Presentation on theme: "Good Clinical Practice (GCP) in Clinical Research"— Presentation transcript:
1Good Clinical Practice (GCP) in Clinical Research Suchart Chongprasert, Ph.D.Food And Drug AdministrationICH GCP for Clinical Research investigators, 16 December 2013, DMSC
2Presentation Outline Practice vs. Research clinical research vs. clinical trialtherapeutic vs. non-therapeutic researchGCP: Introduction and PrinciplesBasic GCP Applications for InvestigatorsEthical Principles in Clinical ResearchInformed Consent Process: Introduction
3Research vs. Practice“Practice” refers to interventions that are designed solely to enhance the well-being of an individual patient or client, and that have a reasonable expectation of success.standard interventions scientifically proven and acceptedThe purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individual.BELMONT REPORT
4Research vs. Practice (2) “Research” designates an activity designed to test a hypothesis, permits conclusions to be drawn, and thereby to develop or contribute to generalizable knowledgeexpressed for example in theories, principles, and statements or relationships) that can be corroborated by scientific observation and inference.BELMONT REPORT
5Research vs. Practice (3) Research is usually described in a formal protocol that sets forth an objective, and a set of procedures designed to reach the objective.BELMONT REPORT
6Research vs. Practice (4) Research represents a systematic investigation (formal), including research development, testing, evaluation, that is designed to develop or contribute generalizable knowledge.methodologyPractice gains more flexibilities compared with research
7GENERALIZABLE KNOWLEDGE [rationale and background] RESEARH vs. PRACTICEGENERALIZABLE KNOWLEDGEQuestionHypothesisEstablished InterventionObjectivesRESEARCHPRACTICEDesignSimilar ConditionsTrialConclusionUNMET MEDICAL NEEDS[rationale and background]
8Clinical Researchresearch that either directly involves a particular person or group of people or uses materials derived from humans such asbehaviors or samples of the tissues, that can be linked to a particular living person (identifiable tissue or bio-specimens)
9Declaration of Helsinki 2013 ethical principles for medical research involving humans subjects, including research on identifiable human materials and data
10Clinical Research : categories  Patient-oriented research: involves a particular person or group of people or uses of materials from humansstudies of mechanisms of human disease;studies of therapies or interventions for diseases;clinical trials; andstudies to develop new technology related to diseases
11Clinical Research  ]: categories  Epidemiological and behavior studies:.. examining the distribution of diseases, the factors that affect health, and how people make health-related decisions Outcomes and health services research: seeking to identify the most effective and most efficient interventions, treatments, and services
12Clinical Trialsone type of clinical research that involves a researcher or researchers who directly observes a person or people, and/or who collect data to answer a scientific or medical question about the safety or potential benefit of an intervention such as medication, device, teaching concept, training method or behavioral change
13Clinical Trialsa prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices) [US NIH]
14Clinical Trialsa controlled study involving human subjects that is designed to prospectively evaluate the safety and effectiveness of new drugs or devices or of behavioral interventions [US DHHS, IRB Handbook]a systematic investigation, including research development, testing, and evaluation that is designed to develop or contribute to generalizable knowledge [US CFR Title 46 Part 102]
15Clinical trial any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are deemed synonymous. [ICH GCP]
20Data Quality vs. Integrity Quality: a measure of the ability of a product, process, or service to satisfy stated or implied needsData Quality: the essential characteristics of each piece of data, in particular, quality data should include:accurate;legible;complete and contemporaneous (recorded at the time activity occurs;original;attributable to the person who generated the data
21Data Quality vs. Integrity Data Integrity: the soundness of the body of the data as a whole, in particular, the body of data should be 1credible, 2internally consistent, and 3verifiableBoth quality and integrity are essential for data to be relied upon for regulatory decision-making
22Good Clinical Practice (GCP) in Clinical Research Suchart Chongprasert, Ph.D.Food and Drug AdministrationICH GCP for Investigators, 31 July 2013, Chaingmai
24Special attentions paid on Human subjects are protectedRights;Safety;Well beingClinical trial data are crediblefor regulatory decision;for scientific use toimprove interventions
25GCP significance..randomized controlled clinical trials form the foundation for “evidence-based medicine”, but such research can be relied upon only if it is conducted according to principles and standards collectively referred to as “Good Clinical Practice” (GCP)…Source: WHO Handbook for GCP: Guidance for Implementation
27Clinical trial...any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are deemed synonymous.ICH GCP [1.12]
28Clinical Trial the objective is to discover or verify investigation/research in humansusing pharmaceutical productsinvestigational phase or approved onethe objective is to discover or verifyclinical / pharmacological / pharmacodynamic effectsabsorption/ distribution / metabolism / excretionso as to ascertain the safety and efficacy of investigational products
29What is ICH GCP…. international ethical and scientific quality standard for the designing, conducting, recording, performing, monitoring, auditing, reporting a clinical trial that involves human participation...ICH GCP: Introduction
30ICH GCPquality system being used in a clinical trial from the beginning to the endquality standardencompassing both scientific, and ethical aspects
