Ø Quality (Q) that is those relating to chemical and Pharmaceutical quality assurance.

Ø Safety (S) that is those relating to in vitro and in vivo preclinical studies.

Ø Efficacy (E) that is relating to clinical studies in human subject.

Ø Multidisciplinary topics (M), that is cross – cutting topics which do not fit uniquely into one of the above categories.

Table No.1 Quality topics

Q1	Stability
Q2	Analytical Validation
Q3	Impurities
Q4	Pharmacopoeias
Q5	Quality of Biotechnological products
Q6	Specifications
Q7	GMP for APIs
Q8	Pharmaceutical development
Q9	Quality Risk Management
Q10	‘Quality Management’ agreed ‘in principle’

THE ICH:

The international conference on harmonization of technical requirements for the registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a tripartite venture representing regulatory bodies and research – based industry. The major aim of ICH is to provide a forum for constructive discussion on the real and perceived differences in technical requirements for the registration of new chemical entities.

Other Objectives:

To achieve greater harmonization in the interpretation and application of technical guidelines for the registration of mew active substances of products obtained by biotechnology by its members.

Ø To improve the efficiency of global drug development.

Ø To reduce redundant studies

Ø To improve pharmacovigilance activities and quality assurance.

DETAILS OF ICH:

ICH thus represents 17 countries comprising 15% of the world’s population and accounting for 90% of the us 320 billion global Pharmaceutical sales of the year 2000. ICH regulatory authorities are among the first to evaluate new chemical entities and new products obtained from biotechnology.

The international federation of Pharmaceutical Manufactures Associations (IFPMA) provides the ICH secretariat. WHO, Canada and European free trade Association (EFTA) hold observer status in ICH and its steering committee.

To date, ICH has produced more then 45 guideline describing technical requirements related to specific components of specialists from drug regulatory process, drawn up by groups of the drug regulatory authorities and the Pharmaceutical industry of the ICH countries. The scientific level of each guideline is high and reflects state-of-the art technology. The cost related to toll implementation of the guidelines may in some cases be considerable but it is argued, this is offset be more rapid registration of new drugs in the ICH countries.

The current ICH terms:

v To maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the technical registration fro product registration in the EUI USE and Japan in order of ensure a more timely introduction of new medicinal products and their availability to patients

v To contribute to the protection of public health from an international perspective.

v To monitor and update harmonized technical requirements leading to a greater mutual acceptance of research and development data.

v To avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies fro the production of medicinal products.

v To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices where these permits a more economical use of human animal and material resources, without compromising safely.

v To facilitate the dissemination and communication of information on harmonized guidelines and their use such for encourage the implementation and integration of common standard.

PRODUCTION OF ICH GUIDELINE:-

The process of production of a harmonized ICH guideline consists of several steps.

Step 1: An initial draft of the guideline is prepared by the ENG and circulated through successive revisions until a consensus is reached. The draft is then forwarded to the steeping committee.

Step 2: When the steering committee agrees that there is sufficient scientific consensus on the technical issues for the draft guideline or recommendation to proceed to the next stage of regulatory consultation.

Step 3: Draft guideline leaves the ICH bodies and becomes the subject of regulatory consultations in the three ICH regions. An opportunity is also offered to industry associations and regulatory authorities in non-ICH countries to comment on draft documents, which are distributed using IFPMA and who contact lists.

Step 4: Final text of the guideline is prepared by the EWG and submitted to the steering committee fro adoption, which takes the form of signature by the three regulatory parties to ICH affirming that the guideline is recommended for adoption thought the regions.

Step 5: The tripartite harmonized text moves immediately in to the final step of the process which is its regulatory implementation. This is carried out according to separate national/regional procedures identical to those that apply to the endorsement of other regulatory decisions in the EU, Japan and the USA. The importance of final step should be stressed and only then do individual guidelines become effective in the countries concerned.

GOOD CLINICAL PRACTICE GUIDELINES (GCP):

The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and world health organization (WHO).

This guideline should be followed when generating clinical trial data are intended to be submitted to regulatory authorities.

The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety dwell-being of human subjects.

HISTORY OF GCP- MILESTONES IN THE EVOLUTION OF GCP:

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the Principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

The present day guidelines on Good Clinical Practice have evolved through a series of regulations and policy formulations. The major milestones in the evolution of GCP are as follows:

Table 2 Major Milestones in the Evolution of GCP

Federal Food and Drugs Act	1906
Sulfanilamide Disaster	1937
Food, Drug and Cosmetic Act	1938
Durham-Humphrey Amendment	1951
The Nuremberg Code	1946
Thalidomide Disaster	1962
Kefauver-Harris Amendments	1962
Declaration of Helsinki	1964
Medical Device Amendment	1976
Good Clinical Practice	1996
ICH - Good Clinical Practice (GCP)	1997

1. Federal Food and Drugs Act of 1906:-

The purpose of the Federal Food and Drugs Act is to prohibit adulterated or misbranded food or drugs from interstate commerce. The Act originally enacted in 1906 brought "Truth in Labeling".

