MEDLINE INDIA - GOOD CLINICAL PRACTICE GUIDELINES

Physical, chemical, pharmaceutical properties and the formulation of the Investigational Product must be documented to permit appropriate safety measures to be taken during the course of a study. Instructions for the storage and handling of the dosage form should be documented. Any structural similarity(ies) to the other known compounds should be mentioned.

2.2. Pre-clinical supporting data

The available pre-clinical data and clinical information on the Investigational Product should be adequate and convincing to support the proposed study.

A well designed study relies predominantly on a thoroughly considered, well-structured and complete protocol.

2.3.1. Relevant components of Protocol

2.3.1.1. General information

a. Protocol title, protocol identifying number and date. All amendments should bear amendment number and date(s)

b. Name, address & contact numbers of the sponsor and the monitor / CRO

c. Name and title of the persons authorised to sign the protocol and the protocol amendments for the sponsor

d. Name, title, address and contact numbers of the sponsor's medical expert for the study

e. Name(s), title(s), address(es) and contact numbers of the investigator(s) who is / are responsible for conducting the study, along with their consent letter(s)

f. Name(s), address(es) and contact numbers of the institution(s) - clinical laboratories and / or other medical and technical departments along with the particulars of the head(s) of the institution(s) and the relevant department(s)

2.3.1.2. Objectives and Justification

a. Aims and objectives of the study, indicating the Phase to which the study corresponds

b. Name and description of the investigational product(s)

c. A summary of findings from non-clinical studies that potentially have clinical significance and from clinical studies that are relevant to the study

d. Summary of the known and potential risks and benefits, if any, to human subjects

e. Description of and justification for the route of administration, dosage regimen and treatment periods for the pharmaceutical product being studied and the product being used as control. Dose-response relationships should be considered and stated.

f. A statement that the study will be conducted in compliance with the protocol, GCP and the applicable regulatory requirements

g. Description of the inclusion & exclusion criteria of the study population

h. References to the literature and data that are relevant to the study and that provide background for the study

2.3.1.3. Ethical Considerations

a. General ethical considerations related to the study

b. Description of how patients / healthy volunteers will be informed and how their consent will be obtained

c. Possible reasons for not seeking informed consent

2.3.1.4. Study design

The scientific integrity of the study and the credibility of the data from the study depend substantially on the study design. Description of the study design should include:

a. Specific statement of primary and secondary end points, if any, to be measured during the study

b. Description of the type of the study (randomised, comparative, blinded, open, placebo controlled), study design (parallel groups, cross-over technique), blinding technique (double-blind, single-blind), randomisation (method and procedure) and placebo controlled.

c. A schematic diagram of the study design, procedures and stages

d. Medications/treatments permitted (including rescue medications) and not permitted before and / or during the study

e. A description of the study treatments, dosage regimen, route of administration and the dosage form of the investigational product and the control proposed during the study

f. A description of the manner of packaging and labelling of the investigational product

g. Duration of the subject participation and a description of the sequence of all study periods including follow-up, if any

h. Proposed date of initiation of the study

i. Justification of the time-schedules e.g. in the light of how far the safety of the active ingredients, medicinal products has been tested, the time course of the disease in question

j. Discontinuation criteria for study subjects and instructions on terminating or suspending the whole study or a part of the study

k. Accountability procedures for the investigational products including the comparator product

l. Maintenance of study treatment randomisation codes and procedures for breaking codes

m. Documentation of any decoding that may occur during the study

n. Procedures for monitoring subjects’ compliance

2.3.1.5. Inclusion, Exclusion and Withdrawal of Subjects

a. Subject inclusion criteria: specifications of the subjects (patients / healthy volunteers) including age, gender, ethnic groups, prognostic factors, diagnostic admission criteria etc. should be clearly mentioned where relevant.

b. Subject exclusion criteria, including an exhaustive statement on criteria for pre-admission exclusions

c. Subject withdrawal criteria (i.e. terminating investigational product treatment / study treatment) and procedures specifying – when and how to withdraw subjects from the treatment, type and timing of the data to be collected from withdrawn subjects, whether and how subjects are to be replaced and the follow-up on the withdrawn subjects

d. Statistical justification for the number of Subjects to be included in the Study

2.3.1.6. Handling of the Product(s)

a. Measures to be implemented to ensure the safe handling and storage of the pharmaceutical products.

b. System to be followed for labelling of the product(s) (code numbering etc.)

c. The label should necessarily contain the following information: the words - “For Clinical Studies only”, the name or a code number of the study, name and contact numbers of the investigator, name of the institution, subject’s identification code.