31Why GCP…. compliance with this guideline assures the public that the rights, safety, and well-being of trial subjects are protected, and that trial data are credible .ICH GCP : Introduction
32Importance is given to Human subjects are protected Rights Safety, Well beingClinical trial data are crediblefor regulatory decisionfor scientific use toimprove interventions
33ICH GCP - Objective…….to provide a unified standard for European Union, United States, and Japan to facilitate mutual acceptance clinical data by regulatory authorities in the three jurisdictionsno repetition of quality clinical trials conducted previously in any of these regionsensuring the quality for the protection of humans as well as the quality and integrity of clinical data
34ICH GCP - Development...developed with the consideration of the current GCP of the EU, Japan, US as well as Australia, Canada, the Nordic Countries, and the WHO.combined together principles and guidelines implemented in advanced countries or organizationpromoting global acceptance of clinical data generatedICH GCP: Introduction
35Applicability When to apply the ICH GCP? ….should follow when generating clinical data that are intended to be submitted to regulatory authorities in the three regions.support a regulatory decision for marketing authorization of pharmaceutical productsICH GCP: Introduction
36other applicabilities .. the principles established in this guideline can also be used for other clinical investigations that may affect safety and well-being of trial subjects.can be applied to broader than a clinical trial
37considerations..some principles of GCP may not apply to all types of research on human subjects; consideration of these principles is strongly encouraged wherever applicable as a means of ensuring the ethical, methodologically sound and accurate conduct of human subject’s research..Source: WHO Handbook for GCP: Guidance for Implementation
38Applications of GCPstudies of a physiological, biochemical, or pathological process, or of a specific interventioncontrolled studies of diagnostic, preventive or therapeutic measuresstudies designed to determine the consequence for individuals and communities of specific preventive or therapeutic measuresSource: WHO Handbook for GCP: Guidance for Implementation
39Applications of GCP studies concerning human health-related behavior in a variety of circumstances and environmentsstudies that employ either observation or physical, chemical, or psychological interventionmay generate records or make use of existing records containing biomedical or other information about individuals who may or may not be identifiable from the records or information
43ICH GCP: STRUCTURE & CONTENT GlossaryPrinciples of ICH GCPIRB/IECInvestigatorSponsorClinical Trial ProtocolInvestigator’s Brochure (IB)Essential Documents for theconduct of Clinical TrialsStandard arrangementPersonnelDocuments
46ICH GCP Principles ethical principles established in the Declaration of Helsinki (updated 2013)  favorable risk and benefits ratio at the beginning and continuing of a clinical trial  rights, safety, and well-being of trial subjects most important consideration, and precede the interests of science and society  nonclinical and clinical data (if any) available to support the proposed trial
47ICH GCP Principles  trial scientifically sound and written in a clear protocol  protocol receives prior approval from IEC/IRB  medial care and medical decision made be responsible by qualified physicians or dentists  investigator and staff qualified by education, training, and experience  freely informed consent obtained from individual subject prior to his/her participation
48ICH GCP Principles  clinical trial information be managed in a way that allows accurate reporting, interpretation, and verification  confidentiality of trial subjects  investigational product manufactured, handles, and stored according to GMP  QA system and procedures implemented throughout the trial
49Advantages of GCPimportance is given to (1) the protection of human subjects and (2) the quality and integrity of clinical dataclear assignment of key individuals involving in a clinical trial i.e., investigator, EC, sponsorstandardized glossary of termsstandardized elements of informed consentstandardized IRB/IEC membershipemphasize on principles, de-emphasize on “how to”
50Limitations of GCPvery high standards to be applied in for the Thai context (in general);subject to easy deviation;require intensive resources to implement;sponsor QAmay not be practical in a resource-poor setting;require adequate resources and investment in a regulatory authority
51Ethics in Clinical Research and Independent Ethics Committee Suchart Chongprasert, Ph.D.Food and Drug AdministrationICH GCP for Investigators, 16 December 2013, DMSC
53Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirementsICH GCP Principle 1
54Research involving humans should be scientifically sound and conducted in accordance with the basic ethical principles, which have their origin in the Declaration of Helsinki.Three basic ethical principles of equal importance, namely respect for person, beneficence, and justice permeate all GCP principles.WHO GCP Principle 1
55summarized from Dr. Henry Beecher’s Article “… the two more important things needed for ethical clinical research i.e., informed consent and virtuous investigators.”summarized from Dr. Henry Beecher’s Article
56Basic Ethical Principles Respect for personAutonomy (independence)Beneficence and [non-maleficence]maximizing benefit; minimizing harms;do no harmJusticedistributive justice
57Respect for PersonRespect for person requires that subjects, to the degree that they are capable, be given opportunities to choose what shall or shall not happen to them.Belmont Report
58Respect for Person People should be treated as an autonomous agent subject autonomySubjects with diminished autonomy need special protectionvulnerable subjects
