Introduction

The primary goal of research based pharmaceutical organizations around the globe is to discover, develop and procure regulatory approvals for marketing new drugs for the treatment or prevention of diseases in humans and animals. A clinical trial is a research study in human volunteers to determine safety and efficacy of a treatment i.e. an investigational new drug, method of diagnosis and screening¹. Chemicals and biologics that do show promise in preclinical studies face extensive, strict and thorough clinical trials in healthy volunteers and in high-risk population. Preclinical research allows evaluation of the pharmacokinetics, pharmacodynamics, dose-response profiles and toxicological potential of a drug. Preclinical studies also determine the optimal formulation and dose for phase I clinical trials, analyze physicochemical characteristics of the testing compound and provide the rationale for the proposed therapeutic indication. Approval to initiate human clinical trials is based on the results from preclinical pharmacological and animal toxicity studies. The design of the clinical trials is based on the chemical nature of the product being tested, results of preclinical animal studies and intended clinical uses. This is particularly relevant for biopharmaceuticals that frequently demonstrate complex and multiple pharmacological activities.^2-10

Types of Clinical Trials¹¹

Treatment trial for new combination of drugs and new approaches to therapy.

Prevention trial to search more effective ways to prevent disease in new patients and to prevent disease from returning.

Diagnostic trial to find better tests to diagnose a particular disease.

Screening trial to examine the best way to detect certain diseases.

Quality of life trials to explore way to improve comfort and the quality of life for patients with a chronic disease.

Good Clinical Practices (GCP)

Good clinical practice is a set of guidelines for biomedical studies that encompasses the design, conduct, termination, audit, analysis, reporting and documentation of the studies involving human subjects.

The guidelines Seek to Establish Following Cardinal principles^12-15

Protection of the rights of human subjects involving informed consent procedures and ethics committee consultation.

Standardization of activities with in the sponsor company achieved by the use of good management system and written standard operating procedures (SOPs).

Documentation and archiving to a standard that provides an intact paper trial which will confirm all events occurring during the study.

Monitoring and audit of investigation procedures and documentation by the sponsor.

Authenticity of biomedical data generated i.e. verification of trial documentation by regulatory authority audit, though these procedures are developed to a different extent in the various systems.

Sponsor and investigator¹⁶

The sponsor takes responsibility for and conducts the clinical trials and may be an individual or pharmaceutical manufacturer, research institute or private organization. Sponsors are responsible for selecting qualified investigators and monitors, informing investigators, reviewing and monitoring studies and maintaining trial record.

Investigators, such as physicians and other professionals qualified by training and experience, conduct or supervise the clinical study. They prepare a general outline of the planned studies that specifies the duration of the study, number of subjects that will be involved, and clinical observations and laboratory tests to be performed.

Monitor

The monitors are responsible for ensuring the quality and integrity of the data obtained from clinical trials, as well as the rights and safety of human subjects participating in the study. The monitor must visit the clinical site frequently to ensure that clinical trials are carried out according to the scheduled plan and that investigators have followed the specified regulations. The monitor also reviews the reports that are prepared by the investigator and submitted to the sponsor.

The objectives of the monitoring are to verify that^17,18

The rights and well being of human subjects are protected.

The reported trial data are accurate, complete and verifiable from source documents, hospital case records, laboratory reports, X-rays scan etc.

The conduct of the trial is in compliance with the protocol/amendment(s) approved by regulatory authorities and ethics committee with GCP and with the applicable regulatory requirement(s).

The monitor’s role is to be¹⁹

Messenger between the investigator and the sponsor.

Organizer of investigator meetings, key documents and trial logistic.

Negotiator of agreements and budget.

Inspector of case record forms, source data, ethics and consent documents.

Trainer of investigator and his team.

Observer trial conduct at the hospital site through monitoring.

Reporter of trial status protocol deviations, site issues.

Monitors, to function effectively, have to be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP and the applicable regulatory requirement(s).

