Everything You Write Can Be Used Against You in a Court of Law – Understanding Proper Documentation
If It Is Not Documented, Then It Did Not Happen
In clinical trials, it is vital for subjects’ rights and well being to be protected, and it is imperative for the data to be accurate. If you were asked to prove that a study upheld these standards, would you be able to? Common sense and good clinical practice prevails: if it is not documented, then it did not happen as far as the scientific and legal communities are concerned. Documentation is the only defense in the face of lawsuits, contractual disputes, and stringent regulatory oversight. Therefore, proper collection and storage of data and other pertinent clinical trial information are essential. This chapter discusses important considerations and requirements for achieving proper clinical trial documentation. Although this chapter provides a general outline of good documentation practices and mentions a few forms that are often applicable, it should be noted that specific documentation requirements vary according to where the trial is being conducted.
Documentation Is The Way To Certainty
Clinical trials may be conducted over several years. The review of trials for the drug approval process can take place years after a study is completed. It is unlikely that you will remember exactly what happened at the time of a study if it is not properly and clearly documented. For example, if a protocol deviation occurs and the reason for the deviation is not properly documented, it might be difficult to understand what transpired at a later date.
Incorrect Or Incomplete Records Cast Doubt On The Study And The Product
An investigational drug or device cannot be “ready for market” without having gone through federal regulatory approval. Documentation is a vital part of this process and is necessary for analysis of trial results and meeting regulatory requirements. When data are not recorded accurately and properly, they may be incorrectly interpreted.
Getting Organized
According to the World Health Organization (WHO), documentation refers to all written, electronic, magnetic, and optical records; including scans, x-rays, and electrocardiograms that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, or any action taken during the trial. Documentation of clinical studies includes all financial documents, contracts, correspondence regarding the trial, and subject records, all of which must be collected and stored in compliance with applicable regulations. The information collected is generally housed in several distinct files or binders.
Financial Files
The financial binder houses all documents relating to the financial aspects of the trial. The contractual agreement between the principal investigator (PI) and the clinical trial sponsor or clinical research organization (CRO) is one such document. It is important for both the PI and the sponsor to be aware of their obligations concerning the trial, for these obligations to be stated clearly, and for these obligations to be documented through a written agreement that both parties have filed securely. All documentation related to the purchase of supplies, the payment of clinical trial staff, remuneration of subjects, and payment for advertising or other applicable financial aspects of the trial should be kept in the financial binder.
Regulatory Files
The regulatory binder serves as a repository for all correspondences between the study site and regulatory bodies such as the United States Food and Drug Administration (FDA), the Institutional Review Board (IRB)/Research Ethics Committee (REC), and the sponsor. All correspondence, both formal and informal, should be documented. For example, record the date/time and content of important telephone conversations and print relevant emails to include with other more formal correspondences. The regulatory binder also holds the Investigators Brochure and study protocol.
When conducting a clinical trial for which the data will be used for filing in the United States, the FDA requires the PIs to complete an FDA 1572 Form, also known as a Statement of Investigator Form (Title 21, CFR Part 312). The FDA 1572 Form must be sent to the sponsor before a site may begin the study. This form asks the PI to provide an outline of the study protocol (or a general outline of the investigation for Phase 1 trials), information supporting his or her expertise, and signed confirmation that the PI will conduct his or her investigation in accordance with the information provided in the form, as well as FDA and IRB/REC guidelines. In addition, FDA 1572 addresses where the research will take place and clarifies the clinical laboratories involved, as well as the IRBs, subinvestigators and other personnel who will assist in the investigation. The PI must also provide on this form signed confirmation that adequate and accurate records will be kept and made available for potential inspection. Any changes to the information stated in the FDA 1572 Form should be communicated to the appropriate party, be that the FDA, the IRB/REC, or the trial sponsor. The FDA 1572 Form and all related documentation should be kept in the study regulatory binder.
