UNIT-I:

Licensing authorities-roles and responsibilities

ICH GCP

( Note : throughout the syllabus, in some topics you will find the serial numbers like 3.1 , 4.1 , 5.1…..so on etc which is extracted from the guidelines of ICH, GCP,FDA etc and it is mandatory to present because it gives authentication of the data. During examination, a student need not to mention the serial numbers.)

3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

3.1 Responsibilities

3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.

3.1.2 The IRB/IEC should obtain the following documents:

trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written information to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities.

The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following:

- approval/favourable opinion;

- modifications required prior to its approval/favourable opinion;

- disapproval / negative opinion; and

- termination/suspension of any prior approval/favourable opinion.

3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.

3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects.

3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.

3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations).

3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.

3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.

3.2 Composition, Functions and Operations

3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:

(a) At least five members.

(b) At least one member whose primary area of interest is in a nonscientific area.

Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s).

3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.

3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.

3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.

FDA

Roles and Responsibilities

The main role of the Thai FDA is to protect consumer,s health, especially, to ensure safety, quality and efficacy of health products within its remit. These include: foods, drugs, psychotropic substances, narcotics, medical devices, volatile substances, cosmetics and hazardous substances available in the country. This has to be implemented in accordance with national legislation and international agreements as follows:

Drug Act, B.E. 2510 (1967)
Psychotropic Substances Act B.E. 2518 (1975)
Food Act, B.E. 2522 (1979)
Narcotics Act, B.E. 2522 (1979)
Medical Devices Act, B.E. 2531 (1988)
The Emergency Decree on Prevention of Abuse of Volatile Substances, B.E. 2533 (1990)
Cosmetics Act, B.E. 2535 (1992)
Hazardous Substances Act, B.E. 2535 (1992)
The Single Convention on Narcotic Drugs 1961, commentary on the protocol amended in Geneva on March 25, 1972.
The International Convention on Psychotropic Substances, 1971.
The International Code on Marketing of Breast Milk Substitute, 1981
The United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988.

By law, certain important issues are decided by committees, whose members, all experts in their fields, are appointed by the Minister of Public Health. Currently, there are six committees : Drugs, Food, Cosmetics, Narcotics, Psychotropic Substances and Medical Devices.

There are two committees whose members are appointed by the other ministries. They are the Committee on the Prevention of Abuse of Volatile Substances appointed by two ministers (Industry and Public Health), and the Hazardous Substance Committee appointed by three ministers (Public Health, Industry and Agriculture).

At the national level, the Cabinet appoints three committees: the National Drug Committee, the National Food Committee and the National Chemical Safety Committee. The national committees are mainly assigned policy and development issues and collaborative action with other agencies to facilitate the implementation of the food, drug and chemical safety program as well as the control system.

The roles and responsibilities of the FDA may be grouped into five main areas:

1. Pre-marketing control

This includes control of manufacturing facilities, product quality and advertising before product-launch to the market. In each case, compliance is required with the relevant legislation and regulations.

2. Post-marketing control

The aim of this activity is to investigate manufacturing facilities and product quality and to ensure that they maintain compliance with previously-approved standards and with legislation and regulations. For example, samples of products are regularly inspected and taken to check for compliance and quality. Previously-approved products are revisited periodically to ascertain the consistency of manufacturing and product standards over time.

3. Surveillance program for consumers' safety

The aim of this Program is to detect any adverse effects or unexpected outcomes from consumer use of products. Research and epidemiological data on adverse effects, including technical information, is collected, summarized, interpreted and reported. There are also operational centers, such as the Adverse Product Reaction Monitoring Center (APRMC) and the International Program on Chemical Safety (IPCS). Information is exchanged with other agencies at local and international level.

4. Consumer Education

Consumers are supplied with sufficient, accurate information to enable them to choose products wisely. Access to such information, provided by the FDA, is available from many sources: television, radio, newspaper, leaflets, internet, and so on. FDA,s campaigns on priority topics have been regularly conducted in department stores, schools and villages in many parts of the country. There are many sources for consumers to use so that they can obtain further useful information and be in a better position to protect themselves.

5. Technical Support and Cooperation with other agencies

The FDA has conducted many interesting seminars and workshops, with participants from both public and private sectors. On the other hand, officials from the Thai FDA are sent to join seminars and conferences, both local and abroad. As a result, with a widened perspective, they can work more effectively at home. The Good Manufacturing Practice (GMP) program is another example demonstrating successful cooperation with other organizations, in this case, with universities and drug manufacturers. In relation to cooperation in terms of research and development, the FDA is continually supportive of such endeavor, and some research projects are partly or wholly funded by the agency.

EU Clinical Trial Directive

General Information

Clinical trials are investigations in humans intended to discover or verify the effects of one or more investigational medicinal products ("IMPs").

Requirements for the conduct of clinical trials in the EU are provided for in " Directive 2001/20/ECpdf of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use" (" the Clinical Trials Directivepdf ").