59Respect for Personautonomous agent means individuals who are able to make their own decision regarding their goal and the process to achieve such goalsfocus paid on choice and opinion of each autonomous individual upon one’s determinationright to self-determination
60People with Diminished Autonomy Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of a retaliatory response from senior members of a hierarchy in case of refusal to participate
61People with Diminished Autonomy (2) Examples are members of a group with a hierarchical structure such as medical, pharmaceutical, and nursing students, subordinate hospital and laboratory personnel, employees of pharmaceutical industry, members of the arm forces, and persons kept in detention.
62People with Diminished Autonomy (3) Other vulnerable subjects include patients with incurable diseases, persons in nursing home, unemployed or impoverished persons, refugees, minors, and those incapable of giving own consent
63special safeguard measures additional safeguards to protect the rights, safety, and well-being of subjects with diminished autonomyspecial justification to the ethics committee that research could not be carried out equally well with less vulnerable subjectsseeking permission of a legal guardian or other legally authorized representativesimpartial witnessmonitoring the conduct of the study
64Respect for Person right for self-determination; human’s dignity; informed consent;vulnerable subjects;privacy and confidentiality
65Beneficencemoral obligation to maximize the benefits and to minimize harmrequiring thatrisks of research be reasonable in the light of the expected benefitsresearch design be soundinstigators be competent both to conduct the research and to safeguard the welfare of the subjects
66Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefits for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risksICH GCP 2.2
67Clinical trials should be scientifically sound and described in clear detailed protocol ICH GCP 2.5
68The medical care given to, and medical decision made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a dentistICH GCP 2.7
69Beneficencein addition to maximizing benefits and minimizing risks or harmbeneficence sometimes expressed as a separate principle of non-maleficence (do no harm)
70“Risks and benefits of research may affect the individual subjects… and society at large (or special groups of subjects in society).” “In balancing these different elements, the risks and benefits affecting the immediate research subjects will normally carry special weight.”Belmont Report
71The rights, safety, and well-being of the trial subjects are the most important considerations, and should prevail over the interests of science and society.ICH GCP 2.3
72Justice “distributive” justice who bears the burden/risk of researchwho takes benefitsgiving rise to moral requirements that there be fair procedures and outcomes in the selection of trial subjects
73Justice justice in the selection of research subjects requires attention in two respectsindividualsocialequity requires that no group or class of persons should bear more than its fair share of the burdens of participation in research
74Justice Subject should be drawn from qualifying population in the general geographic area of the trial without regard to race, ethnicity, economic status, or gender unless there is a sound scientific reason to do otherwiseCIOMS Guideline 12
75Practical Applications Informed consent [Respect for Person]informed decision makingRisk/benefit assessment [Beneficence]favorable ratioSelection of trial subjects [Justice]fair and equitable procedures and outcomes
76Suitability of Informed Consent sufficiency of information given;basic minimum elementsunderstanding;understood consentvoluntariness;freely given without undue influence
77Remember!The three ethical principles are originally derived from the Western cultureIn applying these principles, please take into account local norms, cultures, and traditions as appropriateConsult IEC, if needed
79A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) /independent ethics committee (IEC) approval or/favorable opinion.ICH GCP Principle 2.5
80A trial should be conducted in compliance with the protocol that has received prior IRB/IEC approval/favorable opinion.ICH GCP Principle [2.6]
81Institutional Review Board An independent body constituted of medical, scientific, and non-scientific members whose responsibility is to ensure the protection of rights , safety , and well-being  of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendment (s) and of the methods and material to be used in obtaining and documenting informed consent of the trial subjectsICH GCP [1.31]
82Independent Ethics Committee An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility is to ensure the protection of the rights , safety , and well-being  of human subjects involved in a trial, and to provide public assurance of that protection by, among other things, reviewing and approving / providing favorable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining informed consent of the trial subjectsICH GCP [1.27]
83IRB/IEC Institutional Review Board (IRB) used in the US Independent Ethics Committee (IEC) used in Europedeem synonymousin Thailand, both are used interchangeablyERC, REC
84IRB/IECindependent board / committee (free of any undue influence to perform their task and make the decision)exist in several levels depending on situations e.g., institutional (CU, MU) , national (MOPH), regional (EU), or supranationalmembers with medical and non-medical professionsresponsible for protection of human subjects in a trial (rights, safety, and well being)
85IRB/IECassuring the public of their achieved responsibilities by performing the following tasksreviewing and approving the trial protocol;suitability of the investigator and the team (through most update CVs);adequate facilities to conduct the trial;methods and materials to be used in obtaining informed consentetc.
