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					                                       Appendix A-1

                            POLICY ON RECRUITMENT OF
                      TMC STUDENTS AND STAFF FOR RESEARCH


DEFINITIONS

     “Student” means any individual who is enrolled at TMC and those individuals who are in
     training as, Residents, Fellows, or Postdoctoral trainees, including individuals enrolled at
     a training facility other than TMC training or work program.

     “Staff” means all other TMC employees, including faculty.

POLICY GUIDELINES

     TMC students and staff have the same rights as any other potential subject to participate
        in a research project, irrespective of the degree of risk, provided all of the following
        conditions exist:

             The research must not bestow upon participating TMC subjects any competitive
              academic or occupational advantage over other TMC students or staff who do
              not volunteer, and the researchers must not impose any academic or
              occupational penalty on those TMC students or staff who do not volunteer.

             TMC students and staff must not be systematically treated differently from non-
              TMC subjects as part of the project.

             Due to the potential for perceived or real coercion to participate, TMC students
              and staff who desire to participate in the research (especially those under the
              direct supervision of the principal investigator or listed research collaborators)
              must be reviewed by Director TMC.




                                               1
                                       Appendix A-2

             POLICY ON THE RECRUITMENT OF RESEARCH SUBJECTS


SPECIFIC RECRUITMENT GUIDELINES

     (1) In addition to its review for scientific merit and protection of subjects from
         unnecessary research risks, the HEC will evaluate all protocols for subject
         recruitment especially with respect to women with childbearing potential, minority
         groups and children.        Exclusion of minorities, women or children will be
         recommended or approved when inclusion is inappropriate with respect to the
         health of the subjects or the purpose of the research.

     (2) TMC PATIENTS - Patients may be identified as potential research subjects through
         direct contact of the PI with his or her patients, collaboration with physicians of other
         medical specialties, contact with individual attending physicians, posted written
         notices, radio announcements, or other HEC approved methods.

        a. Inpatients - May be recruited by the investigator or other member of the research
           team only after consultation with the patient's attending physician.

        b. Outpatients -

            (i) For minimal risk research which does not bear directly upon a specific
            continuing therapeutic relationship between the individual and a TMC physician,
            outpatients may be recruited* without prior notification of their personal
            physicians. However, when possible, each subject‟s personal physician should
            be notified of the study and informed that the patient has been entered into a
            minimal risk study.

            (ii) For more than minimal risk research or any research bearing directly upon a
            specific diagnosis or treatment, the subject‟s personal physician should be
            notified before enrolling* the subject.

            * If the potential research subject is a minor, then contact must be via a parent or
            legal guardian.




                                               2
                                 Appendix A-3



               POLICY ON RESEARCH COSTS TO SUBJECTS



If a research participant may have to bear any costs, which would be unnecessary if the
subject had declined to participate in the research, all potential subjects must be fully
informed of the nature and estimated extent of these costs when obtaining consent.
Examples of additional research costs include:

1)     Prolongation of treatment or hospitalization.

2)     Extra diagnostic tests necessary for the research.

3)     Extra clinical or laboratory assessments to evaluate research treatment outcome.

4)     A research treatment (whether randomly assigned or not) which may be more
       costly that a standard treatment.

5)     Other substantial costs associated with extra visits to TMC.




                                        3
                                     Appendix A-4

              GUIDELINES ON COMPENSATION FOR RESEARCH SUBJECTS

COMPENSATION FOR PARTICIPATION (ICMR Code 2000)

Subjects may be paid for the inconvenience and time spent, 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 HEC.

Care should be taken:
1) 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;

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

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

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.

During the initial review of a research protocol, the HEC is required to review both the amount of
compensation proposed and the method and timing of disbursement to assure that neither are
coercive or present undue influence. The following are some additional guidelines:

1) Any compensation should not be contingent upon the subject completing the study, but
   should accrue as the study progresses.

2) Unless it creates undue inconvenience or a coercive practice, compensation to subjects who
   withdraw from the study should be made at the time they would have completed the study,
   had they not withdrawn.

3) Compensation given as a “bonus” or incentive for completing the study is acceptable,
   providing that the amount is not coercive. The HEC is responsible for determining if the
   incentive amount is not so large as to be coercive or represent undue influence.

4) The amount of compensation should be clearly set forth in the informed consent document.


Reference: ICMR Code 2000




                                                4
                                          Appendix A-5

              POLICY ON THE USE OF THIRD PARTY/SURROGATE CONSENT
                               IN RESEARCH AT TMC


APPLICABILITY

When a TMC investigator proposes to conduct a research project utilizing adult subjects who by
virtue of age, physical impairment, mental impairment, language barrier or any other reason
may not be able to personally execute legally effective informed consent, the HEC shall review
the project on the basis of "risk" and "benefit" and shall determine that each project be assigned
to one of the categories below. This policy does not mean to imply that the requirement for
written documentation of consent is waived. Rather, it applies to those studies in which
third party/surrogate consent is obtained from a legally authorized representative.
Investigators must complete and submit an HEC Form for review and approval of inclusion of
subjects who are decisionally impaired.

Category I - Risks to subjects are minimal, direct benefits may or will accrue to subjects.

Category II - Risks to subjects are minimal, direct benefits will not, or are unlikely, to accrue to
subjects but potential societal benefits are inherent in research.

Category III - Risks to subject are greater than minimal, direct benefits may or will accrue to
subjects.

Category IV - Risks to subjects are greater than minimal, direct benefits will not, or are unlikely,
to accrue to subjects but potential societal benefits are inherent in the research.

EC RECOMMENDATIONS TO THE ADMINISTRATION

When categorization has been accomplished, the HEC will recommend to the TMC
Administration to consider implementation or non-implementation of the project based upon the
level of benefit to be gained by the individual or society from this project as compared to the
level of risk involved.

It is the intent of the HEC to cause to recommend Category I projects to be initiated.

It is the intent of the HEC not to recommend initiation of any Category IV projects.




                                                 5
                                         Appendix A-6

             POLICY ON BLOOD WITHDRAWAL FOR RESEARCH PURPOSES


APPLICABILITY

For many studies where the only research intervention is the collection of blood for analysis, the
HEC categorizes the following procedures for obtaining blood from children and adults as
minimal risk:

A. General Requirements
    1) There are no special health reasons (e.g., anemia) to contraindicate blood withdrawal.

    2)   In patients from whom blood is already being drawn for clinical purposes, there are no
         other health reasons to preclude additional blood collection.

    3)   In subjects from whom blood is not already being drawn for clinical purposes, the
         withdrawal method is by cutaneous sticks (e.g., heel or finger) or by standard
         venipuncture in a reasonably accessible peripheral vein, and the frequency of
         punctures does not exceed two per week.

    4)   The volume of blood drawn from lactating or known pregnant subjects does not exceed
         20 ml per week.

    5)   All blood withdrawals and collections are carried out by experienced professional or
         technical personnel.

B. Additional Requirements for Adults (Subjects over 18 years of age)

    1)   If less than 50 ml is being collected, there are no additional restrictions with regard to
         hemoglobin or hematocrit.

    2)   If a volume greater than 50 but less than 200 ml is being collected for “no-benefit”
         studies, hemoglobin levels should be >11.0 g/dl for males and >9.5 g/dl for females
         with MCVs >85 fl (These restrictions would not apply if iron deficiency anemia or other
         forms of anemia were critical for inclusion in the study.).

    3)   The cumulative volume withdrawn or collected may not exceed 450 ml per twelve-week
         period (this maximum includes blood being drawn for clinical purposes) from patients
         18 years of age or older in good health and not pregnant.

C. Additional Requirements for Children (Subjects under 18 years of age

    1) No more than three (3) skin punctures are to be made in any single attempt to draw
       blood, and the frequency of punctures does not exceed twice per week.
    2) The volume of blood withdrawn, including blood for clinical purposes, does not exceed
       the lesser of 50 ml or 3 ml/kg in an eight week period and collection may not occur
       more frequently than 2 times per week.
    3) The cumulative volume of clinical and research blood withdrawn per eight-week period


                                                6
   does not exceed six per cent (6.0%) of the child's total blood volume.

4) In patients from whom blood is already being drawn for clinical purposes and when the
   research is directly related to the child's condition, there is no maximum number of
   extra volume specimens which can be collected as long as the preceding requirements
   are met.

5) In subjects from whom blood is not already being drawn for clinical purposes, the
   maximum number of allowable separate specimens (again, within the limits of the
   preceding restrictions) depends upon the child's age and whether the research is
   directly related to the child's condition.

D. Cord Blood

  Cord blood from newborns can be used without restrictions when blood is extracted from
  the placental side of the cord after it has been clamped and severed.

E. Consent

  Oral consent is generally sufficient to collect additional volume (within the limits specified
  above for minimal risk) from patients in whom blood is being drawn for clinical purposes.




