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June 15, 2009 (Vol. 29, No. 12)

Spotlight on the FDA

Biosimilars, Guidelines for Clinical Studies, and New Policies on cGMP Inspections and Reference-Listed Drug Choice

  • Conducting Clinical Studies—Ignoring the Basics Is Perilous

    Terrence Chew, M.D.

    Biomedical companies, especially start-ups new to or unfamiliar with the FDA environment, that are developing a new drug/device combination or a nutritional product may enter a clinical trial unaware of regulatory requirements or may feel their company is too small to be subject to the usual requirements. This is not true—FDA maintains a single set of standards to which all companies, regardless of size, must adhere.

    In order to ensure clinical trial compliance, the FDA has an ongoing bioresearch-monitoring program that includes inspections designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects have been protected. FDA periodically publishes findings of inspections, which is a great resource to assess potential investigative sites or pharmaceutical partners.

    A recent inspection of a small pharmaceutical company revealed that the company had failed to submit an IND for the conduct of a clinical investigation with an investigational new drug. In addition, it failed to obtain necessary documentation to ensure compliance with the clinical protocol and subject protection such as a Statement of investigator that includes a commitment from the investigator to comply with the protocol, personally oversee the investigation, meet informed consent requirements, ensure that IRB review and approval requirements are addressed, and disclose financial information. 

    In addition, the sponsor did not maintain adequate records regarding investigational drug disposition and did not monitor the progress of the trial with a qualified monitor. All of the above are required by law and relevant FDA guidelines. Companies often feel that they are exempt from these regulations as they are not developing a new drug or they are just conducting pilot studies to make decisions. 

    Common clinical investigator compliance issues include failure of the investigators to conduct the study in compliance with the protocol and signed investigator plans. In addition, investigators may incorrectly feel that they can modify the protocol for specific patients, which is different from the protocol’s standard of care. FDA inspectors compare the protocol inclusion and exclusion criteria versus the patient records to look for such violations.

    Although, investigators may ask the sponsor for an exemption—these must be considered carefully to determine their impact on the study results and statistics.  FDA may examine the quality of the informed consent for adequacy in terms of explaining risk, and to ensure that informed consent was obtained prior to the patient being treated on the protocol. FDA may also audit IRB adherence to its own rules and regulations. 

    Companies that sponsor clinical trials are responsible for the compliance of their investigators. Since many trials are being performed outside the U.S., companies must ensure that investigators are properly trained equivalent to U.S. medical standards of practices and monitored to maintain compliance.

    Although costs may be less in certain ex-U.S. regions, this must be balanced by the increased cost of properly monitoring distant sites. There are many valid reasons to conduct trials outside of the U.S., but sponsor companies must be sure that the lower cost is not due to lower quality, especially since EMEA and FDA have increased the inspection of non-U.S. pivotal studies.

    Terrence Chew, M.D. (
    [email protected]), is a clinical development expert with over 25 years experience in FDA regulatory and clinical studies issues.

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