Clinical trials documentation source documents

Despite the anecdotal nature and sometimes poor documentation, publication of case reports in journals remains one of the most useful primary sources of information on ADRs. ADR reports in the literature can be identified in several different ways. Prepublication manuscripts describing a spontaneous case report or an event from a clinical trial are sometimes provided by authors to the manufacturer of the drug and the regulatory authority in that country. Pharmaceutical companies are required to be aware of the literature as to the safety of their approved therapeutic products, and are assumed (by law) to be cognizant of such. 

CRAs achieve these tasks through frequent visits to the clinical trial site. During these visits, the monitor will verify source data, audit regulatory documents for accuracy and completion, perform drug accountability assessments, and communicate any concerns, problems, or new information with the study staff. 

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. 

The clinical trial monitor is a temporary member of the site team. A good monitor will conduct scheduled visits, and the investigator and the site staff should provide sufficient time to answer questions and correct data in the CRF that has been transferred incorrectly from source documents. Common errors are omitting negative answers and signatures. The monitor will need space to work and should be provided with requested documentation, including medical records, for review. 

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. 

Many investigator sites employ part- or fulltime nurses to support the clinical trials. Nurses should never be considered to be an extravagance, because without them, the onus of administration and QC is solely on the investigator. The clinical trial nurse can help the investigator in many ways, but two of the most important are ensuring that the CRT reflects what is present in the source documents, such as essential events of the medical history of the subject, and close liaison with the sponsor s monitor. 

The investigator should prepare an informed consent form for every study to be performed at the institute and should obtain an approval by the IRB that covers the institute. GCP listed a dozen points to be covered by the informed consent (1C) form (see Table 23.6). The new GCP allows a reasonable amoimt of pa)unent to the patient, such as transport cost. Patients should allow clinical trial monitors, auditors, IRB members and inspectors from the regulatory authority to verify the source documents. This new requirement of obligatory written 1C is regarded as a... 

In some cases, it may be prudent to obtain a certified copy for the subject s clinical trial file. For example, if the records are not owned by the investigator or under his or her control, such as patient medical records held by the hospital, depending on the hospital s archiving procedures it would be advisable to obtain certified copies for the clinical trial file in case the hospital loses, misplaces, or intentionally destroys the documents under an established record retention schedule. This is all part of CQA s oversight role regarding the appropriate transfer and authentication of raw data and source documents. 

The second component of a successful clinical manufacturing program is appropriate quality assurance systems for the production of cell or viral banks, raw materials, in-process materials, and final product. Much has been written about the production and testing of cell and viral banks for use in manufacturing. Both FDA guidelines and other reference information are available (http // www.fda.gov.cber/guidelines.htm http //www.ich.org, http //www. emea.eu.int). The production of AAV vector batches for use in clinical trials should use qualified cell, viral, and/or plasmid banks as appropriate. Documentation on the source materials for these banks is also crucial in assuring the quality and safety of the clinical trial materials. 

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 ... 

MacKintosh, D.R. Zepp, V.J. Source documentation a key to GCP compliance in clinical trials. Appl. Clin. Trials Mar. 1996, 42 6. 

There is a tendency to assume that the principles of informed consent are self-evident. In fact, evidence that this is not the case comes from many sources, such as ethics committees that are frequently dissatisfied with proposed informed consent documents, and sophisticated Western governments that, from time to time have conducted clinical trials without it (e.g. the Tuskeegee travesty). A recent gene therapy accident in the eastern United States, which led to the death of the participant, led to litigation which was centered not around whether the clinical trial was unduly hazardous but rather on whether the consent that the patient gave was truly and fully informed. 

An adverse event is unexpected when its nature or severity is not consistent with information in the relevant source document(s) . Relevant source documents include the investigator s brochure for investigational drugs, and the master data sheet or core safety data sheet, or local product labeling for marketed products. The determination of whether an adverse event is unexpected usually resides with the company that sponsors the clinical trial or markets the product. 

Source documentation-source data, as defined in the ICH Guidelines 1.51, is all the information in original office or hospital records, and certified copies of original records of clinical findings, observations, and other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Original data is contained in source documents. 

Source documents are composed of hospital records, office charts, laboratory data sheets, subject diaries, pharmacy dispensing records, recorded data from automated instruments, x-rays, etc. Source documents should be legible and should document that the subject is participating in a clinical trial. Some of the key areas to cross reference source documents to case report forms and regulatory criteria are the informed consent process, inclusion/exclusion criteria, adverse experiences, investigational product administration, concomitant medications administered to the subject during the trial, withdrawal from the study for any reason, and subjects lost to follow-up. 

Determine and document all data sources (e.g., clinical trials, observational studies). 

The generation of bioactive peptides during microbial fermentation of milk and soybean is now well documented. Such peptides have been shown to exert several bioactivities that have been demonstrated in animal and human studies. Potential health benefits associated with bioactive peptides have been subject of growing commercial interest, especially in the context of functional foods. Milk proteins are the best-known source of bioactive peptides, but peptides with similar properties have also been identified in soybean. Anti-hypertensive peptides derived from milk proteins have already found commercial applications both in Japan and in Europe. This trend is likely to continue, although controversial results in clinical trials and global differences in health claim regulations call for further scientific and clinical research. 

Clinical research coordinators (CRCs) are the research personnel who assist with pahent visits, and perform study-related procedures that do not require a physician (phlebotomy, vital signs, adverse event, and concomitant medicahon discussions, etc.). CRCs provide the PI or physician with data required for interpretation, medical decisions (inclusion/exclusion, dosage adjustment, patient withdrawal, adverse event causality, etc.), and trial oversight. In addition, CRCs are usually responsible for transcribing source documentation (medical records, clinic notes, laboratory reports, etc.) into case report forms (CRF) supplied by the study sponsor. 

Audit notes are indispensable to allow QA auditors to write an accurate report after the audit. Detailed notes allow the auditor to prepare a meaningful audit report which is based on verified observations. All information collected during an audit is considered audit evidence. Information sources in an audit are, for example, document review, interviews and observation of activities. If applicable, sampling techniques may be applied, for example for SDV and verification of information in tables and listings. Audit observations are only considered audit findings if it is determined after comparison with audit criteria that these are not or insufficiently fulfilled. And finally, audit conclusions can be drawn to assess whether the audit findings impact the validity of the clinical data and the safety of the trial subjects. 

The PI is responsible for maintaining records associated with the clinical study. These include case histories designed to record all observations or other pertinent data on each enrolled subject, independent of whether the subject received active treatment. Data for each trial subject is normally recorded on a case report form provided by the sponsor. The sponsor may also require study data to be recorded in a source document (patient chart). It is the responsibility of the PI to assure that the forms are filled out with the correct information and according to guidelines established by the sponsor. 

Careful documenfation is always very important since the report on a trial is usually written a long time, sometimes years, after the first patient is entered. The study protocol therefore serves not only as a basis of decisions made during the trial but also as the source of those decisions. The protocol is also important since clinical investigators may change or new ones join the study. In fact, a protocol should be written clearly in order to help researchers to repeat the trial elsewhere. All documents (including patient data collecting forms) should be kept for a long time to provide the possibility to reanalyze the trial if needed. 

---