                                            7
                                         Appendix A-7

                       POLICY FOR REVIEW OF HUMAN RESEARCH
                         INVOLVING INVESTIGATIONAL DRUGS


Research on investigational drugs or DCGI/RA-approved drugs being used in non-approved
ways, or for non-approved populations (e.g., children) must be reviewed by the HEC. If the
investigational drug is DCGI/RA-approved and is to be used in a non-approved fashion or with a
non-approved population, the HEC may require that the investigator obtain approval from the
DGCI/RA. The investigator must supply the approval before the research can be commenced.
Following approval by the HEC, the HEC office will send a copy of the approval letter to the
Dispensary Department. The investigator should supply the Dispensary with a copy of the
research protocol as well as the investigational use material generated by the drug company
prior to starting the study.

The Department of Medical Oncology/PI will be responsible for the storage, and dispensing of
the drugs used in oncology protocols. The drugs should be physically located in the TMH
Dispensary. It will be the responsibility of the PIs in the Adult and Pediatric Oncology groups to
insure that patients receiving these drugs have signed the appropriate consent forms and that
the patient record contains an investigational drug information sheet containing a brief
description of the drug action, possible side effects, dosage and phone number of the
investigator.




                                                8
                                         Appendix A-8

                        IND APPLICATION EXEMPTION CHECKLIST

This checklist is intended to be used by the investigator as a preliminary test of whether an IND
application needs to be submitted to the DCGI for studies involving DCGI/RA-approved drugs.
If any question is answered "yes", an IND application must be submitted to the DCGI. If the
answers to all questions are "no", then the study may meet the criteria for an exemption from an
IND.


1.     Name of drug

       Dosage

       Route

2.     Does the study involve a different route of administration of the marketed drug than
       already approved?                 YES           NO

3.     Does the study involve the administration of different drug dosage levels that
       significantly increase risk or decrease the acceptability of risk to study subjects?
              YES            NO

4.     Does the study involve the administration of the drug to a different patient population for
       whom there may be increased risk or decreased acceptability of risk?
             YES           NO

5.     Does the study entail any other factor that significantly increases the risk or decreases
       the acceptability of risk to study subjects?        YES           NO

6.     Are the results of the study intended to be reported to the DCGI/RA in support of any
       significant change in labeling or advertising for the drug (only for corporate sponsored
       studies)?            YES            NO




       Signature of Investigator                                                  Date




                                                9
                                    APPENDIX A-9

               PROCEDURES FOR FILING A NOTICE OF CLAIMED
               INVESTIGATIONAL EXEMPTION FOR A NEW DRUG


A.   INTRODUCTION

     1.   Before a new drug may be tested on human subjects, the sponsor (usually a
          pharmaceutical firm or possibly a physician) must give the DCGI/RA the
          information specified as a "Notice of Claimed Investigational Exemption for a
          New Drug" (IND)

B.   REQUIREMENTS FOR THE IND

     1.   Complete composition of the drug, its source, and manufacturing data to insure
          its safety.

     2.   Results of all pre-clinical investigations including animal studies. These data
          must demonstrate that there will be no unreasonable hazard in using the drug
          with humans. Further animal studies may be conducted concurrently with the
          clinical studies.

     3.   A detailed outline (protocol) of the planned investigation.

     4.   Information regarding the training and experience of the investigators.

     5.   Copies of all informational material supplied to each investigator.

     6.   An agreement from the sponsor to notify the DCGI/RA and all investigators if any
          adverse effects arise during either the animal or human tests.

     7.   The investigators agreement to obtain the consent of the person on whom the
          drug is to be tested prior to the testing.

     8.   Agreement to submit annual progress reports and commitments regarding
          disposal of the drug when studies are discontinued.

C.   PHASES OF INVESTIGATIONAL DRUG TESTING

     1.   Phase I Studies are designed to determine the toxicity, metabolism absorption
          and elimination, pharmacological actions, preferred route of administration and
          safe dosage range. These studies generally involve a small number of subjects
          and are conducted under the careful direction of people trained in Medical
          Oncology.




                                           10
     2.     Phase II Studies are clinical trials on a limited number of patients for a specific
                  disease treatment or prevention. Additional pharmacological studies on
                  animals may be performed concurrently in order to indicate safety.

     3.     Phase III Studies are in order if the information obtained for Phase I and II
            studies demonstrate reasonable assurance of safety and effectiveness, or
            suggests that the drug may have a potential value that outweighs its possible
            hazards. Phase III studies are intended to assess the drug's safety, specific
            disease in a large group of subjects.


D.   INVESTIGATOR QUALIFICATIONS

     The following information is generally required about the clinical investigator:

     1.     Education, training and experience.

     2.     Information about the hospital or medical institution where the study will be
            conducted.

E.   OBLIGATIONS OF INVESTIGATORS

     1.     The investigator must keep careful records of his study and retain them for at
            least two years after IND approval.

     2.     The records must be made available to the sponsor and the DCGI/RA when
            required.

     3.     Regular progress reports must be sent to the sponsor.

     4.     Reports of adverse reactions must be sent to the sponsor immediately.

     5.     The investigator must observe the regulations regarding consent of human
            subjects involved in research.




                                              11
                                      APPENDIX A-10

                 GUIDELINES AND POLICY ON INFORMED CONSENT

A   GENERAL REQUIREMENTS

    Except as described below, investigators may not enroll human subjects in research
    unless they have obtained the legally effective, written, informed consent of the subject
    or the subject‟s legally authorized representative, prior to enrollment of the subject in the
    research.     Investigators are responsible for insuring that subjects, or their
    representatives, are given sufficient opportunity to consider whether or not to participate
    and must seek to avoid coercion or undue influence. Information given to potential
    subjects or their representatives must be in language that is understandable to the
    subject or representative. No process of obtaining consent may include language
    through which the subject waives any of their legal rights or releases or appears to
    release the investigator, sponsor, or institution or its agents from liability for negligence.

B   ELEMENTS OF INFORMED CONSENT

    A current sample informed consent document with required phraseology may be found
    in Appendix B-2. The sample consent form contains all the required elements of
    consent. The HEC requires that all consent forms be written in the first person, e.g., “I
    understand that…”. The following are the basic required elements:

    1) A statement that the study involves research, an explanation of the purpose of the
       proposed research, the duration of the subject‟s participation, a description of the
       procedures, and which procedures are experimental;

    2) The number of subjects that will be involved with the study, totally and at TMC;

    3) A description of reasonably foreseeable risks or discomforts that the subjects may
       encounter, and, if appropriate, a statement that some risks are currently
       unforeseeable;

    4) A description of possible benefits, if any, to the subject and others which may be
       reasonably expected. It should be stated that since it is an experimental treatment or
       procedure, no benefits can be guaranteed;

    5) A discussion of possible alternative procedures or treatments, if any, which are
       available to the subject. One alternative might be to choose not to participate in the
       research and this will not affect the usual standard of care;

    6) A discussion of how confidentiality of records associated with the subject will be
       maintained;

    7) A description of any compensation or reimbursement for time, inconvenience, travel,
       parking, and other similar costs to the subject;

    8) A description of any provisions for treatment of or compensation for research related
       injury;


                                             12
    9) A statement of whom to contact for answers about the research and in the event
       there is a research related injury. (This is generally the PI or another staff member
       closely associated with the study.) A separate contact must be named for questions
       concerning the subject‟s rights;

    10) A statement that the subjects‟ participation is voluntary, that refusal to participate will
        not involve penalty or loss of benefits to which the subject is entitled, and that the
        subject may discontinue participation at any time without penalty or loss of benefits;

    11) If appropriate, any circumstances under which the subjects participation may be
        terminated, with or without the subjects consent; and

    12) A description of additional costs for which the subject will be responsible, that are
        likely to result from participation in the research study.

C   WAIVER OF INFORMED CONSENT

    The HEC may waive the requirements for obtaining informed consent or approve a
    consent procedure which does not include, or which alters, some or all of the elements
    of informed consent listed above, provided that:

    1) The research involves no more than minimal risk to the subjects

    2) The waiver or alteration will not adversely effect the rights and welfare of the
       subjects

    3) The research could not practicably be carried out without the waiver or alteration;
       and

    4) Whenever appropriate, the subjects will be provided with additional pertinent
       information after participation.


D   DOCUMENTATION OF INFORMED CONSENT

    Informed consent must be documented by the use of a written consent form reviewed
    and approved by the HEC and signed by the subject or subject‟s legally authorized
    representative. A copy must be given to the subject or person signing the form. For
    TMC patients, a copy of the signed consent form should also be placed in the subject‟s
    medical record. It is assumed that the consent form is only part of the total consent
    process in which the investigator, perhaps using the written consent form as an outline,
    describes all facets of the study and answers the subject‟s questions. The investigator
    is responsible for insuring that research subjects understand the research
    procedures and risks. Failure of the subjects to ask questions should not be
    construed as understanding on the part of the subject.




E   RECORD RETENTION REQUIREMENTS FOR SUBJECT CONSENT FORMS


                                              13
1) The principal investigator or project director shall maintain, in a designated location, all
    executed subject consents. These consent forms are to be available for inspection by
    authorized officials of the HEC, DSMSC, regulatory agencies and sponsors. For
    DGCI/RA regulated test article studies, all signed subject consent forms shall be
    retained by the principal investigator for the appropriate period(s) specified below.

    Drugs: Two (2) years following the date a marketing application is approved or the
    study is discontinued.

    Devices: Two (2) years after a study is terminated or completed and the records are
    needed to support DCGI/ RA approval.