Protocol

A document that states the background, objectives, rationale, design, methodology and statistical considerations for study. It also states the condition under which the study shall be performed and managed. The content and format of the protocol should take into consideration the adopted SOPs, the regulatory requirements and the guiding principles of GCP. The prerequisites for the study include¹⁶

Investigational Pharmaceutical Product.

Preclinical supporting data.

Protocol.

Relevant components of protocol

General information.

Objectives and justification.

Study design.

Inclusion, exclusion and withdrawal of subjects.

Handling of the product(s).

Assessment of efficacy.

Assessment of safety.

Statistics.

Data handling and management.

Quality control and quality assurance.

Ethical and safety consideration.

Clinical Trials from Phase-I to Phase-IV

There are four stages of clinical trials and they are summarized as follow:

Phase-I Trial (Human/Clinical Pharmacology trial)^20,21

A Phase-I study represents the initial evaluation of an investigational new drug in people. The primary objective is to assess the safety of the new drug by testing a range of doses or dosing intervals in a sequential manner. The total number of subjects included in Phase-I studies is usually in the range of 20-80 and these studies require fewer than 12 months to complete. These studies are often carried out in healthy adult volunteers using clinical, physiological and biochemical observations. At least 2 subjects should be used on each dose. Investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects usually carry out phase-I trials. These may be carried out at one or two centers.

Other Objectives in Phase-I Studies May also Include;

Determining the extent of drug metabolism.

Identifying interactions with other medications.

The mechanism of action.

Identifying preferred route of administration.

Gaining early evidence on drug effectiveness.

Conducting thorough dose ranging and dose response studies early in the product development reduce the possibility of later failed phase-II or III studies.

The Major Functions of Phase-I Trial Unit May be Grouped as Follows

Maintenance of an Ethics Committee

Secretarial organization e.g. checklists of members, documents sent and received, taking and typing minutes.

Recruitment of committee members ensuring a balance of medical and lay members and that they are independently minded.

Help with elections of chairman or other officers.

Contact with other departments e.g. legal department on questions of indemnity.

Contact  with  other  organizations  for guidelines.

Recruitment and Care of Volunteers

Pretrial tests for hepatitis antigens and in some cases HIV.

Records of participation in trials, including blood taken.

Records of honoraria paid.

Contact with general practitioners.

Contact with pathology laboratories re sample.

Pretrial (group) discussions for each trial.

Pre and post trial medical examinations.

Instructions during trial e.g. declaration of all concomitant treatments, avoidance of alcohol, strenuous exercise and driving a car.

Organization of Trials

Protocol development and circulation.

Drug supplies, labeling and dose allocation schedule.

Instructions to nurses and technicians recording data.

Dipstick pathology tests on blood and urine samples.

Storage of samples for assay, etc.

Maintenance of equipment and quality control.

Records of results, especially adverse reactions.

Practice of emergency procedures.

Organization, analysis and presentation of data.

Report writing.

Dissemination and interpretation of results

Ethics Review Board (ERB)

Clinical research in healthy subjects can result in benefits for society. Ethical aspects of research include reasoned analyses of moral obligations including²²:

The moral duty of justice requires the investigators to be fair in the treatment of research subjects. Thus, the treatment of participants in clinical studies should be compensated adequately for inconvenience, discomfort and loss of time when participating in studies.

Beneficence requires that the research activities benefit study subjects and other people.

Nonmalfeasance, not doing harm.

Respect for autonomy i.e. allowing the individual to determine what happens to him/ her.

It is an independent body constituted of medical/scientific professionals and non-medical/ non-scientific members whose responsibility is to ensure the protection of rights, safety and well being of human subjects involved in clinical trial.

An ideal ERB should include²³;

At least five members (quorum).

At least one member whose primary area of interest is in non-scientific area.

At least one member who is independent of the institution/trial site.

The main responsibility of ERB is²⁴;

To safeguard the dignity, rights, safety and well being of the potential research participants.

To ensure and verify that universal ethical values and international scientific standards are followed with a view on local community values and customs.

To help in the development and the education of a research community responsive to local health care requirements.

