Invited Article
Practical Guide to Understanding Clinical Research Compliance J. Gail Neely, MD1, Randal C. Paniello, MD1, Evan M. Graboyes, MD1, Jeffrey D. Sharon, MD1, David J. Grindler, MD1, and Brian Nussenbaum, MD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Noncompliance with federal regulations, as monitored through institutional review boards for the ethical conduct of clinical research, can occur, even to seasoned investigators. The cause of this noncompliance can be that an investigator is overloaded, does not know the regulations, or does not take the time to pay attention to the details. Sometimes it happens just because of inevitable human error that can befall us all at any time. The authors begin by citing the inherent differences between clinical practice and clinical research. This is followed by an illustration of common noncompliance errors, with examples, followed by general and specific concepts and methods to minimize noncompliance events. The objective of this article is to condense the myriad details involved in conducting clinical research into a set of manageable recommendations that can be recalled easily before and during the research. The material supporting these recommendations comes from years of institutional review board work at several institutions and consultation with experienced principal investigators and their research coordinators. Keywords clinical research, institutional review board, Federalwide Assurance, human research protection, Code of Federal Regulations Received January 15, 2014; accepted January 31, 2014.
Introduction The stimulus for this paper was the observation that even seasoned clinical investigators, at times, may have compliance problems as monitored by institutional review boards (IRBs). The situation is far worse with inexperienced investigators. Problems are especially prevalent among physicians with predominantly clinical practice experience, who are not given appropriate levels of guidance and mentorship and who do not completely understand the significant
Otolaryngology– Head and Neck Surgery 2014, Vol. 150(5) 716–721 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599814524895 http://otojournal.org
fundamental differences between clinical practice and clinical research (Table 1). Efforts to construct an educational tool useful to efficiently orient new clinical investigators, and briefly remind more experienced ones, are confounded by the myriad details involved in designing and conducting clinical research. In this paper, we examine the details in depth and offer some simple formulas that may help improve clinical research performance to reduce noncompliance.
Clinical Research Regulations and Seriousness of Noncompliance Clinical research is defined by the National Institutes of Health (NIH) as research involving human subjects, including materials (tissues, fluids, etc) from human subjects. Excluded from the definition are in vitro research studies involving human tissue, existing data that cannot be linked to living individuals, and research involving educational investigations in which individuals cannot be identified.1 However, it is strongly recommended that the IRB be contacted before conducting any research to get its ruling and to be sure that a formal IRB protocol is not required.
Differences among a Research Protocol, a Manual of Procedures or Standard Operating Procedure, and an IRB Protocol Three components of clinical research are the research plan or protocol, the operational details for conducting the protocol, and external oversight of the research. The details that drive a project are contained in the research protocol. Obviously, a prospectively designed, well-thought-out research protocol, defining exactly what is to be done, is fundamental to any research, even if it is a retrospective review of chart data. The National Institute of Neurological Disorders and Stroke makes 1 Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
Corresponding Author: J. Gail Neely, MD, Facial Nerve Clinical Center, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, 660 S Euclid Avenue, Box 8115, St Louis, MO 63110, USA Email: [email protected]
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Table 1. Fundamental Differences between Clinical Practice and Clinical Research.
Table 2. Institutional Review Board New Application Protocol Categories.
Clinical Practice
I. Demographics II. Research team III. Source(s) of support IV. Waiver of consent V. Other institutional reviews/requirements VI. Participants VII. Project information a. Basic project information b. Drugs and devices c. Genetic research d. Recruitment and consent e. Methods VIII. Risks IX. Benefits X. Privacy and confidentiality XI. Data analysis XII. Future research
Qualitative Flexible Physician directed Fewer external controls and oversight Visit time relatively short Event timing flexible Attention to care details important Focus: health of the patient
Clinical Research Quantitative Rigidly fixed Protocol directed Significant external controls/rules/oversight Visit time extremely long Event timing fixed and crucial Attention to research details crucial Focus: a valid answer to research question
available an excellent protocol template for the construction of a clinical trial.2 Operational details for the protocol describe exactly what the protocol is and when, how, and to whom each step of the protocol is to be performed, as well as exactly how and when those involved in the research will be trained. These details are often part of the research protocol; however, a separate document may be required, such as a manual of procedures or a standard operating procedure. When developing these operational details, it is crucial to think through each and every step and try to predict how a reallife mistake could happen and to design fail-safe methods to avoid these mishaps. For example, describe such details as requiring adequate light to see properly so that the exact medication can be checked or changed at midnight in a sleeping patient’s room. Mistakes have been made, with significant consequences, in just such a scenario. The National Institute of Neurological Disorders and Stroke offers a useful template for constructing a manual of procedures.3 The NIH and many non-industry-supported clinical trial grants require a manual of procedures, whereas industrysponsored grants use the research protocol for that purpose. An investigator brochure is the means of communicating operational details to investigative sites in multicenter trials, usually for industry-sponsored trials. An IRB protocol is a separate document that uses the research protocol to describe the basic research plan. A generic IRB protocol used at our institution is outlined in Table 2.
