Module 9: Investigational Product Accountability, Essential Documents and Routine Monitoring Visits
Electronic medical records
Medical documentation, entered directly into a computer system, is considered to be the original or true copy of the data whether it is printed out as a hard copy or stored as computer files.
Source documents ICH
"original documents and records (e.g. lab notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays and subject files) kept at the pharmacy, the laboratories, and at technical departments involved in the clinical trial"
Examples of source documents
Medical records, nurses notes, progress notes; medical history and physical exam reports; consultations; operative reports; patient diaries; patient assessments; test and examination reports; lab results; x-ray, ct scan, MRI results; pathology reports
Case histories - investigator required to
prepare and maintain adequate and accurate case histories that record 1.) all observations and data pertinent for each individual administered the IP or participating as a control. 2.) investigators are to maintain these records even though the sponsor may also have such records. 3.) Case histories must document that informed consent was obtained prior to participation in the study.
CRC - specific preparations for monitoring visit
refer to module checklist in the workbook for the responsibilities of the monitor and the specific activities the CRC should follow and/or prepare to facilitate the monitoring process
CRF common errors
1.) Logical (i.e., the date of the second visit is earlier than the first visit). 2.) inaccurate information (i.e. source document says one thing, the CRF says another) 3.) omissions (i.e. an AE is recorded on the CRF but not on the source document 4.) Transcription errors (i.e. date errors, 11-2-59 instead of 2-11-59. 5.) Abbreviations (be sure to utilize approved medical abbreviations, i.e. TID, BID, H/A etc.) Spelling errors. Illegible entires/"write-overs"
An acceptable computerized data collection system
1.) allows data entry only by authorized individuals 2.) controls the ability to delete or alter previously entered data 3.) provides an audit trail for data changes 4.) Protects the database from being tampered with 5.) ensures data preservation (e.g. automatic back-ups)
Essential documents
1.) protocol and amendments 2.) investigator brochure and other safety information 3.) logs and forms (i.e. signature/delegation log, 1572, etc.) 4.) correspondence with sponsor/monitor and IRB 5.) investigational product records 6.) records of IRB approval 7.) master approved informed consent forms/documents 8.) CVs and medical licenses 9.) training records 10.) laboratory records 11.) manuals, instructions and or other communications on the study
Clarity in monitoring report writing
A CRA should be careful to only state the facts and avoid making judgment statements. Securing compliance and bringing closure to action items is vitally important. Common problems: 1.) no follow-up of outstanding issues from visit to visit 2.) reports don't describe suggested solutions (what the CRA told the site to do) or resolution 3.) an emotional statement is contained in the report obscuring the true issue
monitoring log
A record of all on-site lists. Identifies the sponsor representative, date of contact, and purpose of the visit. Usually signed by the visiting sponsor representative and possibly site personnel. Maintained in the regulatory binder at the site. Copy may be obtained at study completion for sponsor files.
IP accountability during the study
AN investigator is required to maintain adequate records of the receipt, use and disposition of the product (e.g. dates dispensed, quantity used by subject, etc.) Info to include: patients initials, study number, visit number, serial or lot#, date and amount dispensed (initialed by personnel) date and amount returned (initialed by personnel)
Monitoring reports
After each site visit, the CRA writes a monitoring report for the sponsor (electronic report templates are often used). Reports should include the date, site, CRAs name and the names of the investigator and other individual(s) contacted. Includes the CRAs statements concerning the site's enrollment status and the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or other actions recommended that assure compliance. The review and follow-up of the monitoring report with the sponsor should be documented.
Essential document storage and retention
All study documents should be maintained in a dedicated and secure area throughout the duration of the trial. TO ensure that only authorized site personnel or sponsor/CRO representatives have access to the data. Protects both the confidentiality of the subject and proprietary information of the sponsor. The sponsor will discuss their specific requirements for secure storage of the documents during the site qualification visit; some sponsors require these documents be kept in a locked file cabinet; others may only require they be stored on a bookshelf in a locked office.
Monitoring visit activities
Assess patient accrual at the site. If behind schedule try to ascertain the cause(s) and offer solutions; discuss your findings with the principal investigator. Verify CRFs against source documents. Assess protocol and regulatory compliance. Verify essential documents are up-to-date and accurate. Assess drug/device storage and perform product accountability.
