International Conference on Harmonisation; Good Clinical Practice: Consolidated Guideline |
Background Good Clinical Practice |
[Federal Register: May 9, 1997 (Volume 62, Number 90)] _______________________________________________________________________ Part II Department of Health and Human Services _______________________________________________________________________ Food and Drug Administration International Conference on Harmonisation; Good Clinical Practice: Consolidated Guideline; Notice of Availability DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration[Docket No. 95D-0219] International Conference on Harmonisation; Good Clinical Practice: Consolidated Guideline; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is publishing a guideline entitled ``Good Clinical Practice: Consolidated Guideline.'' The guideline was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guideline is intended to define ``Good Clinical Practice'' and to provide a unified standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. The guideline also describes the minimum information that should be included in an Investigator's Brochure (IB) and provides a suggested format. In addition, the guideline describes the essential documents that individually and collectively permit evaluation of the conduct of a clinical study and the quality of the data produced. DATES: Effective May 9, 1997. Written comments may be submitted at any time. ADDRESSES: Submit written requests for single copies of ``Good Clinical Practice: Consolidated Guideline'' to the Drug Information Branch (HFD-210), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4573. Send two self-addressed adhesive labels to assist that office in processing your requests. Submit written comments on the guideline to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Two copies of any comments are to be submitted, except that individuals may submit one copy. The ``Good Clinical Practice: Consolidated Guideline'' and received comments are available for public examination in the Dockets Management Branch (address above) between 9 a.m. and 4 p.m., Monday through Friday. FOR FURTHER INFORMATION CONTACT: Regarding the guideline: Bette L. Barton, Center for Drug Evaluation and Research (HFD-344), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1032. Regarding ICH: Janet J. Showalter, Office of Health Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-0864. SUPPLEMENTARY INFORMATION: In recent years, many important initiatives have been undertaken by regulatory authorities and industry associations to promote international harmonization of regulatory requirements. FDA has participated in many meetings designed to enhance harmonization and is committed to seeking scientifically based harmonized technical procedures for pharmaceutical development. One of the goals of harmonization is to identify and then reduce differences in technical requirements for drug development among regulatory agencies. ICH was organized to provide an opportunity for tripartite harmonization initiatives to be developed with input from both regulatory and industry representatives. FDA also seeks input from consumer representatives and others. ICH is concerned with harmonization of technical requirements for the registration of pharmaceutical products among three regions: The European Union, Japan, and the United States. The six ICH sponsors are the European Commission, the European Federation of Pharmaceutical Industries Associations, the Japanese Ministry of Health and Welfare, the Japanese Pharmaceutical Manufacturers Association, the Centers for Drug Evaluation and Research and Biologics Evaluation and Research, FDA, and the Pharmaceutical Research and Manufacturers of America. The ICH Secretariat, which coordinates the preparation of documentation, is provided by the International Federation of Pharmaceutical Manufacturers Associations (IFPMA). The ICH Steering Committee includes representatives from each of the ICH sponsors and the IFPMA, as well as observers from the World Health Organization, the Canadian Health Protection Branch, and the European Free Trade Area. In the Federal Register of August 17, 1995 (60 FR 42948), FDA published a draft tripartite guideline entitled ``Good Clinical