                                            14
                                         APPENDIX A-11

                 POLICY FOR DOCUMENTATION OF INFORMED CONSENT


I. INFORMED CONSENT PROCESS
1. Informed Consent of Subject : For all biomedical research involving human subjects, the
investigator must obtain the informed consent of the prospective subject or in the case of an
individual who is not capable of giving informed consent, the consent of a legal guardian.
Informed consent is based on the principle that competent individuals are entitled to choose
freely whether to participate in research or not. Informed consent protects the individual‟s
freedom of choice and respect for individual‟s autonomy.
When research design involves not more than minimal risk (for example, where the research
involves only collecting data from subject‟s records) the HEC may waive off some of the
elements of informed consent.
Waiver of informed consent could also be considered during conditions of emergency. However,
this would be permissible only if HEC has already approved the study or use of drug. However,
the patient or the legal guardian should be informed after she/he regains consciousness or is
able to understand the study.
2. Obligations of investigators regarding informed consent : The investigator has the duty
to -
i. Communicate to prospective subjects all the information necessary for informed consent.
There should not be any restriction on subject‟s right to ask any questions related to the study
as any restriction on this undermines the validity of informed consent.
ii. Exclude the possibility of unjustified deception, undue influence and intimidation. Deception of
the subject is not permissible. However, sometimes information can be withheld till the
completion of study, if such information would jeopardize the validity of research.
iii. Seek consent only after the prospective subject is adequately informed. Investigator should
not give any unjustifiable assurances to prospective subject, which may influence the subject‟s
decision to participate in the study.
iv. As a general rule obtain from each prospective subject a signed form as an evidence of
informed consent (written informed consent) preferably witnessed by a person not related to the
trial, and in case of incompetence to do so, a legal guardian or other duly authorised
representative.
v. Renew the informed consent of each subject, if there are material changes in the conditions
or procedures of the research or new information becomes available during the ongoing trial.
vi. Not use intimidation in any form which invalidates informed consent. The
investigator must assure prospective subjects that their decision to participate or
not will not affect the patient - clinician relationship or any other benefits to
which they are entitled.
3. Essential information for prospective research 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;



                                                15
       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 maintained ie., the limits to
       which the investigator would be able to safeguard confidentiality and the anticipated
       consequences of breach of confidentiality;
       viii. responsibility of investigators;
       ix. free treatment for research related injury by the investigator / institution;
       x. compensation of subjects for disability or death resulting from such injury;
       xi. 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;
       xii. the identity of the research teams and contact persons with address and phone
       numbers;
       xiii. 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;
       xiv. risk of discovery of biologically sensitive information;
       xv. 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.
This is accomplished as part of the total consent process by using a consent form that has been
reviewed and approved by the HEC. Confusion sometimes arises as to who can obtain consent
and who can be designated to sign the consent form. The following are the acceptable methods
for documentation of informed consent of human research subjects at TMC:

       1. The HEC must be made aware of the person (s) who will be conducting the consent
          interviews. These faculty/staff members should be the only personnel allowed to
          obtain consent unless indicated otherwise. The HEC requires that the person
          obtaining consent is medically trained.

       2. Each subject (or their legally authorized representative) must be provided adequate
          time to read and review the consent form, in addition to being advised of the
          procedures, risks, potential benefit, alternatives to participation, etc. This is
          frequently accomplished using the consent form as an outline for the interview
          process.

       3. After completing the consent interview and assuring that the subject (or their
          representative) has no further questions and agrees to participate in the research
          activity, the interviewer should instruct the subject to sign and date the consent form
          in the appropriate spaces.

       4. A witness must sign and date in the appropriate spaces. The witness cannot be the
          person conducting the consent interview, but is not further restricted.

       5. The person conducting the consent interview must then sign and date the consent
          form in the appropriate spaces (PI or designee). It is assumed that in most cases, all
          persons signing the consent form will do so at the conclusion of the consent
          interview.


                                               16
6. Each subject (or their representative) must be given a copy of the signed consent
   form. The original consent form should be filed in such a manner as to insure
   immediate retrieval when required by auditing entities, HEC, or sponsor monitors.

7. The regulations are clear that written documentation informed consent is required.
   Therefore, obtaining consent from an authorized third party via the telephone is not
   acceptable.

8. The regulations also include provisions for approval of a waiver or alteration of part
   or all of the consent process. The HEC will consider written requests for waiver or
   alteration of the process when accompanied by sufficient justification.

9. Obtaining informed consent from subjects must be accomplished prior to performing
   the research activity and using only an HEC approved consent form. Written
   requests for amendments to an existing consent form must be approved by the HEC
   prior to implementation.

10. Upon receipt of an HEC approved consent form, all old versions should be
   discarded to prevent inadvertent use of an outdated consent form. Copies of the
   most recently approved consent form may be made and should be used until
   superceded by an amended consent form. The consent form must be reviewed at
   least annually as part of the continuing review process.




                                       17
                                          APPENDIX A-11


   POLICY ON REPORTING SERIOUS ADVERSE EVENTS AT TATA MEMORIAL CENTRE

APPLICABILITY

When a person who is participating in research protocol experiences a serious adverse reaction,
the principal investigator is required to report the incident to the HEC.

If the adverse events were anticipated as a part of the protocol and the research subject was
informed in the consent form, the HEC does not need to be notified unless the adverse event was
unexpectedly serious, life threatening or fatal.

If the adverse events were unanticipated, required that the subject be hospitalized or death has
occurred, the adverse event(s) must be reported to the HEC within 24 hours.

If the research project is being supported with funds from outside the institution, the investigator is
responsible also for notifying the sponsor. The sponsor may also be required to notify the
DCGI/RA or other government agencies within 24 hours of the occurrence of the adverse event(s).
If the faculty member holds an Investigational New Drug (IND) or Investigational Device Exemption
(IDE) in his/her name, he/she is required to notify the DGCI/RA within 24 hours of any
unanticipated adverse reactions in addition to notifying the HEC.
Notifying the HEC does not relieve the investigator from his/her responsibility to notify the sponsor,
DGCI/RA.

PROCEDURES

Within 24 hours of learning about an adverse event, the principal investigator is responsible for
notifying the HEC Office. The investigator is to submit a written report to the HEC within 10
working days.




                                                  18
                                           Appendix A-12

    EXAMPLES OF CATEGORIES OF RESEARCH THAT MAY BE REVIEWED BY THE HEC
                 THROUGH AN EXPEDITED REVIEW PROCEDURE

An expedited review procedure consists of a review of research involving human subjects by the
HEC chairperson or by one or more experienced reviewers designated by the chairperson from
among members of the HEC.

Applicability

A    Research activities that
        1 present no more than minimal risk to human subjects, and
        2 involve only procedures listed in one or more of the following categories, may be
      reviewed by the HEC through the expedited review procedure. The activities listed should
      not be deemed to be of minimal risk simply because they are included on this list.
      Inclusion on this list merely means that the activity is eligible for review through the
      expedited review procedure when the specific circumstances of the proposed research
      involve no more than minimal risk to human subjects.

B    The categories in this list apply regardless of the age of subjects, except as noted.

C The expedited review procedure may not be used where identification of the subjects and/or
their responses would reasonably place them at risk of criminal or civil liability or be damaging
to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing,
unless reasonable and appropriate protections will be implemented so that risks related to
invasion of privacy and breach of confidentiality are no greater than minimal.


D The standard requirements for informed consent (or its waiver, alteration, or exception)
apply regardless of the type of review, expedited or convened, utilized by the HEC.

E Categories one (1) through seven (7) pertain to both initial and continuing HEC review.

        1     Clinical studies of drugs and medical devices only when condition a or b is met.

                a Research on drugs for which an investigational new drug application is not
      required. (Note: Research on marketed drugs that significantly increases the risks or
      decreases the acceptability of the risks associated with the use of the product is not
      eligible for expedited review.)

                 b Research on medical devices for which
                         ii      an investigational device exemption application is not required; or
                         iii     the medical device is cleared or approved for marketing and the
            medical device is being used in accordance with its cleared/approved labeling.

        2 Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as
      follows:
               a from healthy, non-pregnant adults who weigh at least 110 pounds. For these
        subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection
        may not occur more frequently than 2 times per week; or


                                                  19
                 b from other adults and children, considering the age, weight, and health of the
          subjects, the collection procedure, the amount of blood to be collected, and the
          frequency with which it will be collected. For these subjects, the amount drawn may not
          exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not
          occur more frequently than 2 times per week.

        3 Prospective collection of biological specimens for research purposes by noninvasive
means. Examples:
              a hair and nail clippings in a non-disfiguring manner;
              b deciduous teeth at time of exfoliation or if routine patient care indicates a
              need for extraction;
              c    permanent teeth if routine patient care indicates a need for extraction;
              d excreta and external secretions (including sweat);
              e uncannulated saliva collected either in an unstipulated fashion or stimulated
      by chewing gumbase or wax or by applying a dilute citric solution to the tongue;
              f placenta removed at delivery;
              g amniotic fluid obtained at the time of rupture of the membrane prior to or
during labor;
              h supra- and subgingival dental plaque and calculus, provided the collection
procedure is not more invasive than routine prophylactic scaling of the teeth and the process is
accomplished in accordance with accepted prophylactic techniques;
              i mucosal and skin cells collected by buccal scraping or swab, skin swab, or
mouth washings;
              j sputum collected after saline mist nebulization.

