Risky business

Featured Blog by Denni O. Day

When the US Food and Drug Administration (FDA) issued its draft guidance for industry “Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring” in August 2011, the response ranged from enthusiastic acceptance to wary skepticism.

The last time the FDA had issued a guidance document related to study monitoring was in January 1988 (“Guideline for the Monitoring of Clinical Investigations”). Prior to that time, most data forms were mailed back and forth between study sites and the sponsor or CRO, or they were collected and delivered by the field monitor at each site visit. As technology evolved, faxing of data forms became the prevalent method, which significantly shortened the review and error correction cycle. Eventually, scanning technology improved to the point where real-time data form review and error correction was possible. This made remote monitoring feasible, resulting in shorter timelines and more cost efficient trials.

The FDA’s apparent intent in issuing the risk-based guidance was to introduce even more efficiency to the review process and “. . . assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for clinical investigations of human drug and biological products, medical devices, and combinations thereof.” In essence, sponsors were encouraged to become more creative in their study monitoring by focusing selectively on “critical study parameters” and employing “a combination of monitoring activities to effectively oversee a study.”1

Risk-based monitoring is not a new concept. The idea first appeared shortly after the birth of clinical trials, although no one called it that back then. In its most basic form, the study management team, together with the field monitors, determined which aspects of the study protocol required the greatest attention. More detailed plans were tailored to individual study sites when previous study performance was known.

As sponsors compile more data on individual site performance, their ability to employ risk based monitoring successfully increases. Predicting a site’s performance in a new trial becomes easier when information about that site’s past screening failure rate, enrollment against target, visit-to-visit attrition, protocol deviations, adverse events, data queries, test article accountability, record keeping, and other quality metrics is available. Once the new study begins, any significant variation in a site’s performance from past patterns usually would indicate the need for increased scrutiny of that site.

In theory, risk-based monitoring presents tempting potential. However, is that potential…or the risk… realized in day-to-day practice? Several CROs that manage human trials have expressed concern that less robust monitoring plans requested by sponsors as cost-cutting measures will inevitably lead to lower quality data, extended timelines, and/or increased cost. While Good Clinical Practice guidelines deem the study sponsor, and not the CRO, as ultimately responsible for overall oversight of trial activities, these CROs fear that the sponsor will hold them accountable for these problems. However, other human trial CROs view risk-based monitoring as more time- and cost-efficient utilization of scarce study resources that allows them to price their services more competitively.

Currently, there is no guidance from CVM regarding risk-based monitoring for veterinary trials. If this approach becomes more prevalent…and, more important, successful…on the human side, it would be logical to expect that CVM would issue its own version for the veterinary industry. For the moment, though, I have serious reservations.

Anything that is “risk-based” is a form of gambling. And, as anyone who has been to Las Vegas or Monte Carlo knows, virtually all of the games are stacked against the player. We all know that even the best monitors and investigators miss things and make mistakes; and, every once in a while, those mistakes are serious. Therefore, do we really want to be gambling with the long-term financial success of new products…not to mention the health and well-being of the animal population…by monitoring less?

In the 1984 movie Risky Business, Tom Cruise’s character, Joel Goodsen, takes his father’s cherished Porsche for a ride with a “lady of the night” while his parents are away on a trip. Distracted by his date, he fails to set the parking brake, and the Porsche ends up in the lake. After a little hysteria, his date orchestrates some “risky business” to raise funds to restore the Porsche before Joel’s parents return from their trip. In the movies, things usually end well. In real life, risky activities can sometimes leave you all wet.

1FDA website, 28 August 2011.