Basic Protections for Human Subjects in International research, The FDA Perspective:

Stuart L. Nightingale, M.D., Food and Drug Administration

DR. SHAPIRO: Okay. First of all, let me welcome Stuart Nightingale. Thank you very much for coming today. We very much appreciate it. Dr. Nightingale is Associate Commissioner for Health Affairs in the Food and Drug Administration. Heíll speak to us on the FDA perspective on the issues that weíre trying to address. Thank you very much for being here.

DR. NIGHTINGALE: Thank you. Iím very pleased to be invited here. I think the FDA has an important contribution to make to the work of the group. We do have a number of differences from others that youíve heard from. Iím going to try to describe what we do and how we do it. You have some background about FDA in general and what we do as an agency. I am going to try to provide basic information today, not to get too deep into some of the issues, but to tell you more of what the process is. But I will make a few additional comments about some of our involvement in related areas.

Basically, we do regulate the clinical trials when they involve products that FDA regulatesódrugs, biologics, medical devices, and other products. While our requirements are similar to OPRR/HHS regulations, they are not identical, and I will get into some of that a little later. But basically, a very major difference is that we have an inspection program that we use to enforce the regulations. And a major hook that we have in these, as far as studies go, is that unless the studies are conducted in an ethical manner, we donít accept them if they are studies submitted for approval of applications for licensing.

At the last meeting, there were some questions about FDA. One was, do we have information about the funding of foreign clinical trials? The answer is no. I think the secretary was going to get that information from PHARMA. What I can say is that there is an increasing number of foreign clinical trials that are occurring and this is reflected in the increased number of inspections that are occurring overseas.

In order to approve the applications, we have to have information that meets the criteria of the agency. And, therefore, when they are submitted to us, they are looked at for meeting our requirements. And as far as foreign data are concerned, it has to be whether the clinical trials are considered to be pivotal in showing safety and efficacy. And it is those trials that we inspect specifically to see if they meet our requirements.

We are not prohibited from approving a product solely on the basis of foreign data. This has occurred. We have approved products based on foreign data only a number of times with drugs. There is some variation across FDA in terms of whether or not the centers like to have clinical trials done in the U.S. as well as foreign trials. The Center for Biologics usually does require domestic clinical trials.

Of the foreign clinical trials that are inspected, only about half are performed under INDs. However, if theyíre not performed under an IND, they still must adhere to the same kinds of requirements that are we have domestically. The non-IND studies are accepted as a basis for showing stage and efficacy for approval with requirements are, we think, similar to ours but not exactly the same. You have some background on that in the handouts.

As you have seen, the Declaration of Helsinki itself has a special status for FDA. It is not just an international code, it is actually mentioned in our regulations and it appears there. And it is the international standard that we refer to if there is not an IND in place. So it is the Declaration of Helsinki or the domestic legislation/regulations, whichever are the higher standard.

Before going into further detail about the specifics about how we do our work, Iíd like to return to FDAís approach as compared to OPRR/HHS. We have process regulations and as a regulatory agency we perform compliance inspection to enforce them. We do not have an assurance mechanism. Instead, we have trained inspectors and headquarters experts who make site visits to assess compliance with the regulations. The same compliance program is used internationally thatís used domestically. This is actually true whether youíre dealing with an IND or non-IND approach.

We have what we call a Bio-research Monitoring Program, which has two purposes. One is to ensure the validity and reliability of the data that are collected, and also to assure the protection of human subjects of research. This program covers many different areas. Some of them are pre-clinical, like good laboratory practices. But there is a constellation of regulations that Iím going to talk about today which we informally refer to as good clinical practices. This is the complex that includes IRB regulations, informed consent regulations, clinical investigator regulations, the IND or the IDE, and sponsor monitor and contract research organization regulations. Some of these occur with guidelines, and it is this constellation that weíll be mostly discussing.

I also will touch upon some international harmonization issues, particularly a program called the International Conference on Harmonization, which is different from some of the things youíve heard about so far and I think is a major issue for the group to hear something about.

Now, I talked about the foreign clinical studies, the earlier slide, and showed that if there are two adequate and well-controlled U.S. studies there may not be a foreign inspection occurring at all. However, when the international study provides a basis for a drug approval, for example, and itís needed, then a study is done. Again, this is for pivotal studies.

With the IND studies, if there is an IND in place, the IND regulations, the IRB regulations, and the informed consent regulations are all in place. These, again, are the same domestically as they are internationally.

