Clinical trials documentation protocol

In accordance to GCP, the sponsor should appoint clinical trial monitors. These act as the main communication interface between the sponsor and the trial site, and should regularly visit the site to oversee that the trials are being conducted and correctly documented in accordance with the protocol and GCP. Reports should be supplied to the sponsor after each visit. It is also good practice for the sponsor to establish an auditing system for independently verifying that the activities in relation to the collection and processing of data at the trial site, and at related laboratories or sponsor s facilities, are conducted in accordance with applicable protocols, procedures, regulations, GCP and GLP. 

Summary The summary presents the case for the drug s approval. It includes discussion about the drug s mechanism of action, its effect on animals, results of clinical trials, manufacturing and tests methods, its stability, and proposed dosage and treatment protocol. The summary may run into hundreds of pages. It is one of the few documents being read by all the different reviewers as such, a good summary will assist with the review process. 

A Sponsor submits a clinical trial application to the Competent Authority in each member state where the trials are to be conducted. The Competent Authority has 60 days to review and approve or reject the application. Application is in prescribed forms and covers the proposed clinical trial protocol, manufacturing, and quality controls on the drug, and supporting data, such as (1) chemical, pharmaceutical, and biological data, (2) nonclinical pharmacological and toxicological data, and (3) clinical data and previous human experience. The supporting data are submitted in the Common Technical Document (CTD) format (see Section 7.11). 

This document describes the objectives, design, methodology, statistical considerations and organisation of a trial. Other information should be present, such as the background and rationale, for the clinical trial. It is a document key to any clinical trial. There should be a logical approach to preparing a protocol (see Box 7.2). 

The protocol should specify what should be recorded directly into the CRF and what will also be recorded in the medical records. The CRF will contain all the pertinent data associated specifically with the clinical trial but some will be repeated in the medical records, for example, the protocol identification number, date of consent, date of commencement of the study, key baseline medical findings, visit dates, start and finish dates of the study drug/placebo or treatment, concurrent medication, adverse events and key efficacy and any unscheduled or scheduled actions or interventions (such as escape medication). Additional information obtained from biopsy reports, radiographs and similar documents will provide confirmation that the data in the CRF are recorded correctly. Monitors, QA auditors and inspectors need to see all the medical records available to the investigator. It is not appropriate to create copies of data from CRFs or checklists derived from medical records and claim that these are source documents. 

Many scientists confuse the terms QC and QA. In terms of clinical trials, there is a very real difference. QC is the operational techniques and activities undertaken by all participants to verify that the quality requirements of the clinical trial have been fulfilled whereas QA verifies that the QC has satisfied these requirements. In other words, QC is where the data recorded is checked with source documents, and that measurements and procedures followed are those described in SOPs and the protocol. QA is where independent individuals establish that QC is in place and report any deficiencies without bias. 

No matter what its design, a well-planned clinical trial requires development of a suitable trial protocol prior to its commencement. The protocol documents outline all pertinent aspects of the trial (Table 2.8) and should be made available to trial participants and other interested parties. A core prerequisite of any trial is that participants be fully informed regarding the intervention and any likely associated effects. 

Case report forms (CRFs) are used throughout clinical trials to record data collected during a trial. They record all of the information specified in the protocol for each subject (all data recorded on the CRF must be verifiable from original source documentation). While the traditional paper CRF format is still used, electronic data collection is becoming more common. Voorhees and Scheipeter (2005) discussed CRF development in detail, highlighting some of the fundamental aspects of their purpose, design, and nature ... 

The identification and selection process is only the first step. The second aspect involves monitoring the CSOs to ensure that the research studies are conducted according to the research protocol, that the results are obtained using appropriate techniques and procedures, and that the data generated are correctly recorded and documented in the study report. Many clients hire firms, such as other CSOs or consultants, to monitor outsourced research studies, particularly clinical trials and manufacturing projects. In doing so, the clients should use the same techniques to select and evaluate the monitors as they use to identify a CSO. Monitoring studies at CSOs should include but are not be limited to ... 

Hence, the standards for conducting clinical trials must be known before they can be applied. Standards are either international (e.g. ICH GCP), European (e.g. European Union Clinical Trials Directive (2001) and GCP Directive (2005)), national (i.e. national drug laws and GCP regulations) or even more local, such as State laws in the United States (Isidor and Kaltmann, 1999). Apart from the regulations, the clinical trial protocol, SOPs and other internal or external instructions document procedures how the trial should be carried out from start to finish. Compliance with these standards is expected. 

Complete, consistent and accurate trial documentation is the basis for any inspection by regulatory authorities or sponsor/client audit and is a proof that the study was conducted according to GCP regulations, the trial protocol and SOPs. The TMF plays a vital role in providing confidence to auditors and inspectors that the clinical data are valid and that the trial was conducted properly. 

The information on the IMP in the CTA is necessarily not as complete as in a MA, and the overall intent is that the extent of information should be proportional to the clinical phase of the protocol, while complying with the new Guidance document for Good Manufacturing Practices as they apply to IMPs (Annex 13, Rev 1 of the document). A further guideline is forthcoming on the requirements to the chemical and pharmaceutical quality documentation concerning IMPs in clinical trials (see European Commission Directive 2003/94/EC). 

In Western Europe, in spite of the Clinical Trials Directive, there is still no uniformity in the order of approval/submission of documentation by the various parties involved. For example, although all countries now require review and approval of phase I clinical protocols, in some countries, approval of a study by the local or national ethics committee is required before documentation is submitted to the competent national authorities, whereas in others, this order is reversed. The documentation that is required to be submitted to the authorities is also quite variable (Table 50.2). Some countries require brief summaries of available information, whereas others require detailed information on the preclinical, pharmacy, chemistry and other clinical data to be submitted. 

Before a trial is initiated, the FDA requires the protocol to be approved by an institutional review board (IRB) or independent ethics committee. The IRB must address the investigator s qualifications to conduct the proposed trial. It does so by reviewing a current curriculum vitae and other relevant documentation. Pharmacists seeking approval by an IRB must demonstrate experience in the conduct of clinical trials similar to the one for which approval is being sought. The investigator provides information to the IRB, but does not participate in the committee s deliberations. 

For this reason, it is remarkable that, in many cases, clinical pharmacists lead the follow-up process for the clinical trials. It was in a pharmacy-promoted audit that a serious deviation in GCP recommendations was detected. In this study, it was concluded that compliance was adequate in 50% of protocols, so-so in 25% of cases, and poor in the remaining 25%. Surprisingly, in 13% of the patients, the informed consent document was not signed in 15% of the cases, the patient s clinical records did not reflect that the patients were included in a clinical trial. 

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