      4 Collection of data through noninvasive procedures (not involving general anesthesia
or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or
microwaves. Where medical devices are employed, they must be cleared/approved for
marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are
not generally eligible for expedited review, including studies of cleared medical devices for new
indications.) Examples:
                 a physical sensors that are applied either to the surface of the body or at a
                 distance and do not involve input of significant amounts of energy into the subject
                 or an invasion of the subject's privacy;
                 b weighing or testing sensory acuity;
                 c magnetic resonance imaging;
                  d electrocardiography, electroencephalography, thermography, detection of
naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging,
doppler blood flow, and echocardiography;
                  e moderate exercise, muscular strength testing, body composition assessment,
and flexibility testing where appropriate given the age, weight, and health of the individual.

       5     Research involving materials (data, documents, records, or specimens) that have
been collected or will be collected solely for non-research purposes (such as medical treatment
or diagnosis).
       6 Collection of data from voice, video, digital, or image recordings made for research
purposes.

      7      Research on individual or group characteristics or behavior (including, but not limited
            to, research on perception, cognition, motivation, identity, language, communication,
            cultural beliefs or practices, and social behavior) or research employing survey,


                                                  20
          interview, oral history, focus group, program evaluation, human factors evaluation, or
          quality assurance methodologies.

      8   Continuing review of research previously approved by the convened HEC as follows:

                  A where (i) the research is permanently closed to the enrollment of new
subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research
remains active only for long-term follow-up of subjects; or
                  B where no subjects have been enrolled and no additional risks have been
identified; or
                  C where the remaining research activities are limited to data analysis.

      9   Continuing review of research, not conducted under an investigational new drug
          application or investigational device exemption where categories two (2) through eight
          (8) do not apply but the HEC has determined and documented at a convened meeting
          that the research involves no greater than minimal risk and no additional risks have
          been identified.




                                                 21
                                         Appendix A-13

                                  HEALTH RECORD RESEARCH


       The following is the HEC policy concerning research involving the study of medical
records or other forms of health information.

         Research projects may involve the study of Patient case files with the stipulations
described below. Such studies raise issues of confidentiality that must be carefully addressed
by the investigator and the official custodian of the records. If it is anticipated that an
individual's records or specimens will likely be used for research purposes, the potential subject
should be informed of the potential use of such materials upon entry into the institution or
program in which the materials will be developed or collected and be given an opportunity to
either provide or refuse consent to such research. Patient case files may always be used or
disclosed for research purposes if it has been de-identified and linkage back to a specific patient
would not be possible.
         To use or disclose identifiable Patient case files without authorization of the research
participant, the investigator must accomplish one of the following:
         1) complete and submit an HEC Form to request waiver of the requirements for
obtaining informed consent;
         2) provide written documentation that the use of disclosure of patient case files is solely
used to design a research protocol or to assess feasibility of conducting a study, or;
         3) document that the use or disclosure is solely for research on the patient case files of
decedents.
         Investigators must maintain in their files a letter from the HEC identifying the date on
which the waiver or alteration of the requirements to obtain informed consent was approved by
the HEC, and a statement that the HEC has determined that the waiver or alteration satisfies
the following criteria:

       1) The use or disclosure of patient case files involves no more than minimal risk to the
           research participants;

       2) The alteration or waiver will not adversely affect the privacy rights and welfare of the
           subjects;

       3) The research cannot practicably be conducted without the alteration or waiver;

       4) The research could not practicably be conducted without access to or the use of the
          patient case files;

       5) The privacy risks to individuals whose Patient case files is to be used or disclosed are
          reasonable in relation to the anticipated benefits, if any, to the individuals, and the
          importance of the knowledge that may reasonable be expected to result from the
          research;

       6) There is an adequate plan to protect the identifiers from improper use and disclosure;

       7) There is an adequate plan to destroy the identifiers at the earliest possible opportunity
          consistent with the conduct of the research, unless there is a health or research
          justification for retaining the identifiers, and;


                                                22
       8) There are adequate written assurances that the Patient case files will not be reused or
          disclosed to any other person or entity, except as required by law, for authorized
          oversight of the research project, or for other research for which the use or disclosure
          of Patient case files would be permitted by this policy.

        The HEC letter should also contain a brief description of the Patient case files for which
use or access has been determined by the HEC to be necessary, a statement that the waiver or
alteration was approved by Expedited Review or at a convened meeting, and the letter should
be signed by the HEC Chair or the Chair‟s designee.

       Research use or disclosure of identifiable Patient case files with authorization of the
research participant is permitted providing that use or disclosure is for only the Patient case files
that was originally authorized. In order to use or disclose additional information, the investigator
would either have to obtain consent or request a waiver of the requirements to obtain consent.




                                                 23
                                         Appendix A-14

              GUIDELINES FOR RESEARCH PROTOCOLS WHICH REQUIRE
               COLLECTION AND STORAGE OF GENETICS MATERIALS

For the purpose of these guidelines, "Genetic Materials" are defined as human tissue samples
(blood, serum, tumor, etc.) on which genetic related research, such as biochemical studies of
inherited human traits or identification of DNA mutations, may be performed.

A. Previously acquired samples
    1. Previously acquired genetic material may be used if identifiers are stripped irrevocably
    from samples.

    2. If identifiers are present, experiments not described in present protocols must be
    submitted for HEC review.


B. Prospectively acquired samples

  1. Anonymous samples (further identification made impossible)

       a) Ownership of genetic material will generally remain with the institution. This must be
       stated in the consent form.

       b) The general scope of the investigations must be explained in the consent form, but
       new avenues of investigation in the future are permissible if this possibility is explained
       in the consent form.

       c) Whether the genetic material will be shared by other investigators should be explicit in
       the consent form.

       d) The consent form should make clear that no specific information relative to the
       individual donor will be forthcoming; however, information that accrues from the study
       that is valuable to society may be shared with the individual.

  2. Identified samples

       a) If genetic material is linked to the donor by specific identifiers, ownership of the
       material will generally remain with the institution. If a commercial use is anticipated for
       the genetic material, the individual must be notified. The general policy of ownership
       should be stated in the consent form using the following wording:

       "I understand that additional or "leftover" (blood, serum, tumor, etc.) tissue may be used
       for future research which may result in financial gain for TMC and the researchers. I
       also understand that my donated tissue will be one of many that are used in the
       research and it will be virtually impossible to attribute findings to any one sample. I
       understand, however, that I am not otherwise waiving any of my legal rights by
       participating in this study."

       b) If identifiers are present, new experiments must be reviewed by the EC and new
       consent obtained from the research participant regardless of the details of ownership.


                                                24
       c) The investigator may include a provision in the consent form for new experiments not
       requiring new consent if identifiers are irrevocably removed from the samples. If the
       investigator anticipates future experiments without identifiers, this possibility should be
       present in the original consent form. The methods for removal of identifiers must be
       approved by the EC. Removal of identifiers must not be employed as a method of
       avoiding ownership issues.

       d) A satisfactory method for sharing or withholding information gained by the research
       must be in the research protocol and clearly indicated in the consent form.

       e) Details for sharing or not sharing the genetic material with other investigators must be
       present in the protocol and clearly indicated in the consent form.

       f) The length of time the genetic material will be maintained must be indicated in the
       consent form.

C. Donation of genetic material as a requirement for participation in a research protocol.

   1. Donation of genetic material may be required for participation in a protocol only if the
   presence of the genetic material is necessary to satisfy the central question of the research.

   2. The investigator will be required to make a clear case in the research protocol for the
   necessity of the genetic material, if donation of genetic material is mandatory.

               3. This policy applies to genetic material with or without identifiers.




                                                 25
                                         Appendix A-15


GUIDELINES FOR SUBMISSION AND EC REVIEW OF GENE THERAPY/GENE TRANSFER
                              PROTOCOLS

As of October 10, 2000 the ICMR formulated Ethical Guidelines for Biomedical Research on
Human Subjects. ICMRs goal is to insure that no research participant is enrolled in a human
gene therapy/gene transfer research protocol before the local HEC have the benefit of the broad
perspective and experience in protocol review and risk assessment.

In November 2001, the Department of Biotechnology also finalised the Ethical Policies on the
Human Genome, Genetic Research and Services.
Guidelines are available at the Office of Biotechnology Activities Internet site
http://dbtindia.nic.in/ethical.html

The following items are required to be addressed in the protocol to provide the necessary
information for EC review:

A Background and justification

   Why is this disease a good candidate for gene transfer or gene therapy?

   What previous work has been done, including studies of animals and cultured cell models?
    Does the work demonstrate effective gene delivery? How does the proposed study relate to
    previous work?

   Is the disease course sufficiently predictable to allow for meaningful assessment of the
    results of the treatment proposed?

   What level of gene expression is presumed to be required to achieve the desired effect?

   Given responses to the above questions, is there a sufficient justification for the investigator
    to proceed at this point to a clinical trial?

