Dr. GAURAV YADAV

NUREMBERG WAR CRIMES

Drowning in Seawater, Hypothermia & High Altitude

Experiments at Dachau

Tuskegee Study

28 deaths

100 cases of disability

19 cases of congenital Syphilis

HISTORY 1000 BC : Charaka Samhita

to 1-2 AD

1947 : Nuremberg Code

1956 : Code of Medical Ethics, MCI

1964 : Helsinki Declaration

1979 : Belmont Report 1980 : Policy Statement on Ethical Considerations

involved in research on Human Subject (ICMR)

1982/1992 : Proposed International Guidelines (WHO/CIOMS)

1988 : Schedule Y

1997 : Guidelines for Exchange of Human Biological Material for Biomedical Research Purposes

2000 : Revised ICMR Ethical guidelines

2001 : Indian GCP Guidelines

INTRODUCTION

GENERAL STATEMENT

Medical and related research using human beings as research participants must

necessarily ensure

1. PURPOSE - should be directed towards increase of knowledge about the condition

and for betterment of all human beings.

2. CONDUCT - under conditions of professional fair treatment and transparency, in a

manner consistent with dignity and well being of human subjects.

3. EVALUATION - research must be subjected to evaluation at all stages of the study.

GENERAL PRINCIPLES

1. Principles of essentiality

2. Principles of voluntariness, informed consent and community agreement.

3. Principles of non-exploitation.

4. Principles of privacy and confidentiality.

5. Principles of precaution and risk minimisation.

6. Principles of professional competence.

7. Principles of accountability and transparency.

8. Principles of the maximisation of the public interest and of distributive justice.

9. Principles of institutional arrangements.

10. Principles of public domain.

11. Principles of totality of responsibility.

12. Principles of compliance.

The need for evaluation of research proposals has been emphasized

under the principle of precaution & risk minimisation.

It is mandatory that all proposals on biomedical research involving human

participants should be cleared by an appropriately constituted Institutional

Ethics Committee (IEC), also referred to as Institutional Review Board

(IRB), Ethics Review Board (ERB) and Research Ethics Board (REB) in

other countries, to safeguard the welfare and the rights of the participants.

The Ethics Committees are entrusted not only with the initial review of the

proposed research protocols prior to initiation of the projects but also have

a continuing responsibility of regular monitoring of the approved

programmes to foresee the compliance of the ethics during the period of the

project.

INSTITUTIONAL ETHICS COMMITTEE

(IEC)

Committee comprising of medical, non-medical, scientific and

non-scientific members whose responsibility is to ensure the

protection of the rights, safety and well-being of human

subjects involved in the trial and it shall be responsible for

reviewing & approving the protocol, the suitability of the

investigators, facilities, methods & adequacy of information to

be used for obtaining and documenting informed consent of

the study subjects and adequacy of confidentiality safeguards.

STRUCTURE OF IEC

Composition:

Multidisciplinary and multi sectorial in composition

Number of persons- 8-12 (not less than 7)

Specific members of IECs:

Chair person should preferably be from outside the

Institution to maintain the independence of the

Committee.

Member secretary, from same institution should conduct

the business of the Committee

MEMBERS OF IEC

Chair person

1-2 basic medical scientists

1-2 clinicians from various institutes

One legal expert or retired judge

One social scientist/representative of NG voluntary

agency

One philosopher/ethicist/theologian

One lay person

Member Secretary

As per revised Schedule Y of Drugs & Cosmetics Act, 1940, quorum should

consist of:

1. One basic medical scientist (preferably one pharmacologist).

2. One clinician

3. One legal expert or retired judge

4. One social scientist/ representative of non-governmental

organisation/philosopher/ethicist/ theologian or a similar person

5. One lay person from the community.

(EC) can have as its members, individuals from other institutions or

communities with adequate representation of age and gender to safeguard the

interests and welfare of all sections of the community/society.

If required, subject experts could be invited to offer their views. Similarly, based

on the requirement of research area, for example HIV, genetic disorders etc. it is

desirable to include a member from specific patient groups in the Committee.

MEMBERSHIP REQUIREMENTS

The members representing medical scientists & clinicians should have post

graduate qualifications.

The duration of appointment is initially for a period of 2-3 years

At the end of 2-3 years, as the case may be, the committee is reconstituted, and

50% of the members will be replaced by a defined procedure.

A member can be replaced in the event of death or long-term nonavailability

A member can tender resignation from the committee with proper reasons to do

so.

