1. INTRODUCTION:

Good clinical practice (GCP) is an internationally accepted ethical, scientific quality standard, used to design, conduct, record and report clinical trials that involve the participation of human subjects. It encompasses all aspects and facets of clinical trials, i.e. from the stage when the trials are initiated, right up to the stage where the clinical trial results are reported.

Compliance with these principles provides assurance that the rights, safety and well-being of subjects participating in clinical trials are protected, and the data generated from the clinical trials are credible.¹ GCP statute dates to one of the oldest traditions in medicine, The Hippocratic Oath, which is primarily known for its principle to cause no harm to the subject. However, modern medical research requires a more efficient set of guidelines to facilitate a healthcare professionals ethical as well as scientific responsibilities while involved in drug development and research.² Hence, GCP is a key requirement for personnel involved in the conduct of clinical studies and can be termed as a standard to which all research is conducted. The most fundamental ideology of GCP is that in research on human beings, the interest of science and the society as a collective should never take priority over the well-being of the subject involved in the study. Hence, it is considered necessary to conduct clinical trials per international council for harmonization, ICH/WHO clinical practice standards.^3,4

The two most prime tenets set down by the GCP guidelines are;⁵

· Protection of Human Subjects

· Authenticity and Reliability of the biomedical data produced.

These guidelines are purposed and aimed at ensuring that the clinical studies are ethically and scientifically secure and sound and that the properties of the drug or pharmaceutical substance under exploration are properly documented.

While GCP was only a recommendation in commercial studies at the time it was introduced, over the years, the importance of GCP has risen significantly and on1^stMay 2004, an EU Directive became applicable in Danish Law, which stated that GCP was no longer a mere recommendation but a legitimate requirement when carrying out clinical trials on new drugs and medical products.⁶ Clinical trials for medical devices, after this directive, were required to follow the ISO Standard: DS/EN 14 155 which is found to be equivalent to GCP for medical devices.

1.1. Advantages of GCP:

GCP has ensured that clinical studies conducted in different regions of the world are identical, by prescribing uniform standards for planning, conducting and reporting the studies. It has secured the privacy of subjects and has also protected the confidentiality of the biomedical data generated. The guidelines assure the public that the trials subjects are being treated with dignity and respect and that the wellbeing of the subjects outweighs the interests of the study itself. This has further helped motivate and encourage people to take part in clinical studies, without which the clinical studies could not have been initiated.

The GCP guidelines guarantee that the quality standards, followed at various trial conducting centers, are the same and that the results generated can extend an application to patients, irrespective of their gender, race etc.The establishment and acceptance of GCP guidelines have sent out a strong message to sponsors and investigators initiating new clinical trials to refrain from malpractices and misconduct, as such instances are likely to be detected rather quickly.⁷

From the view point of the drug development process, the enactment of GCP has resulted in reduced costs for pharmaceutical companies during drug development, which in turn has resulted in reduced costs for the healthcare fraternity.

2. HISTORY OF GCP:

It may be essential to comprehend the background of the development of the ICH-GCP principles. The present form of GCP has evolved through various revisions and amendments happened over a century, as discussed below.

2.1. The Federal Food and Drugs Act, 1906:

The motive of this act was preventing the manufacture, sale or distribution of adulterated or misbranded food or drugs. Although, the act was deemed as inoperative because of a fallacious declaration which was made regarding the drug by the manufacturer were held not to be mislabelled by the court, the act was not expanded to cosmetics and it was not given the authority to prohibit the use of hazardous drugs.⁸

2.2. Sulphanilamide Tragedy, 1937:

Sulphanilamide, it was a drug which was used to treat streptococcal infections, was seen to have a therapeutic effect and was safely used for a short period in the form of tablet or powder. Various scientific investigations proved that sulphanilamide would dissolve in diethylene glycol. It was found acceptable after the company control lab carried out trials on the mixture for flavour, appearance and fragrance and later the product was marketed as “Elixir of Sulphanilamide”. Instantly, the company formulated large quantities of elixir and sent shipments to all over the nations. The elixir which was newly compounded had not been tested for its integrated toxicity. No studies were conducted on the pharmacological activity of the new elixir preparation and hence because of this negligence, there was a failure in identifying the specific feature of the solution. Diethylene glycol, a chemical which is normally used as an antifreeze, deemed to be lethal, killing more than 100 people around 15 states after using a drug that was clearly unsafe.

