Clinical Trials: A General Overview

A clinical trial is an organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease. In some instances, clinical trials attempt to improve a patient’s quality of life¹. Clinical trials, also known as clinical studies, test potential treatment in human volunteers to see if they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as vaccine, blood product, or gene therapy. Potential treatments however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatment having acceptable safety profiles and showing the most promise are then moved into clinical trials².

History of Clinical Trials

Clinical trials are used to test new drugs and therapies on human volunteers. Now a days, all human studies are carried out using protocols that adhere to accepted standards of safety, patient care and data interpretation. However, history shows that patient welfare was not always such a high priority.

The earliest recorded clinical trial is documented in the Old Testament. It describes how Daniel followed a diet of pulses and water instead of the meat and wine, recommended by King Nebuchadnezzar II. Daniel remained healthy while his companions became ill, convincing Nebuchadnezzar to change his mind that diet of pulses and water is more advantageous to health than wine and meat. The Renaissance surgeon Ambroise Parè conducted the first clinical trial of a novel therapy unintentionally in 1537. He used a concoction of turpentine, rose oil and egg yolk to prevent the infection of battlefield wounds, noting that the new treatment was much more effective that the traditional formula. James Lind carried out one of the first known controlled clinical trial. He documented the fact that citrus fruits in the diet could prevent scurvy. Lind carried out this trial at Salisbury in 1747. All scurvy patients were given the same general diet but this was supplemented with various additional items, including cider, elixir vitriol, vinegar, seawater, nutmeg and (crucially) oranges and lemons. In just six days, those patients taking citrus fruits were fit for duty. From 1800 onwards, clinical trials began to proliferate and more attention was paid to study design. Placebos were first used in 1863, and the idea of randomization was introduced in 1923. The first trial using properly randomized treatment and control groups was carried out in 1948 by the Medical Research Council, and involved the use of streptomycin to treat pulmonary tuberculosis. Since 1945, the ethical impact of clinical trials has become increasingly important, resulting in strict regulation of medical experiments on human subjects³.

Importance of Clinical Trial

It is often said that good things take time. Clinical trials may be a prime example. In U. S., for example, it usually takes just over fourteen years and $500 million for and experimental drug to make the arduous journey from laboratory to patients. Through clinical trials one can compare or extrapolate the result of study from a small group to large population.

Randomized controlled trials provide information about the natural history of a disease and evaluate the worth of a particular therapy. Moreover, they allow for the testing of biological hypotheses and, thus, provide a mechanism whereby the scientific method can be applied to clinical problem solving. Clinical trials play a major role in transforming the practice of medicine from an art to a science. Clinical trials are a vital component of the “search chain,” clinical trials are an essential link between the laboratory and the clinic and provide means for determining whether the laboratory findings can be used in treatment of patients. Without trials, much of the scientific information currently could not be evaluated for its therapeutic worth. When properly employed, clinical trials supply definitive information about the value of the therapies before their widespread use. Trials help to resolve current therapeutic uncertainties and to provide frameworks for future decisions. Through clinical studies, doctors find new and better ways to prevent, detect, diagnose, control, and treat illnesses. Clinical trials are extremely important in discovering new techniques to fight disease⁴.

Need For Clinical Trials

Though, we are getting impressive data through animal studies with respect to safety and /or efficacy for an experimental drug, human study can not be avoided as most of the diseases models developed in animals do not simulate the human diseases in aetiology, progression or prognosis.In animals, sometimes the metabolic enzymes involved may be different or the metabolites formed in-vivo could also be significantly different. In some cases, long-term use of drugs may give rise to some highly toxic effects like carcinogenesis that cannot be identified in animal studies during preclinical trials. For example, thalidomide tragedy. Hence the need of clinical trial aroused. Since the first priority in drug discovery is to ensure that the new drug is safe to patients, phase 1 clinical trial are meant for establishing safety in humans, by understanding the profile of the drug and its behavior in human volunteers and patients. Phase 2 trial concentrates on dosing for efficacy. Phase 3 trial is multicentric trial. When all these phases are successfully completed in statistically significant way, the drug can be approved for marketing. The drug is further evaluated through post-marketing surveillance studies to identify unacceptable adverse reactions. This is an accepted model of new drug development though not 100% fool proof⁵.

