Ethical guidelines for biomedical research in human participants

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Ethical guidelines for biomedical research in human participants

  1. 1. ETHICAL GUIDELINES FOR BIOMEDICAL RESEARCH IN HUMAN PARTICIPANTS
  2. 2. INDEX1. Introduction2. History3. Institutional Ethics Committee4 Terms of reference and review procedures5. General statement6. General Ethical Principles7. 12 Basic Principles8. Specific Ethical Principles9. Submission of application10. Check list for protocol11. Decision-making12. Record keeping13. Quality Assurance14. Guidelines for Drug Trials15. Guidelines for Vaccine Trials16. Principles of Human Genetic Research17. Appendix I - The Nuremberg Code18. Appendix II - The Declaration of Helsinki19. Bibliography
  3. 3. ABBREVIATIONSCDSCO : Central Drugs Standard Control OrganizationCECHR : Central Ethics Committee on Human ResearchCIOMS : Council for International Organization of Medical SciencesDTAB : Drugs Technical Advisory BoardFDA : Food and Drug AdministrationFDC : Food, Drug and Cosmetic ActGCP : Good Clinical PracticeICH : International Conference on HarmonizationICMR : Indian Council of Medical ResearchICH GCP 6.0 : Document E6 of the ICH guidelines, Conserving GCPIEC : Institutional Ethics CommitteeSOP : Standard Operating ProcedureWHO : World Health OrganizationQA : Quality Assurance
  4. 4. INTRODUCTION Advances in the Biomedical Science and Technology and their application inthe practice of medicine are provoking some anxiety among the public andsociety with new ethical problems. Society is expressing its concern about what itfears would be abuses in scientific investigation and biomedical technology. Thenew advances in science and medicine are a cause for celebration and jubilations,but at the same time, they need careful evaluation of risks against benefits and itraises some delicate and difficult issues of ethics. These need to be dealt withextreme sensitivity of human values with utmost care, and development ofethical guidelines for the clinical research. In view of the complexity of thesubject, the guidelines can neither be exhaustive nor be static. They need to beupdated, consistent with the change in the realms of science and technology.HISTORY The first International Code of Ethics for Research involving humansubjects ‘The Nuremberg Code’ was a response to the cruelties committed byNazi Research Physicians revealed at the Nuremberg war crimes trials. Thus, itwas to prevent any repetitions by physician of such attacks on the rights andwelfare of human beings that human research ethics came into being. TheNuremberg (1947) laid down standards for carrying out human experimentations,emphasizing the subject’s voluntary consent. World Medical Association (1964)took a step further to reassure society by adopting the ‘Declaration of Helsinki’,which laid down the ethical guidelines for research involving human subjects. The Indian Council of Medical Research (ICMR), New Delhi had brought adocument in February 1980, ‘Policy Statement of Ethical Considerations involved
  5. 5. in Research on Human Subject’ prepared by the Ethical Committee which is beingused ,not only by ICMR, but also by Research Institutions, Government Agencies,Non-government Agencies. However, need to update this was required keepingin view the modern biology and recent developments in different medical fields.Therefore, the Central Ethics Committee on Human Research (CECHR) wasconstituted to consider various issues related to ethical, social and legal aspects.The Committee identified the following major areas and set up sub-Committeesof experts for drawing up a set of guidelines related to clinical evaluation of drugs,epidemiological research, human genetic research, transplantation research,assisted reproductive technologies and many more. It was proposed that theseguidelines be updated periodically, paripasu, with the development of the area ofmedical science. In view of the circumstances of developing countries in regard tothe applicability of ‘Nuremberg Code and Declaration of Helsinki’, the Council forInternational Organizations of Medical Sciences (CIOMS) and the World HealthOrganization (WHO) undertook and issued the proposed international guidelinesfor biomedical research involving human subjects (1982). The purpose ofproposed guidelines was to indicate the ethical principles that should guide theconduct of biomedical research involving human subjects, as set inthe ‘Declaration of Helsinki’ which could be applied effectively and efficiently indeveloping countries. Good Clinical Practice (GCP) is an ethical and scientific quality standard fordesigning, conducting and recording trials that involve the participation of humansubjects. Compliance with this standard provides assurance to public that therights, safety and well-being are protected, consistent with principles inthe ‘Declaration of Helsinki’. A need was however felt to develop our own Indianguidelines to ensure uniform equality of clinical research throughout the countryand to generate data for registration for new drugs before use in Indianpopulation. An Expert Committee set by Central Drugs Standard ControlOrganization (CDSCO) in consultation with experts has formulated the GCPguidelines for clinical data generation on drugs. The Drug Technical AdvisoryBoard (DTAB), the highest Technical Body under D&C Act, has endorsed adoption
  6. 6. of GCP guidelines for streamlining the clinical studies in India which would beuseful to Research Institutions, Investigators, Institutional Ethics Committee (IEC)in providing desired direction, protection of rights and welfare of human subjectsof biomedical research.INSTITUTIONAL ETHICS COMMITTEE (IEC)Ø “Institutional Ethics Committee (IEC) is an independent body constituted ofmedical / scientific professionals and non-medical / non-scientific memberswhose responsibility is to ensure the protection of the right, safety, and well-being of human subjects involved in a trial and to provide public assurance of thatprotection.Ø All proposals on biomedical researches involving human subjects should becleared by Institutional Ethics Committee (IEC), to safeguard the welfare of therights of the subject involved.Ø The sponsor and / or investigator should seek the opinion of InstitutionalEthics Committee regarding suitability of the protocol, methods and documents tobe used in recruitment of subjects and obtaining theirinformed consent includingadequacy of the information being provided to the subjects. The EthicsCommittee is entrusted not only with the initial view of the proposed researchprotocols prior to the initiation of the projects but also have a continuingresponsibility of regular monitoring for the compliance of the ethics of theapproved programme till the same are completed. Such an ongoing review is inaccordance with the‘Declaration of Helsinki’.
  7. 7. BASIC RESPONSIBILITIES OF IEC:1. To protect the dignity, rights and` well-being of potential researchparticipants.2. To ensure that universal ethical values and International ScientificStandards are expressed in terms of local community values and customs.3. To assist in the development and the education of a researchcommunity responsive to local health care requirements.SALIENT FEATURES OF IEC:1. Multidisciplinary and multi-sectorial in composition2. Independent3. CompetentTERMS OF REFERENCE AND REVIEW PROCEDURES:1. The IEC should be aware of their role and responsibilities asCommittee Members.2. Each Committee should have its own operating procedures availablewith each member3. Any change in the regulatory requirement should be brought to thenotice of members, keeping in view the National and International developments.
  8. 8. 4. The terms of references should include a statement on terms ofappointment with reference toa. the duration of the term of membershipb. the policy for removal / replacementc. the resignation procedure etc.5. The ethical review should be done through formal meetings anddiscussion should not be taken through circulation of proposals.6. Every research proposal on human subjects should be reviewedscientifically, evaluated in terms of risks and benefits with proper justification7. Scientific evaluation should be done completely prior to ethicalreview8. The Committee should evaluate for the adequacy of documentationto ensure privacy confidentiality and legal aspects.9. All proposals on biomedical researches involving human subjectsshould be cleared by an appropriately constituted Institutional Ethics Committee(IEC), to safeguard the welfare of the rights of the subject involved.10. The sponsor and / or investigator should seek the opinionof Institutional Ethics Committee regarding suitability of the protocol, methodsand documents to be used in recruitment of subjects and obtaining their informedconsent including adequacy of the information being provided to the subjects.The Ethics Committees are entrusted not only with the initial view of theproposed research protocols prior to the initiation of the projects but also have acontinuing responsibility of regular monitoring for the compliance of the ethics ofthe approved programme till the same are completed. Such an ongoing review isin accordance with the ‘Declaration of Helsinki’.11. Interim review : can be resorted to instead of waiting for thescheduled time of the meeting and decisions can be taken urgently and should bebrought to the notice of the main committee for the following reasons :
  9. 9. a. Re-examinations of a proposal already examined by the IECb. Research study of a minor nature such as examination of case records etc.c. An urgent proposal of national interest.GENERAL STATEMENT:Medical and related research using human beings as subjects must necessarilyensure that:1. The PURPOSE of research should be directed towards the increase ofknowledge about human condition and for the betterment of all.2. The research is CONDUCTED in a conducive manner. The dignity, well-being, transparency and fair professional treatment should be maintained.3. EVALUATION must be done at all stages ensuring the safety of humanlife.GENERAL ETHICAL PRINCIPLES: All research involving human subjects should be conducted in accordancewith three basic ethical principles, namely respect for person, beneficence andjustice. The present guidelines are directed at the application of these principlesto research involving human subjects.