However, the 1906 Act was considered inadequate because:

1. False statements made about a drug by a manufacturer were held by the courts not to be misbranding.

2. The act did not extend to cosmetics.

3. The act did not grant the authority to ban unsafe drugs.

In 1912, Congress cured the false statement problem and included within the definition of misbranding false or fraudulent claims for the curative powers of drugs.

2. Sulfanilamide Disaster of 1937:-

Sulfanilamide was widely hailed as the first of the "miracle drugs". Every soldier was trained to sprinkle a wound with "sulfa powder" to prevent infection. The anti-infective properties of the drug appeared limitless. A manufacturer decided to market the drug in a liquid form for sore throats but the problem was it does not dissolve in water or alcohol. The chemist discovers that it dissolves in sweet tasting solvent: di ethylene glycol- the same stuff one uses today as antifreeze in car radiators. Di ethylene glycol had, it seems, a pleasant color-light pink- and a not unpleasant taste. It was also, of course, a deadly poison. No clinical tests were made prior to marketing. Presumably, some chemist somewhere must have stuck his finger in a batch, licked off the results, and approved the taste prior to marketing effort. There were 107 reported deaths from this product. Predictably, new legislation was passed the following year - Food, Drug and Cosmetic Act of 1938.

3. Food, Drug and Cosmetic Act of 1938:-

The public furor over the sulfanilamide disaster finally resulted in a legislative demand for safety. The new act required that drugs be adequately tested for safety. Because all drugs are to some degree harmful infused contrary to common sense or the manufacturer's intent, "safe" meant nontoxic when used in accordance with the conditions set forth on the label.

The term label is a term of art. It means "a display of written, printed, or graphic matter upon the immediate container of any article". The law requires that if certain information is required to be on the label of a drug, the information must also be on the outer container or wrapper of the retail package, or the inner label clearly visible through such outer wrapper. The law can, for instance, require that certain information accompany a drug as part of its labeling (a package insert) while not requiring the information to appear on the drug's label.

This new law, in addition to requiring proof of safety, expanded the meaning of adulteration and misbranding that previously had been strictly construed by the courts. Labels were now required to provide adequate directions for use to the consumer.

4. Durham-Humphrey Amendment of 1951:-

The Durham-Humphrey Amendment of 1951 exempted certain drugs from the requirement that their labeling contains adequate directions for use. These drugs, which could be taken safely only under medical supervision, were exempted provided they were sold pursuant to order of a licensed prescriber or administered under a prescriber's supervision. This amendment provided that such an exempt drug, instead of adequate directions for use, must have on its label prior to dispensing the words or legend "Caution: Federal law prohibits dispensing without a prescription ".

5. The Nuremberg Code of 1946:-

The Nuremberg Code includes 10 principles to guide physician-investigators in experiments involving human subjects. These principles, particularly the first principle on "voluntary consent", primarily were based on legal concepts because medical codes of ethics existence at the time of the Nazi atrocities did not address consent and other safeguards for human subjects. "Societal necessity" to protect soldiers and civilians from the ravages of wartime conditions invoked also in the United States during World War II and later during the cold war- was advanced by the Nazi physicians asa justification for conducting experiments to find immediate answers to pressing problems, but they did not offer any justification for the brutal ways in which the research had been conducted.

The need to define the basic principles for the conduct of human research was focused towards patient protection and made no distinctions between research with patient-subjects and healthy persons, be they prisoners or volunteers.

In Germany the Nuremberg Code is regarded as a guideline for medical research. Many of the principles are still valid today, i.e. the necessity of informed consent, the rule that the patient can withdraw from the experimentation at any time and the ban against experimentation that in any way could result in major injury or death of the experimental subject. The 10 principles of Nuremberg are rarely applied nowadays is due mostly to the fact that they do not distinguish between therapeutic and purely scientific experimentation and that they have been superseded by the Revised Declaration of Helsinki of the World Medical Association.

6. Thalidomide Disaster of 1962:-

In 1962, thalidomide, a sleeping pill developed and widely used abroad, was being studied for use in the United States. William S. Merrell Company of Cincinnati was using the drug investigationally when it was discovered that the drug could harm a fetus when taken by a pregnant woman during the first trimester of pregnancy. Children born to such mothers often were born without arms or with other severe deformities. Whatever else may be said about the thalidomide disaster, drugs, all drugs, were publicly unfrocked. It was clear that people were taking drugs and neither the prescriber nor the manufacturer had a clear know ledge of their effects.