The Clinical Trials Directive is concretised further by " Commission Directive 2005/28/ECpdf of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products" (Good Clinical Practice - " the GCP Directivepdf ").

Clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials Directive. If the clinical trials are conducted outside the EU, but submitted in an application for marketing authorisation in the EU, they have to follow the principles which are equivalent to the provisions of the Clinical Trials Directive (cf. Annex I, point 8 of the " Directive 2001/83/ECpdf of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use" - " the Community Code for medicinal productspdf ").

Guidelines

There are a number of guidelines further specifying various aspects of clinical trials, and in particular:

The information to be submitted to the competent authorities and to the ethics committees

The requirements on safety monitoring and the reporting of adverse reactions

The requirements regarding Good Clinical Practice, including the documentation, of the clinical trials

The specific requirements regarding the products and the clinical trials

The inspections of competent authorities and the applicable procedures

These guidelines have been published by various bodies:

By the European Commission: In this case, they are published in Volume 10 of "EudraLex - The rules governing medicinal products in the European Union"

By the European Medicines Agency ("EMA") These guidelines concern in particular:

Inspection procedures and guidance for GCP inspections conducted in the context of the Centralised Procedure

Requirements relating to the quality, safety and efficacyof products, as well as specific types of products. Volume 3 of EudraLex

Moreover, the Heads of Medicines Agencies have established a Clinical Trials Facilitation Group ("CTFG") (in which the Commission and EMA are observers), in order to discuss ongoing technical issues.

Clinical trial application

The Clinical Trials Directive harmonises the rules in the EU for the approval of a clinical trial conducted in a Member State. As regards national competent authorities, the details are set out in the 'Commission Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)' published in EudraLex Volume 10.

EudraCT

A European database - EudraCT - contains all ongoing or completed clinical trials falling within the scope of Directive 2001/20/EC, i.e. with at least one investigator site in the EU (incl. the European Economic Area) and commencing after implementation of Directive 2001/20/EC by the Member States. This database gives the competent authorities of the Member States, the EMA and the Commission the necessary information to communicate on clinical trials and to maintain oversight of clinical trials and IMP development. This provides for enhanced protection of clinical trial subjects and patients receiving IMPs. More information, including a user manual for EudraCT is available on the EudraCT Supporting Documentation web page.

Paediatric clinical trials that form part of a Paediatric Investigation Plan (PIP) but are conducted in third countries will also be included in the near future (paediatric clinical trials with sites in the EU/EEA are already included).

Transparency of information related to clinical trials

Union legislation provides that certain information contained in EudraCT is to be made accessible to the public. This public accessibility concerns clinical trials with paediatric as well as non-paediatric participants. It englobes protocol-related information and result-related information. And it covers both negative and positive results.

To implement the legislation further, the Commission has issued a set of guidelines, which are accessible via chapter V of EudraLex, Volume 10.

These guidelines consist of three "mother guidelines" (Guideline 2008/C168/02; Guideline 2009/C28/01, Guideline 2012/C302/03), setting out the principles, responsibilities, and procedural aspects. The "mother guidelines" are further concretised by way of a number of very detailed "daughter guidelines".

With regard to protocol-related information, this information is public under clinicaltrialsregister.eu, which is part of the public database EudraPharm.

With regard to result-related information, this information is presently not contained in EudraCT at all. Therefore, prior to making anything public, the necessary guidelines had to be adopted and published. These are published in EudraLex, Volume 10. Programming of the relevant databases is currently ongoing. More information is available here.

For all additional information, reference is made to the applicable guidelines in chapter V of EudraLex Volume 10.

Safety reporting

The Clinical Trials Directive introduces rules on safety reporting in the context of a clinical trial. Further details are set out in 'the Commission Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’)' published in EudraLex Volume 10. Regarding suspected unexpected serious adverse reactions (SUSARs), this guidance provides inter alia the rules for reporting directly to the national competent authority. In order to obtain the national address for the direct reporting, click on the relevant Member State:

Revision of the Clinical trials Directive

Adoption of the proposal for a "Clinical Trials Regulation"

On 17 July 2012, the Commission has adopted a "Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/ECpdf(767 KB) Choose translations of the previous link" (hereinafter "Clinical Trials Regulation") .

The proposal has been submitted to the European Parliament and the Council who engage in ordinary legislative procedure. You find an overview of this procedure here. To follow the proposal in the different steps of the procedure, please consult the "legislative observatory" of the European Parliament or PreLex, the EU-database on interinstitutional procedures.

Preparation of the Commission proposal

In its Communication of 10 December 2008 to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on “Safe, Innovative and Accessible Medicines: a Renewed Vision for the Pharmaceutical Sector”, the Commission announced that an assessment would be made of the application of the Clinical Trials Directive.

This assessment would consider, in particular, various options for improving the functioning of the Clinical Trials Directive with a view to making legislative proposals, if appropriate, while taking the global dimension of clinical trials into account.