  10. 10. (A) RESPECT FOR PERSONS includes at least two fundamental ethicalconsiderations, namely1. Respect for autonomyIt includes the idea that an individual is free to choose and to act. Both rationalcapacity and freedom from constraint are necessary elements. “Respect forpersons” includes respecting the decisions of autonomous beings.2. Protection for those with impaired or diminished autonomyIt means a recognition by the commission that these people are not capable ofself determination at all times and in all circumstances.(B) BENEFICENCE – includes the ethical obligation to maximize benefits andminimize harms and wrongs.(C) JUSTICE – In the ethics of research involving human subjects the principleprimarily refers to distributive justice, which means equitable distribution of bothburden and the benefits of participation in research.TWELVE BASIC PRINCIPLES:(Common to all areas of biomedical research)1 All biomedical researches on human subjects should be absolutelyessential after a due consideration of all alternatives for the advancement ofknowledge and human beings (Principle of Essentiality).2 The concept of voluntariness and informed consent shall apply to thecommunity as a whole and to each individual member who is subject ofresearch (Principle of voluntariness and Informed Consent).3 Irrespective of the socio-economic status and educational levels, researchsubject should be fully appraised of all risks arising as a result ofresearch (Principle of Non-exploitation).
  11. 11. 4 The identity of records of human subjects of research should be keptconfidential and should not be disclosed without valid scientific and legalreasons (Principle of Privacy and Confidentiality).5 Due care and caution is taken to ensure that research subjects are put tominimum risks / no irreversible risks (Principle of Precautions and RisksMinimisation).6 The Research is conducted at all times by the competent and qualifiedpersons (Principle of Professional Competence).7 The research is committed in a fair, honest, impartial and transparentmanner and records and data are maintained for a reasonable period (Principle ofAccountability and Transparency).8 The research is conducted to benefit all human kind and not just sociallybetter off. (Principle of Maximisation of Public Interest and of DistributiveJustice).9 All institutional arrangements required to be made in respect of researchare made in a bonafide and transparent manner and records are properlymaintained and preserved. (Principle of Institutional Arrangements).10 After due experimentation and due evaluation, results are brought intopublic domain through scientific and other publications under the law in force atthat time (Principle of Public Domain).11 It is the responsibility of all directly and indirectly involved with theresearch to monitor, review constantly and take remedial action at all stages ofresearch (Principle of Totality and Responsibility).12 All persons concerned directly and indirectly should scrupulously observethe laid down rules, guidelines, norms, directions (Principle of Compliance).
  12. 12. SPECIFIC ETHICAL PRINCIPLES:1. For all biomedical research involving human subjects, the investigator mustobtain the informed consent of the prospective subject or, in the case of anindividual who is not capable of giving informed consent, the proxy consent of aproperly authorized representative.2. Before requesting an individual’s consent to participate in research, theinvestigator must provide the individual with the following information, inlanguage that he or she is capable of understanding :Ø That each individual is invited to participate as a subject in research, and theaims and methods of the research – the expected duration of the subject’sparticipation – the benefits that might reasonably be expected to result to thesubject or to others as an outcome of the researchØ Any foreseeable risks or discomfort to the subject, associated withparticipation in the researchØ Any alternative procedures or courses of treatment that might be asadvantageous to the subject as the procedure or treatment being testedØ The extent of the investigator’s responsibility, if any, to provide medicalservices to the subjectØ That therapy will be provided free of charge for specified types of research-related injuryØ Whether the subject or the subject’s family or departments will becompensated for disability or death resulting from such injury andØ That the individual is free to refuse to participate and will be free towithdraw from the research at any time without penalty or loss of benefits towhich he or she would otherwise be entitled.3. The investigator has a duty to :
  13. 13. Ø Communicate to the prospective subject al the information necessary foradequately informed consentØ Give the prospective subject full opportunity and encouragement to askquestionsØ Exclude the possibility of unjustified deception, undue influence andintimidationØ Seek consent only after the prospective subject has adequate knowledge ofthe relevant facts and of the consequences of participation, and has had sufficientopportunity to consider whether to participateØ As a general rule, obtain from each prospective subject a signed form asevidence of informed consent andØ Renew the informed consent of each subject if there are material changes inthe conditions or procedures of the research4. Subjects may be paid for inconvenience and time spent, and should bereimbursed for expenses incurred, in connection with their participation inresearch ; they may also receive free medical services. However, the paymentsshould not be so large or the medical services so extensive as to induceprospective subjects to consent to participate in the research against their betterjudgement (“undue inducement”).5. Pregnant or nursing women should in no circumstances be the subjects ofnon-clinical research unless the research carries no more than minimal risk to thefetus or nursing infant and the object of the research is to obtain new knowledgeabout pregnancy or lactation. As a general rule, pregnant or nursing womenshould not be subjects of any clinical trials except such trials as are designed toprotect or advance the health of pregnant or nursing women or fetuses ornursing infants, and for which women who are not pregnant or nursing would notbe suitable subjects.
  14. 14. 6. Before undertaking research involving children, the investigator must ensurethat :Ø Children will not be involved in research that might equally well be carriedout with adultsØ The purpose of the research is to obtain knowledge relevant to the healthneeds of childrenØ A parent or legal guardian of each child has given proxy consentØ The consent of each child has been obtained to the extent of the child’scapabilitiesØ The child’s refusal to participate in research must always be respectedunless according to the research protocol the child would received therapy forwhich there is no medially – acceptable alternative7. Prisoners with serious illness or at risk of serious illness should notarbitrarily be denied access to investigational drugs, vaccines or other agents thatshow promise of therapeutic or preventive benefit.8. For several types of epidemiological research individual informed consent iseither impracticable or inadvisable. In such cases, the ethical review committeeshould determine whether it is ethically acceptable to proceed withoutindividual informed consent and whether the investigator’s plans to protect thesafety and respect the privacy of research subjects and to maintain theconfidentiality of the data are adequate9. Individuals or communities to be invited to be subjects of research should beselected in such a way that the burdens and benefits of the research will beequitably distributed. Special justification is required for inviting vulnerableindividuals and, if they are selected, the means of protecting their rights andwelfare must be particularly strictly applied.
  15. 15. 10. The investigator must establish secure safeguards of the confidentiality ofresearch data. Subjects should be told of the limits to the investigator’s ability tosafeguard confidentiality and of the anticipated consequences of breaches ofconfidentiality.11. Research subjects who suffer physical injury as a result of their participationare entitled to such financial or other assistance as would compensate themequitably for any temporary or permanent impairment or disability. In the case ofdeath, their dependants are entitled to material compensation. The right tocompensate may not be waived.12. All proposals to conduct research involving human subjects must besubmitted for review and approval to IEC. The investigator must obtain suchapproval of the proposal to conduct research before the research is begun.13. An external sponsoring agency should submit the research protocol forethical and scientific review as per the guidelines for the IEC.14. After scientific and ethical approval in the country of the sponsoring agency,the appropriate authorities of the host country, including a national or localethical review committee or its equivalent, should satisfy themselves that theproposed research meets their own ethical requirements.15. In the treatment of the sick person, the physician must be free to sue to anew diagnostic and therapeutic measure, if in his or her judgement it offers hopeof saving life, re-establishing health or alleviating suffering.16. The potential benefits, hazards and discomfort of a new method should beweighted against the advantages of the best current diagnostic and therapeuticmethods.17. In any medical study, every patient – including those of a control group, ifany – should be assured of the best proven diagnostic and therapeutic method.18. The refusal of the patient to participate in a study must never interfere withthe physician-patient relationship.