Practice.'' In the Federal Register of August 9, 1994, FDA published draft tripartite guidelines entitled ``Guideline for the Investigator's Brochure'' (59 FR 40772) and ``Guideline for Essential Documents for the Conduct of a Clinical Study'' (59 FR 40774). The notices gave interested persons an opportunity to submit comments. After consideration of the comments received and revisions to the guidelines, the three guidelines were consolidated into one guideline on good clinical practice. The consolidated guideline was submitted to the ICH Steering Committee and endorsed by the three participating regulatory agencies at the ICH meeting held on April 30, 1996. The guideline defines ``Good Clinical Practice'' and provides a unified standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with Good Clinical Practice provides public assurance that the rights, well-being, and confidentiality of trial subjects are protected and that trial data are credible. The guideline should be followed when generating clinical data that are intended to be submitted to regulatory authorities. The principles established in this guideline should also be applied to other investigations that involve therapeutic intervention in, or observation of, human subjects. The guideline also describes the minimum information that should be included in an IB, such as information on the drug's physical, chemical, and pharmaceutical properties, and its effect in humans; a suggested format for the IB is also provided. The guideline also describes the purpose of essential documents in a clinical study and explains whether the documents should be filed in the investigator's files or the sponsor's files. This guideline represents the agency's current thinking on good clinical practices. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both. As with all of FDA's guidelines, the public is encouraged to submit written comments with new data or other new information pertinent to this guideline. The comments in the docket will be periodically reviewed, and, where appropriate, the guideline will be amended. The public will be notified of any such amendments through a notice in the Federal Register. Interested persons may, at any time, submit to the Dockets Management Branch (address above) written comments on the guideline. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of this document. A copy of the guideline and received comments may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday. An electronic version of this guideline is available via Internet. Type http://www.fda.gov/cder and go to the ``Regulatory Guidance'' section. The text of the guideline follows: TABLE OF
CONTENTS 1.
GLOSSARY 3.
INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 3.2 Composition, Functions and Operations 4.
INVESTIGATOR 4.1 Investigator's Qualifications and Agreements 4.3 Medical Care of Trial Subjects 4.4 Communication with IRB/IEC 4.6 Investigational Product(s) 4.7 Randomization Procedures and Unblinding 4.8 Informed Consent of Trial Subjects 4.12 Premature Termination or Suspension of a Trial 4.13 Final Report(s) by Investigator 5.
SPONSOR 5.1 Quality Assurance and Quality Control 5.2 Contract Research Organization (CRO) 5.5 Trial Management, Data Handling, and Record Keeping 5.7 Allocation of Duties and Functions 5.8 Compensation to Subjects and Investigators 5.10 Notification/Submission to Regulatory Authority(ies) 5.11 Confirmation of Review by IRB/IEC 5.12 Information on Investigational Product(s) 5.13 Manufacturing, Packaging, Labelling, and Coding
Investigational Product(s) 5.14 Supplying and Handling Investigational Product(s) 5.17 Adverse Drug Reaction Reporting 5.18.1 Purpose 5.19.2 Selection and Qualification of Auditors 5.21 Premature Termination or Suspension of a Trial 5.22 Clinical Trial/Study Reports 6.
CLINICAL TRIAL PROTOCOL AND
PROTOCOL AMENDMENT(S)
6.3 Trial Objectives and Purpose 6.5 Selection and Withdrawal of Subjects 6.10 Direct Access to Source Data/Documents 6.11 Quality Control and Quality Assurance Procedures 6.13 Data Handling and Record Keeping 7.2.1 Title Page 7.3 Contents of the Investigator's Brochure 7.3.1 Table of Contents 7.3.4 Physical, Chemical, and Pharmaceutical Properties and
Formulation 7.3.5 Nonclinical Studies 8.
ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL
TRIAL 8.2 Before the Clinical Phase of the Trial Commences 8.3 During the Clinical Conduct of the Trial 8.4 After Completion or Termination of the Trial Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects. 1.1 Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.2 Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.3 Amendment (to the protocol) See Protocol Amendment. 1.4 Applicable Regulatory Requirement(s) Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products. 1.5 Approval (in relation to Institutional Review Boards) The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements. 1.6 Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 1.7 Audit Certificate A declaration of confirmation by the auditor that an audit has taken place. 1.8 Audit Report A written evaluation by the sponsor's auditor of the results of the audit. 1.9 Audit Trail Documentation that allows reconstruction of the course of events. 1.10 Blinding/Masking A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). 1.11 Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. 1.12 Clinical Trial/Study 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 synonymous. 1.13 Clinical Trial/Study Report A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports). 1.14 Comparator (Product) An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial. 1.15 Compliance (in relation to trials) Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements. 1.16 Confidentiality Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity. 1.17 Contract A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract. 1.18 Coordinating Committee A committee that a sponsor may organize to coordinate the conduct of a multicenter trial. 1.19 Coordinating Investigator An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial. 1.20 Contract Research Organization (CRO) A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions. Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor's proprietary information. 1.22 Documentation All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. 1.23 Essential Documents Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial). 1.24 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee) An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. 1.26 Impartial Witness A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. 1.27 Independent Ethics Committee (IEC) An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical/scientific professionals and non-medical/nonscientific members, whose responsibility it 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 and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline. 1.28 Informed Consent A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization's (CRO's) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). 1.30 Institution (medical) Any public or private entity or agency or medical or dental facility where clinical trials are conducted. 1.31 Institutional Review Board (IRB) An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the 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 amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects. 1.32 Interim Clinical Trial/Study Report A report of intermediate results and their evaluation based on analyses performed during the course of a trial. 1.33 Investigational Product A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. 1.34 Investigator A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator. 1.35 Investigator / Institution An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements". 1.36 Investigator's Brochure A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator's Brochure) 1.37 Legally Acceptable Representative An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial. 1.38 Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 1.39 Monitoring Report A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor's SOPs. 1.40 Multicenter Trial A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator. 1.41 Nonclinical Study Biomedical studies not performed on human subjects. 1.42 Opinion (in relation to Independent Ethics Committee) The judgement and/or the advice provided by an Independent Ethics Committee (IEC). 1.43 Original Medical Record See Source Documents. 1.44 Protocol A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments. 1.45 Protocol Amendment A written description of a change(s) to or formal clarification of a protocol. 1.46 Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s). 1.47 Quality Control (QC) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. 1.48 Randomization The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. 1.49 Regulatory Authorities Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities. 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) Any untoward medical occurrence that at any dose: o results in death, o is life-threatening, o requires inpatient hospitalization or prolongation of existing hospitalization, o results in persistent or significant disability/incapacity, or o is a congenital anomaly/birth defect (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.51 Source Data All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). 1.52 Source Documents Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial). 1.53 Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. 1.54 Sponsor-Investigator An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator. 1.55 Standard Operating Procedures (SOPs) Detailed, written instructions to achieve uniformity of the performance of a specific function. 1.56 Subinvestigator Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator. 1.57 Subject/Trial Subject An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control. 1.58 Subject Identification Code A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data. 1.59 Trial Site The location(s) where trial-related activities are actually conducted. 1.60 Unexpected Adverse Drug Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.61 Vulnerable Subjects 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. 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. 1.62 Well-being (of the trial subjects) The physical and mental integrity of the subjects participating in a clinical trial. 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT
ETHICS COMMITTEE (IRB/IEC) 3.1.1 3.1.2 trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g., advertisements), written information to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator's current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill its responsibilities. The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following: o approval/favorable opinion; o modifications required prior to its approval/favorable opinion; o disapproval/negative opinion; and o termination/suspension of any prior approval/favorable opinion. 3.1.3 3.1.4
3.1.5 3.1.6 3.1.7 3.1.8 3.1.9 3.2 Composition, Functions and Operations 3.2.1 a. At least five members. b. At least one member whose primary area of interest is in a nonscientific area. At least one member who is independent of the institution/trial site. Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter. A list of IRB/IEC members and their qualifications should be maintained. 3.2.2 3.2.3 3.2.4
3.2.5
3.2.6 The IRB/IEC should establish, document in writing, and follow its procedures, which should include: 3.3.1 3.3.2
3.3.3 3.3.4 3.3.5 3.3.6
3.3.7 3.3.8 a. Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4). b. Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2). c. All adverse drug reactions (ADRs) that are both serious and unexpected. d. New information that may affect adversely the safety of the subjects or the conduct of the trial. 3.3.9 a. Its trial-related decisions/opinions. b. The reasons for its decisions/opinions. c. Procedures for appeal of its decisions/opinions. The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies). The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists. 4.1 Investigator's Qualifications and Agreements 4.1.1 4.1.2
4.1.3
4.1.4
4.1.5 4.2.1
4.2.2 4.2.3
4.2.4
4.3 Medical Care of Trial Subjects 4.3.1 4.3.2 4.3.3 4.3.4
4.4 Communication with IRB/IEC 4.4.1 4.4.2 4.4.3 4.5.1 4.5.2 4.5.3
4.5.4 a. to the IRB/IEC for review and approval/favorable opinion, b. to the sponsor for agreement and, if required, c. to the regulatory authority(ies). 4.6 Investigational Product(s) 4.6.1
4.6.2 4.6.3
4.6.4
4.6.5 4.6.6
4.7 Randomization Procedures and Unblinding The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken 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
4.8.2
4.8.3 4.8.4 4.8.5 4.8.6 4.8.7
4.8.8 4.8.9 4.8.10 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 4.8.12 4.8.13 4.8.14 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/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable 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 4.9.1 4.9.2 4.9.3 4.9.4 4.9.5 4.9.6 4.9.7 4.10.1 4.10.2 4.11.1 4.11.2 4.11.3 4.12 Premature Termination or Suspension of a Trial If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition: 4.12.1 4.12.2 4.12.3 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. 5.1 Quality Assurance and Quality Control 5.1.1 5.1.2 5.1.3 5.1.4 5.2 Contract Research Organization (CRO) 5.2.1 5.2.2 5.2.3
5.2.4 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. 5.4.1 5.4.2 5.5 Trial Management, Data Handling, and Record Keeping 5.5.1 5.5.2
5.5.3 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
5.5.5 5.5.6 5.5.7 5.5.8 5.5.9
5.5.10 5.5.11 5.5.12 5.6.1 5.6.2 5.6.3 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/favorable 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 Duties and Functions 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 5.8.2 5.8.3 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 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/favorable 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 5.11.3 5.12 Information on Investigational Product(s) 5.12.1 5.12.2 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) 5.13.1 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 5.13.3 5.13.4 5.13.5 5.14 Supplying and Handling Investigational Product(s) 5.14.1 5.14.2 5.14.3 5.14.4 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 position of unused investigational product(s) and for the documentation of this disposition. 5.14.5 h. Take steps to ensure that the investigational product(s) are stable over the period of use. i. 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. 5.15.1 5.15.2 5.16.1 5.16.2
5.17 Adverse Drug Reaction Reporting 5.17.1 5.17.2
5.17.3 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 5.18.4
Monitor's Responsibilities 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 Brochure, 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 enrolling 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 initialed 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 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. If or when sponsors perform audits, as part of implementing quality assurance, they should consider: 5.19.1 Purpose 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. 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. 5.20.1 5.20.2 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 abbreviated study reports may be acceptable in certain cases.) For multicenter trials, the sponsor should ensure that: 5.23.1 5.23.2 5.23.3 5.23.4
5.23.5 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) The contents of a trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator's Brochure. 6.1.1 6.1.2