PIs conducting clinical trials in the United States are also required to report adverse events to the FDA. The FDA 3500A Form, also known as the MedWatch Form FDA 3500A or the MedWatch Mandatory Form, is used for reporting this information. The FDA 3500A Form is one such example of documents used for reporting adverse event information. These types of documents are referred to by the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) as Individual Case Safety Reports. The ICH and the WHO’s Council for International Organizations of Medical Sciences (CIOMS) have developed guidances for adequately completing many of these types of forms.
While PIs must provide documentation to 1 or more governmental regulatory agencies, they are also responsible for supplying documents to their IRB/REC. Before a study commences, the PI may be asked to fill out a form supplied by the site’s IRB/REC, sometimes called an Application for New Protocol Review. This form outlines the study protocol, states the benefits and risks associated with conducting the trial, provides background information related to the PI and his or her institution, and requests IRB/REC review and oversight of the clinical trial. If necessary, forms must also be completed for protocol amendments, exemptions, and continued review. All correspondence with the IRB/REC, including the initial application, renewals, amendments, adverse event reports, updated consent forms, and the final report, should be held in an easily accessible place in the regulatory binder.
Correspondence with the sponsor and/or regulatory bodies about the conduct of the trial should also be kept in the regulatory binder. This can include information such as notices of anticipated protocol changes, reports from monitoring visits, and new information about the investigational product.
The results of a clinical trial are ultimately presented in a summary report, also known as a clinical trial summary or study summary, which aims to express the trial results, as well as relevant details, in a way that is easy to understand. This form is often created by the sponsor or an outside institution specializing in the creation of such documents. A PI can add this document to the regulatory binder after completion of the study.
Study Personnel Files
For each study, a record of personnel, including their study-specific responsibilities and documentation demonstrating that each person had the appropriate qualifications at the time of the study to perform his or her assigned duties, must be kept. A binder containing the curriculum vitae or resume of each member of the clinical trials staff, signed and dated at the time of study inception, will serve this purpose.
Subject Records
The single most important document in the subject record is the consent form. A properly signed and dated consent form must be present in each subject’s records and readily accessible for review by the sponsor, CRO, IRB/REC, or federal regulatory agencies.
When subjects present for study-related visits, information collected from those visits is generally recorded on a source document that is created by the PI and designed to fit the needs of the study site. Used by study staff members during patient interactions, this source document should provide a user-friendly way, often through checklists and note boxes, for staff to ensure that the study protocol is being followed for every subject. Information to be provided in the source document may include answers to the following questions: is this patient’s consent form complete; does this patient belong to group A or group B; and has the drug been dispensed to this patient today? The patient source document can also be used by staff members to write down reminders particular to interactions with a certain patient. A progress note, which provides more information than is collected on the source document, may be written, should further clarification be necessary. This progress note also serves as the proper location for documentation of telephone and email correspondence with subjects. The data collected from the source document are then transferred to the Case Report Form (CRF), also known as the Data Collection Form, which is used to collect trial data and adverse event information to be submitted to the sponsor. The CRF allows for complete and accurate data collection, so that the sponsor has the closest approximation to an answer to the study questions that the clinical trial results can reasonably offer. CRFs, which are significantly more formal than patient source documents, are developed by the sponsor, and each sponsor individualizes their form to the needs of the trial.
Data from the CRF, however, may not be wholly accurate or complete. To clarify entries made on the CRF, a sponsor might issue a formal query to the PI using a Data Query Form (DCF). DCFs are preferred over informal communication, such as phone calls or emails, because they make queries easy to document, and, when designed well, aid in standardizing terms and other communication. After queries in the DCF are addressed, a revised CRF must be sent to the sponsor. Copies of all revised CRF versions, along with all DCFs, must be retained in the PI’s files. Computer software for creating CRFs and DCFs is available.
Study Logs
It is important to file all logs and forms used during the recruitment and enrollment process. This includes documents containing names and personal information of both those who did and did not end up enrolling in the study. Appropriate drug dispension logs must be maintained by the personnel in charge of storing and dispensing the study drug.