Phase-II Trial (Exploratory trials)

In Phase-II trials a limited number of patients are studied carefully to determine possible therapeutic uses, final formulation, dose and dosing regimens and further evaluation of safety and pharmacokinetics. Normally10-12 patients should be studied at each level. These studies are usually limited to 3-4 centers and carried out by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety.²⁵

Element of Phase-II protocol include front page, introduction, objectives, ethical aspects including payments to patients, drug supply, labeling and randomization code, patient selection, methods, statistical analysis, dropouts, protocol amendments, adverse events, timetable, resources and personnel, financial indemnity, publication of results and record form.²⁶

Phase-III (Confirmatory Trials)

The purpose of these trials is to obtain sufficient evidence about efficacy and safety of the drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. Clinicians in the concerned therapeutic areas, having facilities appropriate to the protocol, may carry out these trials. If the drug is already approved/marketed in other countries, Phase-III data should generally be obtained on at least 100 patients distributed over 3-4 centers primarily to confirm the efficacy and safety of the drug, in Indian patients when used as recommended in the product monograph for the claims made.^27,28 Phase-IV (Studies performed after marketing of the pharmaceutical product)

Trials in Phase-IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. The major objectives of phase IV studies are to obtain additional data of the drug’s safety and effectiveness and determine new uses for or abuse of the drug²⁹. The FDA requires that the manufacturer maintain and establish post marketing records and reports. This is necessary for two reasons³⁰;

An investigational drug is tested in a relatively small number of patients compared with the number of patients who may use the drug after it is marketed.

Long term adverse effects may not be discoverable before approval.

As a result of post marketing information, the FDA may withdraw its approval of an NDA.

Under this provision, the manufacturer must submit to the FDA reports of any serious adverse drug reactions and any new information relating to the drug’s safety and efficacy, including information about;

Current clinical studies.

The quantity of drug distributed.

Labeling and advertising.

Informed Consent Process

Informed consent involves the process whereby explicit information is provided to participants regarding the treatment in clinical trials. It also describes the obligation of the investigator to inform the subject about the personal benefits and risks the individual faces in the study as well as the significance of the research for the advancement of medical knowledge and social welfare.

The informed consent is designed so patients participating in a clinical trial can obtain an adequate understanding of the objective and procedures of the clinical trial. Patients participate in such trials voluntarily. The information given to the subjects must be written in lay terms and include the following key components³¹:

A statement explaining the objective of the study, duration of the subject’s participation and procedures of clinical trial.

Description of any possible risk, adverse reactions, discomforts and benefits to the subject.

A statement that the confidentiality of the subject’s records will be maintained.

An explanation of whether compensation and medical treatment are available if injury occurs during the clinical trial.

A statement that participation is voluntary and refusal to participate will not involve penalty or loss of benefits to the subject.

A list of persons to contact for questions related to the clinical trial and trial related injury.

The law requires the investigator to secure the informed consent of the patient or a representative for the administration of an experimental drug. The patient consent must be in written in phase 1 and 2. In phase 3 consent may be oral if the physician decides it is necessary or it is preferable to written consent and this decision is recorded in the patient’s medical record. Patient consent may not be necessary when it is not feasible to obtain the consent of the patient or a representative or when in the professional judgment of the physician, informed consent is not in the best interest of the patient.³²

Clinical data management

Clinical Data Management (CDM) is the entire process involved with taking original raw data from the clinical sites with compiling and validating it, so that it is suitable for reporting purpose. In CDM process, the clinical trial data are collected and organized by using a computerized database that completely and accurately reflects the findings and events of the trial. CDM is key component of the multi-disciplinary team involved in setting up, running and reporting clinical trials. A data manager defines how these data are collected, tracks the data and checks their completeness, accuracy and consistency. Data management is involved in all aspects of processing clinical trial data, working with a range of computer applications and database system to support collection, cleaning and management of subject or patient data. CDM preferably includes³³:

Input into the design of protocol, which defines what data are to be collected and at what times.

Design and approval of case report forms, on which subject’s data are collected.