2.3.1.7. Assessment of Efficacy

a. Specifications of the effect parameters to be used

b. Description of how effects are measured and recorded

c. Time and periodicity of effect recording

d. Description of special analyses and / tests to be carried out (pharmacokinetic, clinical, laboratory, radiological etc.)

2.3.1.8. Assessment of Safety

a. Specifications of safety parameters

b. Methods and periodicity for assessing and recording safety parameters

c. Procedures for eliciting reports of and for recording and reporting adverse drug reactions and / or adverse events and inter-current illnesses

d. Type and duration of the follow-up of the subjects after adverse events

e. Information on establishment of the study-code, where it will be kept and when, how and by whom it can be broken in the event of an emergency

2.3.1.9. Statistics

a. Description of the statistical methods to be employed, including timing of any planned interim analysis

b. Number of study subjects needed to achieve the study objective, and statistical considerations on which the proposed number of subjects is based

c. Detailed break-up of the number of subjects planned to be enrolled at each study site (in case of multi-center studies)

d. The level of statistical significance to be used

e. Procedures for managing missing data, unused data and unauthentic data

f. Procedures for reporting any deviations from the original statistical plan (any deviations from the original statistical plan should be stated and justified in protocol and / in the final report, as appropriate)

g. Selection of the subjects to be included in the final analyses (e.g. all randomized subjects / all dosed subjects / all eligible subjects / evaluable subjects

2.3.1.10. Data handling and management

A statement should be clearly made in the protocol that “The investigator(s) / institution(s) will permit study related monitoring, audits, ethics committee review and regulatory inspection(s) providing direct access to source data / documents”.

A copy of the CRF should be included in the protocol. Besides, the following details should be given:

a. Procedures for handling and processing records of effects and adverse events to the product(s) under study

b. Procedures for the keeping of patient lists and patient records for each individual taking part in the study. Records should facilitate easy identification of the individual subjects.

2.3.1.11. Quality control and quality assurance

a. A meticulous and specified plan for the various steps and procedures for the purpose of controlling and monitoring the study most effectively

b. Specifications and instructions for anticipated deviations from the protocol

c. Allocation of duties and responsibilities with-in the research team and their co-ordination

d. Instructions to staff including study description (the way the study is to be conducted and the procedures for drug usage and administration)

e. Addresses and contact numbers etc. enabling any staff member to contact the research team at any hour

f. Considerations of confidentiality problems, if any arise

g. Quality control of methods and evaluation procedures

2.3.1.12. Finance and insurance

a. All financial aspects of conducting and reporting a study may be arranged and a budget made out.

b. Information should be available about the sources of economic support (e.g. foundations, private or public funds, sponsor / manufacturer). Likewise it should be stated how the expenditures should be distributed e.g. payment to subjects, refunding expenses of the subjects, payments for special tests, technical assistance, purchase of apparatus, possible fee to or reimbursement of the members of the research team, payment of the investigator / institution etc.)

c. The financial arrangement between the sponsor, the individual researcher(s) / manufacturer involved, institution and the investigator(s) in case such information is not stated explicitly

d. Study Subjects should be satisfactorily insured against any injury caused by the study

e. The liability of the involved parties (investigator, sponsor / manufacturer, institution(s) etc.) must be clearly agreed and stated before the start of the study

2.3.1.13. Publication policy

A publication policy, if not addressed in a separate agreement, should be described in the protocol.

