Oversight of Clinical Investigation – a risk-based approach

FDA has recently introduced a guidance document titled—“Oversight of Clinical Investigations: A Risk Based Approach to Monitoring”.  FDA has not released a similar guidance for over twenty three years.

The guidance is intended to assist sponsors of clinical investigations with clinical trials relating to human drugs, biologics, and medical devices. Although the overriding theme of the guidance is the protection of human subjects, FDA is clear in making known that on site visits are not always necessary and that “centralized monitoring” may be the preferred method for clinical trial monitoring. The FDA is not discouraging on site visits, such as when a protocol is complex or the subject population carries a high rate of co-morbidity. Rather, the FDA encourages a variety of approaches when looking to fulfill sponsor monitoring duties. The guidance does not discourage on site monitoring, but rather strongly encourages a sponsor look at the possibility of centralized monitoring.

For purposes of the guidance “monitoring” is the method that a sponsor or (CRO) uses to gather data from a study site. The guidance points out in several places that whether on site or off site monitoring is used, the protection of human subjects is paramount.

This guidance raises several opportunities for sponsors to conduct clinical investigations. Initially, the obvious advantage to off site or centralized monitoring is the time and money saved by centralized monitoring. It will simply be less time consuming and human intensive, to gather study data remotely. In addition, it will allow the more efficient use of sharing data with investigators and FDA. Again, FDA does not suggest in the guidance that centralized monitoring is the gold standard for monitoring clinical trial data, but rather encourages its use where appropriate. The overall goal of the FDA is to look at all possibilities, hence a risk based approach, when deciding the best way to obtain study data. Guidelines to follow in choosing either approach have to do with the resources, training, safeguards in place, the experience of the investigator, as well as the severity of illness experienced by the study population. One size does not fit all, but FDA is adamant in having a sponsor consider centralized monitoring.

Steps FDA is Taking to Facilitate Wider Use of Alternative Monitoring Approaches

“The Agency also is initializing operational measures to ensure that its review, compliance, and other functions reflect this view of monitoring. Specifically, FDA:

Has withdrawn the 1988 guidance on monitoring of clinical investigations

Is issuing this draft guidance encouraging risk-based monitoring approaches,
including adoption of alternative monitoring methods

Will ensure that bioresearch monitoring compliance program guidance manuals
(CPGMs) for sponsors, CROs, monitors, and for clinical investigators and sponsor
investigators are compatible with the approaches described in this guidance

Will ensure that all affected program areas within FDA are aware of the goals and
purposes of this guidance and its compatibility with current CPGMs

Will consider establishing processes within CDER for sponsors to voluntarily
and prospectively submit and receive feedback on proposed monitoring plans.
Sponsors of IDE studies wishing to solicit feedback on their monitoring procedures
Prior to the submissions of the IDE application may either submit a pre-IDE, or
Contact CDRHs Division of Bioresearch monitoring.”

FDA is quick to point out that, although many factors affect study quality, the number one variable that contributes to the quality and integrity of a clinical study is a well-designed and articulated protocol.

This could mean that much attention be paid to any type of meeting the sponsor has with FDA relating to trial design. The better the protocol, the greater the chances for centralized monitoring to occur

Types of Monitoring

1. On-Site Monitoring

“On site monitoring is an in person evaluation carried out by sponsor personnel or representatives at the site at which the clinical investigation is being conducted.”

2. Centralized Monitoring

“Centralized monitoring is a remote evaluation carried out by sponsor personnel or representatives, or clinical monitors at a location other than the sites at which the clinical investigation is being conducted.” The beauty of centralized monitoring is that it can retain many advantages of on- site monitoring without the drawbacks. And in some instances carries with it additional capabilities. This is why the FDA is now encouraging centralized monitoring where appropriate. It is no secret FDA is strongly now encouraging centralized monitoring. Again, the most solid basis to support centralized monitoring is a solid study protocol that identifies procedures and data that are crucial to the reliability of the study findings.”

Factors to Consider when Developing a Monitoring Plan

1. Complexity of study design
2. Types of study endpoints
3. Clinical complexity of study population
4. Geography
5. Relative experience of the clinical investigator and of the sponsor with the investigator
6. Electronic data capture (EDC)
7. Relative safety of the investigational product
8. Stage of the study
9. Quantity of data

These are all variables to consider in determining which type of monitoring the sponsor will engage in. There is no one right answer that determines whether monitoring should occur on or off site. What is clear is that FDA is strongly encouraging through this guidance the use of centralized monitoring.

Monitoring Plan

“For each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The plan should provide those involved in monitoring with adequate information to effectively carry out their duties. All sponsor and CRO personnel who may be involved with monitoring, including those who review and/or determine appropriate action regarding potential issues identified through monitoring, should review the monitoring plan. The components of a monitoring plan might include the following:”

1. Description of monitoring approaches
2. Communication of monitoring results
3. Management of Non-Compliance
4. Training and study specific information
5. Monitoring Plan Amendments

Conclusion

What is most important for sponsors to take away from this guidance is that there is no ambiguity; FDA is encouraging centralized off-site monitoring of clinical trials. The FDA made clear that the paramount foundation for centralized monitoring begins with a well-designed protocol, complexity of the study, experience of investigator, and severity of illness of the study subjects.

This guidance ushers in a whole new era of clinical trial monitoring. A sponsor can now with some level of comfort take advantage of all the technologies that allow off-site monitoring. This likely will result in reduced time it takes for investigators to supply data to sponsors, and sponsors to FDA. It could even be postulated that centralized clinical trial monitoring could speed up drug development times. At the same time it must be made clear, that FDA is encouraging a risk based approach to trial monitoring. This means there may be some instances when on site monitoring is most appropriate. In this guidance FDA clearly expresses that on-site monitoring probably takes place more than is necessary and that centralized monitoring be placed in the risk assessment mix.

Centralized monitoring may be “disruptive” to some sponsors that maintain organizations and cultures conducive to mainly on site monitoring. It would seem to follow that those sponsors who can adjust to the centralized monitoring “learning curve” stand a better chance of working more smoothly with FDA as well as possibly expediting the approval of their products.

The Food and Drug Practice at Arnall Golden Gregory, LLP is well versed in helping sponsors make this transition and stands ready to help clients and prospective clients achieve their goals relating to centralized monitoring Contact P. Terrence Gaffney at (202) 677-4044, or terrence.gaffney@agg.com for more information.

Comments on the draft guidance should be submitted by November 28, 2011.

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republished and adapted with permission from P. Terrence Gaffney

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