Cardinal Principles of Clinical Research Documentation

Documentation is a central part of clinical research but it is a Herculean task – stretching up to 5 to 15 years depending upon the type of trial. Documents generated from the conduct of the trial are known as Essential Documents (ED). EDs cover the whole spectrum of the trial or research from communications among the sponsor, principal investigator (PI), the institution involved, Case Record forms (CRFs), Informed Consent forms (ICFs), Clinical Trial Agreements, Investigator’s Brochure, and randomization lists. Documentation is a cauldron of technical and non-technical aspects of the clinical trial.

According to ICH-GCP guidelines, EDs are ‘those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced’. To get through this maze of documentation, five cardinal principles must be adhered to.

Document, document, and document 
As they say, if it is not documented, it is not done! Documentation in CR can be divided into three parts – before, after, and during the trial. The ‘before’ list consists of regulatory and ethics committee approvals, ICFs, subject information sheets, investigator brochures, finance and insurance agreements, investigational product specific guidelines, protocol, randomization lists, pre-trial monitoring reports, shipping records, and all important communications between the sponsor and the PI.

Documentation ‘during’ the trial includes amendments, updates and approvals for them, ICFs and CRFs – completed, signed and dated. Adverse events (AE) reports and notifications, site staff logs, reports of monitoring visits, source documents are also filed.

The ‘after’ list reads – audit certificates, final reports to be submitted to the regulatory authorities, trial close out monitoring report, clinical trial materials accountability records, decoding documentation and investigational product destruction records. All these documents are filed in the trial master file and the site master file and they serve to demonstrate compliance with GCP and regulatory norms.

Deadlines and discrepancies 
The documents should be legible, clear, complete, and accurate. But most importantly, they should be completed and filed in the pre-determined timeframe. All documents are protocol specific and hence can be rendered ineffective if the necessary data is inadequate or incorrect. Important evidence can be lost in this way. Therefore, time management and vigilance form the backbone of clinical research documentation.

When data is incomplete or incorrect, it is known as a discrepancy. A query is generated by the data entry operator, a data clarification form is sent to the site, and the query is resolved. However, it is not as easy as it sounds because a single data query causes loss of vital time and may cost up to $100 for a paper CRF. Incorrect entries on paper CRFs have to be corrected according to standard operating procedures (SOPS) – the incorrect entry is cancelled and the correct data is written down with the date, signature of the person making the correction and the reason for it. This is known as the ‘audit trail’. However the previous entry should be readable.

Confidentiality concerns
Confidentiality of the documents and of the data generated in the trial has to be maintained at all levels and ends. The PI ensures that the subject’s personal and medical information is not disclosed to unauthorized persons – name, address, diagnosis, and prognosis are all kept confidential. Health Insurance Portability and Accountability Act is the legal watchdog in USA to safeguard the private, personal information of the subject. It governs the use and publication of the information obtained from the research and makes it compulsory for the sponsor to remove all subject identifiers like name, address, phone numbers and photo in the data to be published.

Confidentiality is a necessity at the sponsor’s end too, where only a few copies of important documents are signed by an authorized person. These are official copies and are distributed among select persons responsible for the classified information they contain such as copies of protocol, investigator’s brochure, and randomization lists. Confidentiality of the documents can be regulated by restricting access – physical barriers in case of paper CRFs and electronic signatures for electronic documents. 21 CFR part 11 of the US FDA regulations, mandates that ‘all persons accessing the clinical data must have electronic signatures of their own’. However, parallel laws have not yet developed in India.

So whose baby is this? 
Responsibility of this endeavor is shared between all the personnel involved, i.e., the medical director who ensures that documents from the sponsor’s end are authorized and confidential, the project manager who overlooks the filing of reports, approvals and maintaining the Trial Master file, the Clinical Research Associate/Monitor who is the vital link between the sponsor and the site and who has to ensure that the documentation is complete and accurate on the site, the investigator who has the responsibility of the conduct of the trial and it’s documentation and the Clinical Research Coordinator to whom the investigator sometimes delegates the duty of completing the documentation and filing it. Coordination and clear communication are a must among all of them to guarantee the success of the trial.

Archival and retrieval
The documents generated from the clinical trial have to be retained for a stipulated period of time, depending upon country specific guidelines. The ICH-GCP gives a timeframe of at least two years. The archival facilities should be constructed to accommodate the documents and designed so as to protect them from environmental hazards, fires and leakages. Qualified, trained staff and suitable infrastructure should be available to restrict access and maintain security. Retrieval of the stored documents is also an important issue and should be tackled in advance. Procedures of retrieval, the personnel authorized and the timeframes of returning the documents have to be defined. Records of the visitors should be maintained.

The raw data obtained from the trial is analyzed statistically and conclusions are drawn, hence incomplete and inaccurate data can dilute the power of the research statistically and can give rise to inaccurate conclusions. An excellent drug for a particular disease may be refused approval due to this. In this way documentation is the foundation of the clinical trial upon which approvals can be sought for launching the new drug. The success of the trial depends on it and conscientious efforts are necessary for clinical research documentation.