Federal Regulations Compliance is expected and required by federal regulations that establish oversight mechanisms to protect the rights and welfare of human research participants. Institutions that seek authorization to conduct research involving human subjects must first obtain a Federalwide Assurance and register an IRB. Subsequently, they must periodically update
and/or renew the IRB registration. This registration and continued certification are conducted through the Office for Human Research Protections,4 a division of the Office of the Assistant Secretary for Health in the Office of the Secretary, US Department of Health and Human Services. The rules under which IRBs operate are defined in the Code of Federal Regulations (CFR). The IRB at Washington University in St Louis has the following mission: ‘‘The mission of the IRB is to protect the rights and welfare of participants in ‘human research’ as defined in 45 CFR 46.102(d) and (f) and ‘clinical investigations’ as defined in 21 CFR 50.3(c).’’5 Each institution must have its own IRB; however, each must comply with the federal guidelines for accreditation. To help investigators stay compliant and properly conduct clinical research within the United States, Europe, and Japan, ‘‘Good Clinical Practice guidelines’’ are published in the Federal Register. These were established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use to ensure the ‘‘scientific validity and credibility of the data collected in human clinical studies’’ across nations and that ‘‘the rights, safety, and well-being of the trial subjects’’ are maintained.6-8 These guidelines participate as a standard by which trials are monitored, audited, and authorized.
Seriousness of Noncompliance In extreme cases, failure to comply with these federal regulations can result in loss of clinical research privileges for an individual, a department, or an institution, which can have a profound impact on the scholarly mission and financial security of each. For example, in 1 instance of a protocol violation, an investigator was removed as principal investigator (PI), and the study was closed. (All examples
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Table 3. The 5 Most Common Violation Categories and Examples. Category
Description
Protocol nonadherence
Failure to follow the protocol or to notify the IRB of changes and/or violations
Clinical records not well documented
Incomplete, inaccurate, out of date, data trail cannot be followed
Informed consent problems
Missing, incomplete, backdated, non-English-language interpretation rules not followed
Investigational product supply chain problems
Failure to account for every pill/product
Adverse event collection and reporting
Errors in determining severity, errors in timely reporting
throughout this paper are from real cases; however, they have been modified so that any association with real persons or institutions is purely coincidental.) In another instance, NIH funds were frozen and not released until alleged pilot trial violations were fully investigated and reconciled. In another instance, a complete project was done without prior IRB authorization; it was only when the PI attempted to publish the results that this was discovered. The paper could not be published, and the investigator was severely reprimanded. In another example, an investigator had significant financial conflicts of interest that could not be reconciled without the investigator’s being removed from the study.
Most Common Types of Noncompliance and Examples The 5 most common serious violations involve protocol, clinical records, informed consent, investigational products, and adverse events.9 Examples are from real cases, not from the article by Pierce9 (Table 3).
Methods to Improve Compliance General Concepts Oversight entities are the IRB, the funding source, the data and safety monitoring board, and government agencies, such as the US Food and Drug Administration. Fundamental for compliance is the establishment of an adequate filing system and mechanisms to keep track of specific items in the files. Basic folders and binders, subfolders,
Example A subject was given the wrong dose of a medication because the person prescribing the dose did not refer to the protocol and administered a dose commonly given in clinical practice. The clinical record indicated that the criterion for giving a potent medication was checked before the medication was given when, in fact, the criterion test was not available until after the medication had been given. Five informed consent forms were missing in a study population of 100. This implied that investigational interventions had occurred without the subjects’ being fully informed and agreeing to the procedure; these data had to be removed from the study. There was no record of what happened to unused investigational medication in 6 subjects. The implication was that the medications could have been sequestered and dispensed or sold to others. During an auditing visit, a serious adverse event was discovered to have occurred months before that had not been reported. This called into serious question the integrity of the safety claims made.