B Research design

   What are the objectives of the proposed study (e.g., establishing feasibility or relative safety
    of the gene transfer, determining therapeutic effectiveness, establishing a safe dose range,
    demonstrating proof of principle, etc.)?

   Is the goal of the study to ameliorate or cure disease or to enhance healthy individuals?

   What is the target tissue for gene transfer (e.g., bone marrow cells, skeletal muscle cells,
    respiratory epithelial cells, central nervous system tissue, etc.)?

   What method(s) (e.g., direct injection, inhalation, ex vivo genetic modification with injection
    of modified cells) and reagent(s) (e.g., vectors based on retroviruses, adenoviruses, adeno-
    associated viruses, herpes viruses) will be employed for gene delivery? What is the



                                                 26
    rationale for their use? Are other methods or reagents known that are more appropriate with
    regard to efficacy, safety, and stability?

   How will the investigator determine the proportion of cells that acquires and expresses the
    added DNA?

   How will the investigator determine if the product is biologically active?

   Is the planned statistical treatment appropriate: i.e., is it likely to provide valid answers to
    the study question?

   Is it reasonable to expect that the research design proposed will meet the investigator‟s
    objectives?

C Procedures

   What research-specific procedures and research-specific investigations are required by the
    study over and above those that would be required for patients receiving standard clinical
    care (e.g., physical examinations, venous or arterial blood tests, collection of target cells,
    imaging procedures, irradiation, chemotherapy, direct injection of vector, re-injection of
    genetically modified cells, organ or tissue transplantation, surgery, tissue/tumor donation,
    questionnaires, interviews)?

   Is long term follow-up appropriate or essential for this protocol? If long term follow-up is
    proposed, is there justification for the number of visits and the length of time required? Is
    such follow-up feasible in the case of this protocol (e.g., have provisions been made for
    subjects who move? Is adequate funding available for such follow-up?)?

   What are the procedures for obtaining or maintaining information in a data/DNA bank (e.g.,
    use of identifiers, limitation on access, need for consent, sharing with other investigators,
    duration of storage, future subject contact)?

   Are all of the research-specific procedures necessary? In combination with data collected in
    the course of clinical care, is it reasonable to expect that the information produced by this
    study will be sufficient to answer the research question?

D   Confidentiality

   Are the practical steps for maintaining confidentiality of data/records/database information
    clearly specified and adequate (e.g., encryption, use of unique identifiers, sequestering of
    records, security measures)?

E Subject selection

   How has the study population been defined?

   Has an adequate rationale been provided for each eligibility criterion (e.g., safety
    considerations, definition of disease, avoidance of additional concurrent therapies,
    administrative considerations)? Do they strike a defensible balance between scientific



                                                 27
    validity and generalizability (i.e., is the study population sufficiently, but not unduly, restricted
    so as to yield interpretable results)?

   How will subjects be recruited? If a cohort of eligible patients exists, how will selection be
    made amongst them? If several trials exist for which the same patients are eligible, how will
    this be presented to prospective subjects?

   Does the definition of the research population reflect appropriate scientific, clinical, and
    ethical norms? In recruiting and negotiating with potential subjects, have the norms of
    nondiscrimination been respected?

F Risks, discomforts, and benefits

   What risks and discomforts are associated with the research-specific procedures and
    investigations (e.g., surgery, chemotherapy, radiation, bone marrow transplantation)? Have
    they been minimized?

   If a virus-mediated gene transfer is proposed, what is the potential for the presence of a
    replication-competent or pathological virus or other form of contaminants? How sensitive
    are the tests to detect such viruses or contaminants? What level of viral presence or other
    form of contamination would be tolerable in this protocol?

   Has the possibility of vertical transmission (i.e., gene insertion into germ cells or a fetus) or
    horizontal transmission (e.g., to family members or health care staff) been considered?
    What measures have been taken to minimize the risks of transmission? Are other measures
    possible? If transmission were to occur, what would be the consequences?

   What are the risks for the vector to activate an oncogene or inactivate a tumor suppressor
    gene leading to vector-related malignancy?

   Are the risks and discomforts of the study justified given the potential benefit to subjects and
    the scientific importance of the research?

F   Information to subjects

   Have prospective participants been adequately informed of the following:

    1. What is being studied and why, giving details about study procedures, known or
       potential risks, discomforts and benefits, and alternatives to participation;

    2. Their rights: (a) to information on an ongoing basis, confidentiality with regard to their
       participation and handling of their data, and the right to consult with others before
       making a decision whether to participate; and (b) to withdraw from the study without
       penalty or loss of benefits, as well as of any health consequences of withdrawal for
       themselves or their immediate contacts, or limitations on withdrawal, if any;

    3. Any special issues related to this gene therapy trial, such as uncertainty associated with
       short and long term risks and benefits or the possibility of media attention; and

    4. Any commercial or financial interests in the research.


                                                   28
   Have prospective participants been provided this information in simple language, using
    translation where necessary, with answers to their questions, referral to other sources of
    information, and adequate time to make up their minds whether to participate?

   If there is no individual benefit from participation in the research, has this been appropriately
    disclosed?

   Will the general study results be made available to subjects?

   Do all of the elements of the consent process combine to allow subjects a full opportunity to
    make an informed choice?


1. Reference: Ethical Guidelines for Biomedical Research on Human Subjects ICMR 2000




                                                 29
                                         APPENDIX A-16

      HEC POLICY FOR DATA AND SAFETY MONITORING IN CLINICAL RESEARCH


Concerns for assuring the safety and welfare of subjects participating in clinical research studies
have prompted the issuance of guidance and policies on oversight of clinical trials. More
specifically, investigators are now required to establish plans for ongoing, real time data and
safety monitoring. Specific responsibility for and methods of data and safety monitoring depend
on the sponsor of the study and the phase of the study. The methods and amount of monitoring
required are somewhat dictated by the degree of risk involved to the individual subjects and the
complexity of the clinical research. Some clinical research activities may require the
establishment of a Data and Safety Monitoring Board/Committee to review interim analyses of
data and cumulative toxicity data to determine if the research activities should continue as
originally designed, be changed, or be terminated.

The following policy describes the parties responsible for data and safety monitoring and the
acceptable methods of conducting the monitoring.

Industry Sponsored

For these types of studies, it is the responsibility of the sponsor (person or persons initiating the
clinical trial) to notify the DCGI/RA of any serious and/or unexpected adverse event. Most
sponsors establish their own Data and Safety Monitoring Committee (DSMC) to review interim
analysis, toxicity data and adverse events, and recommend a course of action to the sponsor if
it appears that there are unreasonable risks to subject safety. Investigators are required to
promptly report adverse events to the HEC and the sponsor. If review of adverse event reports
from TMC or other sites raises concerns that subject safety and welfare are at increased risk,
the HEC may suspend the study locally even if the sponsor decides to continue with the study.

Supported Studies

1. Phase I and II studies may be monitored by the investigator/project manager, or a designee,
   or by both. There is no requirement for establishment of a DSMC but there is a requirement
   for written policies and procedures that describe the monitoring and reporting processes.
   HEC must approve these policies and procedures.

2. Phase III clinical studies must be monitored by a DSMC. If the studies are to be conducted
   at multiple sites, the DSMC must be established by the “study leadership” that may or may
   not be at TMC. The HEC must be informed of the composition and location of the DSMC in
   either case. In addition, a plan for DSMC submission of a periodic summary of adverse
   events to the HEC must be in place. This does not relieve the investigator of his/her
   responsibility of promptly reporting adverse events that occur at TMC.




                                                 30
Investigator Initiated Clinical Studies

Investigator initiated studies are defined as clinical research activities with a drug or device that
are not supported by or solicited by an industry sponsor, although the study may receive
support from an industry sponsor. The Data and Safety Monitoring Sub Committee of the HEC
will monitor the studies at TMC sites. If they involve multiple sites with a TMC investigator acting
as the “study leadership”, an independent DSMC must be established.


Detailed information of the Data and Safety Monitoring Subcommittee is available in the SOPs
of the DSMSC.




                                                 31
                                        APPENDIX A-17

                      POLICY FOR SUBMISSION OF AUDIT REPORTS


The HEC is responsible for local oversight of all human subject research and for assuring, to the
greatest extent possible, the safety and welfare of the research subjects. To carry out its
responsibilities, the HEC reviews all new proposals, provides continuing review of research
activities, reviews adverse event reports, and, if necessary, undertakes on-site audits of
investigator research records.

Conducting research utilizing human subjects, by regulation and from a practical standpoint, is
based on a system of trust in the integrity of the investigator. Specifically, the HEC trusts that
the investigator will conduct responsible research and keep the safety and welfare of the
subjects in mind at all times. It also assumes that when inadvertent protocol deviations occur,
the investigator will notify the HEC of the deviation and the corrective actions taken to prevent
future occurrences.

Oversight of clinical trials may occur by several methods, one of which is the audit process
conducted by a Contract Research Organization (CRO), sponsor monitor etc. The audit
process, often viewed in a negative sense, can also be viewed as a valuable oversight function.
The audits may identify potential issues of concern regarding subject safety and welfare that
can be corrected, thereby preventing injury to a research subject.

