Clinical Research Regulation: FDA vs. ICH

On May 9th, 1997, the US Food and Drug Administration (FDA) published in the FEDERAL REGISTER (vol. 62, No 90), the latest rendition of the International Conference on Harmonization (ICH) Guideline covering the conduct of clinical research studies in the seven member nations. Guidelines represent the agency's current thinking on Good Clinical Practices, but do not bind the FDA or the public. However, most clinical research studies are now being conducted in compliance with this guideline, especially if the results might be used for an international regulatory submission. Here are the major differences.
Notification to Primary Care Physician
ICH recommends that a clinical trial investigator inform a subject's primary physician, if the subject agrees, about the subject's study participation (section 4.3.3). FDA does not mention such a notice.
IRB
ICH requires that the clinical investigator provide the Institutional Review Board (IRB) with a copy of the Investigator Brochure (4.4.2). FDA only requires that the pharmaceutical company sponsor provide it to the investigator; however, many clinical trial sponsors require documentation of receipt from the investigator's IRB (312.55a).
ICH requires a statement from the Institutional Review Board (IRB) that it is organized and operates according to Good Clinical Practices (5.11.1b). FDA does not require clinical research sponsors to obtain such a statement.
Documentation of Protocol Deviations
ICH requires that the investigator document and explain any deviation from the study protocol (4.5.3). FDA does not address this issue.
Study Medication
ICH requires that the clinical investigator maintain records that document adequately that the subjects were provided the doses specified by the protocol AND RECONCILE all investigational products received from the sponsor. FDA requires only the return of unused supplies and does not specify who is responsible for reconciliation (312.62).
ICH prohibits the pharmaceutical company sponsor (or the Contract Research Organization if the responsibility was properly transferred) from providing study medication until all required documentation from the IRB has been obtained (5.14.2). FDA does not address this; however, most sponsors have internal procedures covering this.
Informed Consent
The elements differ between ICH (4.8.10) and FDA (50.25a, 50.25b).
ICH requires that the subject receive a SIGNED and DATED copy of the written informed consent (4.8.11). FDA requires that a copy be given to the subject but does not state that it must be a SIGNED copy (50.27).
Financial Records
ICH requires that the clinical investigator make ALL clinical trial-related records available for direct access by the Clinical Research Associate, auditor, IRB, or regulatory agency (4.9.7) and that financial aspects of the trial be in the investigator's files (8.2.4). FDA currently does not require financial records, nor mandate "direct access" (312.62).
Signed Protocols
ICH requires that the sponsor and clinical investigator sign the study protocol (5.6.3). FDA doesn't have this requirement; however, most sponsors require signatures.
Indemnification
ICH requires that the sponsor provide insurance or indemnify the investigator against claims arising from the trial (5.8.1). FDA does not have such a policy; however, most investigators request and obtain it from the pharmaceutical company or Contract Research Organization.
Case Report Form Changes
ICH requires the monitor (Clinical Research Associate or CRA) ensure that changes/additions/deletions to the case report form (CRF) are made, dated, explained (if necessary), and initialled BY THE INVESTIGATOR or an authorized member of the investigator's staff, such as the Study Coordinator. This authorization must be documented (5.18.4n). FDA does not require documentation of authorization to initial CRF changes.
Monitoring Reports
ICH requires the sponsor document management review and follow-up of the monitoring report as prepared by the Clinical Research Associate (5.18.6d). FDA does not require sponsors to document review of the Clinical Research Associate's monitoring report.
ICH requires a copy of the Clinical Research Associate's Study Initiation Monitoring Report be stored in the investigator's files (8.2.20). This is not required by FDA at this time.
Study Documentation
ICH puts responsibility for ensuring that all study documents are on file at the investigational site on the Clinical Research Associate and requires that the Clinical Research Associate confirm that all necessary documents are at the site prior to closing the site (8). FDA holds the investigator responsible for the accuracy and completeness of the records related to the clinical trial.
ICH requires curriculum vitae of both the principal investigator and any sub-investigators (8.2.10). FDA does not require sub-investigator CV's, albeit this is typically a sponsor requirement.
ICH requires a SIGNATURE SHEET to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs in both investigator and sponsor files (8.3.24). FDA does not require documentation of investigator/staff signatures; however, this is typically a sponsor requirement.

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Discussion: "Should a patient sign an Informed Consent Form in his mother tongue or in a language he understands the best?"

• The patient should sign the ICF in the language he understands best as the ICF contains information that need to be understood by the patient so well that he can take decision to participate in the trial and not come up later with complains that he was made a guinea pig.
• The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.

According ICH-GCP
4.8 Informed Consent of Trial Subjects
4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.
4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC’s approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.
4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
4.8.4 None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.
4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.
4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.
4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable representative.
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.
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 the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, 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 subjec! t’s legally acceptable representative.
4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the probability for random assignment to each treatment.
(d) The trial procedures to be followed, including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that are experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of trial-related injury.
(k) The anticipated prorated payment, if any, to the subject for participating in the trial.
(l) The anticipated expenses, if any, to the subject for participating in the trial.
(m) That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
(n) 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.
(o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.
(p) That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.
(s) The expected duration of the subject’s participation in the trial.
(t) The approximate number of subjects involved in the trial.
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.
4.8.12 When a clinical trial (therapeutic or non-therapeutic) 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.
4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
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 well-being is minimized and low.
(d) The trial is not prohibited by law.
(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.
4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.

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