2.3.1.14. Evaluation

a. A specified account for how the response is to be evaluated

b. Methods of computation and calculation of effects

c. Description of how to deal with and report subjects withdrawn from / dropped out of the study

2.3.2. Supplementaries and appendices:

The following documents should be appended with the protocol:

a. Information to the Study Subjects and the mode of providing it

b. Instructions to staff

c. Descriptions of special procedures

2.4. Ethical & Safety Considerations

2.4.1. Ethical Principles

All research involving human subjects should be conducted in accordance with the ethical principles contained in the current revision of Declaration of Helsinki (see Appendix 1) and should respect three basic principles, namely justice, respect for persons, beneficence (to maximize benefits and to minimize harms and wrongs) and non malaficence (to do no harm) as defined by “Ethical Guidelines for Biomedical Research on Human Subjects” issued by the Indian Council of Medical Research and any other laws and regulations of the country, which ensure a greater protection for subjects.

The following principles are to be followed:

a. Principles of essentiality whereby, the research entailing the use of human subjects is considered to be absolutely essential after a due consideration of all alternatives in the light of the existing knowledge in the proposed area of research and after the proposed research has been duly vetted and considered by an appropriate and responsible body of persons who are external to the particular research and who, after careful consideration, come to the conclusion that the said research is necessary for the advancement of knowledge and for the benefit of all members of the human species and for the ecological and environmental well being of the planet.

b. Principles of voluntariness, informed consent and community agreement whereby, Study Subjects are fully apprised of the Study and the impact and risk of such Study on the Study Subjects and others; and whereby the research subjects retain the right to abstain from further participation in the research irrespective of any legal or other obligation that may have been entered into by them or by someone on their behalf, subject to only minimal restitutive obligations of any advance consideration received and outstanding.

c. Principles of non-exploitation whereby as a general rule, research subjects are remunerated for their involvement in the research or experiment; and, irrespective of the social and economic condition or status, or literacy or educational levels attained by the research subjects kept fully apprised of all the dangers arising in and out of the research so that they can appreciate all the physical and psychological risks as well as moral implications of the research whether to themselves or others, including those yet to be born.

d. Principles of privacy and confidentiality whereby, the identity and records of the human subjects of the research or experiment are as far as possible kept confidential; and that no details about identity of said human subjects, which would result in the disclosure of their identity, are disclosed without valid scientific and legal reasons which may be essential for the purposes of therapeutics or other interventions, without the specific consent in writing of the human subject concerned, or someone authorised on their behalf; and after ensuring that the said human subject does not suffer from any form of hardship, discrimination or stigmatisation as a consequence of having participated in the research or experiment.

e. Principles of precaution and risk minimisation whereby due care and caution is taken at all stages of the research and experiment (from its inception as a research idea, its subsequent research design, the conduct of the research or experiment and its applicative use) to ensure that the research subject and those affected by it are put to the minimum risk, suffer from no irreversible adverse effects and, generally, benefit from and by the research or experiment.

f. Principles of professional competence whereby, the research is conducted at all times by competent and qualified persons, who act with total integrity and impartiality and who have been made aware of, and mindful of, the ethical considerations to be borne in mind in respect of such Study.

f. Principles of accountability and transparency whereby, the research or experiment will be conducted in a fair, honest, impartial and transparent manner, after full disclosure is made by those associated with the Study of each aspect of their interest in the Study, and any conflict of interest that may exist; and whereby, subject to the principles of privacy and confidentiality and the rights of the researcher, full and complete records of the research inclusive of data and notes are retained for such reasonable period as may be prescribed or considered necessary for the purposes of post-research monitoring, evaluation of the research, conducting further research (whether by the initial researcher or otherwise) and in order to make such records available for scrutiny by the appropriate legal and administrative authority, if necessary.

h. Principles of the maximisation of the public interest and of distributive justice whereby, the research or experiment and its subsequent applicative use are conducted and used to benefit all human kind and not just those who are socially better off but also the least advantaged; and in particular, the research subject themselves.