  16. 16. 19. If the physician considers it essential not to obtain informed consent, thespecific reasons for this proposal should be stated in the experimental protocolfor transmission to IEC.20. The physician can combine medical research with professional care, theobjective being the acquisition of new medical knowledge, only to the extent thatmedical research is justified by its potential diagnostic or therapeutic value for thepatient.21. In the purely scientific application of medical research carried out on a humanbeing, it is the duty of the physician to remain the protector of the life and healththat person on whom biomedical research is being carried out.22. The subjects should be volunteers – either healthy persons or patients forwhom the experimental design is not related to the patient’s illness.23. The investigator or the investigating team should discontinue the research ifin his / her or their judgment it may, if continued, be harmful to the individual.24. In research on man, the interest of science and society should never takeprecedence over considerations related to the well-being of the subject.25. Safeguarding confidentiality – The investigator must safeguard theconfidentiality of research data, which might lead to the identification of theindividual subjects. Data of individual subjects can be disclosed only in the courtof law under the orders of the presiding judge or in some cases may be requiredto communicate to drug registration authority or to health authority.26. Obligation of the sponsor to pay – The sponsor whether a pharmaceuticalcompany, a government, or an institution, should agree, before the researchbegins, to provide compensation for any physical or mental injury for whichsubjects are entitled to compensation or agree to provide insurance coverage foran unforeseen injury whenever possible.27. Research and Publication – The results of the experimental research may bereported in such a way that it would seem that human application is of mainconcern. Premature reports and publicity stunts should be avoided. Researchers
  17. 17. should take care to avoid talking to journalists or reporters about preliminaryfeelings of seemingly promising research.SUBMISSION OF APPLICATION: The researcher should submit an appropriate application in a prescribedformat along with the study protocol at least three weeks in advance. Theprotocol should include the following :1. Clear research objectives and rationale for undertaking the investigation inhuman subjects in the light of existing knowledge.2. Recent curriculum vitae of the Investigators indicating qualification andexperience.3. Subject recruitment procedures4. Inclusion and exclusion criteria for entry of subjects in the study5. Precise description of methodology of the proposed research, includingintended dosages of drugs, planned duration of treatment and details of invasiveprocedures if any.6. A description of plans to withdraw or withhold standard therapies in thecourse of research7. The plans for statistical analysis of the study8. Procedure for seeking and obtaining informed consent in English and / orvernacular language.9. Safety of proposed intervention and any drug or vaccine to be testedincluding results of relevant laboratory and animal research.10. An account of plans to provide medical therapy for research carrying morethan minimal injury, toxicity due to over dosages
  18. 18. 11. Proposed compensation and reimbursement of incidental expenses12. Details of storage and maintenance of data collected during the trial13. Plan for publication of results – positive or negative – while maintaining theprivacy and confidentiality of the study participants.14. A statement on probable ethical issues and steps taken to tackle the same15. All other relevant documents related to the study protocol includingregulatory clearances.16. Agreement to comply with institutional ethical guidelines for clinical trials.17. Details of Funding agency / Sponsors and fund allocation for the proposedwork.18. New proposals will be received every quarter as per followingschedule. Emergency meeting can be called by the Chairman anytime.S.No. Application Submission Dates Review Dates1 2nd Week March 1st Week April2 2nd Week June 1st Week July3 2nd Week September 1st Week October4. 2nd Week December 1st Week January
  19. 19. CHECK-LIST FOR PROTOCOL : Title of study Summary of proposed research Statement of justification of study Summary of previous studies on the topic including the nature, extent and relevance of animal studies and other pre-clinical studies An account of the previous submissions of the protocol for ethical review, if any, and its outcome. Brief description of the site where the research is to be conducted Relevant demographic and epidemiological information Name and address of the sponsor Name, address and qualification of the Principal Investigator The objectives of the trial The design of the trial The number of the research subjects with justification Inclusion and exclusion criteria Description and explanation of all interventions including the method of treatment, route of administration, dose, dose interval treatment period, and other details of the investigational product in case of drug trials Any other treatment that may be given / permitted / contraindicated during the study Clinical and laboratory tests to be carried out during the study Samples of case report forms to be used Methods to determine the compliance with the treatment and its recording Definitive criteria for removing the subjects from the study or trial. Methods of recording and reporting adverse events / reactions Methods of dealing with complications The known side effects of trial drug / vaccine / product used, if relevant
  20. 20.  The potential benefit of the research to the subjects and to others. The informed consent form formatted in English and Hindi. An account of any economic or incentives to prospective subjects such as cash payment / gifts / free medical services etc. Description of plans for statistical analysis of the study including plans for interim analysis, if any, and criteria for pre-maturely terminating the study as a whole, if necessary  A list of references in the protocol.  The source and amount of funding of the research : the organization that is sponsoring .  A detailed account of the sponsor’s financial commitments to the research institution, the investigators, the research subjects, and, when relevant, the community.  The time schedule for completion of the study.Date: ________________Name __________________________Signature _______________________
  21. 21. DECISION MAKING The IEC provides complete and adequate review of the research proposalssubmitted to them. It meets periodically at frequent intervals to review newproposals, evaluate annual progress of ongoing ones and assess final reports of allresearch activities involving human beings through a previously scheduledagenda, amended wherever appropriate. The following guidelines are followedfor decision making.1. The decision must be taken by a broad consensus after the quorumrequirements are fulfilled to recommend / reject / suggest modification for arepeat review or advice appropriate steps.2. A member must voluntarily withdraw from the IEC while making adecision on an application, which evokes a conflict of interest, which should beindicated in writing to the chairperson prior to the review and should be recordedso in the minutes.3. A negative decision should always be supported by clearly definedreasons.4. An IEC may decide to reverse its positive decision on a study in theevent of receiving information that may adversely affect the benefit / risk ratio.5. The discontinuation of a trial should be ordered if the IEC finds thatthe goals of the trials have already been achieved midway or unequivocal resultsare obtained6. In case of premature termination of study, notification should includethe reasons for termination along with the summary of results conducted till date.7. If necessary, the applicant / investigator may be invited to present theprotocol or offer clarifications in the meeting.
  22. 22. 8. Subject experts may be invited to offer their views, but should nottake part in the decision making process. However, her / his opinion must berecorded.9. The following circumstances required the matter to be brought to theattention of IEC :a. Any amendment to the protocol from the originally approved protocol withproper justificationb. Serious and unexpected adverse events and remedial steps taken to tacklethemc. Any new information that may influence the conduct of the study.10. Minutes of the Meeting should be approved and signed by theChairperson.RECORD KEEPING:All documentation and communication of the IEC are dated, filed and preservedaccording to written procedure. Strict confidentiality is to be maintained duringaccess and retrieval procedures.The following records are maintainedi.. The Constitution and composition of the IECii. The curriculum vitae of all IEC membersiii. Standing operating procedures of the IECiv. National and International guidelinesv. Copies of protocols submitted for review
  23. 23. vi. All correspondence, with IEC members and investigators regardingapplication, decision and follow upvii. Agenda of all IEC meetingsviii. Minutes of all IEC meetings with signature of the Chairpersonix. Copies of decisions communicated to the applicantsx. Record of all notification issued for premature termination of a studywith a summary of the reasonsxi. Final report of the study including microfilms, CDs and Video-recordings etc.* It is recommended that all records must be safely maintained after thecompletion / termination of the study for at least a period of 15 years, it is notpossible to maintain the same permanently.QUALITY ASSURANCE:1. The sponsor is responsible for the implementation of a system ofquality assurance in order to ensure that the study is performed and data isgenerated, recorded and reported in compliance with the protocol, GCP andother requirements. Documented standard operating procedures are aprerequisite for quality assurance.2. All observations & findings should be verified for credibility of thedata.3. Statistically controlled sampling may be an acceptable method of dataverification in each study.4. Quality control must be applied to each step of data handling
  24. 24. 5. Audit should be conducted by persons independent of thoseresponsible for study.6. All data and documentation should be available for inspection ofaudit.GUIDELINES FOR DRUG TRIALS:The Ethical Committee while reviewing proposals on Drug Trials will ensure thatfollowing guidelines in this regard are strictly followed.· Clinical trial of drugs is a randomized single or double blind controlledstudy in human subjects, designed to evaluate prospectively the safety andeffectiveness of new drugs.· The proposed drug trials should be carried out, only after approval ofthe Drugs Controller General of India (DCGI), as is necessary under The Schedule Yof Drugs and Cosmetics Act, 1940.· The investigator should also get the approval of Ethical Committee ofthe Institution before submitting the proposal to DCGI.· All the guiding principles should be followed irrespective of whetherthe drug has been developed in this country or abroad or whether clinical trialshave been carried out outside India or not.· The new drug as defined under the Drugs and cosmetic Rules 1945(DCR), and subsequent amendments include. i. A new chemical entity (NCE) ii. A drug which has been approved for a certainindication, by a certain route, in a certain dosage regimen, but which is nowproposed to be used for another indication, by another route, or in anotherdosage regimen
  25. 25. iii. A combination of two or more drugs which, althoughapproved individually, are proposed to be combined for the first time in a FixedDose Combination (FDC).PHASES OF CLINICAL TRIALS: The first three of the following four phases require ethical clearance :-Phase I (Human / Clinical Pharmacology trial) :· The objective of phase 1 of clinical trial is to determine the safety of themaximum tolerated dose in healthy adults of both sexes.· At least two subjects should be administered each dose to establish the safedose range, pharmacokinetic, pharmacodynamic effect, and adverse reaction, ifany, with their intensity and nature.· Investigator trained in clinical pharrmacology should preferably carry outthese studies.· The duration of time lapsing between two trails in the same volunteershould be a minimum of 3 months.· The volunteers should preferably be covered under some insurance scheme.Phase II (Exploratory trial) :· These are controlled studies conducted in a limited number of patients ofboth sexes to determine therapeutic uses, effective dose range and furtherevaluation of safety and pharmacokinetics.· Usually, 20 –25 patients should be studied for each dose.· Studies are limited to 3 – 4 centres
  26. 26. Phase III (Confirmatory trial) :· The purpose of these trials is to obtain adequate data about the efficacy andsafety of drugs in a larger number of patients from both sexes at multiplecenters.· Only after successful completion of phase III trials, permission is granted formarketing the drug.Phase IV (Post Marketing Surveillance) :· It is undertaken to obtain additional information about the drug’s risks,benefits and optimal use· Long term effects and adverse drug reaction if any should be brought to thenotice of Ethics Committee.** Trials of drugs without the approval of the appropriate authority should bedealt according to the law of the land and the Guidelines formulated by thecountry’s regulatory agencies.*** After the trial is over, if need be, it should be made mandatory that thesponsoring agency should provide the drug to the patient till it is marketed in thecountry.**** The criteria for termination of a trial must be defined as a priority in theproposal of the trial and plan of interim analysis must be clearly presented. Thisis important when on interim analysis the test drug is found to be clearly moreeffective or less effective than the standard drugs. The trial can be discontinuedthereafter and better drug should be given to patient receiving less effective drug.***** GCP provide operative guidelines for ethical and scientific standards forthe designing of a trial protocol including conduct, recording and reportingprocedures and should be strictly adhered to while carrying out a trial. Till suchtime that the SOP for Indian GCP are formulated, the international guidelinesissued by WHO and ICH should be followed.