and files for the overall trial are derived from local clinical trials forms and from Good Clinical Practice guidelines.6-8 Folders and subfolders generally refer to electronic documents. Binders, with individual tabs, refer to loose-leaf paper binders. Any systematic recording of data involving patients is considered research and is subject to IRB oversight before the work is started. Critically important general rules for each investigator to remember at the inception and throughout the project are as follows: 1. Organize and prepare everything before launching the project. 2. Obtain advance authorization initially and for any changes. 3. Pay close attention to details. 4. Allocate enough time for each subject and for the project to perform the details; this takes much more time than for a clinical visit. 5. Separate clinical and research personnel, space, and activities. 6. Be sure all research personnel are research certified and project trained. 7. Itemize the exact role of each research team member. 8. Never keep subject-identifying data on nonencrypted computers, and never send sensitive material by e-mail. Always house all subject-identifying paper data behind 2 locks (ie, in a locked cabinet
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in a locked office) to which only authorized persons have keys. All components of the research must be congruent and reconcilable. For example, the consent document, the protocol, and the grant must all say the same thing about any item. As the research progresses, changes may be required. These changes must be approved in advanced and tracked so that the PI, research coordinator, and study personnel know what was changed, and the newly changed documents must be used from that point forward. Renewals must report exactly what is currently being done and what was changed. All oversight entities must be informed of each change. To stay compliant, it is useful to remember 3 basic rules: (1) prove, (2) track, and (3) report. For every item in the research protocol, it is important to prove that it was done correctly. This proof is contained in the source documents. Source documents are data collection documents for all the data captured during the project, such as data collected during a visit, laboratory values, x-ray reports, clinical notes, and so on. Checklists at visits, with signatures and dates (and times if time critical), are fundamental to establish proof of performance throughout the protocol. A useful concept for a physician-investigator is that documentation is like progress notes in a medical record, which record each and every patient visit with details, a signature, and the date, including acknowledgment, interpretation, and appropriate actions for each. Source documents must support everything that is to be formally recorded, signed, and dated, in a clean case report form (CRF). A CRF is a project-specific standardized data recording form, generated for each subject, that records all the variables germane to the research aims. Tracking refers to each subject and to the project as a whole. During the project planning stages, if one likes to outline one’s project in a spreadsheet, it can be useful to see what needs to be tracked by knowing that subject-specific data are in rows and that data pertaining to the project as a whole appear in the columns. Both the subject and project requirements are specified in the research protocol. A simple and useful technique to assist tracking is the use of a footer on each page of each document. The footer should show, from left to right: the document name, version number, date, and page number, as n (the current page number) of N (the total of all pages in document). This allows each page of each document to be tracked and authenticated for use when changes are made. When a document is changed, a useful technique is to copy that file into an ‘‘amended’’ folder with changes tracked, with the word ‘‘amend’’ added to the version and the new date in the footer. That file and a clean copy of it can be submitted. When approved, the new file can be given a new approved date, shown in the footer, this time without the word ‘‘amend’’ in front of version. Another way to keep track of files is to use decimal numbers (version 0.1, version 0.2, etc) for versions in progress and pending approval and whole numbers for approved versions (version 1, version 2,
etc). Again, save these files in the project office to demonstrate a paper trail proving preapproval amendments, submission for approval, and the final approved document and date that will replace all old documents. It is very important to use only the currently approved documents from that time forward for the active research; the old, previously used documents must be destroyed. Reporting to the IRB, sponsor, agencies, and/or data and safety monitoring board is crucial for the integrity of the science. Adverse event reporting is very important and must be done according to the methods and times required by the oversight entities. Details of the reported events, proof of submissions, and records of responses are very important. Reminders or ‘‘tickler’’ systems for adverse event and serious adverse event reports, future renewal deadlines, and other time-dependent documents are very helpful.10 An overview of what compliance is expected and what a monitor or auditor will be evaluating is provided in the checklist in Supplemental Table S1 (available at otojournal .org). Supplemental material too large to be included in this paper is available electronically to illustrate some of the forms used in clinical research. The reader is encouraged to review these items, which include a CRF (http://www.goo gle.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web& cd=7&ved=0CFIQFjAG&url=http%3A%2F%2Fwww.oxfor dradcliffe.nhs.uk%2Fresearch%2Fdocuments%2FTemplateCaseReportForm-ORHv1.doc&ei=zCNsUtKkEsqT2QWNx YHgDA&usg=AFQjCNETirUzpzzqXOv5BJiQfJkKhPj-Ug) and Washington University’s clinical research form library.11
Specific Pitfalls and Compliance Solutions The key to beginning and staying compliant is to spend the time necessary to organize and prepare everything before the trial begins. Be sure to obtain approvals. Study all regulations, funding support documents, guidelines, and forms to be sure the whole planned project is prepared to be compliant and that nothing has been overlooked or forgotten (A. Doyle and S. Heuerman, personal communications, 2013). Prepare the CRF master file for data recording. Construct the source documents using the CRF as a model (do not merely copy), and try to maintain the same order and format of the CRF for easy and accurate data transfer to the CRF. Be sure to study the protocol closely to add any qualifiers to the visit source documents. For example, in recording blood pressure, it may be required for a subject to remain sitting for 5 minutes before the reading is taken; be sure the visit source documents include that qualifier. Organize the project filing system and tracking methods. Organize a subject binder for each subject. Prepare a spreadsheet of the planned project visits. Prepare a separate spreadsheet checklist of items to be done at each visit for each subject. Organize the binder so that everything that is needed for each visit is available in order by visit; this includes source documents forms, checklists for performance, and reminders. Organize laboratory kits and products by visit, label them, and line them up by expiration date; start with the
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first to expire. Double-check all investigational product numbers to be sure accurate. To minimize mistakes on checklists, have ‘‘yes’’ first and then ‘‘no’’ for inclusions and ‘‘no’’ first and then ‘‘yes’’ for exclusions. Everything must be answered so that nothing is ambiguous, for example, ‘‘yes,’’ ‘‘no,’’‘‘not applicable,’’ or ‘‘not done.’’ Explain at the bottom of the source document why something was not done. To minimize visit mishaps (missed appointments, late data, etc), place specific subjects on a calendar and put a sticky note on the subject’s binder with the next visit date and visit number shown. Replace this note with a new note when that visit is completed. During the baseline visit, intentionally question the subject on each and every review of systems and medical history point; this is very important for determining if an adverse event has occurred during the study or was present at the beginning. Be sure to allot enough time to do each step of each visit and document it correctly. This always takes much more time than expected. Consent forms safeguards include the following: (1) be sure the currently approved consent form is used, (2) be sure the subject and the person obtaining the consent sign and date at the same time, (3) be sure only authorized and trained team members obtain consent, and (4) be sure the visit document confirms the required steps in the consent process were observed; use a checklist and add narrative text. Document all events in the equipment log protocol. All equipment used must be calibrated and maintained. The PI must sign and date every piece of data and mark it as clinically significant or not clinically significant. All material to be signed should be placed in a folder to be signed by the PI at regular intervals. Urgent events, such as serious adverse events, must be brought to the PI’s attention immediately. For easy and immediate retrieval, keep all contact information of key people and entities (PI, sponsor, IRB, etc) on the person of the PI and research coordinator in case of an urgent question or serious adverse event. Subject accrual and retention are always major problems in clinical studies. To improve retention and good will that may serve to improve accrual by word of mouth, it is important to personally acknowledge each subject, for example, with a birthday card or recognition of time spent in the study or for other important events.
