Former FDA Inspector Notes From the Field: It’s a Compliance Jungle Out There

Article title
Patrick Stone
In FDA Regulated Industries

Considering that clinical trial compliance responsibility is on the Principal Investigator, your contracted participation should add value. Contract Research Organizations (CROs) and independent Monitors must honor the contractual commitments by documenting site deviations and issuing data correction forms. For fiscal year 2010, Monitor inspections by FDA determined that fifty percent (50%) were not in compliance. Twelve percent were classified as official action indicated for warning letter or worse. I will provide analysis of the fiscal year 2011 numbers when they are released.

Meantime, I helped generate these numbers while at FDA in 2010. The most common compliance deficiencies listed were:

  • Inadequate monitoring
  • Failure to bring investigators into compliance
  • Inadequate accountability for the investigational product

(Bioresearch Monitoring (BIMO) Metrics – FY’10)

The rest of the pie chart in the compliance metrics are for IRB’s Principal Investigators, and Bioequivalence inspections by FDA Consumer Safety Officers/Investigators.

I have recently completed many Sponsor generated Quality Assurance audits. I have issued many notable observations of non-compliance. On my most recent audits I have observed serious adverse event reports (SAE’s) had not been reported over the span of years putting the sponsor out of compliance as well (protocol required SAE report within few days). Inclusion and exclusion violations, missing pages of the informed consent form, not following the protocol for three years for all Subjects, data integrity problems, 21 CFR Part 11 electronic records compliance, and failing to bring the site into compliance. Many simple mistakes when detected early and corrected will compound when left unchecked for years.

It may make sense to audit your trial halfway through, and then at the end, or risk throwing out your highest enrollment sight data for lack of protocol adherence. I have to say I recently observed liquid paper/White Out used on source documents for a clinical trial Subject. It has been many years since I have listed that as an observation. The focus must be risk based with primary efficacy end-points and serious adverse event review at the top of every monitor visit.

Then move through to protocol adherence and test article coverage. Training and hiring qualified monitors are key aspects to providing patient safety and regulatory compliant projects. We have our work cut out for us and FDA is not going to review every study or even more than 2% of them domestically. Fifty percent is not a passing number and you do not want to be listed with the rest of the 483 observation forms on the Internet for all to see.

Patrick Stone is President of TradeStone QA and the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

Showing 2 comments
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    The issue with compliance, FDA and clinical trials is caused by the stupidity of the regulations. Instead of having QAU as an independent entity (as it is, for example, in nonclinical (Part 58)), it is the responsibility of the Sponsor who has a vested interest in the study outcome. Compliance will always be an issue as long as this structural problem exists in the regulation.

    And, please…for the sake of your sanity and that of others, don’t bother to audit 21CFR11 when you do your audits. It’s just not worth the time and effort since (like training findings) there will always be “something” to find if you are persistent–and since it is a subjective issue about how much is “enough”. Stick with HIPAA criteria (that’s onerous enough).

  • Reply


    I will admit the regulations need some updating however they are in place to ensure patient safety and data integrity. An intelligent design protocol partnered with a monitoring plan that ensures patient safety and data integrity are the course corrections necessary. There is nothing “stupid” about enforcing patient safety and data integrity on every clinical trial domestic and foreign. The Quality Assurance Unit in the clinical trial function is useful in the middle and end for clinical compliance determination. The real work starts before the QAU gets involved. The real issue here is execution of a protocol and monitoring the compliance of the study teams execution at the clinic site. Training a study site and documenting the study sites understanding of a clinical trial protocol are crucial aspects of compliance. Nothing is perfect and yes there will always be observations but how significant are the observations. If they include patient safety and data integrity a study projects approval could be in jeopardy. There is much work to be in the electronic records department for sure and the burden is on FDA and industry to produce meaningful guidance for all stakeholders.

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