  27. 27. GUIDELINES FOR VACCINE TRIALS:The Ethical Committee while reviewing proposals on vaccine trials will ensure thatthe guidelines in this regard are strictly followed. The phases of these trials differfrom drug trials as given below :Phase I :· This refers to the first introduction of a vaccine into a human population fordetermination of its safety and biological effects including immunogenicity.· This phase includes study of dose and route of administration and shouldinvolve Low risk subjects. For example, immunogenicity to hepatitis B vaccineshould not be determined in high risk subjects.Phase II :· This refers to the initial trial examining, effectiveness (immunogenicity) in alimited number of volunteers.· Vaccines can be prophylactic and therapeutic in nature.· Prophylactic vaccines are given to normal subjects, therapeutic or curativevaccines may be given to patients suffering from particular disease.Phase III :· This focuses on assessment of safety and effectiveness in the prevention ofdisease, involving controlled study on a larger number of volunteers (inthousands) in multi-centres.Ø Vaccines that contain active or live – attenuated micro-organisms canpossibly posses a small risk of producing that particular infection. The subject tobe vaccinated should be informed of the same.
  28. 28. Ø The subjects in control groups or when subjected to ineffective vaccines runa risk of contracting the diseaseØ The risks associated with vaccines produced by recombinant DNA techniquesare not completely known. However, for all the recombinant vaccines / productsthe Guidelines issued by the Department of Biotechnology should be strictlyfollowed.PRINCIPLES FOR HUMAN GENETICS RESEARCHIn the area of biomedical research, there has been concern for ethical issues inthe field of human genetics. In recent years this concern has grown even furtherbecause of the possibility of commercial eugenics. The advent of recombinantDNA technology has provided one of the most powerful tools in the hands ofmankind to unravel the mysteries of the human genome.Serious issues related to participation of human subjects in genetic research areraised particularly when the intervention involves rights of human embryo andsubjects who are not competent to give informed consent. Besides Human Rights,issues of dignity, autonomy and justice, the Human Genome Project (HGP) hasalso precipitated an unprecedented concern for Intellectual Property Rights.Clinical research in fields of human genetics and human genome, including genetherapy, besides being subject to general ethical considerations of protectionfrom harm and voluntariness of participation has following additionalconsiderations :-Ø The harm may not only be physical, but also psychosocial.Psychologically, the genetic information may produce anxiety and depression ordamage familial relationship, which should be safeguarded.
  29. 29. Ø Written explanation understandable to layman about presentationand natural course of the diseases, interventions available and their outcome, asalso implication of the information for progeny and family, has special place inclinical research in this field.Ø Genetic manipulations have consequences for the future, some ofwhich are unknown. Hence, greater care towards potential dangers is necessary.Ø Careful guidelines need to be evolved by peers in the profession totackle such situation. The professional societies should actively participate inthese activities.Ø The science of Medical Genetics is progressing very rapidly.Therefore, there is a need for frequent updating of any guidelines for research inthis field. To meet this challenge not only the guidelines should be flexible, butthere should also be a built-in mechanism to review the guidelines from time totime.Ø The Institutional Ethical Committees reviewing research proposalsrelated to research on human genetics should have necessary expertise, whichincludes knowledge of latest developments in the field of human genetics. Inareas of doubt, open discussion should be encouraged. This has to be theresponsibility of National agencies e.g. Central Ethical Committee (ICMR) and / orNational Bioethics Committee to organize national debates on such issues toevolve consensus on them.Ø Concerned with the misuse of genetic tests, particularly for the pre-selection of sex, the Government India has enacted a law known as “The PrenatalDiagnostic Techniques (Regulation and Prevention of Misuse) Act 1994”. Allresearchers in this area shall follow the provisions of this act (and such other actswhich may be passed in future).
  30. 30. APPENDIX – ITHE NUREMBERG CODE – 1949 Beginning with the outbreak of World War – II, Criminal Medicalexperiments on non-German Nationals, both prisoners of war civilians werecarried out on large scale by the Nazi Physicians. Evidence given during thesetrials revealed unprecedented suffering, pain and disfigurement. In response tothese findings, the judges proposed 10 principles “moral, ethical and legal”human experimentation, which collectively came to be known as The NurembergCode. Today, it is the basis of GCP in scientific research and is the fundamentaldocument in the history of bioethics.1. The voluntary consent of the human subject is absolutely essential.2. The experiment should be such as to yield fruitful results for the goodof society, unprocurable by other methods or means of study, and not random andunnecessary in nature.3. The experiment should be designed and based on the results of animalexperimentation and a knowledge of the natural history of the disease or otherproblem under study that the anticipated results will justify the performance ofthe experiment.4. The experiment should be so conducted as to avoid all unnecessaryphysical and mental suffering and injury.5. No experiment should be conducted where there is an a priorityreason to believe that death or disabling injury will occur except, perhaps, in thoseexperiments where the experimental physicians also service as subjects.6. The degree of risk to be taken should never exceed that determinedby the humanitarian importance of the problem to be solved by the experiment.