86IRB/IEC interface between the investigator and the subjects possessing a formal authority for the approval of the trial and/or suspending/terminating the trial based upon the applicable laws and regulations
87Declaration of Helsinki !! Why IEC Review?required independent review of a research protocolone of the criteria for determining if the conduct of a clinical trial is ethicalprotection of subjectsensure safety and well being of subjectsDeclaration of Helsinki !!
88PolicyIRB/IEC constituting and operating in accordance with the ICH GCPwritten approval received prior to initiating the trialif no constituted / appropriate IEC, use an independent IEC such as MOPH IEC
89IEC Compositionconsist of a reasonable number of members, who collectively have the qualifications and experiences to review and evaluate the science, medical aspects, and ethics of the proposed trialIf it is not scientifically valid, it is unethical
90Preparation and Submission investigator needs toobtain confirmation of IEC members present and occupationinform IEC of any payments to subjects and advertisements, if anyobtain a list of IEC members
91Documents for Submission Informed Consent/Patient Information Sheetprotocol and amendmentsInvestigator’s Brochure/drug informationEC submissionDiary cardspayment scheduleany advertisements
93Roles of Investigator interface between sponsor and ethics committee satisfies documentation requirementsupdates ethics committee as requiredsafety progress;safety, SAEs;progress report, etc.
94Roles of Investigator  Investigator mustnot be involved in the approval processnot influence / apply pressure to committee memberscommunicate with the IEC in an appropriate manner (e.g., respect for their decision, appeal the decision with supportive new scientific evidence for the protocol etc.)
95IRB/EC Decision unconditional approval documented in writing be signed and dated by Chairman / Secretariatapproval letter bears full the protocol number and title and/or versionNote: a trial must not be begun prior to receiving the IEC approval letter !!
96Summaryindependent review is mandatory in biomedical research, including a clinical trialcompetent IRB/IEC fulfills the requirement of the Declaration of Helsinki, ICH GCP, and applicable regulationsinvestigator should ensure that the trial protocol is reviewed and approved by a competent ethics committee
97Summary investigator should obtain an EC approval letter before commencing the trialinvestigator should ensure a regular contact with the EC in case of new information, amendments, progress report, or safety update etc.
98Informed Consent Process Suchart Chongprasert, Ph.D.Food and Drug AdministrationICH GCP for Clinical Research investigators, 31July 2013, Chiangmai
99Presentation Outline What does it means? Basic Elements of Informed ConsentCertain Important Aspect of Informed ConsentExercise
100Freely given informed consent should be obtained from every subject prior to clinical trial participationICH GCP Principle [2.9]
101Declaration of Helsinki “… each potential subject must be adequately informed of the aims, methods, anticipated benefits and potentials hazards of the study and the discomforts it may entail.”“…the physician should obtain the subject’s freely given informed consent, preferably in writing.”Declaration of Helsinki
102A process1 by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.ICH 1.28
103..an ongoing process, not a form for just signing Informed consent..an ongoing process, not a form for just signingA process by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.
104no coerce or use undue influence Informed consentA process1 by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.no coerce or use undue influence
105….two way communication and answer to subject’s satisfaction Informed consent….two way communication and answer to subject’s satisfactionA process1 by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.
106thoroughly about the trial e.g., purpose, benefits, payment etc. Informed consentA process1 by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.thoroughly about the trial e.g., purpose, benefits, payment etc.