In contrast, consequences of noncompliance for those pursuing careers as physician-scientists can severely affect their progress, even during pilot projects. The information in this paper is designed to assist both groups. Many of the details and forms may be omitted for smaller projects; however, close communication between investigators and their local IRBs is strongly recommended. Oversight issues can easily be thought of as time-wasting impediments to medicine and science. However, oversight is fundamental to the external credibility of the science and safety assurances for patients. It can be a potent stimulus to emphasize the necessity of allocating sufficient time for each subject and for paying considerable attention to detail. Opportunities for further training in clinical research may be obtained through research institutions,12 the NIH,13 and the Association of Clinical Research Professionals.14
Conclusions
Supplemental Material
Clinical research compliance is fundamental to the ethical conduct of any research. However, the level of detail required varies considerably among small clinical projects and larger clinical trials, especially multicenter trials. The consequences of noncompliance may have little effect on transient investigators, unless they are guilty of Health Insurance Portability and Accountability Act and security violations, such as having protected health information on nonencrypted phones, laptops, or other media or transmitting the same by unauthorized e-mail.
Author Contributions J. Gail Neely, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Randal C. Paniello, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Evan M. Graboyes, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Jeffrey D. Sharon, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; David J. Grindler, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Brian Nussenbaum, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published.
Disclosures Competing interests: None. Sponsorships: None. Funding sources: None.
Additional supporting information may be found at http://oto.sage pub.com/content/by/supplemental-data
References 1. National Institutes of Health. Glossary & acronym list. Available at: http://grants.nih.gov/grants/glossary.htm. Accessed February 10, 2014. 2. National Institute of Neurological Disorders and Stroke. Protocol template for definitive/efficacy (phase III) trials.
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3.
4.
5.
6. 7. 8.
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Available at: http://www.ninds.nih.gov/research/clinical_research/ toolkit/protocoltemplate.htm. Accessed February 10, 2014. National Institute of Neurological Disorders and Stroke. Manual of procedures. Available at: http://www.ninds.nih.gov/research/ clinical_research/policies/mop.htm. Accessed February 10, 2014. US Department of Health and Human Services, Office for Human Research Protections. Home page. Available at: http:// www.hhs.gov/ohrp/index.html. Accessed February 10, 2014. Washington University in St Louis, Human Research Protection Office. Home page. Available at: http://hrpohome.wustl.edu. Accessed February 10, 2014. Dixon JJ.The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur. 1998;6(2):65-74. International Conference on Harmonization. Good Clinical Practice guideline E6 R1. Fed Reg. 1997;62:25691-25709. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guidance for industry: E6 Good Clinical Practice: consolidated guidance. Available at: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM073122.pdf.
9. Pierce CH. Common GCP violations and site mistakes: how to avoid them. Monitor. 2012;26(5):55-59. 10. Youngblut JM, Loveland-Cherry CJ, Horan M. Data management issues in longitudinal research. Nurs Res. 1990;39(3):188-189. 11. Washington University in St Louis, Office of the Vice Chancellor for Research. Clinical research forms library. Available at: http://research.wustl.edu/ComplianceAreas/clinical/ Research_forms/Pages/default.aspx. Accessed February 10, 2014. 12. Washington University in St Louis, Clinical Research Training Center. Training programs. Available at: http://crtc.wustl.edu/ index.php/training-programs. Accessed February 10, 2014. 13. National Institutes of Health Clinical Center, Office of Clinical Research Training and Medical Education. Clinical Research Training Program. Available at: http://www.cc.nih.gov/training/crtp/crtp.html. Accessed February 10, 2014. 14. Association of Clinical Research Professionals. PI certification. Available at: http://www.acrpnet.org/MainMenuCategory/ Certification/PICertification.aspx. Accessed February 10, 2014.
