Fundamentals of Clinical Trials

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Fundamentals Of Clinical Trials

Anantha Naik Nagappa and Uday Venkat Mateti

Manipal College of Pharmaceutical Sciences, Manipal University, Manipal-576104, India.

What are clinical trials?

Clinical trials are experiments on human beings to study the safety and efficacy of new drugs.

What are the objectives of different phases of Clinical trials?

Clinical trials are conducted in different phases in an order of Phase 0 - Phase 5 (six phases)

Type of Phase

Objective

Dose

Number of subjects involved

Phase-0

To evaluate the pharmacokinetics- pharmacodynamics (PK/PD), bioavailability and half-life of the drugs.

Micro dosing

10-12

Phase-I

To evaluate the safe dosage range, and side effects

Subtherapeutic dose

20-100

Phase-II

To assess the efficacy and safety

Therapeutic dose

100-300

Phase-III

To confirm the effectiveness and safety

Therapeutic dose

1000-2000

Phase-IV

Post marketing surveillance- watching the long-term use

Therapeutic dose

Any person seeking treatment from their doctor

Phase-V

Translational Research

No dosing

All reported use

Describe the type of Clinical Trials?

Clinical trials are classified as observational studies where the investigators observe the subjects and measure their outcomes. An interventional study where the investigator administers a new medicine or intervention and measures the outcome in comparison to a control group which don't receive any new medicine or intervention.

However the U.S. National Institutes of Health (NIH) classifies clinical trials into five different types:

Prevention trials: Focus on evaluation of new approaches for treatment of diseases using medicines, vitamins, vaccines, minerals, or lifestyle changes. Screening trials are public health measures aiming to diagnose occurrence of a disease or health conditions in a population. Whereas, diagnostic trials are conducted in an individual patient to find a particular disease or condition. Treatment trials are the experiments of treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Quality of life trials (supportive care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness. Compassionate use trials or expanded access trials are the clinical trials of unapproved therapeutics to a small number of patients who have no other realistic options.

The third classifications of clinical trials based on data of the trial are fixed trials and Adaptive clinical trials.

In a fixed clinical trials the consideration for existing data only during the trials design, and do not modify the trial after it begins and do not assess the results until the study is complete. In adaptive clinical trials the use of existing data to design the trial, and then use interim results to modify the trial as it proceeds are allowed.

Enlist the various professionals in Clinical trials?

The Sponsor, Principal investigator, Local site investigators, clinical research associate, clinical research coordinator, auditor, and Institutional review boards (IRBs) and Regulatory agencies are the professionals involved in the Clinical trials

Describe the components of clinical trial protocols?

According to the ICH GCP guidelines, a clinical trial protocol must contain the following shown in the figure 1:

Figure 1: Components of clinical trial protocols

What is Informed consent?

It is the responsibility of clinical trial team to respect the patients' rights. The patients' rights include "the inherent dignity" and the "equal and inalienable rights of all members of the human family". In order to practice the patient rights in clinical trials, it becomes mandatory for the clinical trial team to explain the good and bad, benefits and risks to individual and society being informed to the patient in his own language and shall be included in the clinical trial after the subject agrees to participate in the trial voluntarily in the interest of self and society. The informed consent is a written agreement document where in the patient or the benefiters of patients sign the agreements.

What is subject information sheet?

The subject information sheet is a document explaining the purpose of trial and its benefits for individual participants and society. It contains detailed explanation of information regarding the safety and risk involved while exposing oneself to a new drug or intervention. The overall objective of information sheet is to educate and facilitate the participants regarding joining the clinical trial without confusion or doubt.

What is an Investigator brochure?

While developing a new drug lot of new information is gathered and in ordered to document the information in a systematic manner. The sponsor of the drug development is assigned with the responsibility of development and maintains the Investigator's brochure. It mainly involves information regarding safety, dosing schedule, method of administration and safety monitoring.

What is human ethics committee?

Human ethics committee is a regulatory body looking after the protection of human beings when they subject themselves in drug development such as clinical trials. It is the committee which will scrutinize the protocol with an intention that there is no violation of human rights and exploitation of the participants. It ensures fair practices of clinical research are followed. The committee consists of representatives of clinicians, scientists, philanthropist, social workers, senior citizens and legal experts.

What are the functions of ethics committee in conduct of clinical trials?

Ethics committee after examining the protocol gives approval for conduct of clinical trial and research in human beings. The protocol is examined from the point of necessity, risk and benefits for the participants, advantages for the society. It also scrutinizes the protocol for scientific value along with the fairness exercised while conduct of clinical trial.

What is bias in Clinical trial?

The bias is a tendency to extrapolate an observation either positively or negatively. In an experiment like clinical trial there is a possibility by the observer to exaggerate an observation leading to wrong conclusions. It is very essential to observe the source of bias and try to avoid to maximum extent so that real information is gathered on which basis a rational conclusion can be made. For example the bias has a significant consideration while conducting randomized clinical trials.

Discuss the different approaches to keep bias at minimum?