  31. 31. 7. Proper preparations should be made and adequate facilities provide toprotect the experimental subject against even remote possibilities of injury,disability, or death.8. The experiment should be conducted only by scientifically qualifiedpersons. The highest degree of skill and care should be required through all stagesof the experiment of those who conduct or engage in the experiment.9. During the course for the experiment the human subject should be atliberty to bring the experiment to an end if he has reached the physical or mentalstate where continuation of the experiment seems to him to be impossible.10. During the course of the experiment the scientific in charge must beprepared to terminate the experiment at any stage, if he has probable cause tobelieve, in the exercise of the good faith, superior skill and careful judgmentrequired of him that a continuation of the experiment is likely to result in injury,disability, or death to the experimental subject.APPENDIX – IITHE DECLARATION OF HELSINKI – 1964Unlike the Nuremberg Code the declaration of Helsinki focused on the integrityand the experience of scientific investigators, in the protection of human subjects.According to the declaration of Helsinki issued by World Medical Assembly eachpotential subject involved in a clinical investigation must be adequately informedof the aims, methods, anticipated benefits and the potential hazards of the studyand the discomfort it may entail. The declaration of Helsinki forms the basis ofICH GCP 6.0. Therefore it is a more universally used document than theNuremberg code. It has the following principals.1. The World Medical Association has developed the declaration of Helsinki as astatement of ethical principle to provide guidance to physicians and other
  32. 32. participants in medical research involving human subjects. Medical Researchinvolving human subjects includes research on identifiable human material oridentifiable data.2. It is the duty of physician to promote and safeguard the health of the people.The physicians knowledge and conscience are dedicated to the fulfillment of thisduty.3. The Declaration of Geneva of World Medical Association binds the physicianwith the words, “The health of my patient will be my first consideration”, and theInternational code of medical ethics declares that, “A physician shall at only in thepatients interest when providing medical care which might have the effect ofweakening the physical and mental condition of the patient”.4. Medical progress is based on research, which ultimately must rest in part onexperimentation involving human subjects.5. In medical research on humn subjects, considerations related to the well-being of the human subject should take precedence over the interest of scienceand society.6. The Primary purpose of medical research involving human subject is toimprove prophylactic, diagnostic and therapeutic procedures and theunderstanding of the aetiology and pathogenesis of disease. Even the best provenprophylactic, diagnostic, and therapeutic must continuously be challengedthrough research for their effectiveness, efficiency, accessibility and quality.7. In current medical practice and in medical research, most prophylactic,diagnostic and therapeutic procedures involved risks and burdens.8. Medical research is subject to ethical standards that promote respect for allhuman beings and protect their health and rights. Some research populations arevulnerable and need special protection. The particular needs of the economicallyand medically disadvantaged must be recognized. Special attention is alsorequired for those who cannot give a refuse consent for themselves, for those who
  33. 33. may be subject to giving consent under duress, for those who will not benefitpersonally from the research and for those whom the research is combined withcare.9. Research investigators should be aware of ethical, legal, and regulatoryrequirements for research on human subject in their own countries as well asapplicable international requirements. No national ethical, legal or regulatoryrequirement should be allowed to reduce or eliminate any of the protections forhuman subjects set-forth in this Declaration.WHO GUIDELINES FOR ETHICS IN HUMAN RESEARCH:2. When to Submit an Application to Conduct a Clinical Trial: An application for approval to conduct a clinical trial is required for thefollowing categories of medicines:a. Unregistered medicinesb. Registered medicines where the proposed clinical trials are outside ofthe conditions of approval. These may include changes to:i. indication(s) and clinical useii. target patient population(s)iii. route(s) of administrationiv. dosage regimen(s) An application for authorization to conduct a clinical trial described inAbove paragraph must be made on a form and accompanied by anapplication fee as determined by the Regulatory Authority. No person may conduct a clinical trial using investigational productsincluded in above paragraph above without prior authorisation from theRegulatory Authority. A clinical trial authorised by the Regulatory Authority must be conducted inaccordance with guidelines for Good Clinical Practice (GCP) as may fromtime to time be determined by the Authority. A clinical trial authorised by the regulatory Authority may only proceed at aclinical trial site once clearance has been obtained from a recognisedResearch Ethics Committee. Approval by the Regulatory Authority to conduct post-marketing clinicaltrials of a registered medicine within the approved conditions of
  34. 34. registration of such a medicine is not required. However, approval by arecognised Research Ethics Committee is required prior to initiation ofsuch studies. of an individual patient by a medical practitioner with anunregistered medicine or with a registered medicine outside of theapproved conditions of registration of such a medicine is not considered tobe a clinical trial and would usually require special approval by theRegulatory Authority on a named patient basis.3. Responsibilities Relating to Clinical Trials: An application to conduct a clinical trial may be made by a pharmaceuticalcompany (sponsor), clinical research organisation (CRO), or in the case ofinvestigator-initiated academic research studies, by the researchinstitution or principle investigator. A statement by the applicant must be provided indicating that allinformation contained in, or referenced by, the application is complete andaccurate and is not false or misleading. applicant and all investigators must sign declarations that they arefamiliar with and understand the clinical trial protocol and will comply withGood Clinical Practice standards, as determined by the RegulatoryAuthority, in the conduct of the trial. In the case of multicentre trials, the coordinating investigator must alsosign the application form. Upon signing the application, all parties accept responsibility that allapplicable regulations and requirements will be adhered to. Furthermore,all parties are responsible for ensuring that the trial is based on andimplemented according to well-founded ethical and scientific principles,which are expressed in the Helsinki Declaration and its current revisionsas well as in international guidelines for Good Clinical Practice (GCP). The principle investigator must be an appropriately qualified andcompetent person having practical experience within the relevantprofessional area, who is a resident in the country and who is responsiblefor the conduct of the clinical trial at a clinical trial site. A principleinvestigator must have had previous experience as a co-investigator in atleast two trials in the relevant professional area. investigators in a clinical trial as well as the trial monitor must have hadformal training in Good Clinical Practice (GCP) within the last three years. Multi-centre trials must have a coordinating investigator who will be
  35. 35. responsible for coordinating all local clinical trial sites. This person doesnot necessarily have to be involved with any direct treatment of subjectsinvolved in the trial. If the trial is a part of an international study, information regarding theother participating countries must be provided including how large a partof the trial will be carried out locally.4. Ethical Assessment: clinical trial that has received approval from the Regulatory Authoritymay only proceed once clearance has also been obtained from arecognized Research Ethics Committee for a particular trial site. Ethical evaluations of clinical trials of drugs must take place in accordancewith the principles of Good Clinical Practice as well as the Declaration ofHelsinki and its current revisions.5. Insurance of Trial Subjects: All subjects must be satisfactorily insured against possible injuries thatmight arise during the conduct of the clinical trial. For all sponsor-initiated trials, a valid insurance certificate for the durationof the study must be provided prior to study initiation. For investigator-initiated research trials, proof of current malpracticeinsurance that covers clinical trials must be provided.6. Good Clinical Practice (GCP): Applicants must be able to demonstrate that clinical trials are conductedaccording to generally accepted principles of good clinical practice. Trials must be conducted in accordance with the applicable regulatoryrequirement(s) Before a trial is initiated, foreseeable risks and inconveniences must beweighed against the anticipated benefit for the individual trial subject andsociety. A trial should be initiated and continued only if the anticipatedbenefits justify the risks. The rights, safety, and well being of the trial subjects are the mostimportant considerations and must prevail over interests of science andsociety. The available non-clinical and clinical information on an investigationaldrug must be adequate to support the proposed clinical trial. Clinical trials must be scientifically sound, and described in a clear,detailed protocol. A trial must be conducted in compliance with a protocol that has received
  36. 36. regulatory and ethics approval prior to initiation. The medical care given to, and medical decisions made on behalf of,subjects must always be the responsibility of a qualified physician or,when appropriate, of a qualified dentist. Each individual involved in conducting a trial should be qualified byeducation, training, and experience to perform his or her respectivetask(s). Freely given informed consent must be obtained from every subject priorto clinical trial participation. All clinical trial information must be recorded, handled, and stored in a waythat enables its accurate reporting, interpretation and verification. The confidentiality of records that could identify subjects must beprotected, respecting the privacy and confidentiality rules in accordancewith the applicable regulatory requirement(s). Investigational drugs must be manufactured, handled, and stored inaccordance with applicable good manufacturing practices (GMP) andmust be used in accordance with the approved protocol. Systems with procedures that assure the quality of every aspect of the trialmust be implemented.7. The Clinical Trial Application: The Regulatory Authority will undertake an assessment of a clinical trialonly upon receiving fully completed applications. The following are the requirements when submitting an application toconduct a clinical trial (6 copies of each of the following are to besubmitted):  Covering letter  Completed Application form (CTF1)  Cover sheet  Checklist  Final version of the Clinical Trial Protocol  Patient Information leaflet and Informed Consent form  Investigators Brochure and/or Package Insert  Signed investigator(s) CV(s) in required format  Signed declaration by Principal investigator(s)  Signed joint declaration by Sponsor/National Principal investigator  Signed declaration by Co- or Sub-investigators
  37. 37. Signed declaration by regional monitor and/or study coordinator Indemnity and Insurance Certificate and/or Proof of Malpractice insurance of trialist(s) Ethics Committee(s) approval or Copy of letter submitted to Ethics Committee(s) Electronic copies to be submitted in Microsoft Word format Financial declaration by Sponsor and Principle investigator Documentation must be arranged in separate folders. The extent of thedocumentation requirements will generally depend on the developmentphase of the investigational product.8. The Clinical Trial Protocol: The clinical trial protocol must contain at least the following information,consistent with the requirements of internationally accepted GCPguidelines: Background and purpose of the trial Details of the study population; Design and type of trial Criteria for selection of trial subjects Trial treatments Control groups and control treatments where applicable Choice of method and statistical justification for the number of trialSubjects Monitoring, assessment and reporting of effects, adverse drugreactions and adverse events Clinical and laboratory safety test Assessment of results Quality assurance of data and procedures Drug accountability Ethical assessment To facilitate evaluation as well as provide guidance on the relevance of thestudy, the protocol should clearly indicate the complete development planfor the trial and the investigational product. This should include thefollowing: A plan for the possible discontinuation of previous treatment The rationale for the use of placebo products
  38. 38. Follow-up of trial subjects after the conclusion of the trial A plan for involvement of other personnel The state of readiness in case of complications A plan for the publication of the results (publishing plan) A description of how special lists of the trial subjects and formsrelating to the trial subjects will be kept for each trial subjectincluded in the trial9. The Investigator’s Brochure: The investigators brochure must contain at least following information: The physical, chemical and pharmaceutical properties of the drug The pharmacological aspects of the drug, including its metabolitesin all animal species tested The pharmacokinetics and metabolism of the drug, including thebiological transformation of the drug in all animal species tested Toxicological effects in any animal species tested under a singledose study, a repeated dose study or a special study in respect ofthe drug Results of carcinogenicity studies in any animal species tested inrespect of the drug Results of clinical pharmacokinetic studies of the drug Information regarding drug safety, pharmacodynamics, efficacy anddose responses of the drug that were obtained from previousclinical trials in humans.10. Labelling and Dispensing of Trial Medications: Investigational, comparator and /or placebo products used in a clinical trialmust be properly labelled and contain the following information: A statement indicating that the drug is an investigational drug to beused only by a qualified investigator The name, number or identifying mark of the drug The expiration date of the drug The recommended storage conditions for the drug The lot number of the drug The name and address of the sponsor The protocol code or identification The name and address of the premises where the clinical trial is tobe carried out.