Database design for the study, ensuring it meets requirements for data entry and reporting.

The CDM process starts with design of protocol and it continues till the submission of clinical study report to regulatory authority for marketing approval. The CDM process is complicated, but if all team members perform their role specifically with team spirit then it runs smoothly. The team members involved in CDM process are database designers, data entry operators, data loaders, data managers and statistical programmers and medical writers. Each member involved in CDM process has a unique role and responsibilities.

Softwares used for clinical trial management, patient recruitment process, financial aspects of trials etc. and there are some specialized clinical data management softwares. Some of the softwares which are used for managing clinical research activities are listed below³⁴:

Clintrial

Clinpharma

Teleform

SyMetric

Adventrial

Study Manager

SAS Software

Tanangra-statistical analysis

These software help to achieve better relationships and interactions with regulators, investigators, clinicians and consumers through pre-emptive handling of AE problems based on earlier detection of signals and trends. Costs are reduced while data quality and analytical capability improve. Time to submission and to market is accelerated by controlled and validated reconciliation of data, while the risk of regulatory scrutiny is reduced.

Schedule Y

Schedule Y provides exhaustive information as well as lays down regulatory requirements for conduct of clinical trials. It also consists of information on animal pharmacology, details on types of fixed dose combinations (FDCs) of drugs, conduct of animal toxicity studies, stability testing of drugs (accelerated and real time), contents of proposed clinical trial protocol and report, data elements for reporting serious adverse drug events occurred during the trial, checklist for informed consent document and different phases of clinical trials.^4,35

Clinical Research Organisation (CRO)

An organization to which the sponsor may transfer or delegate some or all of the tasks, duties and / or obligations regarding a clinical study. All such contractual transfers of obligations should be defined in writing. A CRO is a scientific body-commercial, academic or other. Following are some Clinical Research Companies in India^36,37;

Accutest Research Laboratories (I) Pvt. Ltd., Ace Biomed Pvt. Ltd., Actimus Biosciences Pvt. Ltd., Apothecaries Ltd., Asian Clinical Trials, Aurigene Discovery Technologies, Avra Laboratories, Bioserve Biotechnologies (I) Pvt. Ltd., Chembiotek Research International, Clinigene International, Clininvent Research Pvt. Ltd., Clin Tec India International Pvt. Ltd., Clintrac International Pvt. Ltd., D & O CRO, Dr. Reddy’s Laboratories Limited, Eli Lilly and Company (India) Pvt. Ltd., Glaxo Smith Kline Pharmaceutical Limited, Gokula Metro Polis Clinical Laboratories Pvt. Ltd., GVK Biosciences Pvt. Ltd., iGATE Clinical Research International Private Limited, Intas Pharmaceuticals, International Tech Park Ltd., INTOX Private, Jubilant Clinsys, Johnson & Johnson Ltd., Kendle India, Lambda Therapeutic Research Pvt. Ltd., Lotus Labs Pvt. Ltd., Lupin Limited, Magene Life Sciences, Manipal Acunova, Matrix Laboratories Limited, Metropolis Clinical Laboratories, Novo Nordisk India Private Ltd., Omnicare Clinical Research, Pharma-Olam International, Pharmanet, PPD Pharmaceutical Development India, Quintiles Technologies (India) Pvt. Ltd., Ranbaxy Laboratories Ltd., Reliance Clinical Research Services Pvt. Ltd., Reametrix India, Roche Scientific Company (I) Pvt. Ltd., Sanofi-Aventis (Aventis Pharma Limited), Sipra Labs Pvt. Ltd., SIRO Clinpharm Pvt. Ltd., SRL Ranbaxy Limited, Sterling Synergy Systems, Suven Life Sciences Limited, Synchron Research Pvt. Ltd., Triesta Sciences, Torrent Pharmaceutical Limited, Veeda Clinical Research, Vimta Labs Limited, Zydus Cadila.

Acknowledgements

The authors are thankful to Mr. J.P. Singh, librarian, K.I.E.T. School of Pharmacy, for his help to collect the required literature.

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