Under these circumstances, The Durham- Humphrey 1951 Amendment was simply inadequate to protect the public. A series of lawsuits demonstrated that by and large prescribers had been relying on manufacturers for their information about drugs, and that information in some instances had been based on inadequate testing and, in one or two celebrated cases, on deliberate falsification and deception. This resulted in Kefauver-Harris Amendments of 1962, which addressed the issue of effectiveness and safety.

7. Kefauver-Harris Amendments of 1962:-

These amendments, generally referred to as the drug efficacy amendments, were in reality much broader in scope. They provided for registration of manufacturers and inspection of manufacturing sites, and they required an unprecedented program of accountability from manufacturers.

1. Before marketing any new drug, manufacturers were required to supply:

a) Proof of effectiveness, and

b) Proof of safety.

2. Good Manufacturing Practices, the so-called GMP, were established, and if a manufacturer produced a drug without adhering to such practices, that drug was considered adulterated.

3. Prescription drug advertising was placed under the supervision of the FDA, while the FTC continued to supervise the advertising of over-the-counter (OTC) items.

4. The amendments established a procedure for new drug applications and for investigational drug procedures, which required assurances of the informed consent of the research subjects and required reporting of adverse drug reactions. Qualifications of drug investigators were subjected to review.

8. Declaration of Helsinki, 1964:-

The World Medial Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.

Declaration of Helsinki was adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002. Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004

The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will be my first consideration", and the International Code of Medical Ethics declares that, " A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient". Declaration of Helsinki laid down the Ethical Principles for Medical Research Involving Human Subject and is a major landmark in the evolution of Good Clinical Practices (GCPs).

9. Medical Device Amendment of 1976:-

In 1976, medical devices that previously had been subject to control only under the general adulteration and misbranding sections of the Food, Drug, and Cosmetic Act of 1938 (FDCA), were subjected to extensive new requirements. In order to keep pace with a rapidly expanding medical and scientific technology, devices were classified, and subjected to varying degrees of control depending upon an evaluation of their function. For the first time, the safety and effectiveness oflife-sustaining and life-supporting devices are now required to have pre-market approval of the FDA

10. Good Clinical Practice:-

Good Clinical Practice is a set of guidelines for biomedical studies which encompasses the design, conduct, termination, audit, analysis, reporting and documentation of the studies involving human subjects. The fundamental tenet of GCP is that in research on man, the interest of science and society should never take precedence over considerations related to the well being of the study subject. It aims to ensure that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical substances under investigation are properly documented. The guidelines seek to establish two cardinal principles: protection of the rights of human subjects and authenticity of biomedical data generated.

11. ICH - Good Clinical Practice (GCP) of1997:-

The Food and Drug Administration (FDA) has published a guideline entitled "Good Clinical Practice: Consolidated Guideline". The guideline was prepared under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guideline is intended to define "Good Clinical Practice" and to provide a unified ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

The objective of the ICH-GCP Guidelines is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

These guidelines should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well being of human subjects.

Table 3: GCP Participants

Regulatory Authorities	Review submitted clinical data and conduct inspections
The sponsor	Company or institution/organization which takes responsibility for initiation, management and financing of clinical trial
The project monitor	Usually appointed by sponsor
The investigator	Responsible for conduct of clinical trial at the trial site. Team leader
The pharmacist at trial location	Responsible for maintenance, storage and dispensing of investigational products eg. Drugs in clinical trials
Patients	Human subjects
Ethical review board or Committee	Appointed by Institution or if not available then the Authoritative Health Body in that Country will be responsible.
Committee to monitor large trials	overseas Sponsors eg. Drug Companies

THE PRINCIPLES OF ICH-GCP:

1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

2. Before a trial is initiated, foreseeable risks and inconveniencies should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated. Benefits justify the risks.

3. The rights, safety, and well being of the trial subjects are the most important considerations and should prevail over interests of science and society.

4. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5. Clinical trials should be scientifically sound, and describes in a clear, detailed protocol.

6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.

7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task.

9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement( s).

12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Table 4: Reasons for GCP

Increased Ethical Awareness

Improved Trial Methods

Clinical Trial Concept Better Understood

Public/Political Concern over Safety Aspects

Frauds and Accidents during Trials

Growing Research and Development Costs

Increasing Competition

Mutual Recognition of Data

New Market Structure

APPLICABLE GCP GUIDELINES:

The applicable GCP guidelines that govern the conduct of Clinical trials in India include:

1. ICH -GCP Guidelines, 1997

2. Ethical Guidelines for Biomedical Research on Human Subjects,

2000 (ICMR Code)

3. Schedule Y (Amended Version - 2005)

1) ICH-GCP Guidelines, 1997

The Food and Drug Administration (FDA) has published a guidelines entitled "Good Clinical Practice: Consolidated Guideline". The guideline was prepared under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guideline is intended to define "Good Clinical Practice" and to provide a unified ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

2) Ethical Guidelines for Biomedical Research on Human Subjects,

2000 (ICMR Code):-

Indian Council of Medical Research, New Delhi has issued the statement of Ethical Guidelines for Biomedical Research on Human Subjects also known ICMR Code, in the year 2000.