Scheduling the monitoring visit
Best practice schedule the next monitoring visit during the current visit. Confirmation letter should be provided by the CRA in advance of the visit. Consider calling or emailing a day or two in advance just to confirm once more. If investigator/CRC schedule changes, always call (not email) the CRA ASAP
Accountability instructions
Both CRCs and CRAs should count and verify the number of doses of IP dispensed and administered by: 1.) examining the progress notes, operating room records, discharge notes. 2.) examining the medication dispensing record 3.) Checking the physicians initial order, if the IP is in a pharmacy 4.) verifying that drug/device accountability is documented in a timely manner to ensure patient safety 5.) Comparing the number of units recorded as administered with the number of units recorded on the CRF 6.) verifying all discrepancies are noted in the SDs and on CRF 7.) Physically counting the number of returned and unused IP units, noting the patient number, the date returned and the visit number 8.) Comparing the final number of units returned against the CRF and note any discrepancies 9.) discussing discrepancies with investigator and staff, ensure that the discrepancies are recorded in the source documents and report those findings in a monitoring report
Monitoring a study: sponsor responsiblities
Both drug and device sponsors [21 CFR 312.56 and 21 CFR 812.46] monitor the progress of all clinical investigations being conducted. Acts if they discover investigator non-compliance with the investigator agreement, protocol, or regulations by promptly either securing compliance or discontinue shipments of the IP to the investigator and end his/her participation in the trial
Monitoring visit - laboratory facilities
Check sample collection and transport. Verify laboratory reports and results.
Procedures for correcting source documents/CRFs
Draw single line through error. Do not obscure original data. Do not write-over errors or use correction fluid. Only site personnel can make corrections NOT CRAs. The potential for impropriety exists if the sponsor entered data on the CRFs potentially fabricating data to be more favorable.
Monitoring priorities
During routine monitoring visits, time management and prioritization is crucial. Activities can be prioritized as follows: 1.) confirm completion of critical follow-up items from previous visit 2.) patient safety--review 100% informed consents, serious adverse events and confirm new subject eligibility 3.) Review essential documents for new personnel, new IRB directives/.approvals training on amendments, etc. 4.) perform accountability of IP 5.) source document verification of existing subjects and other data not yet reviewed 6.) check supplies, lab aspects, etc. 7.) Remaining essential documents review
Minimum level of dosing compliance
For drugs, in order to demonstrate efficacy of the product the sponsor needs to demonstrate this (rule of thumb is 80%)
CRC - general preparations for monitoring visit
General preparations when planning and preparing for the monitoring visit the CRC should assure that a dedicated workspace has been reserved for the CRA
CRF completion guidelines
If the CRFs are printed on NCR paper, the sponsor usually receives the original and the site retains a copy. In the even of an audit, the auditor will work from the copy and if this is not neat and legible the data will not be verifiable. In some cases, the paper CRFs are designed to be machine readable (e.g., faxed or scanned directly into a database). If the data is not legible, it cannot be entered and this makes for tremendous re-work by the site personnel. For electronic CRFs, the completion guidelines will instruct CRCs in regards to data conventions, how to answer queries, etc.
Visit follow-up activities
Immediately following the monitoring visit send follow-up correspondence to the investigator and study coordinator. This should include 1.) thank staff for accommodating visit; list of what was accomplished who was in attendance. Findings/outstanding items; suggested solutions to findings/issues and confirmation of the next appointment (if already scheduled). submit any retrieved regulatory documents and/or CRFs
Good documentation practice
Importance of creating an audit trail. Procedures for correcting source documents/CRFs. Changes are dated, explained (if necessary) and initialed by the investigator or an authorized member of the staff (CRC). authorization should be documented on the study personnel delegation log.
Case histories
Includes both CRFs and supporting data including, but not limited to signed and dated consent forms, medical records, hospital/clinical chart(s) and the nurses notes
Storage of IP
Investigational drugs/devices must be tainted in a secure area with limited access. under proper environmental conditions (e.g. temperature, light, humidity controlled). Controlled substances must be maintained: in securely locked. substantially constructed cabinet or other enclosure, access to which is limited to prevent theft or diversion of the substance into illegal channels of distribution.
Monitoring visit - supplies
Make sure that the site has an adequate supply of CRFs, patient diaries (if needed), study product, lab requisitions, sample logs, template informed consent forms, mailing supplies (postage, express courier air bills), lab and additional study supplies, etc.
Investigator obligations - control of IP
May transfer the authority to dispense the IP to persons under his/her supervision or: to persons named in the investigators signed statement obligations (FDA form 1572) or in the investigator agreement(device) Needs to be documented on the delegation of authority log (ICH) or in the study agreement. Ultimate responsibility remains with the investigator. May not supply to any other person for use without the sponsor's prior permission. Includes for compassionate use or independent studies. Maintain adequate records regarding the receipt and disposition of all IPs. Return any unused or unusable IP to the sponsor, or dispose of them according to the sponsor's written directions at the conclusion of the study. Take precautions against the theft or diversion of all controlled substance IPs.