The bias can arise in a clinical trial due to errors in selection, conducting, detection, attrition, reporting and trial design.

The selection bias happens due to improper allocation of subjects to control an interventional group. Conducting bias may happen due to errors in poor implementation of protocol. The error in identifying the signals of experiments leads to detection bias. The attrition bias happens due to dropouts of the subjects while conducting the study. Reporting bias happens due to wrong calculations and errors in clinical trials. The Trial design bias can happen if attention is not paid regarding robustness of the design.

What is placebo effect?

Placebo effects are used to evaluate the drug effect in clinical experiments. The placebo effect is usually due to perceptions and bias which are usually psychological. Mainer time it is observed that patients respond due to faith and confidence over treatment and doctor. This may not be due to drugs. It is necessary to discount the placebo effect in a clinical experiment to estimate the true effect of drugs. Hence in clinical trials usually placebo is used as control. The patients and doctors are made to believe and are blinded regarding whether the patient is in control group or treatment group. The control group usually receives the dummy formulation which appears similar like a treatment group. The main idea is to discount the bias which is interfering in the assessment of drug effect in a clinical trial.

What is the role of sponsor in Clinical trials?

The sponsor is the owner of the clinical trial who invest, organizes and manages the clinical trial. The sponsor may be an individual, company, institution or government. The sponsor although the owner of the data. He does not participate directly in conducting of trial but provides support for progress of the trial.

What is the role of Primary Investigator?

Primary Investigator is leader appointed by the sponsor of a clinical trial who is responsible for the patient safety and data management of the trial. He is also responsible for reporting to sponsor the outcomes of the clinical trials. He has to coordinate with multidisciplinary professionals linked to conduction of clinical trials.

What are the requirements of multicentric clinical trials?

The multicentric clinical trials are conducting the clinical trials at different places simultaneously. This is to establish the variations in outcomes due to clinical settings if any. It is also an attempt to globalize the clinical findings of a trial. The multicentric clinical trials demands huge planning in terms of evaluations of infrastructures of different settings and make par with each other's so the clinical trial although conducted in different geographical locations. The basic infrastructure parameters remain same and constant.

What is role of study site coordinator?

Study site coordinator is a person who acts as manager and co-ordinates with various professionals and patients in order to carry out the clinical trials without any obstacle on behalf of principal investigator.

What are e-clinical trials?

The clinical trials data submissions to regulatory agencies was huge and used to be contained several truck loads. The manual data compilation of clinical trials data in hard copy form was laborious and becoming difficult to analyze. The conversion and collision of clinical trial data in the electronic form replaced the physical data forms. The complete submission of clinical data in the electronic form right from the beginning of the trial till the end of the trial was simple and viable both for investigators and regulators. The e-clinical trial uses novel data and devices to conduct clinical trials which are known as e-clinical trial.

References

1. Pocock, SJ (2004), Clinical Trials: A Practical Approach, John Wiley & Sons, ISBN 0-471-90155-5.

2. https://clinicaltrials.gov/

3. http://www.clinicaltrials.com/

4. http://www.centerwatch.com/clinical-trials/overview.aspx

5. ICH Guideline for Good Clinical Practice: Consolidated Guidance

About the Author

Anantha Naik Nagappa's picture

I am professor, intrested in developing the community pharmacy services in India, We have an association called ASSOCIATION OF COMMUNITY PHARMACISITS OF iNDIA. CHECK AT www.acpi.in for further detials

Comments

Ph. Bhagavan P S RPh's picture

Sir

Thanks for the good topic and simple easy-todigest information.

But, can you please clarify my doubt:

Are their instances where any research has been initiated on any molecule on the request / suggestions of the clinicians?

Or

Our clinicians just accept what has been brought out and marketed?

Are there any instances, where clinicians have outright questioned the claims out of their experience with the drug?

Regards

Bhagavan P.S. B Pharm

Rtd. Dy Dir.(Pharmacy),Govt of Karnataka, India
Anantha Naik Nagappa's picture

I regret to say I don't have knowledge of any dialogue or enquiry regarding the topics mentioned in the question. However, the growth in the therapeutics market is usually prompted by feedback of patients and healthcare professionals which are not documented in a systematic manner.

Prof Anantha Naik Nagappa

My Page : http://www.pharmainfo.net/ananthanaik

Albert Ana-Maria's picture

I heard about some of them tests on humans, and they are paid, which are long-term effects? Unknown maybe .. But it is good that happens? All the world is getting sicker?

Anantha Naik Nagappa's picture

Clinical Trials are the experiments on human beings to establish and document the safety and efficacy of drugs. There should be an approach for conducting clinical trials and protecting the interests of the patients. The clinical trials especially the Phase I and II are carrying high risk. The participants can only volunteer if they are protected and given due compensation. However code of ethical practice and conducting clinical trials puts restriction not to lure the patients and pay them huge money leading to unethical practices.

Prof Anantha Naik Nagappa

My Page : http://www.pharmainfo.net/ananthanaik

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