This incident led to the enactment of food, Drugs and Cosmetic Act1938 , which increased the authority to regulate drugs.⁸

2.3. The Nuremberg Code, 1947:

It was designed because of the unethical and dreadful experiments which were performed on living person during the World War II at the Nazi war camps by the German scientist. Nuremberg code established the need for informed consent and clearly designed scientific experiments for the benefit of human participants allowing them to withdraw from the experiment at any time.⁹

2.4. Thalidomide Disaster of 1962:

Thalidomide was first marketed in 1957, in West Germany under the trade name Contergan. In 1962, a sleeping pill was manufactured and broadly used in many countries, was being investigated for use in the United States. Australian obstetrician Dr. William McBride found that the drug could be used for treating morning sickness in pregnant women. He started prescribing the drug to his pregnant patients and set up a trend. There were severe birth defects in the babies he delivered which was probably due to the intake of the so-called harmless compound. He later discovered that the drug caused serious injury to the foetus when it is taken by a pregnant woman during the first trimester of pregnancy. Children were born without a limb or any severe deformities.⁸

2.5. Declaration of Helsinki:

The world medical association, evolved declaration of Helsinki in 1964. It formed the basic structure of the ethical principles that fundament the ICH-GCP guidelines which we have been practicing today. The purpose behind the declaration of Helsinki is to provide advice to the physicians who are engaged in clinical trial and its focus was the responsibilities of an investigator for the protection of rights of a human volunteer participating in the clinical trial.¹⁰ The register is considered as a humanitarian approach even though the declaration of Helsinki is the responsibility of world medical association.

3. INTERNATIONAL VIEW ON GCP:

GCP is considered as an international standard since enormous experiments are conducted not only in several centers but also in multiple nations, examiners attentiveness in abiding GCP can mean the distinction between a safe and effective trial and inappropriately- developed, a failed trial which may take time and materials but produce unacceptable data.

Using a specified and defined protocol the investigators from various countries may register participants in a trial. The results obtained from the clinical trials can be merged into a single study only if all the investigators in each country follow the same guidelines. If a researcher likes to work on large experiments he should comply with the GCP before he is being invited to participate. GCP principles are revealed, explained and categorized in various places and this lead to the interpretation of the guidelines. Compliance with GCP means developing, adopting SOPs into every aspect of research. As per the US, Investigational New Drug Application (IND) each examiner who is involved in conducting the clinical research is required to sign Food and Drug Administration (FDA) form 1572 quoting that the individual will comply with GCP. It is necessary that the form should be signed only after understanding the responsibilities of the principal investigator. The responsibilities include the regional conduct of trial and reporting requirements as stated by FDA and the sponsor involved in the clinical trial. The principal investigators work as a team for conducting clinical research. The team members are given the permission to conduct a specific task by the principal investigator in the form of a written procedure.¹¹

The FDA monitors the systematic studies which are developed to provide evidence and to support the productiveness, potency and safety profile of experimental drugs, biologicals and medical devices. The studies must be conducted by a qualified scientist or expert and should comply with the rules and regulations. The sincerity of data obtained in a clinical trial on product approvals is ensured by these laws and rules. And they are intended to protect the rights, safety andwell-being of human subjects participating in the clinical trial.¹²

3.1. Difference between ICH-GCP and WHO-GCP guidelines:

The ICH-GCP guidelines were framed by the same experts in same parallel manner and hence they are basically similar. The ICH -GCP was designed to promote harmonization in the three prominent ICH regions namely the US, Japan and EU to meet the technical requirements for the registration of pharmaceuticals for human use. The WHO-GCP was developed as an instructional tool for less accomplished pharmaceutical agencies in nations where there was no existence of any other guideline. The main difference in ICH-GCP and WHO-GCP is that the ICH-GCP is comprised of 13 principles and the WHO-GCP is comprised of 14 principles. Principles 5 and 6 in WHO-GCP are combined in ICH-GCP. Apart from that, there is a slight change in the order of principles. GCP is GCP no matter whether it originates from International Council on Harmonisation (ICH) or World Health Organisation (WHO).¹³

4. PRINCIPLES GOVERNING GCP:

The creation of GCP guidelines not only intended to protect the rights and safety of the study subjects but was also intended to serve the interests of all parties involved in the clinical research. The basic principles governing the concept of GCP are as follows:⁹

Ÿ To assist and stimulate the attainment of a unified standard, at a global level, for the conduct of clinical research studies on human beings.

Ÿ To act as an educational tool for personnel interested in clinical research or for clinicians already engaged in research, by furnishing the requisite information with respect to the requirements of GCP and its efficient implementation.

Ÿ Assist clinical research editors to assess the acceptability of the research submitted for publication, and to enable regulatory personnel to evaluate studies that may affect the use and registration of certain medicinal products.