Source docunments
Original data, documents and records used by the investigator/institution. Contain the information that supports and substantiates the information in the case report forms (CRFs)
Investigator review/approval of CRFs
Present CRFs (paper and electronic) to investigator for review and signature when applicable. Signature requirements will vary by sponsor (e.g, some require investigator signs each page others require only a final verification signature). Ensure lab reports have been reviewed and signed by the investigator. Submit CRFs to sponsor upon completion or hold until monitor visits (as directed by the sponsor).
Debriefing with study staff
Review progress and issues with investigator and other appropriate study staff. Share your findings and concerns in a professional, mature and non-antagonistic manner. Compliment if appropriate., Be creative in trying to assist the investigator to identify possible solutions. Discuss everything you plan to document in your report and follow-up letter. No surprises!
"shadow" charts
Separate "research" charts containing all pertinent information on the subject, including copies of various source documents from the larger medical record or clinical chart. Shadow charts are fairly common in large hospitals where access to medical records is restricted or delayed. The original source is the best source to ensure all information is being reviewed for data accuracy, safety events and protocol adherence. If shadow charts are used, the data in these must be validated (i.e. verifying a certain percentage of the original documents from which the shadow charts were created) to assure no information has been omitted.
Source document quality - ALCOA
The FDA has established certain characteristics of source documentation that signify data quality. A= attributable L =legible C=contemporaneous O=Original A=Accurate
ICH defines monitoring as
The act of overseeing the progress of a clinical trial and of ensuring that it is conducted, recorded and reported in accordance with the protocol, GCP and the applicable regulatory requirements
Monitoring visit objectives
The rights and well being of human subjects are protected. The resulting data is of the highest quality and integrity. The trial is in compliance with the currently approved protocol/amendments, GCP and other regulatory requirements; the reported trial data are accurate, complete, and verifiable from source documents.
Document storage and retention
The site is responsible for keeping all study records as follows: 2 years after the last approval of a marketing application (NDA/PMA) or two years after a formal discontinuation of clinical development of the investigational product (e.g., the sponsor decides not to pursue marketing approval of the drug.) e.g. an investigator completing a trial in 2015 but must retain all study records until 2032, if the marketing application (such as an NDA) is not approved until 2030.
Retrieval of IP
The sponsor must assure the return of all unused test article supplies from each site. Alternative disposition (disposal on-site) of unused supplies may be allowable, provide this alternative disposition does not expose humans to risks. The sponsor must keep records indicating that this transfer of obligation has taken place 100% investigational product accountability is documented
Monitoring plans - timing and frequency
The timing of monitoring visits depends on several factors and is specified in the monitoring plan: complexity of the study; rate of subject enrollment; sponsor SOPs. Ideally the first monitoring visit should be scheduled soon after the first subject(s) are enrolled to identify and correct initial problems, thus preventing them for future subjects.
Case report forms and source documents
There are two basic types of records that are maintained by investigators and monitored throughout an investigation: 1.) essential documents 2.) case histories/source documents Case histories - the study protocol and related documentation are the terms used in the code of federal regulations source documents - are the information that supports the participation of the study subject during a clinical trial (ICH GCP uses this term)
IP Accountability: Shipment and Receipt
Upon receipt of the investigational material, the site should receive documentation that includes the following: 1.) date and quantity shipped 2.) serial, batch, lot or other identification number 3.) Expiration date of the investigational product Site personnel should verify contents of the shipment match precisely the documentation and communicate any problems to the sponsor (e.g. condition of the investigational product. Missing boxes/bottles, devices, etc)
CRA responsibilities for IP accountability
Verify the following: 1.) IP is properly stored in a secured location with limited access. 2.) the inventory of the IP agrees with the amount shipped, dispensed and returned to date. 3.) there are sufficient quantities of IP. 4.) expired IP are removed from the site's inventory and accounted for 5.) CRF info is accurate, complete and consistent with source and inventory for the IP dispensing and administration 6.) Subjects complied with dosing and/or follow up as outlined in the protocol 7.) complete and accurate shipping and return records are maintained at the site 8.) IP returned by patients to the site are being handled in accordance with project specifications 9.) IP returns by the site to the sponsor (or designated agent) are being performed in accordance with project specifications 10.) Discrepancies in accountability are documented in the monitoring visit report, and addressed and corrected on the actual IP accountability forms.
Case report forms (CRFs)
a sponsor designated tool used to collect study data from investigators. a printed, optical or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
Investigator/Regulatory binder
contains the essential documents-the documents that individually and collectively allow for the reconstruction of the study. Contains all of the general (non-subject specific) information relevant to the investigation. Sponsor will typically provide a 3-ring binder (or multiple binders) with tabs to organize all the relevant study documentation