i. Principles of institutional arrangements whereby, there shall be a duty on all persons connected with the research to ensure that all the procedures required to be complied with and all institutional arrangements required to be made in respect of the research and its subsequent use or application are duly made in a bonafide and transparent manner; and to take all appropriate steps to ensure that research reports, materials and data connected with the research are duly preserved and archived.

j. Principles of public domain whereby, the research and any further research, experimentation or evaluation in response to, and emanating from such research is brought into the public domain so that its results are generally made known through scientific and other publications subject to such rights as are available to the researcher and those associated with the research under the law in force at that time.

k. Principles of totality of responsibility whereby the professional and moral responsibility, for the due observance of all the principles, guidelines or prescriptions laid down generally or in respect of the research or experiment in question, devolves on all those directly or indirectly connected with the research or experiment including the researchers, those responsible for funding or contributing to the funding of the research, the institution or institutions where the research is conducted and the various persons, groups or undertakings who sponsor, use or derive benefit from the research, market the product (if any) or prescribe its use so that, inter alia, the effect of the research or experiment is duly monitored and constantly subject to review and remedial action at all stages of the research and experiment and its future use.

l. Principles of compliance whereby, there is a general and positive duty on all persons, conducting, associated or connected with any research entailing the use of a human subject to ensure that both the letter and the spirit of these guidelines, as well as any other norms, directions and guidelines which have been specifically laid down or prescribed and which are applicable for that area of research or experimentation, are scrupulously observed and duly complied with.

2.4.2. Ethics Committee:

The sponsor and / or investigator should seek the opinion of an independent Ethics Committee regarding suitability of the Protocol, methods and documents to be used in recruitment of Subjects and obtaining their Informed Consent including adequacy of the information being provided to the Subjects. The Ethics Committees are entrusted not only with the initial view of the proposed research protocols prior to initiation of the projects but also have a continuing responsibility of regular monitoring for the compliance of the Ethics of the approved programmes till the same are completed. Such an ongoing review is in accordance with the Declaration of Helsinki and all the international guidelines for biomedical research

2.4.2.1 Basic Responsibilities

The basic responsibility of an IEC is to ensure a competent review of all ethical aspects of the project proposals received and execute the same free from any bias and influence that could affect their objectivity.

The IECs should specify in writing the authority under which the Committee is established, membership requirements, the terms of reference, the conditions of appointment, the offices and the quorum requirements. The responsibilities of an IEC can be defined as follows :

a. To protect the dignity, rights and well being of the potential research participants.

b. To ensure that universal ethical values and international scientific standards are expressed in terms of local community values and customs.

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

2.4.2.2. Composition

a. IEC should be multidisciplinary and multi-sectorial in composition. Independence and competence are the two hallmarks of an IEC.

b. The number of persons in an ethical committee be kept fairly small (5-7 members). It is generally accepted that a minimum of five persons is required to compose a quorum. There is no specific recommendation for a widely acceptable maximum number of persons but it should be kept in mind that too large a Committee will make it difficult in reaching consensus opinion. 12 to 15 is the maximum recommended number

c. The Chairperson of the Committee should preferably be from outside the Institution and not head of the same Institution to maintain the independence of the Committee. The Member Secretary who generally belongs to the same Institution should conduct the business of the Committee. Other members should be a mix of medical/non-medical, scientific and non-scientific persons including lay public to reflect the differed viewpoints. The composition may be as follows :-

2. 1-2 basic medical scientists (preferably one pharmacologists).

3. 1-2 clinicians from various Institutes

4. One legal expert or retired judge

5. One social scientist / representative of non-governmental voluntary agency

6. One philosopher / ethicist / theologian

7. One lay person from the community

d. The ethical committee at any institution can have as its members, individuals from other institutions or communities if required. There should be adequate representation of age, gender, community; etc. in the Committee to safeguard the interests and welfare of all sections of the community/society. Members should be aware of local, social and cultural norms, as this is the most important social control mechanism. If required subject experts could be invited to offer their views.