If there is no IND in place, then the foreign non-IND studies are governed by a variety of approaches. Basically, about half of the foreign studies that are inspected are non-INDs, about half and half. Clearly, they have to follow the same kinds of criteria in terms of well-designed and conducted, adequate and well-controlled studies, qualified clinical investigators carrying out the studies, and, to go back to Dr. Shapiroís earlier comment, they must be applicable to the U.S. population and practice. So this kind of determination is made by the reviewers looking at the applications for approval.

Then, of course, we have the Declaration of Helsinki with the special role that I mentioned at the outset. And then youíll notice below that we have the ICH Good Clinical Practices Guidelines which Iíll talk about later.

A very important part of what happens occurs before the inspector goes on a foreign inspection, and that is that the sponsors provide by regulation a variety of documents that assist the inspector when he or she actually goes on-site to the foreign country. The cooperation of the sponsor in providing information is extremely important because without this the FDA inspector will not have the information needed to compare on-site when looking at the raw data that exists. And the inspector will go with the case report forms and other data submitted by the sponsor and look at whatís happening on-site. This is an ideal list. It doesnít always occur with international studies. But this is taken care of on-site.

Particularly important is the fact that there is a written assurance given by the sponsor that the records exist, that there is access to the records granted to the inspectors, permission to copy records, acceptable dates and times for inspection are arranged, and a copy of the local GCP requirements is put forth. Again, this means that the inspector has to have national laws and regulations, local IRB or ethical review committee protocols, procedures, and requirements present to compare when the inspector goes on-site. There are, of course, other requirements as well. So all this is done before going there.

At the opening interview, the inspector will look for a number of things inquiring as to who, what, where, when, and how the study was conducted. Unlike a domestic inspection, the inspector will not present credentials, a badge, if you will, or a notice of inspection because this is a foreign country, they really are not conducting this under our jurisdiction in terms of a right to go in and do what weíre doing. However, as I mentioned earlier, the fact that the data is needed to be able to consider approval of the applications is a very potent force and gains entry pretty much universally so that weíre able to go in and perform our review.

The inspection itself, again like a domestic inspection, will look at the clinical investigator issues, how the study was conducted and supervised, it will look for protocol adherence, look at the data and the records that are there, and drug accountability. All the usual things that we do.

The inspection will verify a number of issues. One is the consent and the ethical review committee issues, making sure that the subjectís rights, safety, and welfare are protected. Now, we do not do foreign IRB inspections. So we get at the human subject protection issues like informed consent and how the ethical review was performed by actually looking at the records of the clinical investigator. But the records that we want to see include the actual information on the informed consent. The informed consent will actually have been sent as part of the package by the sponsor prior to the inspector going on the study. Whatís the ethical review committeeís make-up, who is on it, records of what they did and how they did it are all available that way.

So although thereís not an IRB inspection, there is a review of the IRB informed consent issues through the clinical investigator inspection. And by the way, this happens domestically as well but there is the addition of an IRB inspection also. However, the IRB inspections that are done in the United States are not tied ordinarily to pivotal data. So that the IRBs are inspected on some routine basis unless there are problems found with a particular IRB. So itís not really part of the constellation of the New Drug Application approval package. So the overseas in a sense is like the domestic in that respect, going for the clinical investigator that has the data that would be pivotal for approval.

This is just a summary of, I guess over the years, up to September of 1997, of the countries that we have done foreign clinical investigator inspections in. I believe this is for drugs only. You will see there are about 26 countries and the list includes developing and developed countries. There is, obviously, more involvement of the developed countries, but there is a broad spectrum. The mix is there. And there are, as I said at the outset, more and more foreign clinical trials occurring. So back in the early 1990's there were between 10 and 20 foreign inspections of drug trials occurring. The figure for 1997 that I have is 76. So this is part of a trend that is increasing in drugs and biologics, but I donít believe in medical devices.

This in a way is a slightly misleading slide. It talks about most common deficiencies of foreign studiesónon-adherence to protocol, inadequate records, inadequate drug accountability, consent problems. This is quite similar to the kinds of problems we will see with domestic reviews of clinical investigators. So, in a way they are similar. Some of the informal comments that Iíve heard from inspectors that have gone is that clearly a little more training of the clinical investigator might have helped in some of the non-adherence to the protocols, but, quite frankly, as youíre all aware, that same complaint has been leveled against the system here, that thereís not enough training and education for the clinical investigators.

This is what I promised you earlier as a slightly different issue, and that is that there is something called the International Conference on Harmonization dealing with drugs and biologics issues. It is an activity which is really not a conference, it is a series of working groups, with a steering committee and expert working groups, that has been in existence since about 1990 that is developing guidelines for safety, efficacy, and quality areas of the kinds of regulatory requirements that are needed for submissions for approval of products in drugs and biologics.

