Inspection and Enforcement Trends: How Well Do You Know Your CRO?

Inspection trends indicate that The U.S. Federal Drug Administration (FDA) has increased the number and rate of inspections of Contract Research Organizations (CROs) by nearly 300% in recent years.  Additionally, FDA (CDER, CBER, and CDRH) centers published an updated Guidance Document on this topic in March of 2011 (USFDA Compliance Program Guidance Manual 7348.810 for Industry and Staff: Sponsors, Contract Research Organizations, and Monitors (CPGM)).
From the perspective point of industry insiders, the trend and the new publication have significant meaning.  When interpreting inspection trends the following are worth noting:
  • FDA regularly conducts risk management activities that are, in part, used to plan inspection schedules and approaches
  •  Any dramatic increase in inspections scrutinizing a particular area of industry tells us that FDA believes that this area presents significant consumer-centric risk
  • Negative results of these additional inspections almost certainly ensures a continuation, or elevation, of that increased level of scrutiny

Perhaps one of the most recent and visible examples of the application of this intensive scrutiny was the 2010 inspection of Houston-based Cetero Research.  This blog will use this case study and the modernization of CPGM 7348.810 to take a high level view of this inspection trend considering cause, scope, and impact, finally discussing preventative measures that could have been taken to prevent these deficiencies and protect the viability of clinical data.

Changes to CPGM 7348.810
The new release of this Compliance Guide presents significant modifications to the previous version released over a decade ago.  Modifications include:
The addition of several sections:
  • e-Registration of Studies 
– significantly increasing the FDA’s practice of confirming the outcome of study design and implementation and increasing evaluation of documents supporting informed consent of study participants
  • Review of Site Records 

– dramatically increasing the documentation requirements for FDA inspectors when documenting observed deficiencies

  • Financial Disclosure 

– requiring FDA to thoroughly investigate the financial relationship between sponsors and CROs

  • Electronic Records and Electronic Signatures 

– reinforcing the requirement to apply part 11 to EDCs and hybrid systems paying particular attention to the scope of Electronic Records and Signatures, associated procedures, data collection and security, and validation of EDCs and data collection systems

  • Emergency Research 

– detailed inspection requirements if Emergency Research was conducted

  • International Data 

– announces authority to inspect foreign sites, and requires the application of cGCPs to studies conducted outside the USA

  • Non-Clinical Studies 

– listing new regulations, guidance documents, and inspection policies

The significant modification of existing sections, including:
  • Medical Devices 

– including substantial rewrites to clarify and modernize in accordance with recent medical device initiatives, the timing of validation, the control of design, and the interaction between clinicians and sponsors

  • Inspectional 

– pays particular attention to the scope of inspections, the type of deviations to be documented, the need to discuss penalties for the falsification of data with site personnel, and the level of monitoring required and conducted by sponsors