It is the policy of the HEC that a copy all reports of audits performed by CROs, sponsor
monitors, or any other external or internal entity is submitted to the HEC/DSMSC promptly upon
receipt of the report from the auditing entity. This policy exists to ensure oversight by the HEC
and appropriate TMC officials so that research subjects may be better protected.




                                               32
APPENDIX B – FORMS




        33
                                          APPENDIX B1

               REPORT FORM FOR ADVERSE EVENTS IN HUMAN SUBJECTS
                           AT TATA MEMORIAL CENTRE

Within 24 hours of learning about an adverse event, the principal investigator is responsible for
notifying the HEC. Within 10 working days the principal investigator is to submit a written report to
the HEC in the following format:

1)     The title of the project is:
       The principal investigator is:

       Summary of subject with the adverse event: Case No.                Sex:      M      F Age:

2)     Please provide a succinct description of the adverse events (who, what, where and
       when) and attach any other pertinent documentation. (Please indicate if this is a follow-
       up report and if so, include follow-up information only.)

3)     Describe the specific adverse event and check all that apply.
          Anticipated Event      Unanticipated Event
          Death      Hospitalization    Significant Disability  Other

4)     Describe the medical treatment (if any) that was provided to the research subject and the
       subject‟s response.

5)     How far into the protocol had the subject progressed before the adverse event occurred?

6)     What is the long-term prognosis of the patient and will the patient continue to receive
       treatment?

7)     Was the research subject continued on the research protocol?         yes     no

8)     In your opinion, was the adverse event a result of participation in the research protocol?
           probably     possibly    unlikely    unknown or not enough information to judge

9)     Please provide your estimation of the severity of the event by circling the appropriate
       number associated with the descriptions below:

       0. No Disability: No significant resultant discomfort; no cosmetic or functional
          impairment, and no increased length of stay or significant use of additional resources
          as a result of the AE.
       1. Minor Temporary: Minimal to moderate clinical effect requiring no or minimal clinical
          intervention, or no increased length of stay or re-hospitalization for the same or
          related problem.
       2. Minor Permanent: Minimal to moderate clinical effect with permanent residual effect
          but without significant functional or cosmetic impairment.
       3. Major Temporary: Moderate to severe clinical effect with no significant cosmetic or
          functional residual effect. This usually results in increased length of stay or re-
          hospitalization and requires moderate to major clinical intervention.



                                                 34
        4. Major Permanent: Moderate to severe clinical effect with significant functional or
           cosmetic residual effect.
        5. Potential Major or Major Continuing: When doubt exists as to the outcome, but the
           probability is that major impairment or repeated re-hospitalization will be necessary.
        6. Death.


10)     a)        Was the protocol followed in recruitment of the subject?                 yes   no
        b)        Did the patient meet the exclusion/inclusion criteria of the protocol?   yes   no
        c)        Was informed consent obtained as outlined in the protocol?               yes   no
                  If no to any part of question 8, please explain:

11)     In your opinion, does this report require that the consent form for subjects be revised?
        _____ no_____ yes
        If yes, submit two revised consent forms. One with the proposed changes emphasized in
        some fashion (highlighter, bolded, etc.) and another clean copy.

Signature of PI                                                         Date




Upon receipt of this report, the HEC/DSMSC will decide whether additional information is needed
or whether further investigation of the incident is required.



                         Do Not Write Below This Line. For HEC Use Only.

I     agree       disagree with the assessment of the principal investigator.

DSMSC Reviewer                                                               Date



Explanation:




                                                    35
                                                                                                        1




                                         APPENDIX B-2

                                  SUBJECT CONSENT FORM


                                   SAMPLE CONSENT FORM


                                     INFORMED CONSENT
                                        Title of Protocol

You are invited to participate in a study of (state what is being studied). We hope to learn (state
what the study is designed to discover or establish).
You were selected as a possible participant in this study because (state why the subject was
selected).

Your participation in this study is entirely voluntary.
Your decision whether or not to participate will not prejudice you or your medical care. If you
decide to participate, you are free to withdraw your consent and to discontinue participation at
any time without prejudice to you or effect on your medical care.

If you decide to participate, we (or Dr. _______ and his or her associates) will (describe
procedures to be followed, including their purposes, how long they will take and their frequency).
(Describe the discomforts and inconveniences reasonably to be expected and the amount of
blood to be drawn, if any.) (Describe any reasonably foreseeable risks.) (State the approximate
number of subjects to be enrolled, and the total time subjects will be involved.) (Describe any
benefits that may be reasonably expected.) (After describing the potential benefits, state:)

WE CANNOT AND DO NOT GUARANTEE OR PROMISE THAT YOU WILL RECEIVE ANY
BENEFITS FROM THIS STUDY.

You will be told if any new information is learned which may affect your condition or influence
your willingness to continue participation in this study.

While participating in this study, you should not take part in any other research project without
approval from all of the investigators. This is to protect you from possible injury arising from such
things as extra blood drawing, extra x-rays, interaction of research drugs, or similar hazards.
Describe appropriate alternative procedures, if any, that might be advantageous to the subject.
Any standard treatment that is being withheld must be disclosed. If there is no alternative
treatment state: "the alternative is not to participate".

Any data that may be published in scientific journals will not reveal the identity of the
subjects. Patient information may be provided to Governmental and regulatory agencies as
required. (If applicable, state the persons or agencies to whom the information will be furnished
and the nature of the information to be furnished).

(Please include the amount of payment, if any, and the schedule of payment.) If payment is
made in money or gifts the following statement must be included (verbatim): If the patient will not
be paid please use the following statement- No payment will be provided for participation in this
project.



                                                36
(Please include information regarding the cost of participating in the study.) The sponsor will
pay for _________. You or your insurance company will be responsible for ________________.

(Disclose what institution(s) or companies are involved in the study through funding,
cooperative research, or by providing study drugs or equipment. The following generic disclosure
is acceptable __________________________________ (Name of institution /company) is
providing financial support and/or material for this study.

(If consultative or financial relationships exist, include the following statement): One or more
of the investigators has a (state whether paid or unpaid) consultative and/or financial relationship
with the sponsoring organization(s) involved in this research.

At the discretion of the protocol director subjects may be taken out of this study due to
unanticipated circumstances.

Some possible reasons for withdrawing a subject from the study. (Note to investigator: you
may use these reasons and/or add some of your own).

    -   failure to follow instructions
    -   the investigator decides that continuation could be harmful to you
    -   you need treatment not allowed in the study
    -   the study is canceled
    -   other administrative reasons

(If this study falls within the jurisdiction of the DCGI, use the following sentences:) 1) The
purpose of this research is to obtain data or information on the safety and effectiveness of (name
of drug, device, etc.); the results will be provided to the sponsor, Drug Controller General of India,
the Food and Drug Administration and other agencies as required. 2) If you think you have
experienced a research related injury call name of doctor at phone number.

If you have any questions, we expect you to ask us. If you have any additional questions later,
(doctor's name) at (doctor's telephone number) will be happy to answer them.

If the study includes MRI (Magnetic Resonance Imaging) include the following:


1 MRI
(Minimal revisions may be made to fit your study)

This MRI machine uses a strong magnet and radio waves to make images of the body interior.
The scanning procedure is very much like an x-ray CT scan. You will be asked to lie on a long
narrow couch for a certain amount of time (state how long) while the machine gathers data.
During this time you will not be exposed to x-rays, but rather a magnetic field and radio waves.
You will not feel either. You will, however, hear repetitive tapping noises that arise from the radio
antenna around your body. We will provide earplugs or ear phones that you will be required to
wear. The space within the large magnet in which you lie is somewhat confined, although we
have taken many steps to relieve the "claustrophobic" feeling.

There are no known significant risks with this procedure at this time because the radio waves and
magnetic fields, at the strengths used, are thought to be without harm. The exception is if you



                                                 37
have a cardiac pacemaker, or a certain type of metallic clip in your body (i.e., an aneurysm clip in
your brain).

There is a possibility that you will experience a localized twitching sensation due to the magnetic
field changes during the scan. This is not unexpected and should not be painful. However, you
can discontinue the exam at anytime.

The magnetism and radio waves do not cause harmful effects at the levels used in the MRI
machine. National and Stanford guidelines have been developed for these machines, and these
recommendations will be followed. However, because the MR scanner uses a very strong
magnet that will attract metal, all metallic objects must be removed from your person before you
approach the scanner. In addition, watches and credit cards should also be removed as these
could be damaged. (These items will be watched for you).

RISKS:

If you have any history of head or eye injury involving metal fragments, if you have ever worked in
a metal shop, if you have some type of implanted electrical device (such as a cardiac pacemaker)
, if you have severe heart disease (including susceptibility to arrhythmias), if you are wearing
metal braces on your teeth, or ( for women) if you could be pregnant, you should not have an MR
scan.

(optional – only if MRI is done in hospital) If you wish, we can prescribe a mild sedative to help
you to relax during the scan session. Because you may still feel sleepy after taking this
medication, you should not plan on driving yourself after the MRI.

NOTE: IF ALL OF THE SEQUENCING TO BE USED HAS NOT BEEN APPROVED BY THE
FOOD AND DRUG ADMINISTRATION, THIS MUST BE STATED IN THE CONSENT FORM.