So far, there are about 45 guidelines that are under development and about three-quarters of those have been adopted by the tripartite groups involvedóUnited States, Japan, and the European Union. This is where about 90 to 95 percent of drug development occurs, so although itís three countries or regions, it represents a very major portion of the drug development areas. The secretariat for this is the International Federation of Pharmaceutical Manufacturers Association, that is the international trade group that PHARMA is the U.S. representative of. What is very unique about this is that it is a joint industry and government regulatory authority effort which involves, for example, in the United States, the FDA and PHARMA, and in Japan and the European Union, similarly, itís the regulatory authorities and their research-based drug industry associations. There are observers to this process that include WHO, the European Free Trade area, and Canada.

The benefits of the development of these guidelines are quite substantial. The idea is to reduce the need for duplicate pre-clinical and clinical testing. And this covers, as I said, safety, efficacy, and quality as major areas. It maximizes the efficient use of human, animal, and material resources, maintains high scientific standards to safeguard public health, that is not negotiating down in terms of the standards, and fosters a worldwide collaboration and communication on important scientific issues. I would say, in particular, the fact that you donít need to repeat tests is an important ethical precept in this, so by being able to accept data from foreign studies that are done according to the U.S. ethical guidelines. And by the way, these do include the Good Clinical Practices guideline, which is very similar and consistent with FDAís constellation of IRB informed consent, clinical investigator, and sponsor monitor regulations.

There is a global impact of the ICH on clinical trials. Consistency in trial design, a single standard for both conducting trials and reporting trial data, there is a shared understanding of how to analyze trial data and of clinical development principles. Getting at many of the issues actually that were discussed earlier with the group.

The Good Clinical Practice guideline that I mentioned is an extremely important one. It was agreed to by the three regions in 1996, it was adopted in 1997, and itís adopted through the Federal Register in the U.S. and the similar kinds of adoption mechanisms in the two other regions. It does provide for unified standards for preparation, for designing, conducting, recording and reporting, and archiving clinical trial data and information. And it provides a basis for auditing and monitoring of studies.

And what it does do is sort of set up a process-type requirement or guidelines that are very similar to all the FDA Good Clinical Practice requirements as well. So that, therefore, IRB and informed consent issues are quite consistent in this with ours. And frankly, the European and Japanese regulatory requirements increased really to reflect more of what we do.

And then, finally, you might think that this is elitist and only involves the drug development regions and countries. In point of fact, the ICDRA is the International Conference of Drug Regulatory Authorities; it is WHOís grouping of regulatory authorities worldwide. Well over a hundred different authorities are participating in this.

At their last meeting in 1996, the joint WHO member countries got together and came up with recommendations concerning the ICH. The first: Assist globalization of the ICH documents. Utilize the ICH guidelines when drafting WHOís normative global guidelines. That would be the guidelines that come out of WHO for things like Good Clinical Practices themselves, or Good Laboratory Practices, et cetera.

Integrate the ICH guidelines into WHO training and education. In other words, let all countries learn what is happening and incorporate those items in ICH that are the most relevant to their needs. It may only be the quality aspects, for example, of the ICH guidelines.

And then, finally, they said make ICH guidelines available on the Internet. This, of course, has occurred and they are widely available, both through the FDA, IFPMA, and others.

And I just mention this, to finish up, because I think itís a very important issue, especially with globalization. And while these are process issues primarily, and this is not competing with the Declaration of Helsinki, if you will, or the Belmont Report, it is extremely important as a process approach thatís becoming more and more accepted worldwide.

We think it is extremely important; and, certainly, the preamble says they are supposed to be updated to reflect current concerns. I would just echo what you mentioned about the Declaration or areas that clearly need to be worked on and improved. So, we are hoping that will lead to an improved process. All I will say about that, which is a little more than you did, is that what is happening right now is much more open than any other time the Declaration of Helsinki has been realized over the past many years; and that the medical associations worldwide are really jumping into this and offering their views as to what they think needs to be changed and why. What is really interesting about it is that I noticed that the UNAIDS group had commented on those, and I thought that was a rather interesting, somewhat surprising issue. Now, I understand perfectly why that occurred, and is, of course, very welcome. But it is an open process, and I think it is an important process. I think that when you are looking at the codes, the Helsinki really stands up as being an extremely important one, more so than some of the regional or national efforts I think in terms of its importance worldwide. Thank you.

