FDA senior advisor discusses GCP goals

Look for new guidance on risk-based approaches

[Editor’s note: In this Q&A, David A. Lepay, MD, PhD, senior advisor for clinical science and director of Good Clinical Practice (GCP) Programs, for the Office of Science and Health Coordinator, Office of the Commissioner, U.S. Food and Drug Administration, provides readers with an update on federal regulations and guidance governing the clinical trial industry.]

Question: What is the FDA’s most important focus these days with regard to the clinical trial industry?

Lepay: The most important is research subject safety and communications on safety. That’s been a big focus for our agency and office as a whole and it will continue for some period of time. We held a hearing on March 21 on IRBs, and this is a hearing we will follow up on several levels. At the hearing, we heard a consensus opinion that there are problems in the system of reporting of adverse event, and that’s a systemwide view. It’s not a problem restricted to IRBs; it’s an issue we have to deal with at the most fundamental level of how adverse event information is acquired, how it is synthesized, how it is interpreted, analyzed, and ultimately how it is communicated and reported among the parties.

We heard very much from IRBs that single serious adverse event reporting coming to an IRB are almost uninterpretable, and clearly we have to go back and look at what kind of information could be provided in this system. Right now, of course, the drug and biologic regulations don’t provide for direct communication of information between the sponsor and IRB. They all move through the investigator, which also creates a large amount of paper and office time for the investigator and puts them in the very difficult role of interpretation. So we are going to have to look at making some changes in that fundamental direction into which information flows.

I expect we’re going to do as much as we can through guidance. This will be coordinated very closely, not only with the FDA, but also with other agencies that have a stake here, particularly the Office for Human Research Protections (OHRP). I think that would be, probably, one of the very large areas of focus for us.

Question: So do you have any proposed changes or committees that are going to look at making any changes, such as allowing direct communication from the sponsor to the IRB?

Lepay: That would require a regulatory change. We’ll see what we can do in terms of the way the regulations are currently written, what kind of guidance we can provide both to the IRBs under their regulations as well as the sponsors under their regulations. We can see how far we can take that. Ultimately, regulation development and writing is a much slower process.

Question: What’s another area that is of top importance these days?

Lepay: We’re looking very much at the issue of risk and risk-based approaches. We’re trying to figure out how best to use resources in the clinical trials enterprise to achieve the greatest benefit from the standpoint of both subject protection and data quality. This is part of a broader initiative within the agency: The critical path initiative, which also is very much focused on trying to streamline processes in a risk management-based fashion. This is an area where we have solicited public comments and public information with the intention of providing a synthesized list of those comments and the opportunities or areas in which streamlining may be possible, based on those public comments.

But it extends as well to GCP and our oversight of clinical trials. We’re trying to apply risk-based approaches internally, within FDA, in the way we develop assignments and the way we choose sites for inspection, in the way we talk with industry about study monitoring and study oversight. Fundamentally, when we’re talking risk-based approach, the concept here is some sort of analysis of risk goes on prospectively during the developments of the study and development of a monitoring plan. By corollary, a risk-based approach would say, You’re going to put more of your resources into those areas that are of higher risk than you’re going to put into those areas of lower risk.’

Question: What are other big areas and hot points that you’ve been speaking about in FDA updates?

Lepay: There are a few other areas also in the forefront and one is the international. At that level we certainly recognize the positive contributions that GCP harmonization has made between ourselves, Japan, and the European Union since the advent of ICH [International Conference on Harmonisation]. The recapitulation of some of those successes now in the device arena, as harmonized standards are also being embraced, not only in drug and biologic studies, but also in devices studies through harmonization efforts there.

But a lot of our efforts are being directed as well, to the extent that we have resources to do these sorts of things is working with international or foreign regulatory authorities to assist them in capacity building. We try to assist them in putting into place internationally recognized standards, as well as mechanisms to be able to ensure those standards are implemented and enforced. So we’re working with a large number of governments in the world who are interested in developing their own GCP review or GCP inspection unit. We’re also working quite closely with the World Health Organization (WHO), which in October should be coming out itself with some implementation guidance on GCP that is fully harmonized with other venues, such as ICH, which we have worked with, but which WHO will provide more directed implementation information.

We certainly recognize that the pharmaceutical industry is ever globalizing and information that is coming to FDA as to other regulatory authorities is not coming from within a single country. And we have to find ways to be sure there are real-time systems to ensure the quality not only for us when it comes to FDA but also for subjects who are participating in those trials.

The other big issue we’re trying to work through is to increase consistency across government and to work more closely with other government agencies, particularly those within our own department, be that the OHRP, the National Institutes of Health, the Centers of Disease Control and Prevention, the Office of Research Integrity. As we are now working to develop guidance in these areas, we’re also working to share our thinking as well as our contributions to these guidances from one agency to another.