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Practical Guide to Understanding Clinical Research Compliance J. Gail Neely, MD1, Randal C. Paniello, MD1, Evan M. Graboyes, MD1, Jeffrey D. Sharon, MD1, David J. Grindler, MD1, and Brian Nussenbaum, MD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Noncompliance with federal regulations, as monitored through institutional review boards for the ethical conduct of clinical research, can occur, even to seasoned investigators. The cause of this noncompliance can be that an investigator is overloaded, does not know the regulations, or does not take the time to pay attention to the details. Sometimes it happens just because of inevitable human error that can befall us all at any time. The authors begin by citing the inherent differences between clinical practice and clinical research. This is followed by an illustration of common noncompliance errors, with examples, followed by general and specific concepts and methods to minimize noncompliance events. The objective of this article is to condense the myriad details involved in conducting clinical research into a set of manageable recommendations that can be recalled easily before and during the research. The material supporting these recommendations comes from years of institutional review board work at several institutions and consultation with experienced principal investigators and their research coordinators. Keywords clinical research, institutional review board, Federalwide Assurance, human research protection, Code of Federal Regulations Received January 15, 2014; accepted January 31, 2014.
Introduction The stimulus for this paper was the observation that even seasoned clinical investigators, at times, may have compliance problems as monitored by institutional review boards (IRBs). The situation is far worse with inexperienced investigators. Problems are especially prevalent among physicians with predominantly clinical practice experience, who are not given appropriate levels of guidance and mentorship and who do not completely understand the significant
Otolaryngology– Head and Neck Surgery 2014, Vol. 150(5) 716–721 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599814524895 http://otojournal.org
fundamental differences between clinical practice and clinical research (Table 1). Efforts to construct an educational tool useful to efficiently orient new clinical investigators, and briefly remind more experienced ones, are confounded by the myriad details involved in designing and conducting clinical research. In this paper, we examine the details in depth and offer some simple formulas that may help improve clinical research performance to reduce noncompliance.
Clinical Research Regulations and Seriousness of Noncompliance Clinical research is defined by the National Institutes of Health (NIH) as research involving human subjects, including materials (tissues, fluids, etc) from human subjects. Excluded from the definition are in vitro research studies involving human tissue, existing data that cannot be linked to living individuals, and research involving educational investigations in which individuals cannot be identified.1 However, it is strongly recommended that the IRB be contacted before conducting any research to get its ruling and to be sure that a formal IRB protocol is not required.
Differences among a Research Protocol, a Manual of Procedures or Standard Operating Procedure, and an IRB Protocol Three components of clinical research are the research plan or protocol, the operational details for conducting the protocol, and external oversight of the research. The details that drive a project are contained in the research protocol. Obviously, a prospectively designed, well-thought-out research protocol, defining exactly what is to be done, is fundamental to any research, even if it is a retrospective review of chart data. The National Institute of Neurological Disorders and Stroke makes 1 Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
Corresponding Author: J. Gail Neely, MD, Facial Nerve Clinical Center, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, 660 S Euclid Avenue, Box 8115, St Louis, MO 63110, USA Email: [email protected]
Downloaded from oto.sagepub.com at Bobst Library, New York University on May 25, 2015
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Table 1. Fundamental Differences between Clinical Practice and Clinical Research.
Table 2. Institutional Review Board New Application Protocol Categories.
Clinical Practice
I. Demographics II. Research team III. Source(s) of support IV. Waiver of consent V. Other institutional reviews/requirements VI. Participants VII. Project information a. Basic project information b. Drugs and devices c. Genetic research d. Recruitment and consent e. Methods VIII. Risks IX. Benefits X. Privacy and confidentiality XI. Data analysis XII. Future research
Qualitative Flexible Physician directed Fewer external controls and oversight Visit time relatively short Event timing flexible Attention to care details important Focus: health of the patient
Clinical Research Quantitative Rigidly fixed Protocol directed Significant external controls/rules/oversight Visit time extremely long Event timing fixed and crucial Attention to research details crucial Focus: a valid answer to research question
available an excellent protocol template for the construction of a clinical trial.2 Operational details for the protocol describe exactly what the protocol is and when, how, and to whom each step of the protocol is to be performed, as well as exactly how and when those involved in the research will be trained. These details are often part of the research protocol; however, a separate document may be required, such as a manual of procedures or a standard operating procedure. When developing these operational details, it is crucial to think through each and every step and try to predict how a reallife mistake could happen and to design fail-safe methods to avoid these mishaps. For example, describe such details as requiring adequate light to see properly so that the exact medication can be checked or changed at midnight in a sleeping patient’s room. Mistakes have been made, with significant consequences, in just such a scenario. The National Institute of Neurological Disorders and Stroke offers a useful template for constructing a manual of procedures.3 The NIH and many non-industry-supported clinical trial grants require a manual of procedures, whereas industrysponsored grants use the research protocol for that purpose. An investigator brochure is the means of communicating operational details to investigative sites in multicenter trials, usually for industry-sponsored trials. An IRB protocol is a separate document that uses the research protocol to describe the basic research plan. A generic IRB protocol used at our institution is outlined in Table 2.