In 2009, a public consultation document along this line was published herepdf(134 KB). The responses have been published here. A summary document of the responses is available herepdf(61 KB).

A 'roadmap' of the Commission impact assessment, setting out the main structure and the next steps, was made available here.

On 9 February 2011, a public consultation on a concept paper on the revision of the 'Clinical Trials Directive' 2001/20/ECpdf(94 KB) has been launched. The concept paper presented:

- a 'preliminary appraisal' of which option appeared to be the most suitable one to address some of the key concerns of the Clinical Trials Directive, on the basis of the current state of the impact assessment; and

- the main figures used to evaluate the impacts of the different policy options.

(Ref : http://ec.europa.eu/health/human-use/clinical-trials/)

EU Clinical Trials Directive

The European Clinical Trials Directive 2001/20/EC (EUCTD) was introduced to establish standardisation of research activity in clinical trials throughout the European Community. The EUCTD was transposed into UK law as the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/ 1031) which came into force 1st May 2004.

The European Union Clinical Trials Directive (2001/20/EC) provides a framework which sets out how clinical trials investigating the safety or efficacy of a medicinal product in humans must be conducted. It includes medicinal trials with healthy volunteers and small scale or pilot studies.

The Directive aims are to:

Provide greater protection to subjects participating in clinical trials
Ensure quality of conduct
Harmonise regulation and conduct of clinical trials throughout Europe

EU Good Clinical Practice Directive

Good Clinical Practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects.

The International Conference on Harmonisation Guidance on Good Clinical Practice (Topic E6) (CPMP/ICH/135/95) is an international standard for GCP.

The Good Clinical Practice Directive 2005/28/EC supplements the Clinical Trials Directive, strengthening the legal basis for requiring Member States to comply with the principles and guidelines of good clinical practice, as set out in the ICH-GCP guidelines.

The Medicines for Human Use (Clinical trials) Regulations 2004

The EU Clinical Trials Directive was transposed into UK Law as the Medicines for Human Use (Clinical Trials) Regulations 2004 and came into force on 1st May 2004. The UK Clinical Trials Regulations 2004 include additional controls:

Establishment of ethics committees on a legal basis
Each Clinical Trial must have an identified Sponsor who takes responsibility for its initiation, conduct and management
Phase 1 pharmacology studies in healthy volunteers require authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA)
Investigational medicinal products (IMPs) must be manufactured to Good Manufacturing Practice (GMP) standards and the manufacturer must have a manufacturing licence
The MHRA is empowered to carry out statutory inspections of the sponsor, researchers, facilities and manufacturing organisations for GCP, GMP and pharmacovigilance to help ensure required standards are maintained

Failure to comply with the UK Clinical Trials Regulations 2004 can lead to penalties of fines and/or a custodial sentence for non-compliance. A summary of the regulations is available here

Amendments to the Regulations

There have been various amendments to the Medicines for Human Use Clinical Trials Regulations as listed below:

(Ref : http://www.cardiff.ac.uk/racdv/resgov/clintrials/directives/)

Data Protection Act

The Data Protection Act 1998 (DPA) is a United Kingdom Act of Parliament which defines UK law on the processing of data on identifiable living people. It is the main piece of legislation that governs the protection of personal data in the UK. Although the Act itself does not mention privacy, it was enacted to bring UK law into line with the EU data protection directive of 1995 which required Member States to protect people's fundamental rights and freedoms and in particular their right to privacy with respect to the processing of personal data. In practice it provides a way for individuals to control information about themselves. Most of the Act does not apply to domestic use, for example keeping a personal address book. Anyone holding personal data for other purposes is legally obliged to comply with this Act, subject to some exemptions. The Act defines eight data protection principles. It also requires companies and individuals to keep personal information to themselves.

Data protection principles

Schedule 1 to the Data Protection Act lists the data protection principles in the following terms:

Personal data shall be processed fairly and lawfully and, in particular, shall not be processed unless –

(a) at least one of the conditions in Schedule 2 is met, and

(b) in the case of sensitive personal data, at least one of the conditions in Schedule 3 is also met.
Personal data shall be obtained only for one or more specified and lawful purposes, and shall not be further processed in any manner incompatible with that purpose or those purposes.
Personal data shall be adequate, relevant and not excessive in relation to the purpose or purposes for which they are processed.
Personal data shall be accurate and, where necessary, kept up to date.
Personal data processed for any purpose or purposes shall not be kept for longer than is necessary for that purpose or those purposes.
Personal data shall be processed in accordance with the rights of data subjects under this Act.
Appropriate technical and organisational measures shall be taken against unauthorised or unlawful processing of personal data and against accidental loss or destruction of, or damage to, personal data.
Personal data shall not be transferred to a country or territory outside the European Economic Area unless that country or territory ensures an adequate level of protection for the rights and freedoms of data subjects in relation to the processing of personal data.