  39. 39. Registered products that are incorporated in the trial must also be labelledin accordance with 10.1 above. Trial medications must be stored and dispensed by the pharmacy or thepharmaceutical department at the trial site in accordance with gooddispensing practices. The general principle is that investigational productsused in clinical trials should be handled in the same way as registeredmedicines.11. Chemistry and Manufacturing: Clinical trial investigational medicinal products must be manufactured inaccordance with the code of Good Manufacturing Practice (GMP)including Good Manufacturing Practice for Investigational MedicinalProducts. This implies that the manufacture of the investigational productmay be subject to control and inspection in the same way as in the case ofmarketed medicinal products. Certificates of analysis (COAs) must be provided for all investigational andcomparator products. Chemistry and manufacturing information provided in the clinical trialapplication should be presented in a concise manner and should includethe following:a. Drug Substance:_ Names and Source_ Method of Manufacture_ Physicochemical Properties and Structure Elucidation_ Impurities_ Specifications and Test Methods and Batch Analyses_ Stability and Packagingb. Dosage Form:_ Source_ Developmental Pharmaceutics_ Formulation and Method of Manufacture and Packaging_ Specifications and Test Methods and Batch Analyses_ Stability If the pharmaceutical or chemical properties of the investigational producthave been altered compared to those in use during animal testing orprevious clinical trials, such alterations must be described and justified.This, for instance, applies to impurities and degradation products. Pharmaceutical and/or chemical alterations in an investigational product
  40. 40. that is used in an ongoing clinical trial, and that may affect the quality,safety and/or efficacy of the medicinal product must immediately bereported to the Regulatory Authority. If the composition of the medicinal product is altered, additionalbioavailability or bioequivalence studies may be required. Based on stability data, all investigation)In cases where an extension ofthe shelf life for the finished medicinal product is desired, an applicationfor this must be submitted to the Regulatory Authority. In such casesstability data or certificates of analysis (COAs) from reanalysis of therelevant batches must be submitted. The re-labelling of any remaining packages from previously manufacturedbatches must be performed in accordance with established writtenprocedures and Good Manufacturing Practices (GMP).12. Requirements Concerning Informed Consent: It is an important principle that subjects contemplating participation in aclinical trial have access to certain basic information regarding the clinicaltrial. A copy of the written information intended for trial subjects, as it will be setout in the informed consent form, that includes a statement of the risksand anticipated benefits arising to the health of trial subjects as a result oftheir participation in the clinical trial, must be submitted to the RegulatoryAuthority. The following list of items (not exhaustive), should be included in thepatient information leaflet: An introduction including information on participation in thestudy The aims, objectives and goals of the study The methods to be employed and what this will involve forthe trial subject Criteria for selection that apply to the subject Whether the trial has any direct benefit for the trial subject Which medicines are included in the trial; whether thepreparations are available on the market and if inactivesubstances (placebo) will be used. The patient must beinformed of the fact that allocation to a specific treatmentgroup will occur at random Other medicines that may/may not be taken at the same
  41. 41. time as the trial medication. Non-prescription medicationsand complementary products should be mentionedspecifically Pregnant and breast-feeding subjects must be excludedfrom participation in the study and safe contraceptives mustbe used by women of a childbearing age. Informationconcerning safe use of contraceptives for men, if this isrelevant, must be provided Practical consequences of participating (type of involvement,time required) Risks, adverse drug reactions and any possible discomfortshould be detailed If the person does not consent to participate, details ofalternative treatments available must be provided Discontinuing current treatment as a condition ofparticipating Follow-up treatment, if applicable Confidentiality Emphasis that participation is voluntary and that consent canbe withdrawn at any time and without having to providereasons. Subjects must be informed that refusing toparticipate will have no effect on further treatment or therelationship to the treating physician or to the institute Information that Regulatory Authorities and Research EthicsCommittees may require access to subject identifying data.Consent for this access must be a condition for participationin the study Information about who the trial subject can contact. Thisshould include details of the investigator, Research EthicsCommittee and Regulatory Authority Information about indemnity, insurance and compensation inthe event of trial-related injury Information if biological fluids will be used and/or stored forpharmacogenetic sub-studies. Participation in this part ofthe study should be voluntary and a separate informedconsent must be obtained Additionally, the following issues, where applicable, must be addressed in
  42. 42. the process of obtaining informed consent: Trials on under-aged subjects and subjects with reducedcompetence to consent Withdrawal of consent Provision of new information to subjects as these becomeavailable13. Clinical Trial Amendments: Applications for amendments to clinical trial protocols must be submittedto the Regulatory authority for approval prior to their implementation. The applicant must submit the original wording, revised wording, andrationale for the change including a copy of a complete protocolincorporating all amendments. These amendments must also be presented to the Research EthicsCommittee for approval prior to implementation. Approval must be obtained for the following amendments to the clinicaltrial protocol: Changes that affect patient selection and monitoring Changes that affect clinical efficacy and safety requirements(e.g. dosage adjustments, study procedures, etc) Changes that affect patient discontinuation Changes that result in the extension of the duration of theclinical trial Changes that result to the chemistry and manufacturinginformation that may affect drug safety and quality (Forexample: specifications for the drug where the limits of thetest are relaxed or deleted; where a new impurity ordegradation product has been identified; and, the addition ofnew raw materials, solvents, reagents, catalysts or any othermaterial used in the manufacture of the drug substance.)14. Clinical Trial Records: The sponsor must record, handle and store all information in respect of aclinical trial in order to ensure that the clinical trial is conducted inaccordance with good clinical practices and in a way that allows itscomplete and accurate reporting as well as its interpretation andverification. The sponsor must keep all records related to the conduct of a clinical trialin a format that facilitates verification for the purpose of an inspection.
