In any clinical trial, proper collection and storage of study data and other relevant clinical trial information is vital for accurate records. The more vague or imprecise the data, the less weight it bears under the scrutiny of review; in some circumstances, suspect data may even be specifically excluded from a clinical trial dataset. This is not without larger consequence as the exclusion of one site's data may compromise the statistical power of the entire trial, minimizing or eliminating the study's ability to detect drug effect.
Although specific documentation practices and requirements may vary from institution to institution, certain guidelines are generally applicable. All activity pertaining to the conduct of clinical trials must comply with applicable state and federal regulations and adhere to standards outlined in Good Clinical Practice (GCP) and International Committee on Harmonization (ICH) guidelines. With particular regard to documentation, these standards encompass both the maintenance of study-related documents and the capture and documentation of study data. Federal regulations define Investigator obligations for record keeping and the minimum requirements for record retention; you can expect your study monitor to review these with you in detail and, if he or she does not, ask. Your monitor can and should be an invaluable source of information.
In regard to the documentation of study data, the internationally accepted standard suggests that records be Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA). ALCOA serves to establish the weight and credibility of your clinical data and other study documentation: In the eyes of an auditor, if there is no documentation, nothing took place. This month's column will discuss the components of ALCOA and other important considerations and requirements for maintaining proper retina clinical trial documentation.
KEY DOCUMENTS
Documents generated during the course of a clinical trial include financial disclosures and contracts, clinical study protocols, regulatory approvals, subject records, drug accountability logs, and any relevant correspondence regarding the trail. In addition, the US Food and Drug Administration (FDA) requires each Principal Investigator (PI) conducting a clinical trial under an IND to complete an FDA Form 1572, which is “an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic.”1This form includes a consolidated listing of your regulatory obligations and once signed, serves as a contract between investigator and the FDA. As such, this form should only be signed after a full review of the study protocol, Investigator's Brochure, and a commitment to conducting the investigation in accordance with applicable FDA and IRB regulations.
The clinical study protocol outlines the objectives, design, methodology, statistical considerations, and general organization of a clinical trial. The centerpiece of any study, it ensures the necessary data is collected consistently across the investigative sites before it is analyzed and later submitted to the regulatory authorities for review and consideration. Each protocol and any amendment to the initial study protocol must be reviewed and agreed to by the PI and approved by an IRB or other ethics committee.
Another type of documentation that is required concerns the study drug. This documentation serves to demonstrate that there is adequate and appropriate control over the test article provided for use in the study. Such records may include shipping manifests and verification of the test article receipt at a study site; study-specific logs or other records documenting test article storage and dates, quantity, and use by study patients; and evidence of test article destruction or return to the sponsor at the end of the study.
Within each study patient's case history file, the Institutional Review Board (IRB)-approved informed con- sent form (ICF) is the single most important document. Properly signed and dated documentation of consent must be present with each subject's records, and must precede that subject's involvement in any other study procedure. The ICF outlines the potential known risks (or benefits) of participating in a given clinical study, describes the study visit schedule, identifies study-related tests and procedures that may be performed, and fully informs the subject of his or her rights as a subject in a clinical study. As participation in a clinical study is entirely voluntary, it is crucial that potential study subjects be provided adequate time and information to make informed decisions about their partic- ipation in a trial. As with study protocols, a template of each ICF and any amendment to the original ICF must be reviewed and approved by an IRB or other ethics oversight committee prior to use in the study.
Information collected during study visits is first recorded on source documents. This includes original documents, data, and records (ie, hospital records, laboratory notes, subject diaries, and clinical and office charts). Transcription of source data into a Case Report Form (CRF) follows. The CRF is a paper or electronic document designed to capture all the relevant information and study data for each patient, including adverse events and any concomitant medications, and is often the primary means to communicate study data from the PI to the sponsor; it is the means by which each patient's study data is provided to the study database for inclusion in scheduled analyses. Case report forms are typically more formal than source documents and are customized by each sponsor to fit the specific needs of the trial. It is imperative that data are accurately transcribed from source documentation to the CRF, and there are checks in place (eg, monitor verification, and data queries) to ensure that they are. To reduce time and effort required to address source-to-CRF transcription errors, it is important to dedicate enough time to ensure data are carefully and accurately transcribed to CRFs; spending a lit- tle extra time at the outset can return huge rewards by reducing errors and associated follow-up activities.
ALCOA GUIDELINES FOR DOCUMENTATION
Attributable (A) and legible (L).A number of individuals are actively involved in any retina trial. Proper documentation practices must be implemented by all parties to keep patients' data organized and viable for statistical analysis. Signatures are more than a blank to be completed; rather, they are a testament to the accuracy of the study data. An individual's signature or initials is a confirmation that they were, and are, responsible for the data as they are recorded. Every attribution should also have an associated date. In the event that changes are being made to the data, explanations should be noted alongside the date and initial for the correction. What seems to be a self-evident correction made by study personnel may be difficult for auditors to decipher. Simple modifications can have straightforward clarifications, such as “misspelling,” “miscalculation” or “subject clarification,” whereas more complicated changes require a more extensive explanation. On a similar note, data must be legible so that other clinicians, monitors, and third-party inspectors can read and value the data in the same manner. Comments, signatures, dates, and time stamps are all pertinent bits of information, so be sure to take the time to make certain that they are legible.
Contemporaneous (C).Some clinical trials may be con- ducted over a period of several years. In fact, for slow progressing retinal diseases like dry AMD, the longevity of a study is necessary for proper endpoint evaluation. As such, the regulatory review of trials during the drug approval process can take place years after a study commences. For that reason, and as previously mentioned, data entries should be accompanied with the dates when they occurred. It is unlikely that investigators will remember exactly what happened at the time of a study if it is not properly and clearly documented. Dates allow an external reviewer to reconstruct and evaluate the events surrounding the data. Similarly, statements or data recorded at the time an incident occurs makes for a more compelling dataset than one plagued with irreparable holes in the documentation process.
Original (O) and Accurate (A).The originality of the documents and their components maintain the integrity of the entire study. The introduction of duplicate data records draws suspicion that there is no control over study conduct, and may even incite concern that your data has been manipulated. It is difficult to trust your documented data if there are several working copies of any document or if the original is missing, raising questions as to when the copy was made and whether the copy contains the most current data captured in the original source material. Accurate documentation throughout the entire study is particularly important for any post-trial inspections by regulatory authorities. If data are not recorded accurately and consistently, results may be incorrectly interpreted or even exclude
IMPORTANCE OF PROPER DOCUMENTATION
Proper documentation is important, not only for the sake of simply collecting accurate study data at just one site, but also for the future of the investigational medication. If documentation practices are not up to par, data will suffer, as will the integrity of the study. Know the regulations, the proto- col, and ALCOA. A thorough understanding of good documentation practices will help to ensure the success of the study at your site.
Aron Shapiro is Vice President of Retina at Ora, Inc., in Andover, MA. Nour Ziyadeh is Assistant Manager, Training and Compliance; David Waters- Honcu is a Manager of Retina Clinical Operations; Sunita Saigal is a Clinical Research Specialist; and Ashley Lafond is a medical writer at Ora, Inc.
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