DR. SHAPIRO: Well, thank you very much. Let me just ask a small question with respect to your presentation. You refer to inspected foreign trials. You mentioned a couple of times "inspected," and that let me think, well, inspected versus noninspected. Now, is any trial, which is going to submit data to the FDA for some purpose, required to be inspected or not?

DR. NIGHTINGALE: Well, the approach is --the policy is to inspect only those foreign trials that are submitted that would be pivotal to approval. So, there are lots of data on foreign trials in New Drug Applications, for example, at FDAóa great deal of it. But the ones that are inspected by FDA are those that are pivotal studies.

DR. SHAPIRO: Also, I think itís true from what youíve said that any new approval by FDA from trials abroad would have had at least an inspection.

DR. NIGHTINGALE: Yes, thatís right. And it would have been looked at with all of the various criteria that were mentioned in the regulation.

DR. SHAPIRO: Yes, thatís very helpful. Yes, Ruth?

DR. MACKLIN: I have a very specific question, but itís --Iím going to end with a broad point for the NBACís work. At various points, Dr. Nightingale, you referred to the informed consent problems, the informed consent process, inspection of the informed consent, the informed consent standards, etc. Now, there is something that comes up all of the time in the international arena, particularly when studies are conducted in developing countries--and this is both for WHO and UNAIDS. And it is the question of signing consent forms. I am not now talking about having a written form, because there is no country or region that says we should not write out the informed consent and present it. But in very many countries, unlike people in this democracy, and, perhaps, in Western Europe, people are very fearful of signing things. They are fearful of signing things because there has been a history of oppression; because they are afraid they are committing themselves to something; they donít know whoís going to sweep in, etc. So, the resistance to signing consent forms has led to a bone of contention, and people have referred to what they call the United States Standards/United States Principles and other high-sounding words, when what weíre talking about is putting a signature on a piece of paper. Now, my question for Dr. Nightingale is when you do these inspections and look at the informed consent things, does the FDA care about the signing of the consent form? Thatís the question. My suggestion to NBAC is: It would be very useful in the study of the international work to distinguish between ethical principles and standards, on the one hand, and procedures. I consider signing a consent form a procedure that documents that a process took place. And I would not like to place the notion of signing a piece of paper on the same level as an ethical principle. And, yet, when people look in the international arena and worry about adherence to the United States standards, they say, "Well, the United States has this standard of signing a consent form. And if we donít adhere to that, then we canít get our research approved, and then weíve got a problem." So, my question or suggestion to NBAC is, perhaps, there should be a way of clarifying this and distinguishing clearly between what are the procedural requirements in the U.S. regulations, and what are really ethical standards.

DR. SHAPIRO: Thank you. Thatís very helpful. Let me see. Iíll get back to you in a moment, Dr. Nightingale. But let me see if there are questions from the Commission, and then weíre going to take a break. Alex, do you have a question? Stuart, do you have a response for this?

DR. NIGHTINGALE: Yes, basically, itís interesting. We do have that requirement for signing informed consent. It is a process issue. Itís not an ethical issue, in the sense its principles, that I would agree with you on that, are ethical issues. However, the ICH guideline, now with Europe, and Japan, and the observers and all, also go along with this as an important issue that you need to have a signed consent. Now, I know what you are saying that there are certain cultures where you donít sign, or itís very difficult to do. What has FDA done about that? I have seen correspondence between FDA inspectors and headquarters staff addressing this to sponsors saying these are deficiencies. Have we ever allowed that to occur? I really canít give you the answer to how itís being dealt with. But I think itís a very good issue for the Commission to look at, because, clearly, there are cultures wherein even the individual is not empowered to do something like that. How you deal with that and ethical issues deserves some further review.

DR. SHAPIRO: Thank you. Eric.

DR. CASSELL: Well, I wonder how many times it happens that the FDA says, "We wonít accept this study. It doesnít meet the standards," or what negotiations take place. In other words, when inspectors go and do something, what happens when it doesnít go right?

DR. NIGHTINGALE: A variety of things.

DR. CASSELL: First of all, is that a common thing to happen?