Additional Study Sponsor Documentation
The Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD), developed by the ICH, serves as an important interface for the industry-to-agency transfer of regulatory information for the registration of pharmaceuticals for human use. In fact, the CTD is mandatory for clinical trials conducted in Europe, Japan, Canada, and some other regions, and is “highly recommended” in the United States. The CTD is divided into 5 modules: 1) Administrative Information and Prescribing Information; 2) Common Technical Document Summaries; 3) Quality; 4) Nonclinical Study Reports; and 5) Clinical Study Reports. The ICH has developed a 4-part guidance for preparing the CTD, which has been endorsed by the regulatory agencies of the United States, the European Union, and Japan. The guidance outlines the appropriate format for the documentation of acquired information and serves “to reduce the time and resources used to compile applications, ease the preparation of electronic submissions, facilitate regulatory reviews and communication with the applicant, and simplify the exchange of regulatory information among regulatory authorities.” Although this document is usually developed by the study sponsor, much like an Investigational New Drug Application (FDA 1571), it may be provided to the study site as a helpful reference, and should be stored in the PI’s files.
Storage and Confidentiality
Proper storage of clinical trials documents is essential for the maintenance of subject confidentiality and to ensure that the documents will be accessible and organized when they are needed. When a trial is initiated, the PI should designate at least several drawers of a file cabinet, and possibly a separate computer server, for storing all pertinent documents associated with the trial. These files should be updated as relevant documents are acquired. They should be locked or otherwise secured (if electronic), and accessible only to authorized clinical trial staff in order to protect patient confidentiality and the integrity of the study. The duration for storage of documentation should be agreed upon with the sponsor before any contracts are signed. It is also important to note that regulatory bodies may have requirements for the length of time that files must be kept, and the WHO recommends that patient identification codes be kept for at least 15 years after trial completion and that written approval from the sponsor be obtained prior to file destruction.
For electronically stored information, additional measures should be taken to ensure accuracy and security. Authorized staff members, if possible, should each have their own computer login and software login accounts, and they should be diligent about logging out of their accounts before turning the computer over to others. In addition, security software and network security should be in place to prevent unauthorized access by external parties. Of course, both electronic and hard copy documentation should be archived in an orderly and appropriate manner, so that documents can be easily accessed when necessary.
Before data from your site can be disclosed to the public, they must be “de-identified,” meaning that all information allowing the data to be traceable to any individual must be removed. Under the United States Health Insurance Portability and Accountability Act (HIPAA) regulations, there are up to 18 personal identifiers that must be removed from recorded data for that data to be considered “de-identified data.” To assure the IRB/REC that the data have been de-identified, and, thus, are in accord with HIPAA guidelines, PIs in the United States should submit a HIPAA De-Identification Certification Form to his or her IRB/REC.
Summary
Improper or incomplete documentation is ethically irresponsible, because it may result in a product that is unsafe or ineffective. Moreover, after a trial has concluded, if the sponsor or the PI’s institution faces a lawsuit relating to adverse events or something else concerning the trial, proper documentation might greatly affect the legal or financial outcome. Lastly, total privacy and confidentiality of subject information is only possible when clinical trial information is recorded, handled, and stored properly. Thus, proper documentation is an essential element in conducting a successful, lawful, and ethical clinical trial.
Resources
National Institutes of Health. Department of Health and Human Services. HIPAA Privacy Rule: Information for Researchers. Available at: www.privacyruleandresearch.nih.gov. Accessed October 28, 2008.
United States Food and Drug Administration. Center for Biologics Evaluation and Research. CBER Guidances. Available at: www.fda.gov. Accessed June 16, 2008.
United States Food and Drug Administration. Center for Biologics Evaluation and Research. M4: The CTD–General Questions and Answers. Available at: www.fda.gov. Accessed June 16, 2008.
United States Food and Drug Administration. Department of Health and Human Services. Federal Register. Available at: www.frwebgate.access.gpo.gov. Accessed June 16, 2008.
United States Food and Drug Administration. Department of Health and Human Services. Statement of Investigator. Available at: www.fda.gov. Accessed June 16, 2008.
World Health Organization. Available at: www.whqlibdoc.who.int. Accessed June 16, 2008.