2.4.2.3. Terms of Reference

The IEC members should be made aware of their role and responsibilities as committee members. Any change in the regulatory requirements should be brought to their attention and they should be kept abreast of all national and international developments in this regard. The Terms of References should also include a statement on Terms of Appointment with reference to the duration of the term of membership, the policy for removal, replacement and resignation procedure etc. Each Committee should have its own operating procedures available with each member.

2.4.2.4. Review Procedures

The Ethics Committee should review every research proposal on human subjects. It should ensure that a scientific evaluation has been completed before ethical review is taken up. The Committee should evaluate the possible risks to the subjects with proper justification, the expected benefits and adequacy of documentation for ensuring privacy, confidentiality and justice issues. The ethical review should be done through formal meetings and should not resort to decisions through circulation of proposals.

2.4.2.5. Submission of Application

The researcher should submit an appropriate application to the IEC in a prescribed format along with the study protocol at least three weeks in advance. The protocol should include the following:

1. Clear research objectives and rationale for undertaking the investigation in human subjects in the light of existing knowledge.

2. Recent curriculum vitae of the Investigators indicating qualification and experience.

3. Subject recruitment procedures.

4. Inclusion and exclusion criteria for entry of subjects in the study.

5. Precise description of methodology of the proposed research, including intended dosages and routes of administration of drugs, planned duration of treatment and details of invasive procedures if any.

6. A description of plans to withdraw or withhold standard therapies in the course of research.

7. The plans for statistical analysis of the study.

8. Procedure for seeking and obtaining informed consent with sample of patient information sheet and informed consent forms in English and vernacular languages.

9. Safety of proposed intervention and any drug or vaccine to be tested, including results of relevant laboratory and animal research.

10. For research carrying more than minimal risk, an account of plans to provide medical therapy for such risk or injury or toxicity due to over-dosage should be included.

11. Proposed compensation and reimbursement of incidental expenses.

12. Storage and maintenance of all data collected during the trial.

13. Plans for publication of results - positive or negative - while maintaining the privacy and confidentiality of the study participants.

14. A statement on probable ethical issues and steps taken to tackle the same.

15. All other relevant documents related to the study protocol including regulatory clearances.

16. Agreement to comply with national and international GCP protocols for clinical trials.

17. Details of Funding agency / Sponsors and fund allocation for the proposed work.

2.4.2.6. Decision Making Process

The IEC should be able to provide complete and adequate review of the research proposals submitted to them It should meet periodically at frequent intervals to review new proposals, evaluate annual progress of ongoing ones and assess final reports of all research activities involving human beings through a previously scheduled agenda, amended wherever appropriate.

1. The decision must be taken by a broad consensus after the quorum requirements are fulfilled to recommend / reject / suggest modification for a repeat review or advice appropriate steps. The Member Secretary should communicate the decision in writing.

2. A member must voluntarily withdraw from the IEC while making a decision on an application which evokes a conflict of interest which should be indicated in writing to the chairperson prior to the review and should be recorded so in the minutes.

3. If one of the members has her/his own proposal for review, then the member should not participate when the project is discussed.

4. A negative decision should always be supported by clearly defined reasons.

5. An IEC may decide to reverse its positive decision on a study in the event of receiving information that may adversely affect the benefit/risk ratio.

6. The discontinuation of a trial should be ordered if the IEC finds that the goals of the trial have already been achieved midway or unequivocal results are obtained.

7. In case of premature termination of study, notification should include the reasons for termination along with the summary of results conducted till date.

8. The following circumstances require the matter to be brought to the attention of IEC :

a. any amendment to the protocol form the originally approved protocol with proper justification;

b. serious and unexpected adverse events and remedial steps taken to tackle them;

c. any new information that may influence the conduct of the study.

9. If necessary, the applicant/investigator may be invited to present the protocol or offer clarifications in the meeting. Representative of the patient groups or interest groups can be invited during deliberations to offer their viewpoint.

10. Subject experts may be invited to offer their views, but should not take part in the decision making process. However, her/his opinion must be recorded.

