative method of testing samples is not yet discovered. As the basic cell formations of animals are all similar and human’s body performs same tasks of movement, breathing, hearing, digestion, sight and reproduction, it is likely to perform tests on them rather experimenting them on humans first. Before testing ideas on humans, animals such as rats are used for sampling

• What does the animal testing indicate?

It shows that how the biomedical approach will affect a living body and whether it is harmful or not.
However, it may be possible that the approaches working well in labs or on animals are not necessary to show exact results in case of humans. Hence, it is required to perform tests on humans.
As a safety measure, clinical trials are performed on a small group of people on initial stage and it is found out whether it affects or harms humans or not. The later phases of clinical trials involve larger amount of humans on which the study is focused.

Understanding the Trial Phases of a Clinical Trial

The clinical trials are divided into stages called phases. There are three main phases of a clinical trial. Phase zero exist in some trials, which is an early stage. Phase 4 trials are also performed in some cases after the drug is licensed.
Let us consider the phases are being performed for Cancer, as an example to understand the clinical trials easily.
• Phase 0 Phase zero trials are intended to find out whether the drug behaves in the manner it is expected to perform as per the laboratory studies.
Involving a small number of people, phase zero trial volunteers are given a very small dosage of drug. This small dosage of drugs is very small to treat disease like cancer, but the researchers are looking for the answers to the following questions:
1. Whether the drug reaches the cancer or not
2. How is the body affected by this drug?
3. How does the cancer cells respond to this drug?

Because the dosage of drug is very minute in phase zero, there is no immediate effect on the patient, yet there is a benefit of not having any side effects of the drug.
Phase zero studies involve aiming at the speediness of developing new drugs. More useful information can be obtained quickly in this case as testing drugs on animals is eliminated in this phase as the dosage is very small.

• Phase 1
Phase 1 trials, also called as Phase-I, are usually small trials, recruiting few patients only. Variety of cancer patients for example , can be taken for phase-I trial. It means that the trial is open for the treatment of the same disease having different sub-types.

When it is the time to find out a new treatment for curing a disease, Phase -I tests are done to answer following questions:
1. What are the side effects to the drug now?
2. Can this treatment shrink cancer?
3. How is the body reacting to this drug?
4. How much dosage is to be given on an average?

Patients are recruited very slowly for this initial stage of trial. Although less number of patients are involved, it takes a long time to complete the test. The first few patients, also referred as cohort or group, are given the smallest dosage of the drug. If it works well with them, the next group is given a slightly high dosage of drug. The dosage is then slowly increased with each group. The researchers observe the effects of these dosages till it gives the best results and the best dose to give.
Lot of blood tests of the patients are taken as they are constantly under observation of researchers. This helps to identify how the dosage is affecting the patients. How the body is coping up with the drug effects and the resultant side effects are also recorded. In case of cancer, patients who have taken part for Phase-I have already gone through every available treatments for cure. They might be having advanced cancer. They may be benefitted from these trials or may not be benefitted too. The dosages and side effects are repeatedly observed as a main aim in Phase-I. Before expecting any treatment to work well, it is necessary to test them in this phase.

• Phase 2
Phase 2 trials are often longer than Phase-I. Up to 100 or more patients might be involved for this second phase trial. Not every treatments that are tested in Phase-I lead to Phase 2 trials. Also called as Phase-II, these clinical trials are involving same sort of diseased patients . For example, patients suffering from same type of cancer. Or different groups of people which are suffering from similar type of cancer.

These trials are aimed to find out:
1. More about the best dose used
2. For which type of cancer the treatment is working well
3. What are the side effects of drugs and how to manage those?
4. Is the new treatment working enough well to proceed to Phase-3 trials?
Although these treatments are already been tested in Phase-I, it is possible that the drug may show side effects later on, unknown even to the doctors. There are different ways a drug can affect patients.
Sometimes, in Phase-2 trials, the new treatment is compared with an ongoing treatment or with a dummy drug, called as a placebo. If it seems that this drug is showing positive results or is as good as an existing treatment, it is moved to Phase-3. In some cases, it is possible that the new drug may perform better than the existing drug too. These phase-2 trials are randomised. The researchers put people in trials in randomized manner.

• Phase 3 - The standard treatment, also the best available current treatment already in the medical field is compared with the new treatment in Phase-3 trials.

Phase-III trials are used to compare:
1. A completely new treatment with the existing treatment.
2. Different doses or ways of giving a standard treatment.
3. A new way radiotherapy can be given along with the existing standard way.
The number of patients are more in Phase-III in comparison to above Phases. The differences in success rates might be small in Phase-I and II, so it is required to trials are needed to be performed on more patients to be able to show difference.
For an example, 6% patients involved in trials may get a remission with the new treatment in comparison to standard treatment. For example, let us consider there are two groups of 50 people each, if three of the first group of patient are affected, it is possible that testing 5000 people, 300 new remissions are possible.
Thousands of people in different hospitals and even in different countries are possible to be involved for Phase-3 trials. These trials are also randomised. The researchers put large number of people in random manner for treatment.

• Phase 4
This is the last stage of performing clinical trial. If the drug is showing work and is already granted a license, then it is mandatory to let it in for Phase-4 trial.
The intention to undergo Phase-IV trial are:
1. What are the long-term benefits and risks of the drug
2. Learn more about the side effects and safety of the drug.
3. Will it show same effective results if it is used widely? "Each phase of a clinical trial is important to understand the result of any particular drug in detail. Be it an animal or human test, every stage of a clinical trial must be executed with complete accuracy. Even a second's negligence might give a wrong result," says Mr. Ketan Zota, Director of Zota Healthcare Ltd. How are the trials noted?

Most trials may have one Phase. Others might include Phase-I and Phase-II. The highest safe dose of drug is the main aim of Phase-I while Phase-II is to know how well this dosage work. You may find trials written as Phase 1/2 or Phase 2/3.

What are MAMS trials?

Many trials look for just one new treatment while some trials compare several new treatments.
The patients taking part in trials are still put into random groups and there may be three or more different treatment groups. This is called a Multi-arm trial.

Some of the trials are designed so that they stop recruiting into a particular group if the treatment is not working well in its early stages and is having adverse side effects in large number. This is called Multi-arm Multi-stage trial (MAMS). It is capable to add more people to new groups in order to look at more treatments.

Why are the trials randomised?

The trials are randomised by the researchers to avoid bias that may distort results and to make sure that the results are correct.

What are blind trials?

A blind trial is the one where the people involved in trials are unaware of the treatment they are getting. Either they will be given new treatment or may be continued with standard treatment. The patients receive identical treatments and injections which is impossible for the patients to find out what they are being given.

What are double blind trials?

It is a kind of clinical trial where neither the researchers, nor the patients know what they are getting. Each patient is assigned a code number by the computer. And then the treatment groups are allotted code numbers too . The treatment for the patient then arrives with his code number printed on it, where both are unaware what they are giving or getting, that is, if it is a new treatment or the same old one.

Until the end of trial, the list of patients and their code numbers are kept secret. In case of any emergency, doctors can look at their code numbers to find out which trial group they are in.

What are the outcomes of this study?

Different possibilities exist in case of expecting outcome. No certain outcome of a particular medical study can be forecasted. It is possible that the study may not produce any outcomes at all. It may have adverse effects on the patient or it may generate favourable or a positive outcome. If the generated outcome is positive, there is a possibility of getting a new treatment for a specific disease.