DR. NIGHTINGALE: Well, there is a series of things. First of all, in domestic studies, the compliance program used by inspectors is geared and tied directly to what the regulations say. So, they go in and they look at whatís happening, and compare that to what should be happening. They also will look at protocols and procedures that are submitted as part of the application, and then they will compare whatís happening, just like an IRB procedures document, and see how it stacks up to what it was supposed to do. Then the actual field investigators usually fill out a form reporting on what the findings are. That is submitted to headquarters and final action is taken on the situation. And the kinds of things that can occur range from anything from a warning letter to prosecution, depending on what the situation is. You can stop a person from -- you can disqualify a clinical investigator, for example, through a procedure from participating in clinical trials again, or you can place restrictions on a clinical investigator. But when you --the actual site visits are classified as to whether or not there is no action indicated; whether there is voluntary action indicated; or whether there is official action indicated. But as I said, with the foreign studies, since itís a different situation, for example, the key issue for, say, a foreign clinical investigator, really relates to the sponsorís ability to have the data used as part of the application. So, itís a little bit of a different situation. But, of course, as an enforcement agency, we have a wide range of things that we do, and they are done, including prosecution.

DR. SHAPIRO: Let me ask a follow up question. How common is it that you disallow data, foreign trials, because you think they have failed to meet the requirements that you laid down, not only the scientific requirements, but requirements, for example, to protect human subjects that you have adopted?

DR. NIGHTINGALE: I really couldnít answer that here. And itís a very difficult one to --I think we would have to do a survey within the agency on that. And I --although I tried to be as brief as possible on some of these issues, thatís one that you really have to talk to different division directors, and see what the experience is.

PROF. CAPRON: Can we request that information then? You have 215 international inspections?


PROF. CAPRON: Is that right? Out of the 215, how many resulted in a refusal to use data because there had been a lapse in the human subjects protection standards?

DR. NIGHTINGALE: I would have to go back and --I could use that as an example.

DR. SHAPIRO: Well, we would appreciate information like that, if itís available to put together.


DR. SHAPIRO: Steve, then Alta.

MR. HOLTZMAN: Dr. Nightingale in his presentation said that the reasons for rejection of foreign trials were similar to those for rejection of domestic trials. And so, if we are going to seek this information, and we need to get it for the domestic as well. Alta.

PROF. CHARO: First, forgive me if this has already been said. I am suffering from multiple time zones.

DR. SHAPIRO: Caffeine is not strong enough to overcome this.

PROF. CHARO: It never is at these meetings. You need to have somebody come with the stuff that comes in an espresso machine.

DR. SHAPIRO: Yes, I have to remember that.

PROF. CHARO: I appreciate the procedural rules that apply. Itís the substantive rules about this study design that would or would not be applied by FDA that I am still confused about. Letís take both the AZT trials that were the subject of such discussion three or four months ago, and the vaccine trials that Dr. Macklin was talking about. Both are sets of trials that could not be pursued in the United States, because of prevailing norms of treatment. How would the FDA view the data from those trials were they to be submitted in the U.S., because a new application of that information had made itself appear in the U.S. context? Would the FDA be willing to accept data for trials that were designed that way, assuming that you had all of your various forms that had been signed, and youíd had various groups that had been consulted in the review process?

DR. NIGHTINGALE: Well, thatís a very complicated question, in a sense.

PROF. CHARO: Itís kind of a --I mean I thought maybe I had missed it, but itís kind of a bottom line --


PROF. CHARO: --in trying to understand substantively how FDA reacts to the foreign trials, as opposed to the procedural norms.

DR. NIGHTINGALE: Well, I hadnít said that. I think itís very -- itís the sort of individual -- it takes looking at the application, the trial, and everything that goes along with it, at the level of the division. So, itís not even so much as FDA perspective, itís --


DR. NIGHTINGALE: --whatís happening.

PROF. CHARO: But if we could --and I understand that you may not be able to commit anybody at the agency without having have them make this finding. But going back to those particular trials, in both cases, the fundamental dilemma is one that is analogous to the dilemma we face over and over on whether or not we ought to have minimum wage laws, where if people who are miserable ought to be allowed to work for 92 cents an hour, because itís the best thing they can find. I mean itís a classic dilemma of what to do against the backdrop of abject poverty. Have you observed FDA, either the Division of Biologics or the drug approval people (these are two different examples, one biologic, one drug)óreacting to this dilemma, in which they have the procedural reviews by the appropriate parties, they have got the technicalities of consent adhered to; and, yet, there is at the center of it a question about whether or not we are willing to allow people to be exposed to certain kinds of choices. Have you seen FDA react to this dilemma in the past? And, if so, how has it done so?

DR. NIGHTINGALE: I mean I have been present at debates about some of these issues, in a sense. And I think the people at FDA are enthusiastic that the Commission would be looking into some of these issues. But I donít think I could give you a definite answer about that.

DR. SHAPIRO: Thank you. Well, let me suggest that we take a break. Letís try to keep it to ten minutes. [BREAK]