All members should maintain absolute confidentiality of all discussions during the

meeting and sign a confidentiality form.

Conflict of interest should be declared by members of the IEC

REGISTRATION OF ETHICS COMMITTEE

According to rule 122DD of the recent amendments of Schedule Y – “No ethics

committee shall review and accord its approval to a clinical trial protocol

without prior registration with the licensing authority.”

The registration unless it is suspended or cancelled shall be valid for a period of

three years from the date of issue.

If the ethics committee fails to comply with any of the conditions of registration,

the licensing authority may, after giving an opportunity to show cause, by an

order in writing stating the reasons there for, suspend or cancel the registration

of the ethics committee.

The EC whose registration has been cancelled may within 90 days, appeal to

central govt and central govt after giving an opportunity of being heard, confirm,

reverse or modify such order.

FUNCTIONS OF IEC

To provide competent review of all ethical aspects of the research project

Undertake review free from bias and influence

Provide advice to the researchers on all aspects of welfare and safety of

research participants

To protect dignity, rights and well-being of the potential research

participants.

To report all SAE (serious adverse events) to licensing authority.

To provide an opinion on the compensation to research participants, if

any, in case of injury or death during clinical trial

DEATH/ SAE REPORTED BY PI LICENSING AUTHORITY

within 24 hr SPONSOR, EC

DEATH

detail report by SPONSOR/ PI (10 DAYS)

EXPERT COMMITTEE Copy to Licensing authority, Head of institution

ETHICS COMMITTEE

detail report by ethics committee (21 days)

CHAIRMAN OF EXPERT COMMITTEE Copy to licensing authority

expert committee recommendations (30 days)

LICENSING AUTHORITY

(3 months)

decides quantum of compensation

to be paid & pass necessary orders

SAE other than death

detail report by sponsor/PI (10 days)

LICENSING AUTHORITY, EC

HEAD OF INSTITUTION

detail report by Ethics committee (21 days)

LICENSING AUTHORITY

(may constitute independent expert committee)

within 3 months

decides quantum of compensation

to be paid & pass necessary orders

Sponsor shall pay the compensation as per the order of Licensing authority within 30 days of receipt of such order.

IECs should establish standard operating procedures which should include

Functions and duties of the IEC

Determining its composition, quorum requirements.

Scheduling & conducting meetings

Conducting initial & continuing review of trials

Providing according to regulatory requirements, expedited review

and approval of minor changes in ongoing trials that have the

approval of IEC

Specifying that no subject should be admitted to a trial before the

approval of IEC

Specifying that no deviation from or changes of the protocol should be initiated without prior written IEC approval.

Specifying that the investigator should promptly report to IEC

- deviations from the protocol to eliminate the risk to subjects

- changes increasing the risks to subjects

- all ADRs

- new information that may affect the safety of the subjects or conduct of

the trial

Ensuring that the IEC notifies the investigator concerning

- trial related decision

- reason for its decision

SUBMISSION OF APPLICATION FOR RESEARCH TO

IEC

The following documents must be submitted:

- Trial Protocol (in prescribed format)

- Patient Information Sheet and Informed Consent Form and its

translations

- Investigators brochure

- Principal Investigator’s current C.V.

- Insurance policy/ compensation for participation

- Investigators Agreement with the sponsor

REVIEW OF PROJECT

Scientific evaluation should be completed before ethical evaluation

Evaluate possible risks to the subjects with proper justification

Expected benefits

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

Decisions are preferably arrived at by consensus

The IEC’s member secretary shall screen the proposals for their

completeness and depending on the risk involved categorize them

into:

- Full review

- Expedited review

- Exempted from review

FULL REVIEW

All research proposals presenting with more than minimal risk.

Projects that involve vulnerable population (children, psychiatric

patients etc.,)

Full review is carried out in cases involving

(a) collection of blood samples

(b) Prospective collection of biological specimens eg. Skin

appendages, excreta, saliva, placenta, amniotic fluid, sputum etc.

EXPEDITED REVIEW

Those with no more than minimal risk to research participants

may be subjected to this review

1. Minor deviations from originally approved research.

2. Revised proposal previously approved through full review by the IEC

or continuing review of approved proposals

3. Clinical studies of drugs and medical devices only when -

- research is on already approved drugs except when studying drug

interaction or conducting trial on vulnerable population

- adverse Event (AE) or unexpected Adverse Drug Reaction

(ADR) of minor nature is reported.

EXEMPTED FROM REVIEW

Proposals with less than minimal risk

Research on educational practices such as instructional

strategies or effectiveness of or the comparison among

instructional techniques, curricula, or classroom management

methods.