Role of Clinical Trials in New Drug Discovery

The process of discovering and developing a new medicine is complex and risky. It can take up to 15 years to bring a new drug to patients. At the same time, the pharmaceutical industry is one of the most regulated industries in the world and there are many government organizations that regulate what pharmaceutical companies do. It takes a long time for pharmaceutical companies to develop and test new drugs – on average it can take up to 15 years. This is mostly because each company is very careful to make sure that the benefits of the drug are greater than any risks. Pharmaceutical companies conduct clinical trials to test whether the drug can prevent, diagnose, or treat different diseases. A clinical trial is a test, or experiment, using a drug on people. Clinical trials are performed to find out if new drugs are safe and how well they work, and also to see if drugs would be effective for other conditions. There are many types of clinical trials, such as treatment trials, prevention trials, screening trials, and quality of life trials. These trials also allow clinical researchers to have early experience with the new drugs, as well as giving early access of potentially life-saving therapies to patients with serious conditions ⁶.

Phases of Clinical Trials

Phase I: The goal of this phase primarily is to provide information on acute tolerability and safety, dose-plasma concentration profiles, maximum safe doses and concentrations, routes of metabolism and elimination and initial estimates of the variability associated with these measurements.

Phase II: It aims to establish clinical efficacy and incidence of side effects in patient population define most appropriate dose schedule and provide detailed pharmacological data for optimum use of the drug.

Phase III: Here studies are done to check whether the treatment is effective, compare it with available and established treatment, and determine optimum dosage, frequency of administration, usefulness of drug in patients, safety of treatment and common adverse reactions of the compound.

Phase IV: These studies are designed to reveal adverse reactions related to prolonged usage, drug efficacy in long term use, new uses, an assessment of misuse or overuse liability, drug interactions and compatibility with other agents⁷.

New Advances in Clinical Trials

Today FDA’S main aim is to bring new drugs and medical products in market by using new diagnostic, imaging, and clinical evaluation techniques. These new "toolkit" include advances in basic sciences such as in bioinformatics, genomics, and imaging technologies. This should make drug discovery and development cheaper, faster, and more predictable. According to FDA, new medicinal compounds entering Phase I trials today, only an 8% of them reach the market. This is because of inability to predict safety and efficacy problem before human testing or early in preclinical trials. Hence drug development cost rises tremendously. Improving prediction of failure before clinical trials could save millions of dollars in development cost per drug. This has made possible by these new technologies like pharmacogenomics, proteomics, bioinformatics, and new imaging technologies would make it easier to weed out drug candidates destined for failure⁸.

Apart from the technologies like pharmacogenomics, proteomics, bioinformatics and others, new advances are emerging in clinical trials. Some of them are-

Model-based drug development- In these pharmaco-statistical models of efficacy and safety are developed from preclinical and clinical data, offers another significant opportunity to improve drug development decision-making. One industry expert predicts that the value of virtual trials is such that simulation results will eventually make their way into FDA submissions⁸. Clinical trial simulations can be considered as an example of model based drug development.

Clinical Trial Modeling and Simulations- In clinical trials a series of observations regarding pharmacological actions is made. These observations are then embedded in mathematical equations that account for these observations. Now a set of assumptions embedded in a mathematical equation regarding these observations is known as modeling. The drug action in most cases is described by the amalgamation of pharmacokinetics and pharmacodynamics. The connection between drug exposure and drug response can be explained satisfactorily with pharmacokinetic-pharmacodynamic modeling. This science has considerably developed in the past few years to a new method by which one can simulate clinical trials. This method gives the investigators good insight and “virtual” information about the analysis of the pharmacological observations of patients⁹. Clinical trial simulations has received more overwhelming recognition and use of late in drug development as various industries have adopted this method for product development because it is economical and time saving and improves overall efficiency¹⁰.

Internet- The clinical trials that are based on Internet show the relationship between the research based medical institutions and the technological advances in communication. This may well improve the speed and efficiency of the health care research¹¹. It Will Play a Greater Role in Trials Study shows trials on Internet can be successful and less costly. One new study indicates that technology will play greater role in future clinical trials. In one study, trials conducted over the Internet were found to cost half the amount of those conducted in more traditional settings, such as hospitals. Researchers from two Massachusetts university medical centers, Boston University and Tufts University, conducted a randomized trial to determine the effects of the nutritional supplement glucosamine on patients with osteo-arthritis of the knee. The trial had high participant retention and satisfaction rates. One of the disadvantages, however, was that consent and medical records, which are kept on paper, limited the speed in which patients were enrolled and slowed the progress of the trial, said the researchers. Overall, the study led the scientists to conclude that randomized controlled trials can, for the most part, be successful when conducted over the Internet¹².