(Ref : http://ico.org.uk/for_organisations/data_protection/the_guide/the_principles)

Regulations relating to electronic signatures

An electronic signature, or e-signature, is any electronic means that indicates either that a person adopts the contents of an electronic message, or more broadly that the person who claims to have written a message is the one who wrote it (and that the message received is the one that was sent). By comparison, a signature is a stylized script associated with a person. In commerce and the law, a signature on a document is an indication that the person adopts the intentions recorded in the document. Both are comparable to a seal.

Increasingly, encrypted digital signatures are used in e-commerce and in regulatory filings as digital signatures are more secure than a simple generic electronic signature.The concept itself is not new, with common law jurisdictions having recognized telegraph signatures as far back as the mid-19th century and faxed signatures since the 1980s.

In many countries, including the United States, the European Union and Australia, electronic signatures (when recognised under the law of each jurisdiction) have the same legal consequences as the more traditional forms of executing of documents.

Enforceability of electronic signatures

In 1996 the United Nations published the UNCITRAL Model Law on Electronic Commerce.The model law was highly influential in the development of electronic signature laws around the world, including in the US.

The U.S. Code defines an electronic signature for the purpose of US law as "an electronic sound, symbol, or process, attached to or logically associated with a contract or other record and executed or adopted by a person with the intent to sign the record." It may be an electronic transmission of the document which contains the signature, as in the case of facsimile transmissions, or it may be encoded message, such as telegraphy using Morse code.

In the United States, the definition of what qualifies as an electronic signature is wide and is set out in the Uniform Electronic Transactions Act ("UETA") released by the National Conference of Commissioners on Uniform State Laws (NCCUSL) in 1999. It was influenced by ABA committee white papers and the uniform law promulgated by NCCUSL. Under UETA, the term means "an electronic sound, symbol, or process, attached to or logically associated with a record and executed or adopted by a person with the intent to sign the record." This definition and many other core concepts of UETA are echoed in the U.S. ESign Act of 2000.[10] 47 US states, the District of Columbia, and the US Virgin Islands have enacted UETA. Only New York, Washington State, and Illinois have not enacted UETA, but each of those states has adopted its own electronic signatures statute.

Canadian law (PIPEDA) attempts to clarify the situation by first defining a generic electronic signature as "a signature that consists of one or more letters, characters, numbers or other symbols in digital form incorporated in, attached to or associated with an electronic document", then defining a secure electronic signature as an electronic signature with specific properties. PIPEDA's secure electronic signature regulations refine the definition as being a digital signature applied and verified in a specific manner.

In the European Union, the EU Directive on Electronic Signatures or the EU Electronic Signatures Directive was published in the EC Official Journal, as Directive 1999/93/EC of the European Parliament and of the Council of 13 December 1999 on a Community framework for electronic signatures (OJ No L 13 p. 12 19/1/2000).

In India

The Information Technology Act 2000 (also known as ITA-2000, or the IT Act) is an Act of the Indian Parliament (No 21 of 2000) notified on October 17, 2000. This act is being opposed by Save Your Voice campaign and other civil society organizations in India.

Provisions

Information technology Act 2000 consisted of 94 sections segregated into 13 chapters. Four schedules form part of the Act. In the 2008 version of the Act, there are 124 sections (excluding 5 sections that have been omitted from the earlier version) and 14 chapters. Schedule I and II have been replaced. Schedules III and IV are deleted.

Information Technology Act 2000 addressed the following issues:

Legal Recognition of Electronic Documents

Legal Recognition of Digital Signatures

Offenses and Contraventions

Justice Dispensation Systems for Cybercrimes

Declaration of Helsinki 2000 amendment and financial disclosure Law

A. Introduction

1. The World Medical Association 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.

2. It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfillment of this duty.

3. The Declaration of Geneva of the World Medical Association 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.’’

4. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.

5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.

6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best prove prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.

7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.

8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care.

9. Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

B. Basic principles for all medical research

10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.

11. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.

12. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.

13. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed

ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

14. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration.

15. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.

16. Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available.

17. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.

18. Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers.

19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

20. The subjects must be volunteers and informed participants in the research project.

21. The right of research subjects to safeguard their integrity must always be respected. Every precaution should be taken to respect the privacy of the subject, the confidentiality of the patient’s information and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.

22. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject’s freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.

23. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship.

24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.

25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.

26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.

27. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

C. Additional principles for medical research combined with medical care

28. The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

31. The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient–physician relationship.

32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician’s judgement it offers hope of saving life, reestablishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

(ref: http://www.who.int/bulletin/archives/79%284%29373.pdf)

Guidelines and codes of practice; Regulation of drug preparation and packaging

Introduction

FDA ensures the quality of drug products by carefully monitoring drug manufacturers' compliance with its Current Good Manufacturing Practice (CGMP) regulations. The CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations make sure that a product is safe for use, and that it has the ingredients and strength it claims to have.