Federal Regulations Compliance is expected and required by federal regulations that establish oversight mechanisms to protect the rights and welfare of human research participants. Institutions that seek authorization to conduct research involving human subjects must first obtain a Federalwide Assurance and register an IRB. Subsequently, they must periodically update
and/or renew the IRB registration. This registration and continued certification are conducted through the Office for Human Research Protections,4 a division of the Office of the Assistant Secretary for Health in the Office of the Secretary, US Department of Health and Human Services. The rules under which IRBs operate are defined in the Code of Federal Regulations (CFR). The IRB at Washington University in St Louis has the following mission: ‘‘The mission of the IRB is to protect the rights and welfare of participants in ‘human research’ as defined in 45 CFR 46.102(d) and (f) and ‘clinical investigations’ as defined in 21 CFR 50.3(c).’’5 Each institution must have its own IRB; however, each must comply with the federal guidelines for accreditation. To help investigators stay compliant and properly conduct clinical research within the United States, Europe, and Japan, ‘‘Good Clinical Practice guidelines’’ are published in the Federal Register. These were established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use to ensure the ‘‘scientific validity and credibility of the data collected in human clinical studies’’ across nations and that ‘‘the rights, safety, and well-being of the trial subjects’’ are maintained.6-8 These guidelines participate as a standard by which trials are monitored, audited, and authorized.
Seriousness of Noncompliance In extreme cases, failure to comply with these federal regulations can result in loss of clinical research privileges for an individual, a department, or an institution, which can have a profound impact on the scholarly mission and financial security of each. For example, in 1 instance of a protocol violation, an investigator was removed as principal investigator (PI), and the study was closed. (All examples
Downloaded from oto.sagepub.com at Bobst Library, New York University on May 25, 2015
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Table 3. The 5 Most Common Violation Categories and Examples. Category
Description
Protocol nonadherence
Failure to follow the protocol or to notify the IRB of changes and/or violations
Clinical records not well documented
Incomplete, inaccurate, out of date, data trail cannot be followed
Informed consent problems
Missing, incomplete, backdated, non-English-language interpretation rules not followed
Investigational product supply chain problems
Failure to account for every pill/product
Adverse event collection and reporting
Errors in determining severity, errors in timely reporting
throughout this paper are from real cases; however, they have been modified so that any association with real persons or institutions is purely coincidental.) In another instance, NIH funds were frozen and not released until alleged pilot trial violations were fully investigated and reconciled. In another instance, a complete project was done without prior IRB authorization; it was only when the PI attempted to publish the results that this was discovered. The paper could not be published, and the investigator was severely reprimanded. In another example, an investigator had significant financial conflicts of interest that could not be reconciled without the investigator’s being removed from the study.
Most Common Types of Noncompliance and Examples The 5 most common serious violations involve protocol, clinical records, informed consent, investigational products, and adverse events.9 Examples are from real cases, not from the article by Pierce9 (Table 3).
Methods to Improve Compliance General Concepts Oversight entities are the IRB, the funding source, the data and safety monitoring board, and government agencies, such as the US Food and Drug Administration. Fundamental for compliance is the establishment of an adequate filing system and mechanisms to keep track of specific items in the files. Basic folders and binders, subfolders,
Example A subject was given the wrong dose of a medication because the person prescribing the dose did not refer to the protocol and administered a dose commonly given in clinical practice. The clinical record indicated that the criterion for giving a potent medication was checked before the medication was given when, in fact, the criterion test was not available until after the medication had been given. Five informed consent forms were missing in a study population of 100. This implied that investigational interventions had occurred without the subjects’ being fully informed and agreeing to the procedure; these data had to be removed from the study. There was no record of what happened to unused investigational medication in 6 subjects. The implication was that the medications could have been sequestered and dispensed or sold to others. During an auditing visit, a serious adverse event was discovered to have occurred months before that had not been reported. This called into serious question the integrity of the safety claims made.
