Audits

To assure compliance with regulations, government and regulatory agencies throughout the world must perform official inspections of clinical facilities. The FDA employs approximately 1100 investigators and inspectors in 157 cities to inspect almost 95 000 FDA-regulated businesses within the USA. Audits are performed during clinical devel opment to assure the quality of the research data, and routinely after product approval to assure adherence to GMP regulations.

Inspections of clinical study sites can be 'routine' or 'for cause'. The former is usually directed towards pivotal trials of a product that is awaiting approval, and investigators who enroll large number of subjects in a study. The latter is usually reserved for cases where there is reason to suspect the validity of data generated at a clinical site. Further, if significant deviations from regulations are discovered during an audit, a routine inspection may become a 'for cause' inspection and be intensified or expanded to include other studies. When violations are discovered, the FDA can request voluntary corrective action or recall a product from the market if it has already been approved. Failure to voluntarily correct a problem can lead to legal sanctions, seizure and destruction of a product, and criminal penalties. Audits by other regulatory agencies outside the USA follow similar procedures. Given the continuous evolution of oversight activities employed by these nations, their review may be either more or less stringent than that of the FDA.

During its continuing review of product development prior to marketing approval, FDA can request a hold on a clinical development program if it determines that:

• Human subjects would be exposed to an 'unreasonable and significant risk of illness or injury'.

• One or more investigators are not qualified by reasons of scientific training and experience.

• The investigator's brochure is determined to be erroneous, incomplete or misleading.

• The information submitted under the IND is insufficient, or the design of a study or clinical program is deemed to be deficient or lacking in scientific merit.

• The manufacturing, control, and labeling of the investigational product are substandard with respect to identity, quality, or purity, or insufficient quantities exist to adequately conduct a clinical trial.

• A satisfactory alternative therapy becomes available or evidence strongly suggests that the investigational product is unsafe or ineffective.

During a clinical hold, new subjects may not be enrolled in clinical studies or treated with the inves-tigational product. However, in some instances, subjects already receiving the investigational product may be permitted to continue. If significant deviations from the study program occur or serious safety issues are encountered, FDA can request termination of a clinical program or withdrawal of an IND.

A routine investigator site audit will focus on two major areas. First, an auditor will examine the facts surrounding the conduct of the study to determine who did what, the degree of delegation of authority, where specific aspects of the study were performed, how and where data were recorded, how investiga-tional product accountability was maintained, and how the monitor communicated with the investigator and evaluated the progress of the study. Second, the study case report forms for data collection will be compared to all available subject records and source documents that might support the study data. Subjects' records before and after the study can also be audited to evaluate medical histories that pre-date enrollment, and to determine what degree of follow-up occurred after treatment with the investigational product. Informed consent for all subjects enrolled at a site are routinely examined, and an auditor will also want to determine whether all adverse experiences have been properly reported. Nearly 10 000 inspections at more than 4000 investigative sites have been completed since 1964. The most frequently encountered deficiencies continue to be inadequate subject informed consent, failure to adhere to the protocol, inadequate and inaccurate records, and inadequate drug accountability. The most frequently encountered deficiencies in informed consent are failure to identify a contact person for questions about research subjects' rights, incomplete descriptions of study procedures and compensation/treatment for injury, inadequate confidentiality statements, and an incomplete description of available alternative procedures.

FDA can audit the records of the study sponsor, as well as contract research organizations (CROs), to review standard operating procedures and all of the documents related to a particular clinical study, including electronic databases. Since 1981, nearly 200 such inspections have occurred. Departures from regulations requiring voluntary corrective action were reported for 10% of the sponsors and CROs inspected. Two of the inspections resulted in official action. The most frequently reported deficiencies were records that were unavailable, inadequate or inaccurate, inadequate or improper informed consent, inadequate investiga-tional product accountability, deviations from the protocol and, inappropriate payments to volunteer research subjects.

Since 1986, FDA has performed nearly 2100 audits of more than 1400 public (e.g. affiliated with a university, hospital or other institution) and private institutional review boards. Fewer than 20 of these were 'for cause'. Complete compliance was observed for only about 13% of these inspections and 1% uncovered violations that were serious enough to warrant regulatory or administrative sanctions, which included suspension of clinical studies. The most frequently encountered deficiencies have been inadequate meeting minutes, lack of a quorum at meetings; inadequate written procedures, and inadequate continuing review.

At the conclusion of a FDA audit, the inspector will conduct an exit interview to discuss deficiencies observed and, if appropriate, will issue an Establishment Inspection Report (Form 483). For many sites, voluntary action to correct deficiencies will then be requested, some in writing. Failure to voluntarily correct deficiencies, or the occurrence of serious deficiencies at some sites, may result in a delay in the approval of a new drug application (NDA), or disapproval of the application, disqualification of an investigator, restrictions on an investigator, or criminal charges, fines and imprisonment. There are currently about 80 physicians who are ineligible to receive investigational products and more than two dozen others who have agreed to some restriction of their use.

The quality assurance department within a company will frequently conduct audits of investigator sites, either during a clinical study or after it has been completed. Companies that do not have a quality assurance department or unit may contract this service from a consultant or a third party specializing in regulatory audits. The intent and scope of these audits are the same as the FDA, but they afford a company an opportunity to verify compliance and to correct deficiencies that might otherwise delay product approval. These audits also provide a means to assess both the quality of the investigator site and the quality of the monitoring throughout the study. Audits performed outside the USA, in conjunction with multinational studies, can be problematic due to language and cultural differences, as well as a diversity of government regulations.

When the product development program has been completed and the NDA has been submitted for review, the FDA will likely perform routine inspections of the manufacturing facilities to verify GMP compliance and a sample of the clinical study sites to verify GCP compliance.

An audit of manufacturing and control processes will include a thorough review of all of the documentation required to demonstrate that a product meets the requirements for its intended use, including requirements for marketing and consumer use, technical design and performance, regulatory and quality assurance, and product safety. Equipment systems will also be inspected.

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