(The following language is recommended when women of childbearing potential (non-
pregnant) will be enrolled in an investigational drug study.)


WOMEN OF CHILDBEARING POTENTIAL

 If you are a woman who is able to become pregnant, it is expected that you will use an effective
method of birth control to prevent exposing a fetus to a potentially dangerous agent with unknown
risk. If you are pregnant or currently breast feeding, you may not participate in this drug study.
You understand that if you are pregnant, if you become pregnant, or if you are breast-feeding
during this study, you or your child may be exposed to an unknown risk [or state specific risk].

 To confirm to the extent medically possible that you are not pregnant, you agree [to have a
pregnancy test done before beginning this research study] [to begin the study after the onset of
your next menstrual period] (choose one). You must agree to avoid sexual intercourse or use a
birth control method judged to be effective by the investigator and which will not interfere with the
proposed investigation. You must accept the risk that pregnancy could still result despite the
responsible use of reliable method of birth control. You agree to notify the investigator as soon
as possible of any failure of proper use of your birth control method, or if you become pregnant,
either of which may result in your being withdrawn from the study.




                                                 38
CONSENT FOR TISSUE SAMPLING OR BANKING FOR RESEARCH

Research using tissues is an important way to try to understand human disease and/or the role
genes play in disease. You have been given this consent form because the investigators want
to include your tissues in a research project, or because they want to save such samples for
research. There are several things you should know before allowing your tissues to be studied:

1. You are invited to participate in a study of---------------------------------------------------------------------
   --.
       We hope to learn (state what the study is designed to discover or establish).
   You were selected as a possible participant in this study because (state why the subject was
   selected).

2. Your tissues will be stored [under your name or other unique identifier] (choose one). Your
   name or other public identifiers will not be included with any data shared with other
   investigators.

                                                  OR
    Once the sample is taken, it will forever be separated or unlinked from your name. This will
    protect your identity and preserve anonymity. However, once you donate the sample, you
    will not be able to withdraw your tissues from the research project because the samples will
    not be traceable.

3. There are no risks involved in research on the samples provided by you.

4. You will be told the results of the tests, but not of any other research tests in the future.
                                                  OR
   You will not be told the results, even if there might be some potential benefit to you.

5. You have the right to refuse to allow your tissues to be studied now or saved for future study.
You may withdraw from this study at any time. The investigators might retain the identified
samples, e.g., as part of your routine clinical care, but not/and for additional research.

6. The investigator will not provide genetic information about you to your familly members, but
you may wish to.
                                                 OR
   You [ consent / withhold consent ] for the investigator to provide genetic information about
   you to your family members.

7. Investigators in this study may try to recontact you in the future. If you are, understand the
   following possibilities:
   Information may be too sketchy to give you particular details or consequences.
   You may be determined to carry a gene for a particular disease that can be treated.
   You may be determined to carry a gene for a particular disease for which there is no current
   treatment.

8. Any tissues you have donated which are used in research may result in new products, tests
   or discoveries. In some instances, these may have potential commercial value and may be
   developed and owned by the Investigators, of TMC or others. However, donors of tissues




                                                        39
   do not retain any property rights to the materials. Therefore, you would not share in any
   financial benefits from these products, tests or discoveries.


Signature of Participant                                         Date

________________________________
Person Obtaining Consent
I attest that the requirements for informed consent for the medical research project described in
this form have been satisfied. I have discussed the research project with the participant and
explained to him or her in nontechnical terms all of the information contained in this informed
consent form, including any risks and adverse reactions that may reasonably be expected to
occur. I further certify that I encouraged the participant to ask questions and that all questions
asked were answered.
________________________________                        ___________________
Signature of Person Obtaining Consent                             Date

________________________________                       ____________________
Signature of Parent or Guardian                                Date
(If consent is to be obtained from a parent(s), legal guardian

CONSENT FOR GENE THERAPY STUDIES

(If the protocol involves gene therapy the following two items must be included):

1.) The approximate number of people who have previously received the genetic material under
the study;
2.) "To obtain vital information about the safety and efficacy of gene transfer, at the time of death,
no matter what the cause, permission for an autopsy will be requested of your family. Please
advise your family of this request and of its scientific and medical importance".

*All forms of medical diagnosis and treatment -- whether routine or experimental -- involve some
risk of injury. In spite of all precautions, you might develop medical complications from
participating in this study. If such complications arise, the researchers will assist you in obtaining
appropriate medical treatment but this study does not provide financial assistance for additional
medical or other costs. (Additionally TMC is not responsible for research and medical care by
other institutions or personnel participating in this study.) You do not waive any liability rights for
personal injury by signing this form. In addition, if you are not satisfied with the manner in which
this study is being conducted or if you have any questions concerning your rights as a study
participant, please contact the Ethics Committee Tata Memorial Hospital.

*Please add the following Bill of Rights to your consent.

  As a human subject you have the following rights. These rights include but are not limited to
the subject's right to:

   ۰   be informed of the nature and purpose of the experiment;
   ۰   be given an explanation of the procedures to be followed in the medical
       experiment, and any drug or device to be utilized;
   ۰   be given a description of any attendant discomforts and risks reasonably to be
       expected;


                                                  40
   ۰   be given an explanation of any benefits to the subject reasonably to be
       expected, if applicable;
   ۰   be given a disclosure of any appropriate alternatives, drugs or devices that might
       be advantageous to the subject, their relative risks and benefits;
   ۰   be informed of the avenues of medical treatment, if any available to the subject
       after the experiment if complications should rise;
   ۰   be given an opportunity to ask questions concerning the experiment or the
       procedures involved;
   ۰   be instructed that consent to participate in the medical experiment may be
       withdrawn at any time and the subject may discontinue participation without
       prejudice;
   ۰   be given a copy of the signed and dated consent form;
   ۰   and be given the opportunity to decide to consent or not to consent to a medical
       experiment without the intervention of any element of force, fraud, deceit,
       duress, coercion or undue influence on the subject's decision.

NOTE: The following paragraph and signature lines should appear on a page with another part of
the consent, it should not start a page.

YOUR SIGNATURE INDICATES THAT YOU HAVE READ AND UNDERSTAND THE ABOVE
INFORMATION, THAT YOU HAVE DISCUSSED THIS STUDY WITH THE PERSON
OBTAINING CONSENT, THAT YOU HAVE DECIDED TO PARTICIPATE BASED ON THE
INFORMATION PROVIDED, AND THAT A COPY OF THIS FORM HAS BEEN GIVEN TO YOU.

________________________________                        ________________
Signature of Participant                                      Date



                                     Person Obtaining Consent

I attest that the requirements for informed consent for the medical research project described in
this form have been satisfied – that the participant has been provided with the Experimental
Subject‟s Bill of Rights, if appropriate, that I have discussed the research project with the
participant and explained to him or her in nontechnical terms all of the information contained in
this informed consent form, including any risks and adverse reactions that may reasonably be
expected to occur. I further certify that I encouraged the participant to ask questions and that all
questions asked were answered.

________________________________                       ___________________
Signature of Person Obtaining Consent                         Date

(If consent is to be obtained from a parent(s), legal guardian or conservator, signature line(s) for
Parent or Guardian must be included on the consent form.)

________________________________                       ____________________
Signature of Parent or Guardian                               Date

*Approval Date: ____________________ Expiration Date: __________________




                                                 41
                     RECOMMENDED TERMS FOR USE IN CONSENT FORMS

To facilitate understanding of consent forms by the subject, it is recommended that the
language used is at a reading level of an 12 year old. The following lay terms, definitions and
suggestions are recommended to help investigators in this process.


Term                       Lay Definition

abdominal                  the body cavity containing the stomach, intestines, liver, and other
                           organs

acute                      new; recent; sudden

adjuvant                   helpful; assisting; aiding

adverse effect             bad side effect

agitation                  upset

allergic reaction          itching and swelling; rash; trouble breathing

ambulate (-ation –ory)     walk; able to walk; ability to walk

ameliorate                 make smaller or less, reduce

analgesia                  pain relief

anaphylactic reaction      a severe and sometimes dangerous reaction which may cause
                           problems breathing, fainting, itching and skin rash

anemia                     low red blood cell count

anesthetic (local)         a drug used to decrease the feeling of pain by numbing an area of
                           the body, without putting you to sleep.

anesthetic (general)       a drug used to decrease the feeling of pain or eliminate the feeling of
                           pain by putting you to sleep.

anorexia                   lack of appetite

arrhythmia                 abnormal heartbeat

aspiration                 removal by using a sucking machine; fluid entering the lungs

asymptomatic               without symptoms; having no symptoms

barrier method             diaphragm and condom (with spermicide), cervical
                           cap, or sponge




