At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.
In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.
Guest Commentary by Lorraine D. Ellis, MS, MBA
When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.
There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.
The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures. FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.
The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.
How to comment: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!
The Federal Register Docket Number is FDA-2011-D-0597
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On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.
On The Blogroll: On Biostatistics and Clinical Trials- Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
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The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
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