The approval process for new drug and generic drug marketing applications includes a review of the manufacturer's compliance with the CGMP. FDA inspectors determine whether the firm has the necessary facilities, equipment, and skills to manufacture the new drug for which it has applied for approval. Decisions regarding compliance with CGMP regulations are based upon inspection of the facilities, sample analyses, and compliance history of the firm. This information is summarized in reports which represent several years of history of the firms.

FDA can issue a warning letter or initiate other regulatory actions against a company that fails to comply with Current Good Manufacturing Practice regulations. Failure to comply can also lead to a decision by FDA not to approve an application to market a drug.

This web page provides links to resources to help drug manufacturers comply with the Current Good Manufacturing Practice regulations.

Federal Regulations

Code of Federal Regulations (CFR). The final regulations published in the Federal Register (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes. Section 21 of the CFR contains most regulations pertaining to food and drugs. The regulations document the actions of drug sponsors that are required under Federal law.

21 Code of Federal Regulations Part 210. Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs.

21 Code of Federal Regulations Part 211. Current Good Manufacturing Practice for Finished Pharmaceuticals.

Federal Register Notices for Proposed Changes and Final Changes to CGMP. The Office of Compliance, Division of Manufacturing and Product Quality web page provides links to in-process changes in CGMP regulations announced in the Federal Register.

Guidance Documents

Guidance documents represent the Agency's current thinking on a particular subject. These documents are prepared for FDA review staff and drug sponsors to provide guidelines for the processing, content, and evaluation of applications, and for the design, production, manufacturing, and testing of regulated products. They also provide consistency in the Agency's regulation, inspection and enforcement procedures. Because guidances are not regulations or laws, they are not enforceable. An alternative approach may be used if it satisfies the requirements of the applicable statute, regulations, or both.

Guideline on the Preparation of Investigational New Drug Products (Human and Animal) (PDF - 795KB) (Issued 11/1992, Posted 3/2/1998). This guidance provides practices and procedures for preparing investigational new drug products that comply with certain section of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (Title 21 of the Code of Federal Regulations, Parts 210 and 211.)

Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (PDF - 98KB). 10/2006 This guidance provides the Agency’s current thinking on how to evaluate suspect, or out of specification (OOS) test results. For purposes of this document, the term OOS results includes all suspect results that fall outside the specifications or acceptance criteria established in new drug applications.

CDER Manual of Policies and Procedures (MaPPs)

MaPPs are approved instructions for internal practices and procedures followed by CDER staff to help standardize the new drug review process and other activities. MaPPs define external activities as well. All MaPPs are available for the public to review to get a better understanding of office policies, definitions, staff responsibilities and procedures.

4723.1 Standing Operating Procedures for NDA/ANDA Field Alert Reports (PDF - 15KB). (Issued 10/30/1998, posted 11/02/1998). This MaPP establishes a system for evaluating new drug application (NDA) and abbreviated new drug application (ANDA) Field Alert Reports and provides instructions to the responsible CDER units for handling those reports.

Compliance Policy Programs and Guidelines

Compliance References. This web site from the Office of Regulatory Affairs provides links to compliance policy guides, regulatory procedures manuals, and other compliance related information. Chapter 4 of the Compliance Policy Guide covers human drugs.

Compliance Program Guidance Manual. These programs and instructions are for FDA field inspectors.

Consistent Application of Current Good Manufacturing Practice Determinations. FDA cannot approve applications to market new drugs from companies who have been cited for Current Good Manufacturing Practice violations. Similarly, disapproval of any drug marketing application based upon CGMP deficiencies must also lead to regulatory and/or administrative action against other products produced under the same conditions.

(Ref : http://www.fda.gov/drugs/developmentapprovalprocess/manufacturing/ucm090016.htm)

EMEA

The European Medicines Agency (EMA) is a European Union agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the

Evaluation of Medicinal Products.

Roughly parallel to the U.S. Food and Drug Administration (FDA), but without FDA-style centralisation, the European Medicines Agency was set up in 1995 with funding from the European Union and the pharmaceutical industry, as well as indirect subsidy from member states, in an attempt to harmonise (but not replace) the work of existing national medicine regulatory bodies. The hope was that this plan would not only reduce the €350 million annual cost drug companies incurred by having to win separate approvals from each member state but also that it would eliminate the protectionist tendencies of states unwilling to approve new drugs that might compete with those already produced by domestic drug companies. The EU is currently the source of about one-third of the new drugs brought onto the world market each year.

Based in London, the EMA was born after more than seven years of negotiations among EU governments and replaced the Committee for Proprietary Medicinal Products and the Committee for Veterinary Medicinal Products, though both of these were reborn as the core scientific advisory committees.

The European Medicines Agency operates as a decentralised scientific agency (as opposed to a regulatory authority) of the European Union and its main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. More specifically, it coordinates the evaluation and monitoring of centrally authorised products and national referrals, developing technical guidance and providing scientific advice to sponsors. Its scope of operations is medicinal products for human and veterinary use including biologics and advanced therapies, and herbal medicinal products.