  43. 43. The sponsor must submit requested records within 48 hours if safetyconcerns arise. Additionally, the Regulatory Authority can request the submission ofadditional information within seven days to facilitate an inspection of a site. The sponsor must maintain complete and accurate records in respect ofthe use of a drug in a clinical trial, including: A copy of all versions of the investigators brochure for thedrug; Records respecting each change made to the investigatorsbrochure, including the rationale for each change anddocumentation that supports each change; Records respecting all adverse events in respect of the drugthat have occurred locally or internationally, includinginformation that specifies the indication for use and thedosage form of the drug at the time of the adverse event; Records in respect of the enrolment of clinical trial subjects,including information sufficient to enable all clinical trialsubjects to be identified and contacted in the event that theuse of the drug may endanger the health of the clinical trialsubjects or other persons; Records in respect of the shipment, receipt, disposition,return and destruction of the drug; For each clinical trial site, an undertaking from the principleinvestigator that is signed and dated by the principleinvestigator prior to the commencement of his or herresponsibilities in respect of the clinical trial, that states thatthe principle investigator will conduct the clinical trial inaccordance with good clinical practices; For each clinical trial site, a copy of the protocol, informedconsent form and any amendment to the protocol orinformed consent form that have been approved by theResearch Ethics Committee and Regulatory Authority forthat clinical trial site.15. Discontinuance of a Clinical Trial by a Sponsor: If a clinical trial is discontinued by the sponsor in its entirety or at a clinicaltrial site, the sponsor must inform the Regulatory Authority no later than 15days after the date of the discontinuance; and must:
  44. 44. Provide the Regulatory Authority with the reason/s for thediscontinuance and its impact on the proposed or ongoingclinical trials in respect of the drug conducted by thesponsor; As soon as possible, inform all investigators of thediscontinuance and of the reasons for the discontinuance,and advise them in writing of any potential risks to the healthof clinical trial subjects or other persons;16. Reporting of Adverse Drug Reactions and Adverse Events: The term adverse drug reactions is understood as adverse events wherethe connection to the trial medication cannot be excluded (possible orprobable connection). The sponsor must report serious adverse drug reactions that emergeduring trials as individual reports (one report per patient). During the course of a clinical trial, the sponsor must inform theRegulatory Authority and the Research Ethics Committee of any seriousunexpected adverse drug reaction in respect of the drug that has occurredlocally or internationally as follows: If it is fatal or life threatening, immediately but no later thanseven days after becoming aware of the information If it is neither fatal nor life threatening, within 15 days afterbecoming aware of the information. The potential connection to the study drug must be clarified, and updatedreports sent to the Regulatory Authority as soon as these are available. With regard to adverse drug reaction that are serious and already known(described in Investigator’s Brochure or the Summary of Productcharacteristics (SPC)) there are no fixed time limits. These cases must bereported as soon as the necessary information is available.17. Submission of Progress Reports: The applicant conducting the clinical trial must submit progress reports tothe Regulatory Authority on a six monthly basis from the date of initiationof the clinical trial and within 30 days of the completion or termination ofthe clinical trial18. Inspection of Clinical Trials: The Regulatory Authority may inspect clinical trial sites and trial sponsorsto ensure that the generally accepted principles of good clinical practiceare met.
  45. 45. The objectives of the inspection will be to ensure that participants inclinical trials are not subjected to undue risks, to validate the quality of thedata generated or to investigate complaints. The Regulatory Authority may use the information collected as a result ofthese inspections to ensure compliance with the regulatory framework andmay take enforcement action, when deemed necessary.19. Withdrawal of Authorisation to Conduct a Clinical Trial The Regulatory Authority may request additional information on a clinicaltrial or withdraw the authorisation to conduct a clinical trial if the Authorityis of the opinion that the safety of the subjects in the trial is compromised,or that the scientific reasons for conducting the trial have changed.SCHEDULE Y : REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS1. Application for permission.- (1) Application for permission to import ormanufacture new drugs for sale or to undertake clinical trials shall be made inForm 44 accompanied with following data in accordance with the appendices,namely:-(i) chemical and pharmaceutical information as prescribed in item 2 of Appendix I;(ii) animal pharmacology data as prescribed in item 3 of Appendix I and Appendix IV;(a) specific pharmacological actions as prescribed in item 3.2 of Appendix I, and demonstrating, therapeutic potential for humans shall be described according to the animal models and species used. Wherever possible, dose-response relationships and ED 50s shall be submitted. Special studies conducted to elucidate mode of action shall also be described (Appendix IV); (b) general pharmacological actions as prescribed in item 3.3 of Appendix I and item 1.2 of Appendix IV;(c) pharmacokinetic data related to the absorption, distribution, metabolism and excretion of the test substance as prescribed in item 3.5 of Appendix I. Wherever possible, the drug effects shall be corelated to the plasma drug concentrations;
  46. 46. (iii) animal toxicology data as prescribed in item 4 of Appendix I and Appendix III;(iv) human Clinical Pharmacology Data as prescribed in items 5,6,and 7 of Appendix I and as stated below:-(a) for new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I and data should be submitted as required under items 1, 2, 3, 4, 5 (data, if any, from other countries), and 9 of Appendix I;(b) for new drug substances discovered in countries other than India, Phase I data as required under items 1,2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trails are required to be conducted in India before permission to market the drug in India is granted;(c) the data required will depend upon the purpose of the new drug application. The number of study subjects and sites to be involved in the conduct of clinical trial will depend upon the nature and objective of the study. Permission to carry out these trials shall generally be given in stages, considering the data emerging from earlier Phase(s);(d) application for permission to initiate specific phase of clinical trial should also accompany Investigator’s brochure, proposed protocol (Appendix X), case record form, study subject’s informed consent document(s) (Appendix V), investigator’s undertaking (Appendix VII) and ethics committee clearance, if available, (Appendix VIII);(e) reports of clinical studies submitted under items 5-8 of Appendix I should be in consonance with the format prescribed in Appendix II of this Schedule. The study report shall be certified by the Principal Investigator or, if no Principal Investigator is designated, then by each of the Investigators participating in the study. The certification should acknowledge the contents of the report, the accurate presentation of the study as undertaken, and express agreement with the conclusions. Each page should be numbered;
  47. 47. (v) regulatory status in other countries as prescribed in item 9.2 of Appendix I, including Information in respect of restrictions imposed, if any, on the use of the drug in other countries, e.g. dosage limits, exclusion of certain age groups, warning about adverse drug reactions, etc. (item 9.2 of Appendix I). Likewise, if the drug has been withdrawn in any country by the manufacturer or by regulatory authorities, such information should also be furnished along with the reasons and their relevance, if any, to India. This information must continue to be submitted by the sponsor to the Licensing Authority during the course of marketing of the drug in India;(vi) the full prescribing information should be submitted as part of the new drug application for marketing as prescribed in item 10 of Appendix I. The prescribing information (package insert) shall comprise the following sections: generic name; composition; dosage form/s; indications; dose and method of administration; use in special populations (such as pregnant women, lactating women, pediatric patients, geriatric patients etc); contra-indications; warnings; precautions; drug interactions; undesirable effects; overdose, pharmacodynamic and pharmacokinetic properties; incompatibilities; shelf-life; packaging information; storage and handling instructions. All package inserts, promotional literature and patient education material subsequently produced are required to be consistent with the contents of the approved full prescribing information. The drafts of label and carton texts should comply with provisions of rules 96 and 97. After submission and approval by the Licensing3Authority, no changes in the package insert shall be effected without such changes being approved by the Licensing Authority; and(vii) complete testing protocol/s for quality control testing together with a complete impurity profile and release specifications for the product as prescribed in item 11 of Appendix I should be submitted as part of new drug application for marketing. Samples of the pure drug substance and finished product are to be submitted when desired by the regulatory authority.(2) If the study drug is intended to be imported for the purposes of examination,test or analysis, the application for import of small quantities of drugs for suchpurpose should also be made in Form 12.