  • References and Contacts 

– adds considerably to the list of relevant support documents

Cetero Case Study Details: FDA’s Inspection Reports
FDA conducted two inspections of Cetero’s facility in May and December of 2010. This in itself indicates a new trend; in previous years, evaluation of CROs and clinical data were almost exclusively conducted during inspections of sponsor organizations.  The associated regulations allow sponsors to transfer one or more of their responsibilities to contracted research organizations, but both the regulations and the associated guidance document reinforce the fact that the quality and reliability of these contracted services remain the responsibility of the sponsor organization.
The citations noted by FDA included:
  • Falsification of data
  • Manipulation of samples
  • Lack of documentation
  • Inadequate internal investigations
FDA public pronouncements stated that;
“The pattern of misconduct was serious enough to raise concerns about the integrity of the data Cetero generated during a 5 year time frame (April 1, 2005 to June 15, 2010). FDA concurs with the assessment of Cetero’s independently conducted 3rd party audit that stated, “This misconduct appears to be significant enough to cast doubt on the data generated…If the foundation of the laboratory is corrupt, then the data generated will be also.””
A Sampling of Cetero Inspection Results
Falsified Records
Inspectors identified 1,900 instances (over a 5 year period of time) of records claiming that analysts performed activities that were contradicted by attendance records, and additional 875 instances of the same claim for chemists performing sample extraction.
Manipulated Samples
FDA determined that the firm regularly ran “prep” runs in order to ensure that the run data would meet the acceptance criteria before including data in the official study folder. If samples were found during the “prep” run to not meet acceptance criteria, they were regularly physically altered.
Deficient Internal Investigations
Review of documents also indicated that the scope and conclusions of internal investigations were insufficient and unjustifiable.
Impact of the Cetero Case Study
The impact of these findings is, of course, critically concerning to any sponsor that has utilized the research services of Cetero.  Investigating the potential for impact to any one of the subject trials alone will delay trials and approvals, and add considerably to the cost of progressing the subject therapies through the development process.
However, the impact is far more wide-reaching than the viability of continued operation of a single CRO and/or the futures of the studies involved.
Deficiencies of this nature have a ripple effect that pose great danger to the entire industry, their consumers, the health of the American public, and the pace of medical progress.
Let’s take a high level view of the immediate impact:
1. Cetero
FDA has requested that Cetero provide FDA with a list of all testing related to FDA research conducted at their Houston, Texas facility from April 1, 2005, to June 15, 2010.  For each study, FDA has requested the drug name, study number, and the name of the drug sponsor.
In addition, the Agency is asking that Cetero develop, implement, and execute corrective and preventative actions that will serve to prevent the recurrence of these and similar types of violations.
As anyone who has been through the remedial process knows, this effort will inevitably lead to further observations and increased scrutiny, incurring substantial capital expenditures and resulting in incalculable losses of potential opportunity and revenue.
2. Cetero’s Customers
Sponsors of pending applications whose data was collected or generated at Cetero’s Houston facility between April 2005 and June 2010 will be required to review that testing and may need to have the testing repeated.
Cetero currently reports 122 active studies and has serviced studies for large name pharmaceutical companies including Amylin, Eli Lilly, Bristol-Myers Squibb, Johnson & Johnson, Merck, Abbott Labs, AstraZeneca, and UCB.
For these companies, approvals could be delayed, cost to market will be increased, and there is significant potential for development to be halted or ceased for drugs whose early phase clinical results were falsified.
3. Study Participants and Patients Dosed with Implicated Approved Drugs
At this time FDA has stated that they do not feel there is reason to be concerned with the health of any patients but, as with all investigations, determining scope of impact is a lengthy process.
4. Medical Progress
FDA has not yet published a public listing of implicated studies, although sponsors have been notified directly.  As a result, it is not possible to accurately predict which currently approved drugs/therapies or drugs/therapies with pending license applications have been implicated.
However, one prediction can be made; for at least the 122 active studies it will result in delay of approvals, depriving the consumer base of what could be critically needed treatments for an unknown length of time.
There are many, many lessons to be learned from the combination of the recent inspection trends, the review of targeted updates to the decade old CPGM, and the Cetereo case study.  However, we at Coda believe that the most crucial take away is the need to recognize the criticality of identifying deficiencies in CROs prior to utilizing their services, and to maintain oversight of the activities once they have begun.
The scope and ever increasing pace of CRO inspections, the nature of the subsequent enforcement activities and the revision of the inspection guide leave no doubt that FDA recognizes that the most obvious consumer-centric risk factors posed by the use of CROs are data integrity and lack of objective oversight.
  • The effective proactive assessment of the suitability and integrity of these organizations is an obvious and critical mitigation step in the product realization risk management process.
  • The next critically important risk mitigation step is the implementation of independent, objective, aggressive, and time sensitive study monitoring practices.
We suggest beginning the planning phases of these activities with risk management exercises designed to eliminate or mitigate these risks, assuring that any potential for harm is identified and mitigated prior to the execution of even early phase studies.
As members of industry, we would be wise to take note of these trends and activities, and remember that the legal responsibility for minimizing the risk to the integrity of research data belongs to us.  The message here is that we all need to put more effective and stringent CRO audit and monitoring plans into place, as quickly as possible.
Designing these processes with Quality in mind at the onset of the process is the surest way to:
  • Ensure Quality of the product
  • Optimize speed to market
  • Reduce the Total Cost of Quality
  • Protect the Health and Safety of the American public
This is a problem that affects us all, so let us all be part of the solution.
© Coda Corp USA 2011.  All rights reserved.


Gina Guido-Redden and Corrine R. Knight

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One Comment

  1. Posted October 19, 2011 at 5:00 pm | Permalink

    Furthering the trend:

    CMOs and Cancer Drug shortages…read more…

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