Genomic technologies, like Gene Chip microarrays-these are a key ingredient in the change process. Innovative applications using Gene Chip arrays are transforming discovery and development. Some examples are Lead Optimization, Preclinical Trials, Clinical Trials, and Target Identification. The ability to generate sensitive and specific gene expression profiles has proven fundamental in the identification of drug targets. There are hundreds of examples where Gene Chip technology has been used to extend our molecular understanding of disease states, and to identify valuable gene targets The Gene Chip system has been successfully used to classify complex diseases, enabling researchers to identify genetic changes that are more likely to be causative and therefore better diagnostic indicators and possible therapeutic targets .The Gene Chip system is currently being used in a variety of clinical trials. RNA expression profiles can uniquely classify disease and assist in the prediction of clinical trial outcomes. The Gene Chip system provides you with the most comprehensive set of tools for performing RNA and DNA analysis during each phase of drug development research, from target identification through to clinical trials¹³.

Status of Clinical Trials In India

Clinical trials of biotech and medicinal products for approval purposes are done usually in hospitals in India. All types of hospitals carry out clinical trials, large and small as also municipal and government hospital. Large private hospitals and clinics too perform this work. The basic requirement is the presence of doctors who have an interest in this work.

On the basis of preliminary enquiries, there are already companies or agencies engaged exclusively for clinical trials in India. Major clinical trial services in India include-

Central Drug Research Institute (CDRI), Lucknow
Center for Cellular & Molecular Biology (CCMB), Hyderabad
Indian Institute of Chemical Biology (IICB), Calcutta
Institute of Microbial Technology (IMT), Chandigarh
OM-First Limited, Ahmedabad (Has office in London as well)
Quintiles Spectral Limited, Ahmedabad
Specialty Ranbaxy Limited, Andheri (East), Mumbai
Metropolis Health Services (India) Pvt. Ltd., Worli, Mumbai
Reliance Clinical Research Services (RCRS)

Clinigene International Private Limited (Clinigene) is a world-class Clinical Research Organization with strong clinical trial, regulatory and laboratory capabilities for drug development. Clinigene offers a wide range of comprehensive clinical research services including clinical studies and clinical trials and research¹⁴.The Drug Controller General of India has received 24 applications for conducting clinical trials for investigational new drugs IND in 1999-2000. Most of these applications have come from major multinationals and some Indian companies. Out of these, the Indian companies are: Ranbaxy Laboratories, Dabur India, Torrent, Cadilla, Dr. Reddy’s and Lupin. Pfizer, Johnson, Glaxo, SmithKline and Merck are among the multinationals that had applied for clinical trials in India¹⁶. In January 2005, the government of India passed a new rule that allowed foreign pharmaceutical companies and other research institutes to conduct trials of new drugs in India at the same time that trials of the same phase are being conducted in other countries. This new rule follows a directive of India's Drugs and Cosmetics Rules that required a "phase lag" between India and the rest of the world. According to the old rule, if a phase 3 studies had been completed elsewhere, only a phase 2 study was permitted in India. However, all the phase 1 trials are not permitted to be conducted in India. The old rule was basically used to protect Indians from being used like experimental guinea pigs for testing the various foreign drugs that were not as yet approved. In spite of thin new ruling the clinical trials of drugs discovered in India were not subject to this provision. ^{17, 18}

India at present recognizes only process patents. However, by 2005 by virtue of WTO rules, India will have to implement product patents. This will lead to widening of the market for indigenous (say, Ayurvedic products) as they will have the authenticity of internationally recognized product patents. Product patent protection will encourage multinational companies to import technology into India to develop new products. These developments will open up increased opportunities for the clinical trials of biotech and medicinal products¹⁴.

With the patent regime fast approaching, globally all Pharma companies are concentrating on new drug development. The estimated drugs in drug development have gone up from 4194 in 1997 to 7067 in 2002, which clearly indicates the trend and necessity for increased services requirement from CROs. Clinical research is undeniably in its infancy in India. If one wants to take clinical trials forward in India, we need to know the various players involved in a clinical trial. . This is where Contract Research Organization will play its role. A CRO involves the physician, the investigator, the supporting staff, the patient, the drug, the sponsor and finance²⁰.

CRO is a Contract Research Organization, offering clinical studies, monitoring, regulatory and compliance services for new drug development, medical devices and biologics and combination of products. CROs also provide clinical testing services to the pharmaceutical industry for prescription, consumer and over the counter medications¹⁵. Being part of the Reliance Group of Companies, India's largest private sector company, RCRS (Reliance Clinical Research Services) is mandated to emerge as an Indian-based, world-class contract clinical research services organization. RCRS is currently conducting several studies for clients based in the USA, UK, and Middle East¹⁸.

Advantages of Conducting Clinical Trials In India

Availability of a large population of treatment-naive patients: The patient from multiethnic and multiracial backgrounds.

Speed: As the patient recruitment is rapid in India, it reduces the clinical development process significantly.

