Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 47, Num. 2, 2001, pp. 121-130

4. INVESTIGATOR

(a) to the IRB/IEC for review and approval/favourable opinion,
(b) to the sponsor for agreement and, if required,
(c) to the regulatory authority(ies).

4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.

4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.

4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.

4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).

4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.

4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.

4.7 Randomization Procedures and Unblinding The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is poken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).

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, thesubject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’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 empyo, 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.

4.9 Records and Reports

4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.

4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.

4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 5.18.4 (n)). Sponsors should provide guidance to investigators and/or the investigators’ designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.

4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.

4.9.5 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (see 5.5.12).

4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.

4.10 Progress Reports

4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.

4.11 Safety Reporting

4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s pochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.

4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

4.12 Premature Termination or Suspension of a Trial

4.12.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s pochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.

4.12.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

4.12.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

4.13 Final Report(s) by Investigator

Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.

5. SPONSOR

5.1 Quality Assurance and Quality Control 5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)

5.2.1 A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.

5.3 Medical Expertise

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.

5.4 Trial Design

5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.

5.5 Trial Management, Data Handling, and Record Keeping

5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings.

5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:

(a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
(b) Maintains SOPs for using these systems.
(c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to the data.
(e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).

5.5.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.

5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject.

5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).

5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).

5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e. for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.

5.5.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).

5.5.11 The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.

5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.

5.6 Investigator Selection

5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.

5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s pochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

5.6.3 The sponsor should obtain the investigator’s/institution’s agreement:

(a) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see 4.5.1);
(b) to comply with procedures for data recording/reporting;
(c) to permit monitoring, auditing and inspection (see 4.1.4) and
(d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

5.7 Allocation of Responsibilities Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.

5.8 Compensation to Subjects and Investigators

5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

5.8.2 The sponsor’s policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

5.9 Financing The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

5.10 Notification/Submission to Regulatory Authority(ies) Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.

5.11 Confirmation of Review by IRB/IEC 5.11.1 The sponsor should obtain from the investigator/institution:

(a) The name and address of the investigator’s/institution’s IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.

5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.

5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion.

5.12 Information on Investigational Product(s)

5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.

5.12.2 The sponsor should update the Investigator’s pochure as significant new information becomes available (see 7. Investigator’s pochure).

5.13 Manufacturing, Packaging, Labelling, and Coding Investigational

5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).

5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.

5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable peaks of the blinding.

5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.

5.14 Supplying and Handling Investigational Product(s)

5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).

5.14.2The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

5.14.4 The sponsor should:

(a) Ensure timely delivery of investigational product(s) to the investigator(s).
(b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
(c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim).
(d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition.

5.14.5 The sponsor should:

(a) Take steps to ensure that the investigational product(s) are stable over the period of use.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

5.15 Record Access

5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.

5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.

5.16 Safety Information

5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC’s approval/favourable opinion to continue the trial.

5.17 Adverse Drug Rea ction Reporting

5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.

5.17.2Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).

5.18 Monitoring

5.18.1 Purpose

The purposes of trial monitoring are to verify that:

(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

5.18.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).

5.18.3 Extent and Nature of Monitoring

The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.

5.18.4 Monitor’s Responsibilities

The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:

(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):

(i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

(d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
(e) Verifying that written informed consent was obtained before each subject’s participation in the trial.
(f) Ensuring that the investigator receives the current Investigator’s pochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator’s trial staff are adequately informed about the trial.
(h) Verifying that the investigator and the investigator’s trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling only eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
(l) Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
(m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:

(i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
(ii) Any dose and/or therapy modifications are well documented for each of the trial subjects.
(iii) Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.

(n) Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator’s trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

5.18.5 Monitoring Procedures

The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.

5.18.6 Monitoring Report

(a) The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.
(b) Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
(c) Reports should include a summary of what the monitor reviewed and the monitor’s statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.
(d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.

5.19 Audit

5.19.1 Purpose

The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

5.19.2 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

5.19.3 Auditing Procedures

(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
(b) The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be documented.
(d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
(e) When required by applicable law or regulation, the sponsor should provide an audit certificate.

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance.

5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).

5.21 Premature Termination or Suspension of a Trial If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).

5.22 Clinical Trial/Study Reports Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abpeviated study reports may be acceptable in certain cases.)

5.23 Multicentre Tria ls

For multicentre trials, the sponsor should ensure that:

5.23.1All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.

5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.

5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.

5.23.4 All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.

5.23.5 Communication between investigators is facilitated.

This article is also available in full-text from http://www.jpgmonline.com/

© Copyright 2001 - Journal of Postgraduate Medicine