Essential Documents that encompass a Sponsor or CRO’s Trial Master File that pertain to clinical research are referred to as Regulatory Documents or “Reg Docs” for short. These Regulatory documents consist of important contracts, agreements, training and delegation logs to name a few that will be filed with the Sponsor, FDA or both. In addition, the documents being covered will usually be stored in a study specific binder or binders that are provided to each research site that happens to be participating in that particular study. It is the site’s (and ultimately the PI’s) responsibility to fill out all applicable documents fully and correctly, apply real-time captured dates and signatures wherever applicable as well as filing documents in the correct sections of the provided binder in a timely manner. Clinical Research Associate’s (CRA’s) should never write on original site sources or regulatory documents unless specified on the form in question; such as a site visit log. Once the study is completed the sponsor will determine if the site will retain the original regulatory documents or copies of them for storage. The sponsor will also specify exactly how long the source and regulatory documents will be kept after the study has been completed in case an audit should arise within the timeframe specified. As a side note, the Contract Research Organization (CRO) and/or “Sponsor” will typically be much more stringent in terms of regulations than what the U.S. Food and Drug Administration (FDA) already have set in place.
Form FDA 1572 is the statement of Investigator; “No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572 (21 CFR 312.53(c)).” This form is arguably one of, if not, the most important document pertaining to regulatory and clinical research in general. It is required for any clinical research study involving investigational drugs, biologics and/or products. This is an agreement signed by the Principal Investigator (PI) providing specific information of the investigator(s) and the site to assure the sponsor that compliance with FDA regulations regarding the clinical trial will be met. The form will require Investigator(s) information (education, training, experience), site addresses, additional facility locations, Institutional Review Board (IRB) to be used and sometimes additional pages among other specifics. This form FDA 1572 can and will be updated whenever a change is applicable.
Financial Disclosure Forms (FDF’s) are to be completed by any investigators listed on the 1572. The FDF states whether or not any of the listed investigators have any financial interests in the outcome of the specified study. If there is a financial interest, the nature of those interests, arrangements and/or payments must be disclosed and any steps taken to minimize the potential for bias resulting from those interests and arrangements must be described. The maximum allowed monetary or equity investment amounts received will be specified in the FDF.
E-Signature and password confidentiality agreements are to be acknowledged and completed by the Investigator(s) because they are just as legally binding as his/her hand written signature. Password confidentiality is imperative due to the aforementioned fact. With that being said, E-Signatures are needed for various action items but most commonly to sign off on completed electronic case report forms (e-CRF’s) towards the end of the study to certify that the data entered in to the Electronic Data Capture (EDC) system is complete and accurate in comparison to the original source documents.
Protocol Signature Pages and any Training Logs are to be acknowledged and signed by the PI as well as anyone in attendance of the protocol training or amended training (present or future) with the PI signing off to ensure they are adequately trained. By the PI signing this page, he/she is agreeing to the proper conduct of the study in accordance to the protocol as well as FDA and Good Clinical Practice (GCP) guidelines.
Note-To-Files (NTF’s) are a special tool used to elaborate on any special circumstances, discrepancies and/or situations that may not otherwise be clarified properly in a designated place. They can be used for almost anything that requires further explanation, or to provide clarification as to why something was or was not done. For example, if a deviation is performed it can be noted in detail to explain if it was intentional (maybe due to an immediate subject safety issue) or performed in error and why. NTF’s should be used when no other means are adequate enough but when in doubt, extra documentation through NTF’s will not hurt and will only help to aid in clarification. I always tell my study coordinators that “NTF’s are your best friends.”
The Confidentiality Disclosure Agreement (CDA) is one of the first forms completed by the Investigator or site. This agreement is meant to protect and ensure the security of any trial related material or information such as the Investigator Brochure (IB) or protocol that is disclosed to the site. The CDA legally binds the entire site to secrecy in regards to all aspects of the protocol and any other associated intellectual property of the Sponsor.
The Delegation of Duties Log, more commonly known as the Delegation Log or the Site responsibility log, delegation of responsibilities, delegation of tasks, delegation of authorities, etc. This log will do as titled, it specifies which duties are delegated to whom at the site and the tasks listed must be appropriate to the individuals’ education, training and/or experience. All personnel performing any study specific tasks must be listed with the PI signing off on all delegated roles. The PI will also sign off on any dates that any given personnel stop performing tasks at the site and/or seize participation as an investigator for that trial. Delegation logs require information such as: name, role(s), start/end date(s), signatures, initials and tasks assigned.
Institutional Review Board (IRB) correspondence lastly, but also equally important as any of the documentation listed above, is filed and treated with utmost importance as all of this correspondence will typically refer to the protection and safety of study subjects. The IRB will also ensure the site is able to conduct the given study safely, ethically, and in accordance to the FDA and GCP guidelines. There are two types of IRB’s: Central and Local; most independent sites will work with central IRB’s since local IRB’s are usually tied to sites associated with Hospitals and Universities. IRB’s will determine whether or not the site is fit safely and ethically conduct the given study based on all the available information provided such as how many studies are under the PI at the present time, and the qualifications of the PI and/or site and personnel. The IRB’s main concern lies with the safety of subjects regarding the PI’s oversight/involvement and sites capabilities.
This wraps up a brief overview of regulatory documents in clinical research. In our CRA Academy, we cover these and other topics in much greater detail, and ensure that students have a firm grasp of these fundamental principles of clinical research.