107subject’s autonomy to make their own judgment Informed consentA process1 by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.subject’s autonomy to make their own judgment
108….acceptable way under the ICH GCP context Informed consentA process1 by which a subject voluntarily2 confirms his or her willingness to participate in a particular trial, after having been informed3 of all aspects4 of the trial that are relevant to the subject’s decision5 to participate. Informed consent is documented by means of a written6 signed7 and dated8 informed consent form.….acceptable way under the ICH GCP context
110Informed consent Desirable informed consent adequate information disclosedlanguage suitable to the recipientnot too technicalavoid a non-mother languageremember that the readers are not scientific expert/ethics committee members
111Methods for Documenting Informed Consent written informed consentIn accordance with ICH GCPoral witnessed consentsno documented evidencebeyond the scope of ICH GCP
112Elements of IC (ICH GCP) 1. involve research;2. research purpose;3. choice of treatments, including randomization;4. trial procedures, including invasive ones;5. subject’s responsibilities;6. trial aspects that are experimental;7. foreseeable risks/inconvenience
113Elements of IC 8. anticipated benefits, if not any, inform as well;9. treatment alternative if not willing to participate and related risks/benefit;10. compensation/treatment in case of trial-related injury;11. prorated payment, if any;12. expected expenses, if any, for participating;
114Elements of IC  13. voluntary statement; 14. statement for direct access by monitor, auditor, IEC/IRB, authority upon signing the consent form;15. confidentiality of the subject’s private info. kept;16. be informed timely available new information affecting the willingness to continue in the trial;
115Elements of IC 17. contact person for more information or in case of injury;18. circumstances for withdrawal/ termination;19. expected duration;20. approximate number of trial subjects (local vs. global)
116Important Considerations consent must be informed;careful about the uninformed informed consentensure subjects’ understanding (understood consent)subjects given ample time;all questions answered to the subject's satisfaction;no undue pressure/influence;language clearly understood by the subjectsrecommended not higher than grade 8
117Important Considerations  no language causing the subjects or the legally acceptable representatives to waive their legal rights;IC not a legal contract / agreementICF personally signed and dated by the subject and the person obtaining the ICF;a copy of ICF given to subject prior to participation;
118Suitability Considerations for IC informed and [ understood ] consent;respect for subject’s right to self-determination (autonomy)disclose sufficient information;all aspects about the trialsuitable for subject’s capacity (normal vs. diminished);age;educational status;sex;culture, geosocial factors etc.
119Suitability Considerations for IC  voluntariness; andpracticalityamount of the given info. vs. time for consideration in realityshort form??depending on investigator’s explanation
120Importantly!In principle, obtaining informed consent in a clinical research is a mustWaiving of informed consent is an exception which should be well-justified and received prior approval from IEC/IRB before implementation
122Practical Considerations Q: Who should obtain informed consent ?A: In general, the investigator or authorized person obtains the informed consent. According to the Helsinki Declaration, the physician who treats the potential subject should not obtain the consent by him/herself, instead other physician who understands the protocol well does. Avoid doctor/patient dependent relationship.
123Practical Considerations Q: Obtaining informed consent in children / minor ?A: For children with legal incompetence (i.e., age <20 yrs), but able to give assent to the research protocol, an assent form should be obtained besides parent’s informed consent[assent: affirmative agreement to participate in the trial]
124Practical Considerations Q: When to conduct the trial in relation to the time to obtain the informed consent ?A: The study cannot start prior to receiving a written informed consent from the subjects. Also, an unconditional written ethics committee’s approval letter must be obtained before beginning the trial.
125Practical Considerations Q: Informed consent in a clinical pharmacology trials (PK, phase I study)? (i.e., non therapeutic trial)A: Should be conducted in the subjects who can give informed consent by themselves by personally signing and dating on the form.
126Practical Considerations Q: When should the informed consent be amended ?A: When new information that may affect the safety and well being of the subject becomes available, and it may affect the subject’s decision to continue participating in the trial.
127Practical Considerations Q: How long should it take to obtain the informed consent?A: Depending on the situation. Remember that informed consent is an ongoing process, not finished upon the signature of the subject. Specifically, how long it takes until the subject signs and date on the form is what the investigator needs to know. Exact time cannot be established, but the investigator needs to achieve efficient project management and obligation under the GCP on obtaining informed consent.
128SummaryInformed consent is a continuing process to confirm subject's voluntary willingness to participate in the trial.Informed consent should be obtained from each patient prior to enrolling the subject into the trial.Children’s assent form is required in most clinical trials involving children (below majority age) participation