Wide spectrum of disease: In India diseases such as multidrug-resistant pneumonia, hepatitis B, diabetes, and some cancers are far more prevalent than in the West.

Economy: The cost of conducting trials can be reduced up to 30-50% in India GATT/TRIPS/WTO: In 1995 the Indian government as part of the WTO agreed to adhere to the product patent regime by 2005. As part of TRIPS, the pharmaceutical industry will have the right to patent products as well as processes throughout the world, including India. Being a member of the GATT, India will have a process and product patent that will be consistent with the patent laws prevailing in the developed countries.

Investigators: They are mostly trained in Western Europe or the United States, and they now are experienced in participating in multinational trials according to ICH guideline for GCP.

Subject recruitment: Subject recruitment is the most common rate-limiting step in the drug development process. India offers sponsors the opportunity to recruit subjects quickly while maintaining a high level of quality. Subject compliance is an important aspect of clinical trials. Subjects generally recruited in the studies performed in India are not only treatment naïve but also recognize that study participation can offer access to quality health care and medicines that may not be otherwise affordable. As result, subjects are very compliant and are keen to attend all their study visits. An independent study by a global CRO concluded that India has one of the best subject return rates in the world.

A major resource center: Today India is identified as a major resource center for conducting clinical trials and data management services. With its large patient populations, well-trained and enthusiastic investigators, and per-subject trial costs considerably lower than those in developed nations, it is widely recognized as a major center for conducting clinical trials. Its increased regulatory control and its acceptance of the ICH guideline for GCP further enhance India's reputation as a place to conduct clinical trials ¹⁵.

References:

1. http://imaginis.com/breasthealth/clinical_trials.asp

2.U.S. Food and Drug administration: Inside clinical trials: Testing medical products in people, FDA Consumer magazine, September, 2003

3. http://www.healthandage.com/

4. Bernard F: The Importance of Clinical Trials, News from the Commission on Cancer of the American College of Surgeons, 2(2): 1991.

5.Nair MD: The role of clinical research in new drug discovery, 9, 2001.

6. http://www.affymetrix.com.

7.Bhat P, Velingkar VS: Drug Discovery- A General Overview, Indian journal pharm education., 37(2): 2003,94-99.

8.Ted Agres: FDA: New tools cut a critical path, Drug Discovery and Development, 2004.Available at http://www.keepindia.com.

9.http://www.centerwatch.com/career/PTi-trialsimulationv6B.pdf

10.Holford NHG, Kimko HC, Monteleon JPR: Simulations of clinical trials, Annual review of pharmacology and toxicology, 40(1): 2000,209-234.

11.Jenny A: Internet Clinical Trials: examining new disciplinary experiments in health care, Anthropology Matters Journal, 7(1): 2005.

12.U.S.Pharmacist:Internet will play a greater role in trials, Clinical news digest, Available at www.TheraDoc.com.

13.Clinical trial laboratories in India. Available at www.indiaonestop.com

14.Shastry VVLN: Potential trends of CRO industry: An analysis, pharmabiz.com, August 2004.

15.Francis PA: Clinical trials in India, Pharmabiz .com, June 2000.

16.Samiran N, Chir M, Gulhati CM: A New Colonialism? — Conducting Clinical Trials in India, The New England journal of medicine, 352, 2005, 1633-1636.

17.Banerjee A: In full run: Clinical trials to hit Rs 1,100cr in 3 yrs, New Delhi: The Economic Times., November , 2004, 5.

18.India Folio, Reliance Clinical Research Services go global, 5(5): 2004

19.http://www.indiainfoline.com/phar/feat/cro.html

S.P.Ingale*, S.R.Parakh, A.S.Paranjpe, P.L.Ingale

*Author for correspondance

S. P. Ingale

Lecturer in Pharmacology, MAAER, S Maharashtra Institute of Pharmacy,Ex-serviceman colony, S.No-124.MIT campus,Kothrud, Pune-411038

Email ID-: suvarnabhirud@rediffmail.com Mobile no.-: 9822493075

Dr. S.R. Parakh

Principal,Head of Dept.Pharmaceutics,MAAER, S Maharashtra Institute of Pharmacy,Ex-serviceman colony, S.No-124.MIT campus,Kothrud, Pune-411038

A. S. Paranjpe , B.Pharmacy Student, MAAER, S Maharashtra Institute of Pharmacy,Ex-serviceman colony, S.No-124.MIT campus,Kothrud, Pune-411038

P.L.Ingale , Lecturer in Pharmaceutical chemistry , Sinhgad Institute of Pharmaceutical Sciences,Kusgaon (Bk), Lonawala.Pune