  48. 48. (3) For drugs indicated in life threatening/ serious diseases or diseases of specialrelevance to the Indian health scenario, the toxicological and clinical datarequirements may be abbreviated, deferred or omitted, as deemed appropriateby the Licensing Authority.2. CLINICAL TRIAL(1) Approval for clinical trial(i) Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective ethics committee(s). The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics comittee(s) as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site. The trial site(s) may accept the approval granted to the protocol by the ethics committee of another trial site or the approval granted by an independent ethics committees (constituted as per Appendix VIII), provided that the approving ethics committee(s) is/are willing to accept their responsibilities for the study at such trial site(s) and the trial site(s) is/are willing to accept such an arrangement and that the protocol version is same at all trial sites.(ii) All trial Investigator(s) should possess appropriate qualifications, training and experience and should have access to such investigational and treatment facilities as are relevant to the proposed trial protocol. A qualified physician (or dentist, when appropriate) who is an investigator or a sub-investigator for the trial, should be responsible for all trial- related medical (or dental) decisions. Laboratories used for generating data for clinical trials should be compliant with Good Laboratory Practices. If services of a laboratory or a facilities outside the country are to be availed, its/their name(s), address(s) and specific services to be used should be stated in the protocol to avail Licensing Authority’s permission to send clinical trial related samples to such laboratory(ies) and/or facility(ies). In all cases, information about laboratory(ies) / facilities to be used for the trial, if other than those at the investigation site(s), should be furnished to the Licensing Authority prior to initiation of trial at such site(s).(iii) Protocol amendments if become necessary before initiation or during the course of a clinical trial, all such amendments should be notified to the
  49. 49. Licensing Authority in writing along with the approval by the ethics committee which has granted the approval for the study. No deviations from the charges to the protocol should be implemented without prior written approval of the ethics committee and the Licensing Authority except when it is necessary to eliminate immediate hazards to the trial Subject(s) or when change(s) involve(s) only logistic or administrative aspects of the trial. All such exceptions must be immediately notified to the ethics committee as well as to the Licensing Authority. Administrative and/or logistic changes in the protocol should be notified to the Licensing Authority within 30 days.(2) Responsibilities of Sponsor.-(i) The clinical trial Sponsor is responsible for implementing and maintaining quality assurance systems to ensure that the clinical trial is conducted and data generated, documented and reported in compliance with the protocol and Good Clinical Practice (GCP) Guidelines issued by the Central Drugs Standard Control Organization, Directorate General of Health Services, Government of India as well as with all4applicable statutory provisions. Standard operating procedures should be documented to ensure compliance with GCP and applicable regulations.(ii) Sponsors are required to submit a status report on the clinical trial to the Licensing Authority at the prescribed periodicity.(iii) in case of studies prematurely discontinued for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted within 3 months. The summary report should provide a brief description of the study, the number of patients exposed to the drug, dose and duration of exposure, details of adverse drug reactions (Appendix XI), if any, and the reason for discontinuation of the study or non-pursuit of the new drug application;(iv) Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study (see Appendix XI).(3) Responsibilities of the Investigator(s).- The Investigator(s) shall be responsiblefor the conduct of the trial according to the protocol and the GCP Guidelines and
  50. 50. also for compliance as per the undertaking given in Appendix VII. Standardoperating procedures are required to be documented by the Investigators for thetasks performed by them. During and following a subject’s participation in a trial,the investigator should ensure that adequate medical care is provided to theparticipant for any adverse events. Investigator(s) shall report all serious andunexpected adverse events to the Sponsor within 24 hours and to the EthicsCommittee that accorded approval to the study protocol within 7 working days oftheir occurance.(4) Informed Consent.-(i) In all trials, a freely given, informed written consent is required to be obtained from each study subject. The Investigator must provide information about the study verbally as well as using a patient information sheet, in a language that is non-technical and understandable by the study subject. The Subject’s consent must be obtained in writing using an ‘Informed Consent Form’. Both the patient information sheet as well as the informed Consent Form should have been approved by the ethics committee and furnished to the Licensing Authority. Any changes in the informed consent documents should be approved by the ethics committee and submitted to the Licensing Authority before such changes are implemented.(ii) Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent for or authorize an intervention in the patient as provided by the law(s) of India). If the Subject or his/her legally acceptable representative is unable to read/write - an impartial witness should be present during the entire informed consent process who must append his/her signatures to the consent form.(iii) A checklist of essential elements to be included in the study subject’s informed consent document as well as a format for the informed Consent Form for study Subjects is given in Appendix V.(5) Responsibilities of the Ethics Committee.-(i) It is the responsibility of the ethics committees that reviews and accords its approval to a trial protocol to safeguard the rights, safety and well being of all trial subjects. The ethics committee should exercise
  51. 51. particular care to protect the rights, safety and well being of all vlunerable subjects participating in the study, e.g., members of a group with hierarchical structure (e.g. prisoners, armed forces personnel, staff and students of medical, nursing and pharmacy academic institutions), patients with incurable diseases, umemployed or impoverished persons, patients in emergency situation, ethic minority groups, homeless persons, nomads, refugees, minors or others incapable of personally giving consent. Ethics committee(s) should get5document ‘standard operating procedures’ and should maintain a record of its proceedings.(ii) Ethics Committee(s) should make, at appropriate intervals, an ongoing review of the trials for which they review the protocol(s). Such a review may be based on the periodic study progress reports furnished by the investigators and/or monitoring and internal audit reports furnished by the Sponsor and/or by visiting the study sites.(ii) In case an ethics committee revokes its approval accorded to a trial protocol, itmust record the reasons for doing so and at once communicate such a decision tothe Investigator as well as to the Licensing Authority.(6) Human Pharmacology (Phase I).-(i) The objective of studies in this Phase is the estimation of safety and tolerability with the initial administration of an investigational new drug into human(s). Studies in this Phase of development usually have non- therapeutic objectives and may be conducted in healthy volunteers subjects or certain types of patients. Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied in patients. Phase I trials should preferably be carried out by Investigators trained in clinical pharmacology with access to the necessary facilities to closely observe and monitor the Subjects.(ii) Studies conducted in Phase I, usually intended to involve one or a combination of the following objectives:-(a) Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies include both single and multiple dose administration.
  52. 52. (b) Pharmacokinetics, i.e., characterization of a drug’s absorption, distribution, metabolism and excretion. Although these studies continue throughout the development plan, they should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.(c) Pharmacodynamics: Depending on the drug and the endpoints studied, pharmacodynamic studies and studies relating to drug blood levels (pharmacokinetic/pharmacodynamic studies) may be conducted in healthy volunteer Subjects or in patients with the target disease. If there are appropriate validated indicators of activity and potential efficacy, pharmacodynamic data obtained from patients may guide the dosage and dose regimen to be applied in later studies.(d) Early Measurement of Drug Activity: Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later Phases but may be appropriate when drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.(7) Therapeutic exploratory trials (Phase II).-(i) The primary objective of Phase II trials is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side- effects and risks associated with the drug. Studies in Phase II should be conducted in a group of patients who are selected by relatively narrow criteria leading to a relatively homogeneous population. These studies should be closely monitored. An important goal for this Phase is to determine the dose(s) and regimen for Phase III trials. Doses used in Phase II are usually (but not always) less than the highest doses used in Phase I.(ii) Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III.6
  53. 53. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.(ii) If the application is for conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and the patients as well as the justification for undertaking such trials in India shall be provided to the Licensing Authority.(8) Therapeutic confirmatory trials (Phase III).-(i) Phase III studies have primary objective of demonstration or confirmation of therapeutic benefits(s). Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies should be intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationships (relationships among dose, drug concentration in blood and clinical response), use of the drug in wider populations in different stages of disease, or the safety and efficacy of the drug in combination with other drug(s).(ii) For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be initiated in Phase II. These studies carried out in Phase III complete the information needed to support adequate instructions for use of the drug (prescribing information).(iii) For new drugs approved outside India, Phase III studies needs to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information. Prior to conduct of Phase III studies in Indian subjects, Licensing Authority may require pharmacokinetic studies to be undertaken to verify that the data generated in Indian population is in conformity with the data already generated abroad.(iv) If the application is for the conduct of clinical trials as a part of multi- national clinical development of the drug, the number of sites and patients as well as the justification for undertaking such trials in India should be provided to the Licensing Authority along with the application.(9) Post Marketing Trials (Phase IV).- Post Marketing trials are studies (other thanroutine surveillance) performed after drug approval and related to the approved
  54. 54. indication(s). These trials go beyond the prior demonstration of the drug’s safety,efficacy and dose definition. These trials may not be considered necessary at thetime of new drug approval but may be required by the Licensing Authority foroptimizing the drug’s use. They may be of any type but should have valid scientificobjectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approvedindication(s), e.g. mortality/morbidity studies, epidemiological studies etc.3. Studies in special populations:Information supporting the use of the drug in children, pregnant women, nursingwomen, elderly patients, patients with renal or other organ systems failure, andthose on specific concomitant medication is required to be submitted if relevantto the clinical profile of the drug and its anticipated usage pattern. Any claimsought to be made for the drug product that is not based on data submittedunder preceding items of this Schedule should be supported by studies includedunder this item of the Schedule (Appendix I item 8.3).(1) Geriatrics.-Geriatric patients should be included in Phase III clinical trials (andin Phase II trials, at the Sponsor’s option) in meaningful numbers, if-(a) the disease intended to be treated is characteristically a disease of aging; or(b) the population to be treated is known to include substantial numbers of geriatric patients; or(c) when there is specific reason to expect that conditions common in the elderly are likely to be encountered; or7(d) when the new drug is likely to alter the geriatric patient’s response (with regard to safety or efficacy) compared with that of the non-geriatric patient.(2) Paediatrics.-(i) The timing of paediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments. For a drug expected to be used in children, evaluations should be made in the appropriate age group. When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants.

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