The agency is composed of the Secretariat (ca. 600 staff), a management board, six scientific committees (human, veterinary and herbal medicinal products, orphan drugs, paediatrics and advanced therapies) and a number of scientific working parties. The Secretariat is organised into five units: Directorate, Human Medicines Development and Evaluation, Patient Health Protection, Veterinary Medicines and Product Data Management, Information and Communications Technology and Administration. The Management Board provides administrative oversight to the Agency: including approval of budgets and plans, and selection of Executive Director.

The Board includes one representative of each of the 27 Member States, two representatives of the European Commission, two representatives of the European Parliament, two representatives of patients’ organisations, one representative of doctors’ organisations and one representative of veterinarians’ organisations. The Agency decentralises its scientific assessment of medicines by working through a network of about 4500 experts throughout the EU. The EMA draws on resources of over 40 National Competent Authorities (NCAs) of EU Member states.

MRECs

MREC was established on 2002. The objective of MREC secretariat is to provide independence guidance. Advice and decision on health research/specific protocol involving human subjects conducted by staff of MOH or involving MOH facilities. MREC Secretariat is acting as an independent ethics committee for non- MOH institutions. MREC Secretariat is composed of scientist and non-scientist and constituted and operated under director general Of Health Malaysia Authority.

Research involving human subjects requires prior ethics review and approval by the MOH Research and Ethics Committee (MREC)

A human subject (in the context of research) is “a living individual about whom an investigator obtains either data through intervention (eg. Clinical trial) or interaction (eg. Questionnaire in health survey) with the individual, or identifiable private information”
Submission to MREC for ethics review and approval is conducted online at www.nmrr.gov.my

Submission Form & Procedure

It is the responsibility of the investigator to apply to MREC for approval to conduct research involving human subjects if the research is conducted in Ministry of Health Malaysia facilities or institutions.

No research can commence until the investigator has written and dated approval from the MREC.

All investigators must register their research online in the NMRR (National Medical Research Register, www.nmrr.gov.my) to open an account and obtain a password to access the NMRR.

Study documents, any corrections and amendments, are to be submitted online in the NMRR. Please access the NMRR for instructions on how to submit such documents.

The NMRR will automatically generate a notification of receipt of study documents to the investigator.

Review Procedure

MREC Secretary will schedule complete application for MREC meeting. Study documents will be circulated online to MREC members before scheduled meeting.
MREC members will conduct online review and submit recommendations and comments to NMRR before schedule meeting.
MREC members at meeting shall review and discuss all members’ recommendations and comments. Investigator will be invited to present study at scheduled meeting and will be queried if there are issues.
MREC members present at meeting will decide on study and decision will be communicated to investigator: Decision may be:

study is approved / rejected or revision required.
changes to study documents are needed. Corrected documents must be submitted by investigator.

MREC Chairperson will decide whether corrected documents need to be reviewed at MREC meeting or by selected MREC members. If meeting is required, steps 1 to 4 above are repeated.
If corrected documents are reviewed by selected MREC members, the corrected documents are circulated online to those members. Members will conduct online review and submit their recommendations and comments.
Based on the recommendations and comments of the MREC members, the MREC Chairperson will decide on the study and decision will be communicated to investigator as in step 4 above.

Expediated Review

A study qualifies for expedited review if it satisfies the following criteria:

Modification or amendment of approved protocol:

administrative revisions such as correction of typographical errors.
addition or deletion of non-procedural items such as addition of study personnel names, laboratories, etc.
research activity with minimal risk.
minor changes to approved research activities that do not increase risk to subjects.

Protocols involving interviews of a non-confidential nature not likely to be detrimental to the status or interests of subjects, and not likely to offend the sensibilities and sensitivities of subjects.
Those that involve collection of small volumes of blood samples (less than 20 mls) at any one time and not too often (not more than 3 times foe whole duration of study, and not more than twice a week) by venipuncture, finger prick, heel prick, etc.
Those that involve collection of biological samples by non-invasive means (e.g. collection of body fluids or excreta, collection of hair or nail clippings).
Collection of data through non-invasive procedures (not involving general anesthesia or sedation) routinely used in clinical practice and using medical devices approved by national regulatory authorities.
Research involving data, documents or specimens that have already been collected or will be collected for ongoing medical treatment or investigation.
Continuing review of research previously approved with no modification to original protocol and studies that have taken place, and no identifiable additional risk to subjects.
The MREC Secretary will review all submissions and if a study satisfies the above criteria, the MREC Chairperson will be notified. The Secretary will select 2 scientific and 1 non-scientific MREC members to review the study.
Study documents will be circulated online to selected MREC members who will review the documents and submit their recommendations and comments online.
The MREC Chairperson will examine the recommendations and comments of the reviewers, and decide on the study. If the Chairperson is unable to decide or if recommended by the reviewers, the study will be scheduled for a MREC meeting. The decision will be communicated to the investigator.

