These days, can a clinical development program have too much safety?

While risk evaluation and mitigation strategies (REMS) are hardly new, as this list of them on the FDA website attests, they remain only partially understood. In its own conversations with the sponsor community, Quintiles realized that many in the industry are unaware of the full spectrum of techniques to address and anticipate regulatory concerns about drug safety before they become headline fodder.

As a quick evaluation tool, Quintiles developed a simple questionnaire to help sponsors gauge their vulnerabilities and capabilities. “It has become clear that a lot of customers were not prepared for what they had to do,” said John Hall, vice president of global medical affairs at Quintiles. He believes that the industry may not be fully prepared for a more assertive regulatory environment and time lines under the 2007 FDAAA legislation. “I wonder how well prepared pharma actually is for what is about to happen,” he muses.

The Quintiles questionnaire is called RisQ. It’s a simple quiz to help sponsors assess their own potential exposure to safety–based risks with any drug, not to mention related requests for risk management plans.

The RisQ instrument takes only a few minutes to complete and, by generating a number at the end, places the respondent in a context of fellow sponsor companies. “That gives a score,” Hall says. “It kind of compares them to their peers.” Not everyone is as well prepared as they believe, he notes. “There were a few who thought they were prepared,” says Hall. “And when you look at the scale, well, maybe you’re not as prepared as well as you thought.”

Risk Management

Many companies in the industry are moving toward a more long-term, comprehensive approach to thinking about pharmacovigilance and drug safety, and the questionnaire can serve as a nudge toward assessing risk in earlier phases of human studies or even preclinical projects. Says Hall: “Not everybody is good at managing risk and benefit across the life cycle. We have a lot of people who can help with that.”

Even a more extended assessment of the likely safety-related questions from regulators does not require a lengthy engagement, Hall notes. A few days of assistance from his group of pharmacovigilance experts, he suggests, can supply a lot of insight. “We’ll tell you where your gaps are, where the issues are,” he says.

Hall himself is a gallant, unusually charming physician. But Quintiles has other key people on its pharmacovigilance team. The contract research organization (CRO) recently hired an FDA expert who played a role in the analysis of a major diabetes drug and a COX-2 inhibitor that were both the subjects of extensive news coverage and litigation. “We have this new person who is an expert on what FDA finds acceptable in communication and what they might not,” says Hall.

Considering Genetics

Hall notes that the promise of personalized medicine brings still more safety-related quandaries as sponsors and the regulators will be obliged to consider personal genetic variation in a more formal way. Most if not all sponsors should be collecting limited amounts of pharmacogenetic data for every compound, he suggests.

But the most astute companies, he reports, are already doing more, intending to be able to marshal data about individual genetic responses to medications. Needless to say, gathering such information may require changes to the clinical trial protocol and patient consent forms.

Indeed, Hall believes some firms are taking an approach that is, to a degree, inappropriately limited in scope. “It’s not about collecting safety data and sticking it in a safety database," he says. "That is an important part of it. But you need to understand more than that. If all you do is sit back and wait for adverse events to be reported, you’re already losing the game. It’s predicting what’s going to be reported that is the key. You can predict quite a lot.”

For starters, someone on the project team needs more in-depth understanding of the drug's mechanism of action, as well as the therapeutic area and the regulatory landscape for that class of compounds.

Ugly Baby

The firm is naturally prepared to go to bat for clients at the regulatory level when it thinks they have a sound but unappreciated REMS plan. Or it will recommend action to stay ahead of regulatory requests. In one recent instance, Hall reports, the firm recommended not just a retrospective analysis of data already in hand, but a new registry to track the safety issues after regulatory approval.

Many of the rapid Quintiles safety assessments, he reports, can be done inexpensively for “thousands” of dollars. But even in the case of registries that may cost much more, the math is in favor of making the effort. The data from a registry may resolve a safety-related question early, without years of ambiguity or academic criticism. In some cases, Hall suggests, a well-designed registry could make the difference between having a drug withdrawn from the market and having one available and selling well ten years after approval.

At times, he says, the involvement of an unbiased, independent participant can help sponsors be more objective about the risks and benefits of a drug. Even in an ostensibly scientific industry, partisans or supporters of a particular compound can introduce favoritism or emotion. People may have blind spots. Outsiders can supply a certain cold clarity about the REMS.

Hall is particularly pointed on this point: “Human nature doesn’t allow you to take a completely unbiased independent view of your baby. 'Your baby is the most beautiful baby'? Well, your baby is actually pretty ugly.” That may not be a sentiment anyone enjoys hearing. But it may be better to hear it early, while there is still time to design an appropriate response, than in the heat of the cable TV news channels.

Here's a link to an FDA conference on risk minimization plans.