Sponsors and their delegated representatives (that is, contract research organisations, site management organisations) are responsible for ensuring that clinical trials are conducted in accordance with FDA regulations. The FDA reports that monitoring is handled by sponsors (54%) and contract research organisations (31%).
A contract research that assumes any obligations of a sponsor must comply with the specific regulations (21 CFR 312.52[b]). The failure to comply with any obligation assumed will result in the same regulatory actions as will be taken with a sponsor. A sponsor who discovers that an investigator is not complying must promptly either secure compliance or discontinue shipments of the investigational new drug and end the investigator's participation in the investigation as well as notifying the FDA if an investigator's participation is under the [stated] conditions. The failure analysis of sponsor monitoring in recent notorious cases has identified the following problem areas:
• source documents completely absent;
• study subjects completely fabricated;
• study staff performing tasks for which they were unqualified; and
• other significant deviations from regulations.
To protect patient confidentiality, company representatives are instructed not to validate the existence of the patient through a review of clinic visit registrations and the accuracy of medical referral and history documents. As required in Section 505(i) of the Federal Food Drug and Cosmetic Act, companies require the establishment and maintenance of records and making reports by the sponsor as a condition for use of investigational drugs. Monitors need to insist on source data. Examples of source documents include medical history information; medical examination results; all lab results including x rays and ECG tracings; demographic data; concomitant medications; patient identification number; drug dispensing information; and informed consent. Too frequently, the sponsor will accept in lieu of source documents, shadow charts (summary medical information extracted from source data). Companies and their contracts need to have adequate time to review the integrity of data. Often monitoring time is truncated to allow more site visits in a given day, resulting in increased profits for the contract research monitoring organisations. Companies are eager to maintain a good relationship with the investigator and may replace monitors whenever the intensity of the data review becomes too rigorous. Unfortunately, there is no precise method for detecting if a doctor falsifies the underlying lab records or writes down inaccurate results for tests.
The sponsor is responsible for the selection of the clinical investigators based on the latters' training and qualifications, as evidenced by their curriculum vitae. The sponsor must certify that the data and information have been reviewed and are true and accurate. In addition, sponsors are required to certify financial interests and arrangements of the clinical investigator. Providing false statements represents a criminal offence (US Code Title 18, Section 1001).
1993 1994 1995 1996 1997 1998 1999 2000
Figure 7.11 IRB warning letters, 1993-2000.
serious regulatory deficiencies. Among them include the lack of quorum for a committee meeting (25%); insufficiently detailed meeting minutes (21%); inadequate standard operating procedures (15%); and insufficient record keeping (10%). In the most serious cases, the FDA has issued warning letters to IRBs as illustrated in Figure 7.11. The US Office of the Inspector General report of 1998, described the IRB problems as; reviewing too much, too quickly with little experience; facing conflicts that compromise their independence; conducting minimal continuing review of approved research; providing little training for IRB members; and paying little attention to evaluating effectiveness.
In 1999-2000, the leading IRB problems evoking official action and issuance of a warning letter have been: failure to prepare and/or follow written procedures; failure to adequately document activities; failure to conduct adequate continuing review; failure to fulfil requirements for expedited review; and failure to fulfil the requirements of informed consent.
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