6.1.3 6.1.4 6.1.5 6.1.6 6.1.7 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5 6.2.6 6.2.7 6.3 Trial Objectives and Purpose A detailed description of the objectives and the purpose of the trial. The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include: 6.4.1 6.4.2
6.4.3 a. Randomization. b. Blinding. 6.4.4 6.4.5 6.4.6 6.4.7 6.4.8 6.4.9 6.5 Selection and Withdrawal of Subjects 6.5.1
6.5.2 6.5.3 a. When and how to withdraw subjects from the trial/ investigational product treatment. b. The type and timing of the data to be collected for withdrawn subjects. c. Whether and how subjects are to be replaced. d. The follow-up for subjects withdrawn from investigational product treatment/trial treatment. 6.6.1
6.6.2 6.6.3
6.7.1 6.7.2 6.8.1 6.8.2
6.8.3
6.8.4
6.9.1 6.9.2
6.9.3 6.9.4 6.9.5 6.9.6 6.9.7 6.10 Direct Access to Source Data/Documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents. 6.11 Quality Control and Quality Assurance Procedures Description of ethical considerations relating to the trial. 6.13 Data Handling and Record Keeping Financing and insurance if not addressed in a separate agreement. Publication policy, if not addressed in a separate agreement. (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.) The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data. This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB. Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline. The IB should include: 7.2.1
Title Page 7.2.2
Confidentiality Statement 7.3 Contents of the Investigator's Brochure The IB should contain the following sections, each with literature references where appropriate: 7.3.1
Table of Contents 7.3.2
Summary 7.3.3
Introduction 7.3.4
Physical, Chemical, and Pharmaceutical Properties and Formulation To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given. Any structural similarities to other known compounds should be mentioned. Introduction: The information provided may include the following, as appropriate, if known/available: § Species tested § Number and sex of animals in each group § Unit dose (e.g., milligram/kilogram (mg/kg)) § Dose interval § Route of administration § Duration of dosing § Information on systemic distribution § Duration of post-exposure follow-up § Results, including the following aspects: § Nature and frequency of pharmacological or toxic effects § Severity or intensity of pharmacological or toxic effects § Time to onset of effects § Reversibility of effects § Duration of effects § Dose response Tabular format/listings should be used whenever possible to enhance the clarity of the presentation. The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis. §
Nonclinical Pharmacology §
Pharmacokinetics and Product Metabolism in Animals §
Toxicology § Single dose § Repeated dose § Carcinogenicity § Special studies (e.g., irritancy and sensitization) § Reproductive toxicity § Genotoxicity (mutagenicity) Introduction: §
Pharmacokinetics and Product Metabolism in Humans A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available: § Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination). § Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form. § Population subgroups (e.g., gender, age, and impaired organ function). § Interactions (e.g., product-product interactions and effects of food). § Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s). §
Safety and Efficacy A summary of information should be provided about the investigational product's/products' (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials (including those for all the studied indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed. The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s). §
Marketing Experience The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration. 7.3.7
Summary of Data and Guidance for the Investigator Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials. The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product. TITLE PAGE (Example) SPONSOR'S NAME Product: Research Number: Name(s): Chemical, Generic (if approved) Trade Name(s) (if legally permissible and desired by the sponsor) INVESTIGATOR'S BROCHURE Edition Number: Release Date: Replaces Previous Edition Number: Date:
TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example) -Confidentiality Statement (optional) - Signature Page (optional) 1. Table of Contents2. Summary3. Introduction4. Physical, Chemical, and Pharmaceutical Properties and Formulation5. Nonclinical Studies5.1 Nonclinical Pharmacology5.2 Pharmacokinetics and Product Metabolism in Animals5.3 Toxicology6. Effects in Humans6.1 Pharmacokinetics and Product Metabolism in Humans6.2 Safety and Efficacy6.3 Marketing Experience7. Summary of Data and Guidance for the InvestigatorNB: References on 1. Publications 2. Reports These references should be found at the end of each chapter.Appendices (if any)
8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable. Trial master files should be established at the beginning of the trial, both at the investigator/institution's site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files. Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor's auditor and inspection by the regulatory authority(ies). 8.2 Before the Clinical Phase of the Trial Commences During this planning stage the following documents should be generated and should be on file before the trial formally starts
8.3 During the Clinical Conduct of the Trial In
addition to having on file the above documents, the following should be added
to the files during the trial as evidence that all new relevant information
is documented as it becomes available
8.4 After Completion or Termination of the Trial After completion or termination of the trial, all of the documents identified in sections 8.2 and 8.3 should be in the file together with the following
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