11. Meetings are to be minuted which should be approved and signed by the Chairperson.

2.4.2.7. Interim Review

The IEC should decide and record the special circumstances and the mechanism when an interim review can be resorted-to instead of waiting for the scheduled time of the meeting. However, decisions taken should be brought to the notice of the main committee. This can be done for the following reasons:

i) re-examination of a proposal already examined by the IEC;

ii) research study of a minor nature such as examination of case records etc.;

iii) an urgent proposal of national interest.

2.4.2.8. Record Keeping

All documentation and communication of an IEC are to be dated, filed and preserved according to written procedures. Strict confidentiality is to be maintained during access and retrieval procedures. Records should be maintained for the following :

i. the Constitution and composition of the IEC;

ii. the curriculum vitae of all IEC members;

iii. standing operating procedures of the IEC;

iv. national and international guidelines;

v. copies of the Protocol, data collection formats, CRFs, investigational brochures etc. submitted for review;

vi. all correspondence with IEC members and investigators regarding application, decision and follow up;

vii. agenda of all IEC meetings;

viii. minutes of all IEC meetings with signature of the Chairperson;

ix. copies of decisions communicated to the applicants;

x. record of all notification issued for premature termination of a study with a summary of the reasons;

xi. final report of the study including microfilms, CDs and Video-recordings.

It is recommended that all records must be safely maintained after the completion / termination of the study for at least a period of 5 years if it is not possible to maintain the same permanently.

2.4.2.9. Special Considerations

While all the above requirements are applicable to biomedical research as a whole irrespective of the speciality of research, there are certain specific concerns pertaining to specialised areas of research which require additional safe guards / protection and specific considerations for the IEC to take note of. Examples of such instances are research involving children, pregnant and lactating women, vulnerable subjects and those with diminished autonomy besides issues pertaining to commercialisation of research and international collaboration. The observations and suggestions of IEC should be given in writing in unambiguous terms in such instances.

2.4.3. Informed Consent Process

2.4.3.1. Informed Consent of Subject :

Prior to the beginning of the Study the Investigator(s) should obtain the Ethics Committee’s approval for the written informed consent form and all information being provided to the Subjects and / or their legal representatives or guardians as well as an impartial witness.

None of the oral and written information concerning the Study, including the written informed consent form, should contain any language that causes the Subject(s) or their legal representatives or guardians to waive or to appear to waive their legal rights, or that releases or appears to release the Investigator, the Institution, the Sponsor or their representatives from their liabilities for any negligence.

The information should be given to the Subjects and / or their legal representatives or guardians in a language and at a level of complexity that is understandable to the Subject(s) in both written and oral form, whenever possible.

Subjects, their legal representatives or guardians should be given ample opportunity and time to enquire about the details of the Study and all questions answered to their satisfaction.

The Investigator(s), Sponsor or staff of the Institution should not coerce or unduly influence a potential Subject to participate or to continue to participate in the Study. Careful consideration should be given to ensuring the freedom of consent obtained from members of a group with a hierarchical structure- such as medical, pharmacy and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, and members of the armed forces. Persons with incurable diseases, in nursing homes, in detention, unemployed or impoverished, in emergency rooms, homeless persons, nomads, refugees and any ethnic or racial minority groups should be considered as vulnerable population whose mode of consent should be carefully considered and approved by the Ethics Committee.

Prior to the Subject’s participation in the Study the written Informed Consent form should be signed and personally dated by

1. (i) The Subject or (ii) if the Subject is incapable of giving an Informed Consent for example children, unconscious or suffering from severe mental illness or disability, by the Subject’s legal representative or guardian or (iii) if the Subject and his legal representative or guardian is unable to read / write,

2. An impartial witness who should be present during the entire informed consent discussion

By signing the consent form the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the Subject or the Subject’s legal representative or the guardian, and that informed consent was freely given by the Subject or the Subject’s legal representative or the guardian.