Informed Consent

A study may be consider for waiver of informed consent if it satisfies the following criteria:

The study design involves no more than minimal risk.
Medical records and biological specimens taken in the course of clinical care may be used for research without consent of the patients/subjects only if the research poses minimal risk, that the rights or interests of the patients will not be violated, that their privacy and confidentiality or anonymity are assured, and that the research is designed to answer an important question and will be impractical if the requirement of informed consent is to be imposed. Refusal or reluctance of individuals to agree to participate is not evidence of impracticability sufficient to warrant waiving informed consent.
Study involves the collection or use of existing data, documents, records, pathological specimens, or diagnostics if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.
Study design to investigate, evaluate or examine public service programmes.

On receipt of an application for waiver of informed consent, the MREC Secretary will select 2 scientific and 1 non-scientific MREC members to conduct a preliminary review.
Study documents will be circulated online to selected MREC members who will review the documents and submit their recommendations and comments online.
The MREC Chairperson will examine the recommendations and comments of the reviewers and decide on the study. If the Chairperson is unable to decide or if recommended by the reviewers, the study will be scheduled for a MREC meeting. The decision will be communicated to the investigator.

MREC Requirements

All blood samples must be stated in mls and teaspoons/tablespoons per visit and for the whole study.
Assent is required for studies involving subjects aged 7 to less than 18 years. (Ref: Malaysian Guidelines for Research Involving Minors)
Patient information sheet should state whether investigational product contains porcine, bovine or other animal products.
MREC decision and approval is final for all local studies if the subjects are patients from Ministry of Health Malaysia hospitals or facilities. Any subsequent changes to the protocol, patient information sheet, informed consent form, and other supporting documents, as instructed by other ethic committees, will result in the MREC’s approval becoming null and void.

(ref : http://www.nih.gov.my/mrec/index.php/menuer-subpro)

Ethics committees – history structure regulation impact of ICH GCP

1.27 Independent Ethics Committee (IEC)

An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favourable

opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.

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

1.42 Opinion (in relation to Independent Ethics Committee)

The judgement and/or the advice provided by an Independent Ethics Committee (IEC).

3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

3.1 Responsibilities

3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.

3.1.2 The IRB/IEC should obtain the following documents:

The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following:

- approval/favourable opinion;

- modifications required prior to its approval/favourable opinion;

- disapproval / negative opinion; and

- termination/suspension of any prior approval/favourable opinion.

3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

3.2 Composition, Functions and Operations

(a) At least five members.

(b) At least one member whose primary area of interest is in a nonscientific area.

Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.

3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.

3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.

3.3 Procedures

The IRB/IEC should establish, document in writing, and follow its procedures, which should include:

3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is established.

3.3.2 Scheduling, notifying its members of, and conducting its meetings.

3.3.3 Conducting initial and continuing review of trials.

3.3.4 Determining the frequency of continuing review, as appropriate.

3.3.5 Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.

3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial.

3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or

administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).

3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:

(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).

(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).

(d) New information that may affect adversely the safety of the subjects or the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:

(a) Its trial-related decisions/opinions.

(b) The reasons for its decisions/opinions.

6.12 Ethics

Description of ethical considerations relating to the trial.

Recent development with regard to the INDIA/ USA / EU Clinical Trial directive

INIDA

Studies involving non-CE marked medical devices carried out in the UK may be regulated as clinical investigations under the Medical Devices Regulations 2002 and require approval from the UK Competent Authority.

This page provides guidance on how to notify the MHRA of proposed clinical investigations involving non-CE marked medical devices. Please see the links at right-hand side of this page to guidance documents contained on this website. Please note that investigations of In Vitro Diagnostic Medical Devices are regulated as performance evaluations and guidance on the requirements for these is included in our Guidance Note 18 which can be found on our registration of medical devices page.

Prior to submitting a notification to the Competent Authority, you are advised to ensure that you have the information necessary to demonstrate compliance with all the relevant essential requirements except for those that are the subject of the investigation. A significant percentage of the grounds for objection that have been raised have resulted from the failure to supply the necessary data within the 60 day time period allowed by the Regulations. Details of the information required are provided in the guidance documents to the right of this page. Please prepare your notification to the MHRA online by using the Integrated Research Application System (IRAS) (external link). IRAS is a UK-wide system that streamlines the process for applying for permissions and approvals to conduct health and social care research, including clinical investigations of medical devices. It allows users to enter the information for the relevant permissions and approvals once, instead of having to complete several separate application forms for each review body. Filters are used to ensure that data is collected and collated appropriately to the type of study and the approvals and permissions required. IRAS captures the information needed by the MHRA offering the facility for users to print out the completed PCA1 and PCA2 forms and sterilization proforma for signing before making a notification to the MHRA in the usual way.

Notifications will only be accepted by the MHRA once the signed forms, necessary supporting documentation and the appropriate fee have been received by the Agency.

Your notifications should be submitted in the following format:

The documentation should be sent by recorded delivery.
All information must be in English. If any part of the supporting data consists of material in another language, this must be translated. One copy of the original document in its original language should accompany the application.
One hardcopy of the full submission and eight rewritable CD-ROMs are required.

