Catherine Gregor, MBA, CCRC, CCRP CRC Workshop August 1, 2014 Source Documentation Catherine Gregor, MBA, CCRC, CCRP CRC Workshop August 1, 2014

Which of these Study Documents are considered Source documents? Regulatory Binder Medical Record Case Report Form Participant File 7/25/2014 2

Source Data The ICH E6 document, section 1.51, defines source data as "All information in original records and certified copies of original records or 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)." Source Documents The ICH E6 document, section 1.52, defines source documents as "Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, 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)."

Simple enough right? But what about Case report forms?

When Do Case Report forms become source? If allowed by the investigational plan (protocol), data may be entered directly onto the case report forms. The case report form would then be considered a source document. If this case report form is then transmitted to the sponsor, it is necessary for the study site to retain a copy to ensure that the principal investigator can provide access to the source documents to a monitor, auditor, or regulatory agency. Additional information can be found in ICH E6, section 6.4.9.

Why do we need source Documents? Data collected in research studies may be useless without adequate and accurate documents Data that is suspect or cannot be verified may be thrown out Source documents assist researchers in assuring that each study is compliant with IRB policies and other federal regulatory authorities If we cant replicate it then it didn’t happen…… 7/25/2014 6

What are the regulations and policies that govern research documentation at Vanderbilt? 7/25/2014

For any human subjects research conducted at Vanderbilt: 45 CFR 46 Documentation of IRB approval Documentation of informed consent Documentation of management of vulnerable populations in accordance with regulations IRB policies Documentation of compliance with protocol (inclusion/exclusion, study procedures) Documentation of adverse event reporting Documentation of appropriate staff training/qualifications Documentation of compliance with federal, state and institutional regulations/policies

For FDA regulated studies at Vanderbilt 21 CFR 312 For FDA regulated studies at Vanderbilt 21 CFR 312.62 for drugs and 21 CRF 812.140 for devices (a)Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 312.59. (b)Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. 7/25/2014

“The protocol specified that study drugs were to be prepared by the pharmacist or designee who was trained in the safe handling and administration of a cytotoxic agent. The Infusion Preparation Log for Subject 040-001 documents that study drugs were prepared on March 24 by an individual identified only by the initials [JKM]. There was no documentation in the study records that [JKM] was the pharmacist or designee, or that [JKM] had been trained in the safe handling and/or administration of a cytotoxic agent.” –FDA Warning Letter    You failed to personally conduct or supervise the clinical investigation. You failed to ensure that the investigation was conducted according to the investigational plan. You failed to protect the rights, safety, and welfare of the subjects under your care. All of the above. None of the above. 7/25/2014

So where does one begin?

Regulatory Binder: Protocol, all versions Investigators brochures, all versions Clean case report forms, all versions Consent forms, all versions Advertising and recruitment materials, all versions (approval required) 1572, all versions CVs, current copies for everyone listed on 1572 Verification of staff training Financial Disclosure/Conflict of interest statement Lab certifications, reference values, and deliveries 7/25/2014 12

Regulatory Binder (cont) 1. IRB submissions Original submission Continuing reviews Amendments Adverse Events- local and non- local safety reports Non-compliance with the protocol (may include items that did not require IRB submission) 2. Keep copies of all submissions, approvals, and correspondence 7/25/2014 13

Regulatory Binder (cont) Signature/delegation of responsibilities log Screening and enrollment logs Drug/device records (may be maintained by the pharmacy if IDS is utilized) Monitoring Logs Correspondence Telephone logs Notes to file Miscellaneous 7/25/2014 14

A word about notes to file… Should not be used exclusively as devices to explain discrepancies Should not be used exclusively to explain missing or incomplete data Do Not replace “adequate and accurate case histories” (21 CFR 312.62) Are Increasingly requested by sponsor monitoring staff - not generally temporally associated Can be Red Flags

Notes to file the right way….. Be generated on a case-by-case basis Include the subject and protocol it refers to Be signed and dated by the individual who is writing it Be legible if handwritten Explain clearly and specifically the reason for the error/omission/discrepancy or process/policy it aims to address. Should include any corrective and preventative action or follow-up when applicable. Be filed with the document, subject file or behind the study binder tab to which it applies

Regulatory Binder (cont) What not to include: Quality Assurance review findings Personnel issues Invoices to sponsor Contract 7/25/2014 17

Tip for maintaining Study Documents Maintain papers on a regular basis—don’t let a mole hill turn into a mountain. Set time once a week to make sure your binders are in order. 7/25/2014 18

What is a Participant File? A file containing the study documents pertaining to an individual participant in your study The participant file should contain all information needed to reconstruct a participant’s activities on study 7/25/2014 19

What should be in Participant files? Original signed consent form Case report form Questionnaires Records of materials and drugs given to participant, drugs returned Medical history Record of study visits Physician notes Memos to file Adverse Events Diaries Communications (emails and phone calls)

Source Document Tips Do: Don’t: No white-out No pencil No back-dating Have signature lines for portions of your CRF that are used as source documentation Date and initial all notations Use blue or black pen Correct errors with a single strike through, date and initial Include the subject ID on all pages in record Use subject ID instead of names to protect patient privacy Keep files in locked cabinet/room Don’t: No white-out No pencil No back-dating 7/25/2014 21

Case report forms are used in order to collect data in a standardize way and ensure that all data elements are captured. Data are recorded on the forms for each subject in the study and then entered/transfered into a database. Case Report Forms 7/25/2014 10/14/2018 22

Case Report Forms Generally Includes: Inclusion/Exclusion criteria Demographic information Medical history Medications Lab tests Clinical endpoints and outcomes Adverse events Study summary and PI evaluation **If you are developing your own CRF, be sure to pilot it before beginning enrollment. Poorly designed CRFs result in poorly collected data. 7/25/2014

Study Closeout-how long should you maintain study records? Drug or device studies: Two years AFTER the drug approval was granted or denied OR the length of time stated in the contract with the sponsor – whichever is greater HIPAA requires 6 years after study closure Behavioral and Social Science studies: Three years AFTER the study has been closed with the IRB Archive, Archive, Archive ASK BEFORE DESTROYING ANYTHING 7/25/2014 24

Key Points Remember, organizing your paperwork can be as important as dispensing the right drug. Researchers protect human subjects by having paperwork in order. Don’t have multiple collection “dumps” Remember your patients confidentiality—use names as minimally as possible. Keep files in locked cabinet/room. 7/25/2014 25

Questions?