Following are considered for ethical review

Scientific design and conduct of study

Recruitment of Research Participants

Care and Protection of Research Participants

Protection of research participant confidentiality

Informed Consent Process

SCIENTIFIC DESIGN AND CONDUCT OF

STUDY

Appropriateness of study design

Statistical methodology including sample size calculation

Risk vs anticipated benefits for research participants.

Justification for Controls used

Withdrawal criteria of participants

Criteria for termination of trial

Adequacy of monitoring and auditing the conduct of research.

Site facilities for handling emergencies.

Reporting and Publication issues

RECRUITMENT OF RESEARCH PARTICIPANTS

Study population – demographic characteristics

Means by which participants are contacted and

recruited.

Means by which full information is conveyed to

research participants or their representatives

Criteria for recruitment

Inclusion criteria

Exclusion criteria

CARE AND PROTECTION OF RESEARCH

PARTICIPANTS

Suitability of investigator qualifications and experience for

proposed study.

Medical care to be provided to participants during and

after research.

Adequacy of medical supervision

Steps taken if participants voluntarily withdraw from study

Informed consent

Insurance and indemnity arrangements

PROTECTION OF RESEARCH PARTICIPANT

CONFIDENTIALITY

Description of persons who will have access to personal data

of research participants, including medical records and

biological samples.

Measures taken to ensure the confidentiality and security of

personal information concerning research participants.

INFORMED CONSENT PROCESS

Adequacy, completeness and understandability of written and

oral information given to participants or their legal

representatives

Clear justification for intention to include research

individuals who cannot consent

Assurance that participants will receive any new information

that becomes available

Contact details of persons whom the participants need to

contact for any complaints or queries.

DECISION

Out right approval (at most, only very minor changes are

suggested. The application contained all necessary

information.)

Approval with modifications (there is enough

information to judge the study, but clarification or

changes are needed)

Resubmit with more information (there is not enough

information to judge the application appropriately

Outright disapproval (there is no way the researcher can

ethically do study)

RECORDS

○ Constitution & composition of IEC

○ CV of all members & records of training

○ SOPs of the IEC

○ National & International guidelines

○ Copies of protocol submitted for review

○ All correspondence with IEC members and Investigators

regarding application, decision and follow up.

○ Agenda of all IEC meetings and Minutes signed by chairperson

○ Copies of decisions communicated to applicants

○ Notifications issued for premature termination of study

○ Final report of the study

○ All records must be safely maintained after

completion/termination of study for 3 years.

REVIEW PROCESS

Periodic Review:

Ongoing research may be reviewed at regular intervals of six months

to one year

Continuing Review:

The IEC has the responsibility to continue reviewing approved

projects for continuation, new information, adverse event monitoring,

follow up.

Interim Review:

Interim Review – decide special circumstances for review by sub-

committee – re-examination of proposal already examined by IEC.

IEC : CHALLENGES

Inadequate or no standard operating procedures (SOPs)

Noncompliance with the Schedule Y recommendations

Lack of trained manpower

Heavy workload.

Inadequate space allocated for EC operations

Lack of administrative support, and inadequate remuneration offered

to members serving on EC boards.

No legal experts.

Poor record keeping.

Many EC members are ambiguous about their roles and

responsibilities, during a review process

The failure to conduct internal audits

Absence of accreditation

ACCREDITATION AGENCIES

AAHRPP

SIDCER

The Association for the Accreditation of Human Research

Protection Programs (AAHRPP) is an independent accrediting body

that works to protect the rights and welfare of research participants

and promote scientifically meritorious and ethically sound research.

The Strategic Initiative for Developing Capacity in Ethical Review

(SIDCER) is a network of independently established regional fora

for ethical review committees, health researchers and invited

partner organizations with an interest in the development of ethical

review.

SIDCER- It has developed out of the capacity-building activities of WHO/TDR in

cooperation with the national and international research organizations

SIDCER formally began through the formation of these fora.

FECCIS

FERCAP

FLACEIS

FOCUS

PABIN

Partner organizations

MFES

GCPA

ICMR

WHO/TDR

PATH

FERCI

Forum for Ethics Review Committees in India

National chapter of FERCAP

Constituted in 2002

Registered in 2006

Accounts set up in 2007

FERCI operates in close collaboration with important

institutions like the World Health Organization (WHO), Indian

Council of Medical Research (ICMR), Central Drugs Standard

Control Organization (CDSCO), FERCAP, SIDCER

INFORMED CONSENT

The concept of “Informed Consent” for participation in research was first

recorded in 1900 but it was Nuremberg code in 1947 that first highlighted the

essentiality of voluntariness of this consent.