Ÿ To provide a general summary and any other necessary advice on how to apply and how to implement globally accepted GCP principles for clinical research in human beings.

While the basic principles of GCP mentioned above, give a brief sense of the essence of GCP, a highly specific set of core principles established by the WHO in 1995 give an extensive idea of the intent and purposes of GCP. These core principles are as stated below:¹⁴

1) The ethical principles established by the Declaration of Helsinki should be strictly adhered to when carrying out research in human subjects. The three ethical principles namely justice, respect of public and beneficiary, shall be considered above all other GCP principles.

2) All research involving human subjects should have scientific reasoning and should be reported in a detailed, extensive protocol.

3) Any foreseeable risks and potential side effects along with the potential benefits should be intimated to the trials subjects.

4) Clinical studies involving human participation shall be carried out only if the benefits that are anticipated from the studies far outweigh the potential risks.

5) The intended research can be carried out only after obtaining the go-ahead from the institutional review board or the independent ethics committee.

6) The protocol shall be approved prior to initiating the clinical trials.

7) Voluntary informed consent shall be obtained from the trial participants as per national requirements. Incase of pediatric or geriatric patients or when the trial subject is not capable of giving the consent by himself, the consent form can be received from a legally authorized representative.

8) Research studies inculcating human beings, as trial subjects, should be allowed to carry on as long as the risk-benefit analysis remains appropriate and conducive.

9) The medical care of research subjects shall be the responsibility of qualified medical personnel (physician, dentist etc.)

10) Individuals who work on clinical trials as well as other personnel involved in conducting trials shall have requisite qualifications and shall also be adequately experienced in the same.

11) All research data gathered and generated should be recorded and stored in order to ensure accurate reporting, verification and analysis.

12) The privacy of trial subjects shall not be disclosed and shall be closely guarded by maintaining the confidentiality of the reports generated.

13) Good Manufacturing Practices shall be strictly implemented in case of investigational product manufacture, handling and storage.

14) Strategies shall be put in place in order to execute processes that ensure the caliber of every facet of the clinical trial.

5. GOOD CLINICAL PRACTICES IN INDIA:

5.1. GCP and Human Experimentation:

In any field affecting human beings, thorough studies are considered essential to provide data that can help improve the adverse conditions for human beings. This, in turn, demands motivation and encouragement at multiple levels of engagement. The healthcare sector in India has seen ‘research’ add problems and complexities to an already convoluted system, by calling for experimentation on human beings that may expose the subjects to adverse reactions and risks. However, the necessity of these experiments is realised by the society, and hence these researchers are considered acceptable as long as the subjects taking part are safeguarded from the adverse effects. In a nation like India, instead of building a sense of altruism and trust in them, industrial entities are busy cutting corners and providing false data in order to reduce costs and generate higher revenue.¹⁵ Hence, ethical issues are of utmost importance when it comes down to conducting research on human beings. Ideally, clinical trials should be conducted by making the society a true stakeholder in the research process and by winning the trust of the society as a collective, which will encourage further public participation in such research studies or trials. The society must become familiar with the clinical study concept, which can only be achieved if the entire process of conducting the study is crystal clear and transparent.Though the Indian clinical trial scenario is termed as one of the best in the world as of now, it is not as uniform across a defined standard as one would desire. Therefore, it was realised that global trust as well as the trust of the local society, in the Indian clinical scenario, will only be possible when stringent GCP rules are brought into effect.

5.2. The Guidelines:

CDSCO Guidelines:

India has been globally recognised as a nation that offers unique and distinct opportunities for carrying out clinical trials due to the existence of a large patient population, well experienced investigators and leading medical institutions along with the added benefit of low costs per patient used, in contrast with the developed countries. Nonetheless, changing times necessitated the establishment of our own Indian guidelines for GCP in order to provide a steady quality to clinical research studies initiated all over the country. Working towards this goal, an expert committee was set up by the CDSCO, which was provided able support by clinical experts from different parts of the country, to formulate the first recognised document for GCP in India in 2001, which was tailored to Indian requirements. The DTAB, the highest technical body as per the Drugs and Cosmetics Act, strongly endorsed the adoption of these GCP guidelines by the pharmaceutical industry, to help carry out well organised clinical studies in India. These guidelines were constituted keeping in mind already well established and document GCP guidelines like the WHO, USFDA, ICH-GCP and the EU GCP guidelines. Apart from these, inspiration was also drawn from the ICMR Guidelines for Biomedical Research on Human beings.¹⁶

