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Regulatory Update, November 2015

Sunday, November 1, 2015

CRO Warning Letter From FDA Instructional to Sponsors on Overseeing CROs

On June 16, 2015, a contract research organization (CRO) received a Food and Drug Administration (FDA) Warning Letter (WL) for violations of FDA regulations observed during a September 2014 inspection. Many sponsors lack the resources to fully manage their clinical trials in-house and outsourcing to CROs is common, whether for a few trial activities or a full-service CRO to manage essentially all trial activities. Sponsors are responsible for the adequacy of the CROs they choose and are expected to oversee their performance. Sponsors can review the violations in this WL as a “lessons learned” exercise and use those violations for help in assessing their own CROs. Excerpts are provided below but the entire WL is available for interested readers at www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm453979.htm. The inspection covered three protocols for an investigational drug being studied under an Investigational New Drug (IND) application.

  1. Failure to ensure proper monitoring and failure to ensure that the investigations are conducted in accordance with the general investigational plan and protocols contained in the IND [21 CFR 312.50 and 312.56(a)].

As a result of “your inadequate monitoring, you did not identify, and did not correct in a timely manner, the clinical investigators’ failure to report serious adverse events (SAEs) according to protocol-specified timeframes and failure to perform protocol-required laboratory tests.” SAEs, whether or not considered related to study drug, were to be reported to the sponsor within 24 hours of occurrence or the investigator’s knowledge of the event, even if the event did not appear to be treatment-related. Furthermore, the WL states these SAEs were not identified by the monitor in monitoring visit reports, which is of significant concern, as it suggests the CRO’s monitors may not have been qualified to perform their monitoring tasks.

As examples, one SAE (thrombocytopenia) occurred on May 4, 2009, but the site did not report it to the sponsor on an SAE form until April 30, 2013. In another example (leukopenia and neutropenia), the SAEs occurred on June 8, 2010, but the site did not report them until May 2, 2013. The long delay between occurrence and reporting of these SAEs is worrisome on its own but it also suggests the unreported SAEs may have been discovered during a late-stage audit; clearly the SAEs were described somewhere in the subjects’ medical records. Shorter delays also were cited, including one subject’s surgery for knee arthritis that was complicated by phlebitis. The investigator noted the subject’s surgery in a progress note dated March 15, 2013, but the site did not report the hospitalization to the sponsor on an SAE form until April 10, 2013.

Regarding laboratory tests, “Your monitoring failed to identify and correct a clinical investigator’s failure to perform protocol-required laboratory tests.” One protocol required hematologic laboratory tests at many time points and included an array of routine hematologic tests. These were important safety assessments to monitor for study drug-related adverse events such as neutropenia. The WL cited five subjects whose testing was not done at various times. It also cited an example of failure to perform urine dipstick testing and 24-hour urine collection to measure protein. These were safety assessment to monitor for study drug-related renal disorders. Similarly, these missed tests also were not noted in monitoring reports.

Missed protocol-specified tests and delayed SAE reporting are frequent problems in clinical trials, but in the author’s experience, monitors are usually qualified and their reports generally capture these protocol violations; that is, the “easy part.” Securing investigator compliance is the “hard part.” In this case, it appears the CRO’s selection of monitors may have been inadequate. Options to consider for preventing this include:

  1. Conduct a robust vendor qualification of the CRO before you sign a contract to assess your desired services and the senior staff to be assigned your services;
  2. Require the CRO to submit CVs to you for all prospective monitors (whether employees or contractors) for your prior approval;
  3. Conduct a re-qualification audit if many CRO team members delegated to your study (managers, monitors) are reassigned or quit the CRO;
  4. Conduct co-monitoring with a senior level sponsor employee early in the study to focus on SAEs and protocol violations, as an assessment of the monitor(s); and
  5. Conduct audits at (a) early- and (b) middle-stage time points of a clinical trial, to (a) identify problems before they have affected all your study data and (b) evaluate the effectiveness of audit-required corrective actions.
  6. When preparing corrective actions, always include effectiveness checks.  


  1. You failed to ensure proper monitoring of the investigations contained in your INDs because you did not follow the monitoring guidelines you developed.

FDA expects all regulated entities to follow their own standard operating procedures and any other written instructions (such as protocols and monitoring guidelines or plans). This CRO’s monitoring guidelines required that monitoring reports be written by the Clinical Research Associate (CRA) and approved by the Clinical Project Manager (CPM) within specific timeframes, but some monitoring reports were not completed and approved within those timeframes, and in some instances, were not completed at all. FDA provided many examples. The CRO’s monitoring guidelines required that interim monitoring reports be prepared by the CRA within five business days after the visit and approved by the CPM within ten business days after receipt of the report.

The CRO’s report creation, review and approval timeframes were very aggressive and sponsors and CROs should think carefully about imposing such requirements on staff who are routinely very busy (consider each monitor’s/CRA’s visit and travel schedule, and the number of projects the CPM may be juggling). In addition, it is well-known in the CRO industry that the monitoring role experiences significant turnover as monitoring is a very demanding and difficult job. Often, a monitor leaves a CRO before completing his or her reports and these may “fall by the wayside” while the CRO finds a suitable replacement. A more reasonable approach might be to:

  1. Have the monitor send the monitoring visit follow-up letter to the site within five business days (so the site can quickly proceed with corrections and queries);
  2. Allow the monitor 10 business days to write the report; and
  3. Allow the CPM an additional five to 10 business days for review and approval.

FDA Issues Two Final Guidance Documents

FDA recently released two final guidance documents in the Federal Register.  Interested persons may submit electronic or written comments on final FDA guidance documents at any time.  Submit electronic comments www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  Identify comments with the associated Docket number (in parentheses).

Uncomplicated Gonorrhea

On August 18, 2015, FDA announced availability of a guidance titled “Uncomplicated Gonorrhea: Developing Drugs for Treatment.” (Docket No. FDA-2014-D-0640)

Virus or Bacteria-Based Gene Therapy and Oncolytic Products

On August 27, 2015, FDA announced availability of a guidance document titled “Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products.” (Docket No. FDA-2014-D-0852) 

The Regulatory Update is excerpted from Research Practitioner, Volume 16, Number 5, September-October 2015.

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