Declaration of Helsinki further stated it as being essential but it also allows

physicians under special circumstances to use subjects without giving informed

consent.

Various clinical research guidelines require that every adult volunteer must agree

to participate in writing before enrollment in a trial.

Key elements of informed consent : Information, Comprehension,

Voluntariness, Decision making capacity.

INFORMED CONSENT

Written consent is required from each study subject.

Information should be given verbally as well as using a ‘patient information sheet’.

Consent must be obtained in writing using ‘Informed Consent Form’.

Both should have been approved by the ethics committee and furnished to the

Licensing Authority.

Any changes in the informed consent documents should be approved by the ethics

committee and submitted to the Licensing Authority.

Where a subject is not able to give informed consent, the same may be obtained from

a legally acceptable representative

If the Subject or his/her legally acceptable representative is unable to read/write – an

impartial witness should be present during the entire informed consent process.

Checklist for study Subject’s informed consent documents

Essential Elements:

Statement that the study involves research and explanation of the purpose

of the research

Expected duration of the Subject's participation

Description of the procedures to be followed

Description of any risks or discomforts to the Subject

Description of any benefits to the Subject

Disclosure of specific appropriate alternative procedures or therapies

available to the Subject.

Statement describing the extent to which confidentiality of records

identifying the Subject will be maintained and who will have access to

Subject’s medical records

Trial treatment schedule(s) and the probability for random assignment to

each treatment (for randomized trials)

Compensation and/or treatment(s) available to the Subject in the event of a

trial-related injury

An explanation about whom to contact for trial related queries, rights of

Subjects and in the event of any injury the anticipated prorated payment, if

any, to the Subject for participating in the trial

Subject's responsibilities on participation in the trial

Statement that participation is voluntary, that the subject can withdraw from

the study at any time and that refusal to participate will not involve any

penalty or loss of benefits to which the Subject is otherwise entitled

Additional elements

a. circumstances under which the Subject's participation may be terminated by

the Investigator without the Subject's consent.

b. Additional costs to the Subject

c. The consequences of a Subject’s decision to withdraw from the research and

procedures for orderly termination of participation by Subject.

d. Statement that the Subject or Subject's representative will be notified in a timely

manner if significant new findings develop during the course of the research which

may affect the Subject's willingness to continue participation will be provided.

e. A statement that the particular treatment or procedure may involve risks to the

Subject (or to the embryo or fetus, if the Subject is or may become pregnant)

f. Approximate number of Subjects enrolled in the study

Informed Consent FormStudy Title:

Study Number:

Subject’s Initials: _______________ Subject’s Name:_______________

Date of Birth / Age: _________________

(Subject)

(i) I confirm that I have read and understood the information sheet

dated ___ for the above study and have had the opportunity to

ask questions. [ ]

(ii) I understand that my participation in the study is voluntary and

that I am free to withdraw at any time, without giving any

reason, without my medical care or legal rights being affected. [ ]

(iii) I understand that the Sponsor of the clinical trial, others

working on the Sponsor’s behalf, the Ethics Committee and the

regulatory authorities will not need my permission to look at

my health records both in respect of the current study and any

further research that may be conducted in relation to it, even if

I withdraw from the trial. I agree to this access. However, I

understand that my identity will not be revealed in any

information released to third parties or published. [ ]

(iv) I agree not to restrict the use of any data or results that arise

from this study provided such a use is only for scientific

purpose(s) [ ]

(v) I agree to take part in the above study. [ ]

Signature (or Thumb impression) of the Subject/Legally Acceptable Representative:_____________

Date: _____/_____/______

Signatory’s Name: ______________________________________________________

Signature of the Investigator: ____________________________ Date: _____/_____/______

Study Investigator’s Name: __________________________________________________

Signature of the Witness ______________________ Date:_____/_____/_______Name of the Witness: _______________________________________________________

CONCLUSION

ECs continue to play an important role in the ethical conduct of

clinical research. However, ECs as a system are facing challenges

with paucity of trained experts and lack of supervising national

body. This calls for a strong need to focus on capacity building and

establishment of an efficient central body to include all ECs under

its umbrella to bring transparency and accountability in their

functioning. Combined efforts by DCGI, ICMR and individual

ECs will definitely promote a sound culture of clinical research.

Thank U