These guidelines have specified ten ethical principles, all of which are in strict accordance with the most current revision of the Declaration of Helsinki. The ten core principles of the Indian GCP document have been established more or less along the same lines as the GCP guidelines of developed nations and encompass various facets such as informed consent, community agreement, non-exploitation of subjects, subject privacy and confidentiality, risk minimisation, accountability and transparency of investigators and sponsors, and above all, the principle of essentiality, which states that research trials should make use of human subjects only when it is absolutely essential and when any other alternative is unavailable.¹⁶ These guidelines necessitate the formation of an Independent Ethics Committee, which will be responsible for checking the suitability of the Protocol, Reviewing the methods and documents submitted by the sponsors with regards to subject recruitment and also check the authenticity of the Informed Consent forms signed by the trial subjects prior to participating in the trial. The Ethics Committee will initiate an ongoing review and will continuously monitor the clinical trial studies, to ensure compliance of Ethics. The Indian GCP guidelines specify the composition of an Ethics Committee and also mention that any institution can include its members, members from outside institutions or communities if required, when setting up the Ethics Committee.

ICMR Guidelines:

In biomedical research, constituting a standard set of quality guidelines provides credibility to the results generated and also provides the opportunity to accommodate comparisons between clinical studies carried out in different institutions, both locally and globally. This saves a tremendous amount of time, resources, money and at the same time prevents plagiarism or replication of research work carried out elsewhere. Registering the incredible pace and the monumental potential for clinical research in India, the ICMR introduced the Ethical Guidelines for Biomedical Research on Human Subjects in the year 2000 to provide guidance to researchers carrying out biomedical research in India with regards to Ethical practices. At the time of establishing the guidelines, it was decided to conduct a periodic revision of the guidelines. Subsequently, these guidelines were subjected to revision in 2006 to keep abreast with current trends and developments. Certain points in the international guidelines provided for biomedical research, that are relevant to research institutes of international collaboration, have been inculcated in this version. The intent behind periodic revisions is to update the scientific community at large about most recent concepts of bioethics. The exercise of periodic revision is one that is seen in most of the developed countries and is also being undertaken by the emerging developing countries.¹⁷

5.3. CHALLENGES FACED BY GCP IN INDIA:

Just as is seen in the case of most systems operated on a large scale, the GCP system in India too has come across a multitude of problems with respect to the conduct of clinical trials. One of the most common problems encountered is the lack of commitment of clinicians towards conducting proper clinical studies. Certain clinicians, due to their busy schedules, find it difficult to accommodate time for conducting thorough clinical research. In some cases, clinicians cannot even commit to monitoring visits. In such cases, they assign their duties to their colleagues who might be misinformed or may have incomplete knowledge with regards to the trial. A co-ordination breakdown between the investigators and their respective assistants or other personnel can result in the improper conduct of tests.¹⁸ Nonetheless, such difficulties can be overcome provided that the clinicians responsible are willing to put more effort and dedicate more time to the research studies. Also, if India as a nation, is to remain competitive in the modern-day scenario with respect to clinical research conduct, then we must work towards achieving international standards and attaining international recognition for the successful implementation of a dynamic GCP system.

Another glaring issue that requires immediate addressing is the issue of quality and documentation.¹⁹ Many FDA inspections in recent times have unearthed the fact that several sites in India for conducting clinical trials can improve their quality if they choose to pay closer attention to particular areas. Protocol non-compliance, inaccurate records, informed consent problems, adverse event reports see the highest number of quality lapses. In terms of documentation in general, Indian pharmaceutical industry players need to appreciate the value and practice of a meticulous and detailed process.²⁰ Because documentation represents a written record for GCP concurrence. Based on the maintenance of requisite documentation, an institute or an organisation can be deemed to be compliant with the norms stated by GCP guidelines.

Impact of the media and negative reports by the professional press may diminish the trust, support of the public and hamper their participation in clinical trials. To state an example, a popular medical information website once quoted in an article, “Human beings have become a source of experimental animals in India and are being exploited irrationally. Due to rigorous and exhaustive Animal guidelines, the use of animals in India has become a major problem and hence, pharmaceutical companies have shifted their attention to human beings as a replacement for animals, to conduct their studies on.”²¹ In most cases, reports tend to lay an emphasis on only the negative aspects of the data. The Indian people have personal interests on the line with respect to the implementation of a successful and indigenous clinical study environment as such a progressive study environment will bring treatments into the market that will be conducive to their respective needs, and will also support an efficient health care system for the nation which will in turn spur the nation’s economic growth. Hence, media houses engaging in negative press reporting with respect to the clinical study rules and regulations and the GCP guidelines will seriously hamper the development of new drugs which will have a direct effect on public health. In addition to this, rising number of instances of unethical practices in clinical research, which are further sensationalized by the media, has led to sponsors looking at other countries as options for conducting clinical research. International, as well as Indian pharmaceutical companies, are shying away from India and developing new pharmaceuticals in other countries.