and files for the overall trial are derived from local clinical trials forms and from Good Clinical Practice guidelines.6-8 Folders and subfolders generally refer to electronic documents. Binders, with individual tabs, refer to loose-leaf paper binders. Any systematic recording of data involving patients is considered research and is subject to IRB oversight before the work is started. Critically important general rules for each investigator to remember at the inception and throughout the project are as follows: 1. Organize and prepare everything before launching the project. 2. Obtain advance authorization initially and for any changes. 3. Pay close attention to details. 4. Allocate enough time for each subject and for the project to perform the details; this takes much more time than for a clinical visit. 5. Separate clinical and research personnel, space, and activities. 6. Be sure all research personnel are research certified and project trained. 7. Itemize the exact role of each research team member. 8. Never keep subject-identifying data on nonencrypted computers, and never send sensitive material by e-mail. Always house all subject-identifying paper data behind 2 locks (ie, in a locked cabinet
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in a locked office) to which only authorized persons have keys. All components of the research must be congruent and reconcilable. For example, the consent document, the protocol, and the grant must all say the same thing about any item. As the research progresses, changes may be required. These changes must be approved in advanced and tracked so that the PI, research coordinator, and study personnel know what was changed, and the newly changed documents must be used from that point forward. Renewals must report exactly what is currently being done and what was changed. All oversight entities must be informed of each change. To stay compliant, it is useful to remember 3 basic rules: (1) prove, (2) track, and (3) report. For every item in the research protocol, it is important to prove that it was done correctly. This proof is contained in the source documents. Source documents are data collection documents for all the data captured during the project, such as data collected during a visit, laboratory values, x-ray reports, clinical notes, and so on. Checklists at visits, with signatures and dates (and times if time critical), are fundamental to establish proof of performance throughout the protocol. A useful concept for a physician-investigator is that documentation is like progress notes in a medical record, which record each and every patient visit with details, a signature, and the date, including acknowledgment, interpretation, and appropriate actions for each. Source documents must support everything that is to be formally recorded, signed, and dated, in a clean case report form (CRF). A CRF is a project-specific standardized data recording form, generated for each subject, that records all the variables germane to the research aims. Tracking refers to each subject and to the project as a whole. During the project planning stages, if one likes to outline one’s project in a spreadsheet, it can be useful to see what needs to be tracked by knowing that subject-specific data are in rows and that data pertaining to the project as a whole appear in the columns. Both the subject and project requirements are specified in the research protocol. A simple and useful technique to assist tracking is the use of a footer on each page of each document. The footer should show, from left to right: the document name, version number, date, and page number, as n (the current page number) of N (the total of all pages in document). This allows each page of each document to be tracked and authenticated for use when changes are made. When a document is changed, a useful technique is to copy that file into an ‘‘amended’’ folder with changes tracked, with the word ‘‘amend’’ added to the version and the new date in the footer. That file and a clean copy of it can be submitted. When approved, the new file can be given a new approved date, shown in the footer, this time without the word ‘‘amend’’ in front of version. Another way to keep track of files is to use decimal numbers (version 0.1, version 0.2, etc) for versions in progress and pending approval and whole numbers for approved versions (version 1, version 2,
etc). Again, save these files in the project office to demonstrate a paper trail proving preapproval amendments, submission for approval, and the final approved document and date that will replace all old documents. It is very important to use only the currently approved documents from that time forward for the active research; the old, previously used documents must be destroyed. Reporting to the IRB, sponsor, agencies, and/or data and safety monitoring board is crucial for the integrity of the science. Adverse event reporting is very important and must be done according to the methods and times required by the oversight entities. Details of the reported events, proof of submissions, and records of responses are very important. Reminders or ‘‘tickler’’ systems for adverse event and serious adverse event reports, future renewal deadlines, and other time-dependent documents are very helpful.10 An overview of what compliance is expected and what a monitor or auditor will be evaluating is provided in the checklist in Supplemental Table S1 (available at otojournal .org). Supplemental material too large to be included in this paper is available electronically to illustrate some of the forms used in clinical research. The reader is encouraged to review these items, which include a CRF (http://www.goo gle.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web& cd=7&ved=0CFIQFjAG&url=http%3A%2F%2Fwww.oxfor dradcliffe.nhs.uk%2Fresearch%2Fdocuments%2FTemplateCaseReportForm-ORHv1.doc&ei=zCNsUtKkEsqT2QWNx YHgDA&usg=AFQjCNETirUzpzzqXOv5BJiQfJkKhPj-Ug) and Washington University’s clinical research form library.11
Specific Pitfalls and Compliance Solutions The key to beginning and staying compliant is to spend the time necessary to organize and prepare everything before the trial begins. Be sure to obtain approvals. Study all regulations, funding support documents, guidelines, and forms to be sure the whole planned project is prepared to be compliant and that nothing has been overlooked or forgotten (A. Doyle and S. Heuerman, personal communications, 2013). Prepare the CRF master file for data recording. Construct the source documents using the CRF as a model (do not merely copy), and try to maintain the same order and format of the CRF for easy and accurate data transfer to the CRF. Be sure to study the protocol closely to add any qualifiers to the visit source documents. For example, in recording blood pressure, it may be required for a subject to remain sitting for 5 minutes before the reading is taken; be sure the visit source documents include that qualifier. Organize the project filing system and tracking methods. Organize a subject binder for each subject. Prepare a spreadsheet of the planned project visits. Prepare a separate spreadsheet checklist of items to be done at each visit for each subject. Organize the binder so that everything that is needed for each visit is available in order by visit; this includes source documents forms, checklists for performance, and reminders. Organize laboratory kits and products by visit, label them, and line them up by expiration date; start with the
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first to expire. Double-check all investigational product numbers to be sure accurate. To minimize mistakes on checklists, have ‘‘yes’’ first and then ‘‘no’’ for inclusions and ‘‘no’’ first and then ‘‘yes’’ for exclusions. Everything must be answered so that nothing is ambiguous, for example, ‘‘yes,’’ ‘‘no,’’‘‘not applicable,’’ or ‘‘not done.’’ Explain at the bottom of the source document why something was not done. To minimize visit mishaps (missed appointments, late data, etc), place specific subjects on a calendar and put a sticky note on the subject’s binder with the next visit date and visit number shown. Replace this note with a new note when that visit is completed. During the baseline visit, intentionally question the subject on each and every review of systems and medical history point; this is very important for determining if an adverse event has occurred during the study or was present at the beginning. Be sure to allot enough time to do each step of each visit and document it correctly. This always takes much more time than expected. Consent forms safeguards include the following: (1) be sure the currently approved consent form is used, (2) be sure the subject and the person obtaining the consent sign and date at the same time, (3) be sure only authorized and trained team members obtain consent, and (4) be sure the visit document confirms the required steps in the consent process were observed; use a checklist and add narrative text. Document all events in the equipment log protocol. All equipment used must be calibrated and maintained. The PI must sign and date every piece of data and mark it as clinically significant or not clinically significant. All material to be signed should be placed in a folder to be signed by the PI at regular intervals. Urgent events, such as serious adverse events, must be brought to the PI’s attention immediately. For easy and immediate retrieval, keep all contact information of key people and entities (PI, sponsor, IRB, etc) on the person of the PI and research coordinator in case of an urgent question or serious adverse event. Subject accrual and retention are always major problems in clinical studies. To improve retention and good will that may serve to improve accrual by word of mouth, it is important to personally acknowledge each subject, for example, with a birthday card or recognition of time spent in the study or for other important events.
