FDA senior advisor discusses GCP goals
FDA senior advisor discusses GCP goals
Look for new guidance on risk-based approaches
[Editor’s note: 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 (FDA) in Rockville, MD, provides Clinical Trials Administrator readers with an update on federal regulations and guidance governing the clinical trial industry in this Q&A report.]
CTA: 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 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 events, 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 Protection (OHRP). I think that would be, probably, one of the very large areas of focus for us.
CTA: 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.
CTA: In the meantime, what is it you need? Do you need sponsors to start sending in the information in a more systematic way that IRBs can read? What needs to be done?
Lepay: We’re starting to look at comments we received from that public hearing. I expect we will provide agency guidance in this area. But I’m not going to precede what we’re going to do in the way of that guidance. Obviously, when we issue the guidance, it will go out for public comments; and we’ll use those comments to further refine.
CTA: 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. There should be a critical path opportunities list coming from the agencies sometime fairly soon.
But it extends as well to GCP and our oversight of clinical trials. We’re trying to apply risk-based approaches internally, within the 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."
So this is a very fundamental sort of initiative that is going on at multiple levels. It’s going on internally in our agency and starting to develop communication between our reviewers — those who are involved in developing inspection assignments, the policy-makers in the GCP areas, as well as our inspection cadre.
CTA: What would you recommend clinical trial sites do to be proactive? Are there some models or tools they can find to do these risk assessments?
Lepay: There is some guidance available from the FDA. I don’t know if it’s directed to clinical trial sites at this point, because that is again part of a broader initiative than what we are in the process of undertaking. Our expectation is there will be more guidance developing out of the agency in specific areas.
CTA: When will there be more guidance available?
Lepay: I think about two years probably is the time frame over which we are looking at reviewing our GCP program, our bioresearch program of inspection, our processes by which our reviewers assess data quality and data oversight, and some of these risk-related issues to data management. I would expect it will be about a two-year time frame. That’s not to say there will not be meetings or dialogues with our stakeholders — I’m certainly expecting that throughout the course of it — but we have to do some of our internal analysis first, think about the kind of guidance we want to provide, and then start communicating more directly with stakeholders.
CTA: Now with some of the unfortunate media attention that has been paid to pharmaceutical clinical trials in the past year, like with Vioxx and some other drugs, do you have any plans to change the way information is accumulated and reported publicly?
Lepay: Again, I think this is not so much a GCP arena. I think we’re certainly working with groups on several levels. We’re working with industry, as well as the National Library of Medicine, and in the area of clinical trials registries, as well as making information available about clinical trials. This is something again that is being explored very much by industry. We are certainly part of that dialogue.
We have to work within our own authorities. Our authorities are largely in the area of clinical trial posting for serious and life-threatening diseases, but it’s also a broader dialogue to try to get more information out there. Most if not all of the FDA believe it’s important, in fact, for the public to know information that’s part of a clinical trial, whether that information is positive or negative.
CTA: 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.
The recapitulation of some of those successes now in the device arena, as harmonized standards also are 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 that 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, which is fully harmonized with other venues, such as ICH, which we have worked with, but which WHO will provide more directed implementation information.
We worked with the Pan American Health Organization across the Americas to, again, work with those countries that have or are developing inspections, so there’s unified guidance from the Pan American Health Organization on inspecting clinical trials.
So 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 Office of Human Research Protection, the National Institutes of Health, the Centers of Disease Control and Prevention, or 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. We have certainly heard over time how information coming to investigators, to sponsors from government may not all be as consistent as they would like it. So we want to be sure, at least to the extent that we can develop consistency ourselves in what we put out as government agencies, that that’s not going to confound the system for those that we serve.
CTA: Will that make things more efficient and cut down on paperwork for sites?
Lepay: There’s no question that our goal across HHS is to reduce paperwork where it’s not adding value. Those individual safety reports, as we discussed earlier, getting into the system from investigators and ethics committees in ways that are uninterpretable — to us that just adds useless paperwork to the system.
I think we can expect to see some important developments in the area of streamlining, in the area of using resources more effectively, in the international arena within the next year or two years, and it will involve stakeholder participation and process.
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