In a period of 5 years, from 2008-2013, reportedly, India witnessed the death of as many as 2,262 patients registered for clinical trials. This led to a massive public uproar and also raised questions as to how such clinical trial related deaths were occurring, in-spite of having stringent Ethics and GCP guidelines in place. In the end, the Supreme Court intervened, stating that “Uncontrolled clinical trials are causing havoc to human life” and stressing the need to put in place even stricter regulations and norms for conducting clinical trials and to keep a check on the investigators and sponsors conducting clinical trials. The court also questioned the Health Ministry for its inability to stop the use of public as “Guinea Pigs”in the carrying out of clinical trials.²² Additionally, the court also mandated the pharmaceutical industry to provide adequate compensation to the patients participating in clinical trials, as it was observed that, in India, the companies at times, failed to disburse compensation to the patient for putting himself/herself through the risks involved in the experimental procedures.

5.4. SCOPE OF IMPROVEMENT:

The significance of clinical trials in contributing to health services cannot be overemphasized. The lifespan and wellbeing of humans can be improved by the development of new medicament and treatment. With increasing authority, there is a growing requirement for better operation of the system so that research subjects are protected and ethical clinical research, which is the need of the hour in our country, is promoted. Postgraduate teaching institutions must be encouraged to conduct clinical research that is at par with international standards in terms of quality.²³

Responsibilities of ethics committee:

Standard operating procedures (SOP) and a body of fundamental principles should be formulated by the institutional ethics committee. This should include representatives, terms and conditions of nomination, the workplace and quorum requirements. The official procedure, informed consent forms, case record forms, inclusion/exclusion criteria and other source documents regarding the trials are reviewed by the ethics committee. The standard operating procedures must be checked and reviewed regularly. The reviews done by the ethical committee should be free from bias and any sort of influence. The committee should mainly focus on safeguarding the rights, dignity, safety and well-being of the research subject participating in the proposed clinical trials. The committee should ensure that the oversight mechanism is in place (site visit, internal audit, examining the ongoing trials). All the source documents related to the proposed trial must be retained for a minimum of 5 years after the trial is being completed.

Responsibilities of sponsor:

A person or organization which takes responsibility for the initiation, management or financing of a clinical trial is known as a sponsor. When a sponsor transfers clinical trial data to a scientific body or a contract research organization (CRO), stringent measures shall be in place to ensure that any such transfer of data is well recorded and documented. It is the responsibility of the sponsor to ensure that the investigator who is conducting experiments on human subjects is qualified, trained, experienced to conduct the trial. Approval to conduct the clinical trial should be obtained from the Drug controller general of India (DCGI) and institutional ethical committee. Their active participation is necessary for monitoring the data, regulatory reporting and financing.

Responsibilities of investigator:

A clinical investigator involved in a trial is responsible for ensuring that an investigation is conducted per the signed investigator statement, investigational plan and applicable regulations, for protecting the safety, dignity and well-being of potential research participants. The sponsor and the investigator should establish an agreement on protocol, SOP, monitoring the safety, audit procedure, and allot the trial related responsibilities prior to initiation of the trial. An informed consent from each research `participant is a compulsory requirement for a clinical trial. The investigator is expected to report any serious adverse events which take place during the trial within a fixed timeline. The protocol must be followed diligently by the investigator, ensuring that all the individuals promoting the study are aware of obligations and are trained. The investigator is not allowed to perform more than three trials at a time.²⁴

6. CONCLUSION:

Good Clinical Practices in India have come a long way, from being mere ideological concepts to being a set of well-organized and methodical guidelines. They have helped establish and maintain the highest standards with regards to the planning and conduct of clinical trials.The Indian GCP guidelines, governing clinical trials are now at par with internationally followed GCP guidelines. However, taking into consideration the vastness of the country and the enormous population size, the necessity for impartial supervision by efficient and regulated bodies is paramount. It should also be noted that a transparent monitoring system shall be in place, which can be assured by bringing clinical trials results under the domain of the RTI i.e. the Right to Information Act.By emphasizing on the upgradation of already existing infrastructure and control measures in place through an extensive and coordinated programme of clinical research education, a clinical trial environment of zero-tolerance to non-compliance with GCP guidelines can be created.

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Received on 07.02.2018 Modified on 26.03.2018

Research J. Pharm. and Tech 2018; 11(7): 3209-3215.

DOI: 10.5958/0974-360X.2018.00590.5