                                                42
benign                   not malignant; usually without serious consequences

bolus                    an amount given all at once

bradycardia              slow heartbeat

carcinogenic             capable of causing cancer

carcinoma                a type of cancer

cardiac                  heart

catheter                 a tube in a vein for withdrawing or putting fluids into my blood

central nervous system   the brain and spinal cord

cerebral                 the brain; of the brain

cessation                stopping

CHD                      coronary heart disease; heart disease

chemotherapy             treatment of a disease, usually cancer, with chemical agents

chronic                  continuing for a long time

clinical status          state of health, how you are doing and feeling

clinical trial           an experiment in patients

completed                done

congenital               occurring prior to birth, due to parent‟s genetic input

conjunctivitis           irritation and redness of the thin covering of the eye

consequences             result or effects

controlled trial         study in which the experimental treatment is compared to a standard
                         treatment

conventional therapy     standard treatment

coronary                 pertaining to the blood vessels that supply the heart

CT (CAT) scan            computerized series of x-rays

cutaneous                relating to the skin

culture                  take a sample of blood, fluid, or tissue to see if bacteria or
                         viruses can be found in it


                                                43
dehydration         loss of fluids

dermatologic        pertaining to the skin

diastolic           the lower number in a blood pressure reading

dilation            expansion or stretching

discomfort          pain; uncomfortable feeling

disseminated        widely-spread, all through the body

distal              toward the end; away from the center of the body

diuretic            water pill; drug that causes an increase in urination

double-blind        neither the subject nor physician can know what is being
                    given

dysfunction         improper function

dysplasia           abnormal cells

echocardiogram      sound wave test of the heart

edema               fluid in the tissues; puffiness; swelling

efficacy            producing a positive result

electrocardiogram   heart test; tracing of heartbeat or heart rhythm

emesis              vomiting

endoscopic          examination of the inside of the body with a lighted tube

epidural            outside the spinal cord

eradicate           get rid of

erythrocyte         red blood cell

FDA                 Food and Drug Administration; the branch of the government that
                    approves new drugs

fibrillation        irregular heartbeat

fibrous             like scar tissue

gastrointestinal    stomach and intestines



                                          44
granulocyte              white blood cell

hematocrit               number of red blood cells

hematoma                 bruise; black and blue mark

holter monitor           portable machine for recording heartbeats

hormonal therapy         treatment with hormones

hypertension             high blood pressure

hypotension              low blood pressure

hypoxia                  low oxygen level in the blood

immunosuppressive        a drug or therapy that reduces the body‟s ability to fight infection;
                         helps prevent rejection of a transplanted organ

incidence                number of times it happens

infarct                  death of tissue due to loss of blood flow

infectious occurrences   infections

inflammation             swelling which is usually painful, red and warm
infusion                 putting a substance into the body, usually into the blood

intravenous              putting it into the vein

intubate                 the placement of a tube into the airway

ischemia                 decrease in oxygen in a tissue, usually because of decreased blood
                         flow

lactating                producing milk

laparotomy               a procedure where an incision is made in the abdominal wall to
                         enable a physician to look at the organs

lethargy                 sleepiness; lack of energy

lumen                    cavity of an organ; inside a blood vessel

lymphocyte               a type of white blood cell important for defense against infections

malaise                  feeling bad; a feeling of bodily discomfort

malignancy               cancer which usually spreads and may be fatal if not successfully
                         treated



                                               45
marrow suppression      decreased growth of the bone marrow

metastasis              spread of cancer cells from one part of the body to another

monoclonal antibody     very specific, purified antibody

morbidity               sickness/illness

mortality               death

motility                the ability to move

MRI                     pictures of the body created using magnetic rather than x-ray energy

murine                  obtained from mice

myalgia                 muscle aches

myocardial infarction   heart attack

nasogastric tube        a tube from the nose to the stomach

necrosis                death of tissue

neoplasia               a tumor that may be cancerous or non-cancerous

neural                  brain or nerves

neutropenia             decrease in white blood cells

non-invasive            not breaking, cutting or entering the skin

obviate                 to prevent

occlusion               closing; obstruction

occult blood test       testing a stool sample for trace amounts of blood

oncology                the study of tumors or cancer

ophthalmic              pertaining to the eye

orthopedic              pertaining to bones

osteoporosis            bone disorder resulting from loss of bone leading to increased risk of
                        fracture

ovaries                 female sex glands that release the egg cells

pancytopenia            low number of blood cells



                                               46
percutaneous          through the skin

perforation           puncture, tear or hole

phlebitis             irritation or inflammation of a vein

placebo               inactive medication; dummy pill; sugar tablet; containing no
                      medication

platelets             blood cells that help the blood clot normally

post-                 after

prenatal              before birth

probability           chance

prognosis             outlook, probably outcomes

prophylaxis           a drug given to prevent disease or infection

prosthesis            artificial body parts, such as arms, legs, hips

proximal              closer to the center of the body, away from the end

psychosis             major psychiatric problem

pulmonary             pertaining to the lungs

QID                   four times a day

radiotherapy          treatment with radiation

randomly assigned     similar to the toss of a coin; assignment to a treatment group by
                      chance

recur                 happen again

refractory            not responding to treatment

regimen               pattern of giving treatment

relapse               return or reappearance of a disease

remission             disappearance of evidence of cancer or other disease
renal                 kidney

resect                remove or cut out surgically

respiratory failure   lung failure; stop breathing



                                           47
somnolence     sleepiness

staging        a determination of the extent of the disease

stenosis       narrowing of a duct, tube, or blood vessel

stratify       arrange in groups by age, sex, etc., for analysis

subcutaneous   under the skin

subsequent     another, next

supine         lying on the back

symptomatic    having symptoms

syndrome       a condition with a certain set of symptoms

systolic       the top number in blood pressure

tachycardia    fast heart beat

taper          decrease; reduce

therapy        treatment

thrombosis     to get or have a blood clot in a blood vessel

titration      gradual alteration of a drug dose to get the desired effect

topical        applied to the skin

toxicity       harm; problem; poisoning; unwanted side effect

transdermal    through the skin

transient      short-term; brief

trauma         injury; wound

trial          study

uptake         taking a substance into the body and the cells

uremia         kidney failure

varices        enlarged veins, usually in the legs or lining of the tube connecting the
               mouth to the stomach

vasodilation   widening of the blood vessels



                                     48
vasospasm             narrowing of blood vessels due to a spasm of the vessel walls

vehicle preparation   placebo cream; inactive preparation

venipuncture          taking blood from the vein

via                   by

waive                 give up




                                          49
                                           Appendix B-3

                               PROTOCOL REVIEW STANDARDS

                         CHECK QUESTIONS FOR HEC DISCUSSION

1) The proposed research design is scientifically sound & will not unnecessarily expose
   subjects to risk.
   a) Is the hypothesis clear? Is it clearly stated?
   b) Is the study design appropriate to prove the hypothesis?
   c) Will the research contribute to generalizable knowledge and is it worth exposing subjects
      to risk?

2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and
   the importance of knowledge that may reasonably be expected to result.
   a) What does the EC consider the level of risk to be?
   b) What does the PI consider the level of risk/discomfort/ inconvenience to be?
   c) Is there prospect of direct benefit to subjects?

3) Subject selection is equitable.
   a) Who is to be enrolled? Men? Women? Ethnic minorities? Children (rationale for
      inclusion/exclusion addressed)? Seriously-ill persons? Healthy volunteers?
   b) Are these subjects appropriate for the protocol?

4) Additional safeguards required for subjects likely to be vulnerable to coercion or undue
   influence.
   a) Are appropriate protections in place for vulnerable subjects, e.g., pregnant women,
        fetuses, socially- or economically-disadvantaged, decisionally-impaired?

5) Informed consent is obtained from research subjects or their legally authorized
   representative(s).
   a) Does the informed consent document include the eight required elements?
   b) Is the consent document understandable to subjects? „
   c) Who will obtain informed consent (PI, nurse, other?) & in what setting?
   d) If appropriate, is there a children‟s assent?
   e) Is the EC requested to waive or alter any informed consent requirement?

6) Subject safety is maximized.
   a) Does the research design minimize risks to subjects?
   b) Would use of a data & safety monitoring board or other research oversight process
      enhance subject safety?

7) Subject privacy & confidentiality are maximized.
   a) Will personally-identifiable research data be protected to the extent possible from access
      or use?
   b) Are any special privacy & confidentiality issues properly addressed, e.g., use of genetic
      information?

8) Additional considerations
   1. Ionizing radiation.    If ionizing radiation is used in this protocol is it medically indicated
   or for research use only?


                                                 50
     2. Collaborative research. Is this domestic/international collaborative research? If so, are
     SPAs or other assurances required for the sites involved?

                                 Risk/Benefit Assessment
RISK
Definition : Minimal risk means that the probability and magnitude of harm or discomfort
anticipated in the research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine physical or psychological
examinations or tests
Check appropriate risk category:

1.      The research involves no more than minimal risk to subjects.
2.      The research involves more than minimal risk to subjects.
                -The risk(s) represents a minor increase over minimal risk, or
                -The risk(s) represents more than a minor increase over minimal risk
BENEFIT
Definition: A research benefit is considered to be something of health-related, psychosocial, or
other value to an individual research subject, or something that will contribute to the acquisition
of generalizable knowledge. Money or other compensation for participation in research is not
considered to be a benefit, but rather compensation for research-related inconveniences.
Check appropriate benefit category:
1.      The research involves no prospect of direct benefit to individual subjects, but is likely to
     yield generalizable knowledge about the subject‟s disorder or condition.
2.      The research involves the prospect of direct benefit to individual subjects.




                                                 51

				
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