The Subject’s legal representative or guardian (if the subject is incapable of giving an Informed Consent for example children, unconscious or suffering from severe mental illness or disability), the inclusion of such patients in the study may be acceptable if the ethics committee is in principle, in agreement, and if the investigator thinks that the participation will promote the welfare and interest of the Subject. The agreement of a legal representative or the guardian that participation will promote the welfare and interest of the Subject should also be recorded with dated signature. If, however, neither the signed Informed Consent nor the witnessed signed verbal consent are possible – this fact must be documented stating reasons by the Investigator and also brought to the knowledge of Ethics Committee without any delay.

2.4.3.2. Essential information for prospective research on subjects : Before requesting an individual's consent to participate in research, the investigator must provide the individual with the following information in the language he or she is able to understand which should not only be scientifically accurate but should also be sensitive to their social and cultural context :

i. the aims and methods of the research;

ii. the expected duration of the subject participation;

iii. the benefits that might reasonably be expected as an outcome of research to the subject or to others;

iv. any alternative procedures or courses of treatment that might be as advantageous to the subject as the procedure or treatment to which she/he is being subjected;

v. any foreseeable risk or discomfort to the subject resulting from participation in the study;

vi. right to prevent use of his/her biological sample (DNA, cell-line, etc.) at any time during the conduct of the research;

vii. the extent to which confidentiality of records could be able to safeguard, confidentiality and the anticipated consequences of breach of confidentiality;

viii. free treatment for research related injury by the investigator / institution;

ix. compensation of subjects for disability or death resulting from such injury;

x. freedom of individual / family to participate and to withdraw from research any time without penalty or loss of benefits which the subject would otherwise be entitled to;

xi. the identity of the research teams and contact persons with address and phone numbers;

xii. foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research and if the material is likely to be used for secondary purposes or would be shared with others, clear mention of the same;

xiii. risk of discovery of biologically sensitive information;

xiv. publication, if any, including photographs and pedigree charts.

The quality of the consent of certain social groups requires careful consideration as their agreement to volunteer may be unduly influenced by the Investigator.

2.4.3.3. Informed Consent in Non-Therapeutic Study :

In case of a Non-Therapeutic Study the consent must always be given by the subject. Non-Therapeutic Studies may be conducted in subjects with consent of a legal representative or guardian provided all of the following conditions are fulfilled:

1. The objective of the Study can not be met by means of a trial in Subject(s) who can personally give the informed consent

2. The foreseeable risks to the Subject(s) are low

3. Ethics Committee’s written approval is expressly sought on the inclusion of such Subject(s)

2.4.4. Essential Information on Confidentiality for Prospective Research Subjects

Safeguarding confidentiality - The investigator must safeguard the confidentiality of research data, which might lead to the identification of the individual subjects. Data of individual subjects can be disclosed only in a court of law under the orders of the presiding judge or in some cases may be required to communicate to drug registration authority or to health authority. Therefore, the limitations in maintaining the confidentiality of data should be anticipated and assessed.

2.4.5. Compensation for Participation

Subjects may be paid for the inconvenience and time present, and should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgement (inducement). All payments, reimbursement and medical services to be provided to research subjects should be approved by the IEC. Care should be taken :

i. when a guardian is asked to give consent on behalf of an incompetent person, no remuneration should be offered except a refund of out of pocket expenses;

ii. when a subject is withdrawn from research for medical reasons related to the study the subject should get the benefit for full participation;

iii. when a subject withdraws for any other reasons he/she should be paid in proportion to the amount of participation.

Academic institutions conducting research in alliance with industries / commercial companies require a strong review to probe possible conflicts of interest between scientific responsibilities of researchers and business interests (e.g. ownership or part-ownership of a company developing a new product). In cases where the review board/committee determines that a conflict of interest may damage the scientific integrity of a project or cause harm to research participants, the board should advise accordingly. Institutions need self-regulatory processes to monitor, prevent and resolve such conflicts of interest. Prospective participants in research should also be informed of the sponsorship of research, so that they can be aware of the potential for conflicts of interest and commercial aspects of the research. Undue inducement through compensation for individual participants, families and populations should be prohibited. This prohibition however, does not include agreements with individuals, families, groups, communities or populations that foresee technology transfer, local training, joint ventures, provision of health care reimbursement, costs of travel and loss of wages and the possible use of a percentage of any royalties for humanitarian purposes.