These guidelines include statement of general and specific principles on research using human subjects in biomedical research. The statement of general principles include following principles:

Ø Principles of essentiality

Ø Principles of voluntaries, informed consent and community agreement

Ø Principles of non-exploitation

Ø Principles of privacy and confidentiality

Ø Principles of precaution and risk minimization

Ø Principles of professional competence

Ø Principles of accountability and transparency

Ø Principles of the maximization of the public interest and of distributive justice

Ø Principles of institutional arrangements

Ø Principles of public domain

Ø Principles of totality of responsibilities

Ø Principles of compliance

The statement of specific principles includes guidelines for clinical evaluation of drugs, vaccines, devices, diagnostics and herbal remedies etc.

3) Schedule Y (Amended Version - 2005):-

Schedule Y (Amended Version - 2005) contains Indian Good Clinical Practice Guidelines. These guidelines for clinical trials on pharmaceutical products in India have been evolved with consideration of WHO, ICH, US FDA and European GCP guidelines as well as the Ethical Guidelines for Biomedical Research on Human Subjects issued by the Indian Council of Medical Research (ICMR).

The Drug Technical Advisory Board (DTAB), the highest technical body under Drugs and Cosmetic Act, has endorsed adoption of these GCP guidelines for streamlining the clinical studies in India. These guidelines should be followed for carrying out all biomedical research in India at all stages of drug development, whether prior or subsequent to product registration in India.

CONCLUSION:

The importance of GCP lies in the question ‘why’ and ‘how’ GCP trials came about. To know the answer to this, we have to look to the historical background that led to the formulation of GCP guidelines in the United States and Europe and also to the formation of the ICH. The events that led up to the culmination of the ICH-GCP guidelines brought forth public awareness that there was a need to control and regulate clinical trials dealing with drugs and human subjects. The violation of human rights played a large role and that is why the Declaration of Helsinki and The Nuremberg Code remain as the framework of the present guidelines. The ICH-GCP guidelines are therefore considered the ‘bible’ of clinical trials, and have become a global law which safeguards humanity as we know it today.

REFERENCES:

1. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Annex 3 of The Use of Essential Drugs Sixth report of the WHO, Expert Committee. Geneva. World Health Organization, 1995: 97–137.

2. ASCO outlines minimum standards and exemplary attributes for research sites: Previews tools to be provided. J Oncol Pract 4:185-187

3. Singh S. International Conference on Harmonisation an update. The eastern Pharmacist. 1998:61:42-43.

4. Artiges A, Sheinen E, Potter C, Tanimoto T, editors. Pharmacopoeial Harmonisation. Proceedings of the 6^th International Conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

5. Yetter R, editor. Partnership in Harmonisation. Proceedings of the 6^th International Conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

6. Amitava Roy, A Ghosh, the sixth international conference on hormonisation (ICH6)-A Promising Future in Global Pharmaceutical Industry, Research J.Pharm.and Tech. I (3): July-Sept.2008 pg no.161-165.

7. S.D.Seth, Madhu khanna, Hand Book of Good Clinical Practice (GCP): Guidance for implementation, Indian J Med Res 125, May 2007, pp 701-704.

8. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva, CIOMS, 1993, Annex 1.

9. Christley HM. (1998) Conducting Clinical Trials in South Africa. Applied Clinical Trials. September 7(9) 56-59

10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. (1996) ICH Tripartite Guideline. Guideline for Good Clinical Practice. Recommended for Adoption at Step 4 of the ICH Process on 1 May 1996 by the ICH Steering Committee.

11. Malaysian Guidelines for Good Clinical Practice. 2nd edition. Ministry of Health Malaysia, 2004.

12. European Medicines Agency. ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (PMP/ICH/135/95). London: European Medicines Agency, 2002.

13. A Vijayananthan, O Nawawi, The importance of Good Clinical Practice guidelines and its role in clinical trials, Biomed Imaging Interv J 2008; 4(1):e5,pg no.1-4.

14. The World Medical Association. Declaration of Helsinki [Web Page]. 2004; Available at http://www.wma.net/e/policy/b3.htm.

Received on 08.04.2009

Accepted on 10.06.2009

Research J. Pharmacology and Pharmacodynamics 2(1): Jan. –Feb. 2010: 27-32