The hardcopy copy of the proposed clinical investigation, must be presented and collated with all pages in their correct numbered sequence, including reprints, diagrams, tables and other data. The method of reproduction used must allow for legible presentation of the text and any relevant drawings with their captions. All papers should be provided in a folder or bound with dividers separating individual documents.
All documents must be arranged on the CDs as separate attachments. Please include a document index on each CD and ensure that all documents are named appropriately ie clinical investigation plan, investigator’s brochure, patient information, patient consent, essential requirements checklist, summary of pre-clinical data, sterilization validation report, risk analysis, instructions for use etc.
Please provide:

Eight rewritable CD-ROMS, each containing a full set of the supporting documentation
One hardcopy of the full set of supporting documentation
The hardcopy and all CDs must contain identical information

When paying by bank transfer, please provide a copy of the payment transaction receipt, otherwise include the cheque with the submission.

(ref: http://www.mhra.gov.uk/Howweregulate/Devices/Clinicaltrials/)

USA

Clinical Trials

Adherence to the principles of good clinical practices (GCPs), including adequate human subject protection (HSP) is universally recognized as a critical requirement to the conduct of research involving human subjects. Many countries have adopted GCP principles as laws and/or regulations. The Food and Drug Administration’s (FDA’s) regulations for the conduct of clinical trials, which have been in effect since the 1970s, address both GCP and HSP. These FDA regulations and guidance documents are accessible from this site. International GCP guidance documents on which FDA has collaborated and that have been adopted as official FDA guidance are also be found here. Finally, this site includes links to other sites relevant to the conduct of clinical trials, both nationally and internationally.

Bioresearch Monitoring

FDA’s bioresearch monitoring (BIMO) program conducts on-site inspections of both clinical and nonclinical studies performed to support research and marketing applications/submissions to the agency. Links to the compliance programs for each inspection type and contact information for each Center’s BIMO program are also accessible from this site.

(ref : http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ default.htm)

Current status on EU legislation on clinical trials:

The revision of the Clinical Trials Directive Directive 2001/20/CE, adopted on the 4th of April 2001 has entered its final phase. The Commission has finalised its new proposal on the 17th of July 2012 (COM2012/312 FINAL) after years of legislative work. The legislative proposal will now be discussed in the European Parliament and in the Council. It is expected to come into effect in 2016.

What’s new in the proposal:

Fostering EU's attractiveness in clinical research:

Commission proposes to revamp rules on trials with medicines

Boosting clinical research in Europe by simplifying the rules for conducting clinical trials isnwhat today's proposal from the Commission is about. Clinical trials are tests of medicines in humans and give patients access to most innovative treatments. At the same time, clinical research with over 20 billion Euros of investment per year in the EU makes a significant contribution to the growth policy of the Europe 2020 agenda. Clinical trials are vital to develop medicines and to improve and compare the use of already authorised medicines. The data generated in clinical trials are used by researchers in publications, and by pharmaceutical companies applying for marketing authorizations. Once implemented, the measures proposed today will speed up and simplify the authorisation and reporting procedures, while maintaining the highest standards of patient safety and robustness and reliability of data. The measures will also better differentiate the obligations according to the risk-profile of the trial, and improve transparency including on trials done in third countries.

John Dalli, European Commissioner for Health and Consumer Policy, said:

"the proposal significantly facilitates the management of clinical trials, while maintaining the highest standards of patient safety and the robustness and reliability of trial data. 800 million euros per year could be saved in regulatory costs and boost research and development in the EU, thus contributing to economic growth."

The proposed Regulation, once adopted, will replace the 'Clinical Trials Directive' of 2001. It has ensured high level of patient safety, but its divergent transposition and application led to an unfavourable regulatory framework for clinical research. According to the European Commission, this has contributed to a to a decrease of 25% of clinical trials conducted in the period between 2007 and 2011: in 2007, more than 5000 clinical trials were applied for in the EU while by 2011 the number had dropped to 3800.

The new legislation proposed by the Commission will take the form of a Regulation. This will ensure that the rules for conducting clinical trials are identical throughout the EU. In particular, it will make it easier to conduct multinational clinical trials in Europe. Some concrete proposals are:

• An authorisation procedure for clinical trials which will allow for a fast and thorough assessment of the application by all Member States concerned and which will ensure one single assessment outcome.

• Simplified reporting procedures which will spare researchers from submitting largely identical information on the clinical trial separately to various bodies and Member States.

• More transparency on whether recruitment for participating in a clinical trial is still ongoing, and on the results of the clinical trial.

• The possibility for the Commission to conduct controls in Member States and other countries to make sure the rules are being properly supervised and enforced.

(ref : http://www.esicm.org/research/eu-directives)

A TEXT BOOK ON CLINICAL TRIALS AND REGULATORY AFFAIRS

UNIT I

Data protection principles

Clinical Trials

Bioresearch Monitoring