2.4.6. Selection of Special Groups As Research Subject

2.4.6.1. Pregnant or nursing women :

Pregnant or nursing women should in no circumstances be the subject of any research unless the research carries no more than minimal risk to the fetus or nursing infant and the object of the research is to obtain new knowledge about the foetus, pregnancy and lactation. As a general rule, pregnant or nursing women should not be subjects of any clinical trial except such trials as are designed to protect or advance the health of pregnant or nursing women or foetuses or nursing infants, and for which women who are not pregnant or nursing would not be suitable subjects.

a. The justification of participation of these women in clinical trials would be that they should not be deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines or other agents that promise therapeutic or preventive benefits. Example of such trials are, to test the efficacy and safety of a drug for reducing perinatal transmission of HIV infection from mother to child, trials for detecting fetal abnormalities and for conditions associated with or aggravated by pregnancy etc. Women should not be encouraged to discontinue nursing for the sake of participation in research and in case she decides to do so, harm of cessation of breast feeding to the nursing child should be properly assessed except in those studies where breast feeding is harmful to the infant.

b. Research related to termination of pregnancy: Pregnant women who desire to undergo Medical Termination of Pregnancy (MTP) could be made subjects for such research as per The Medical Termination of Pregnancy Act, GOI, 1971.

c. Research related to pre-natal diagnostic techniques: In pregnant women such research should be limited to detect the foetal abnormalities or genetic disorders as per the Prenatal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, GOI, 1994 and not for sex determination of the foetus.

2.4.6.2. Children:

Before undertaking trial in children the investigator must ensure that -

a. children will not be involved in research that could be carried out equally well with adults;

b. the purpose of the research is to obtain knowledge relevant to health needs of children. For clinical evaluation of a new drug the study in children should always be carried out after the phase III clinical trials in adults. It can be studied earlier only if the drug has a therapeutic value in a primary disease of the children;

c. a parent or legal guardian of each child has given proxy consent;

d. the assent of the child should be obtained to the extent of the child's capabilities such as in the case of mature minors, adolescents etc;

e. research should be conducted in settings in which the child and parent can obtain adequate medical and psychological support;

f. interventions intended to provide direct diagnostic, therapeutic or preventive benefit for the individual child subject must be justified in relation to anticipated risks involved in the study and anticipated benefits to society;

g. the child's refusal to participate in research must always be respected unless there is no medically acceptable alternative to the therapy provided/tested, provided the consent has been obtained from parents/guardian;

h. interventions that are intended to provide therapeutic benefit are likely to be at least as advantageous to the individual child subject as any available alternative interventions;

i. the risk presented by interventions not intended to benefit the individual child subject is low when compared to the importance of the knowledge that is to be gained.

2.4.6.3. Vulnerable groups :

Effort may be made to ensure that individuals or communities invited for research be selected in such a way that the burdens and benefits of the research are equally distributed.

a. research on genetics should not lead to racial inequalities;

b. persons who are economically or socially disadvantaged should not be used to benefit those who are better off than them;

c. rights and welfare of mentally challenged and mentally differently able persons who are incapable of giving informed consent or those with behavioral disorders must be protected.

d. Adequate justification is required for the involvement of subjects such as prisoners, students, subordinates, employees, service personnel etc. who have reduced autonomy as research subjects.

2.4.7. Compensation for Accidental Injury

Research subjects who suffer physical injury as a result of their participation in the Clinical Trial are entitled to financial or other assistance to compensate them equitably for any temporary or permanent impairment or disability subject to confirmation from IEC In case of death, their dependents are entitled to material compensation.

2.4.7.1. Obligation of the sponsor to pay :

The sponsor whether a pharmaceutical company, a government, or an institution, should agree, before the research begins, to provide compensation for any serious sphysical or mental injury for which subjects are entitled to compensation or agree to provide insurance coverage for an unforeseen injury whenever possible.

Prerequisites for the study