In contrast, consequences of noncompliance for those pursuing careers as physician-scientists can severely affect their progress, even during pilot projects. The information in this paper is designed to assist both groups. Many of the details and forms may be omitted for smaller projects; however, close communication between investigators and their local IRBs is strongly recommended. Oversight issues can easily be thought of as time-wasting impediments to medicine and science. However, oversight is fundamental to the external credibility of the science and safety assurances for patients. It can be a potent stimulus to emphasize the necessity of allocating sufficient time for each subject and for paying considerable attention to detail. Opportunities for further training in clinical research may be obtained through research institutions,12 the NIH,13 and the Association of Clinical Research Professionals.14
Conclusions
Supplemental Material
Clinical research compliance is fundamental to the ethical conduct of any research. However, the level of detail required varies considerably among small clinical projects and larger clinical trials, especially multicenter trials. The consequences of noncompliance may have little effect on transient investigators, unless they are guilty of Health Insurance Portability and Accountability Act and security violations, such as having protected health information on nonencrypted phones, laptops, or other media or transmitting the same by unauthorized e-mail.
Author Contributions J. Gail Neely, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Randal C. Paniello, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Evan M. Graboyes, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Jeffrey D. Sharon, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; David J. Grindler, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published; Brian Nussenbaum, substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published.
Disclosures Competing interests: None. Sponsorships: None. Funding sources: None.
Additional supporting information may be found at http://oto.sage pub.com/content/by/supplemental-data
References 1. National Institutes of Health. Glossary & acronym list. Available at: http://grants.nih.gov/grants/glossary.htm. Accessed February 10, 2014. 2. National Institute of Neurological Disorders and Stroke. Protocol template for definitive/efficacy (phase III) trials.
Downloaded from oto.sagepub.com at Bobst Library, New York University on May 25, 2015
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3.
4.
5.
6. 7. 8.
721
Available at: http://www.ninds.nih.gov/research/clinical_research/ toolkit/protocoltemplate.htm. Accessed February 10, 2014. National Institute of Neurological Disorders and Stroke. Manual of procedures. Available at: http://www.ninds.nih.gov/research/ clinical_research/policies/mop.htm. Accessed February 10, 2014. US Department of Health and Human Services, Office for Human Research Protections. Home page. Available at: http:// www.hhs.gov/ohrp/index.html. Accessed February 10, 2014. Washington University in St Louis, Human Research Protection Office. Home page. Available at: http://hrpohome.wustl.edu. Accessed February 10, 2014. Dixon JJ.The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur. 1998;6(2):65-74. International Conference on Harmonization. Good Clinical Practice guideline E6 R1. Fed Reg. 1997;62:25691-25709. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guidance for industry: E6 Good Clinical Practice: consolidated guidance. Available at: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM073122.pdf.
9. Pierce CH. Common GCP violations and site mistakes: how to avoid them. Monitor. 2012;26(5):55-59. 10. Youngblut JM, Loveland-Cherry CJ, Horan M. Data management issues in longitudinal research. Nurs Res. 1990;39(3):188-189. 11. Washington University in St Louis, Office of the Vice Chancellor for Research. Clinical research forms library. Available at: http://research.wustl.edu/ComplianceAreas/clinical/ Research_forms/Pages/default.aspx. Accessed February 10, 2014. 12. Washington University in St Louis, Clinical Research Training Center. Training programs. Available at: http://crtc.wustl.edu/ index.php/training-programs. Accessed February 10, 2014. 13. National Institutes of Health Clinical Center, Office of Clinical Research Training and Medical Education. Clinical Research Training Program. Available at: http://www.cc.nih.gov/training/crtp/crtp.html. Accessed February 10, 2014. 14. Association of Clinical Research Professionals. PI certification. Available at: http://www.acrpnet.org/MainMenuCategory/ Certification/PICertification.aspx. Accessed February 10, 2014.
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