John Heldens, CIP, CCRP Director, UCSF Health Care Compliance Association 2011 Compliance Conference IRB review of international research Pre-conference P1 FCPA 3 rd Party Due Diligence for Health Entities Today UCSF experience with international human research OHRP: IRB knowledge of local context Differences between FDA and ICH-GCP 2 1
UCSF Transnational 3 UCSF IRB members knowledge of international local research context Angola Argentina Australia Botswana Brazil Cambodia Canada Chile China Costa Rica Ecuador Egypt France Germany Guatemala Honduras India Ivory Coast Jamaica Japan Liberia Mexico Mozambique Netherlands New Zealand Nigeria Peru Poland Saint Vincent & the Grenadines South Africa Thailand Tobago Trinidad Turkey Uganda United Kingdom 4 2
IRB Knowledge of Local Context 5 45 CFR 46.107(a) The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. 6 3
45 CFR 46.111 (3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted (4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative (7) When appropriate, there are adequate provisions to protect the privacy of subjects 7 45 CFR 46.116 no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. 8 4
(1) minimal risk research The IRB should demonstrate that it has obtained necessary information about the local research context through written materials or discussions with appropriate consultants. IRB application IRB members IRB Consultants 9 (2) No intervention/interaction, principal risk is breach of confidentiality The IRB should (i) demonstrate that it has obtained necessary information about the local research context through written materials or discussions with appropriate consultants; and (ii) determine and specifically document that provisions to protect the privacy of subjects and maintain the confidentiality of data are adequate. Reviewer s checklist 10 5
Necessary information the anticipated scope of the institution's research activities; the types of subject populations likely to be involved; the size and complexity of the institution; institutional commitments and regulations; applicable law; standards of professional conduct and practice; method for equitable selection of subjects; method for protection of privacy of subjects; method for maintenance of confidentiality of data; language(s) understood by prospective subjects; method for minimizing the possibility of coercion or undue influence in seeking consent; and safeguards to protect the rights and welfare of vulnerable subjects. 11 (3) Greater than minimal risk The IRB should demonstrate that it has obtained necessary information about the local research context through one or more of the following mechanisms, or through other mechanisms deemed appropriate by OPRR for the proposed research and the local research context. a) Personal knowledge of the local research context on the part of one or more IRB members, such knowledge having been obtained through extended, direct experience with the research institution, its subject populations, and its surrounding community. b) Participation (either physically or through audiovisual or telephone conference) by one or more appropriate consultants in convened meetings of the IRB. Such consultant(s) should have personal knowledge of the local research context, [as described above]. 12 6
(3) Greater than minimal risk c) Prior written review of the proposed research by one or more appropriate consultants (see (b) above), in conjunction with participation (see (b) above) by the consultant(s) in convened meetings of the IRB, when such participation is deemed warranted either by the consultant(s) or by any member of the IRB. d) Systematic, reciprocal, and documented interchange between the IRB and elements of the local research context. Such interchange should include (i) periodic visits to the research site, occurring several times per year, by one or more IRB members in order to obtain and maintain knowledge of the local research context (see (a) above); (ii) periodic discussion with appropriate consultants knowledgeable about the local research context; (iii) regular interaction with one or more designated institutional liaisons; and (iv) review of relevant written materials. 13 Institutional responsibilities 1) Each institution remains responsible for safeguarding the rights and welfare of human subjects within its local research context. 2) Each institution remains responsible for educating the members of its research community in order to establish and maintain a culture of compliance with Federal regulations and institutional policies relevant to the protection of human subjects. 3) Each institution remains responsible for implementation, within its local research context, of appropriate oversight mechanisms in order to ensure compliance with the determinations of the reviewing IRB. 4) Where institutions holding an OPRR-approved Assurance engage a separate entity to perform human subject protection activities, OPRR must review and approve those portions of the contract and/or other clarifying documentation detailing responsibilities and implementation mechanisms relevant to such activities. (a) (c) [documentation requirements] 14 7
Differences between FDA vs. ICH-GCP 15 Vulnerable subjects ICH-GCP (E6) 1.61 Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. 16 8
Modifications ICH-GCP (E6) 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)). 17 Randomization ICH-GCP (E6) 4.8.10(c) The consent form and discussion should explain: The trial treatment(s) and the probability for random assignment to each treatment. 18 9
Subject s responsibilities ICH-GCP (E6) 4.8.10(e) The consent form and discussion should explain: The subject's responsibilities. 19 Alternatives ICH-GCP (E6) 4.8.10(i) The consent form and discussion should explain: The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks. 20 10
Confidentiality ICH-GCP (E6) 4.8.10(n) The consent form and discussion should include a statement that: The monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access. 21 Consent form signatures ICH-GCP (E6) 4.8.8 Prior to a subject s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion. 22 11
Witness ICH-GCP (E6) 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After [informed consent] the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject s legally acceptable representative. 23 Documentation to subjects ICH-GCP (E6) 4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject s participation in the trial, the subject or the subject s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects. 24 12
Assent ICH-GCP (E6) 4.8.12 When a clinical trial (therapeutic or nontherapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject s understanding and, if capable, the subject should sign and personally date the written informed consent. 25 Non-therapeutic trials ICH-GCP (E6) 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled: (a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally. (b) The foreseeable risks to the subjects are low. (c) The negative impact on the subject s wellbeing is minimized and low. (d) The trial is not prohibited by law. 26 13
Non-therapeutic trials (e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. 27 Federalwide Assurances FWA required for institutions receiving federal research funding FDA requires IRB/ERC registration 28 14
Resources IRB Knowledge of Local Context http://www.hhs.gov/ohrp/policy/local.html International Compilation of s http://www.hhs.gov/ohrp/international/intlcompilation/hs pcompilation-v20101130.pdf ICH-GCP E6 http://www.ich.org/products/guidelines/efficacy/efficacysingle/article/good-clinical-practice.html Bankert, Elizabeth and Amdur, Robert. Institutional Review Board Management and Function. Sudbury, MA: Jones and Bartlett, 2006. 29 15