Panel II of a Hearing of the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee - The Food and Drug Administration's Foreign Drug Inspection Program: Weaknesses Place America at Risk

Statement

Panel II of a Hearing of the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee - The Food and Drug Administration's Foreign Drug Inspection Program

REP. STUPAK: I'd like to call up our second panel of witnesses and ask them to come forward here in a few moments.

Dr. Gail Cassell, Vice President, Scientific Affairs, Distinguished Lilly Research Scholar for Infectious Diseases at Eli Lilly And Company; Dr. Marcia Crosse, Director of Public Health and Military Health Care Issues at the U.S. Government Accountability Office; Mr. William Hubbard, former FDA Associate Commissioner and current Senior Advisor for the Coalition for a Stronger FDA; Mr. Ben England of Benjamin England and Associates and fdaimports.com -- Mr. England previously held several senior level regulatory positions at the FDA; and Dr. Carl Nielsen, retired director of the Division of Import Operations within the Office of Regulatory Affairs at the FDA.

We'll give everybody a minute or two here to assemble before we do the oath.

Looks like we have everybody available. It's the policy of the subcommittee to take all testimony under oath. Please be advised that witnesses have the right under the rules of the House to be advised by counsel during your testimony. Do any of you wish to be represented by counsel? Shaking of the heads indicate no; therefore let's take the oath.

(The witnesses are sworn in.)

Let the record reflect that witnessed replied in the affirmative. You are now under oath. We will now hear a five minute opening statement from each of our witnesses on the second panel. You may submit a longer statement for inclusion in the hearing record.

Dr. Crosse of the Government Accountability Office, shall we start with you, please?

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REP. STUPAK: Thank you, and thank you to everyone for your testimony today.

Mr. Hubbard, Mr. Nielsen, Mr. England, I believe you were here when the commissioner testified. What would each of you, if you'd just give me quickly, what would you each do if you were the commissioner? How would you have come to address this issue? Give me the top three things you would do, starting with you, Mr. Hubbard.

MR. HUBBARD: Well, first, you've got to know who's making our drugs and sending them to us. So you need registration. And I think you've mentioned that.

REP. STUPAK: Okay, that's foreign vendor registration program we're talking about.

MR. HUBBARD: You need to know everyone that's in the supply chain, all the way back to the pig -- to the pig farmer and his -- (inaudible) -- so at least we know who they are and where they are. That's, I think, number one.

Second, you need to get over there and look at all these facilities and see what you find because we don't know now because we don't go there.

REP. STUPAK: Okay.

MR. HUBBARD: And thirdly, I think as these gentlemen mentioned, you've got to have some sort of IT system to track it. And there are many more things you need to do, but I would put those three things as sort of the sequential first things to do to begin to get a grip on this problem.

MR. STUPAK: Mr. Nielsen.

MR. NIELSEN: I do believe IT has to be the first item, and there has to be funding. It's for the center, it's for the ORA.

Coupled with that, I would say number two is a functional organizational structure to deal with the issues at hand. And I do concur with what Ben said that there does need to be a separate entity. I also recommended that in my written statement that the foreign inspection oversight, border operations and oversight of the importers are all extremely related as far as risk. And I do believe a formation of an organization with the responsibility, funded and empowered, will provide solutions that will work.

And certainly, funding is still a big issue. But the funding needs to be attached to very specific events with articulated outcomes or expected outcomes.

REP. STUPAK: Mr. England.

MR. ENGLAND: I think there's two levels. One is, what do you do in the incident event? And I think that FDA is doing probably the best they can in trying to figure out where this product came from.

REP. STUPAK: This is on heparin you mean.

MR. ENGLAND: Right, to the specific heparin situation. I men, I disagree entirely with the theory that the inspection couldn't have had a significant impact in preventing this. I mean, I think if we could keep in mind that the inspection that we have now seen the 483 for occurred after the adverse events. And we still saw the conditions we saw. I mean, if FDA had been there prior to the adverse events during a pre-approval inspection, I'm inclined to believe that they would have seen a facility in even worse condition, in which case they would not have been in a position to be a source for this product.

REP. STUPAK: Okay.

MR. ENGLAND: So I think that the foreign inspection component is absolutely critical and it has been for years.

I also think that because of the mandate that FDA has to inspect the domestic industry every two years, I think FDA ends up trying to reach that mandate to the exclusion of the foreign market where it doesn't have the mandate and that it tries to do the best it can.

Most of the foreign inspections, in reaction to the idea that, well, even some foreign inspections were conducted and yet there was still contaminated product that came from perhaps those facilities, those inspections probably were two-day pre-approval inspections. The inspection we just saw at this facility regarding heparin was probably a five-day, I believe, inspection, far more deep. In the United States, that would have been a 10 to 12 to 16-day inspection.

And maybe that's not necessary to find the appearance of a violation and prevent that product to come in. But I would agree that a two-day inspection may not be able to produce this, to be able to find these kinds of problems.

So I think inspections -- but if we don't have the IT, it really doesn't matter what you do. You can't put together a risk-based program. I mean, even Customs work, the integration with international trade data systems, FDA still has to have data to bounce that data against. And without integration on the FDA side, you can go one place to get the data, but you can't really do much with it anyway.

REP. STUPAK: We're going to have a hearing next week, actually next Tuesday, on heparin. And I don't mean to belabor the heparin point, but, Mr. England, you brought up, and I think Mr. Melancon brought up, too, it's our understanding that this plant was never inspected, but Baxter did inspect it. Where is the corporate responsibility here? Why would Baxter inspect it and we still have all these problems that were highlighted in the document that you indicated with the FDA inspection?

I mean, if the FDA did inspections, wouldn't that also pressure Baxter then, in this case, to make sure that what they're doing as inspections are robust and complete and safe for the American people?

MR. ENGLAND: First, I don't know that I want to get into a liability question because I just don't. I have not seen any of the documents from those inspections. I have no idea what the scope of the Baxter review was.

REP. STUPAK: It's called responsibility and liability then. And there's some responsibility there, right?

MR. ENGLAND: I mean, I think the importer of a product has the responsibility to ensure that the product they're importing is in compliance with U.S. law. In the case of an API, that means that they should be able to make some assertions as far as the product having been manufactured in compliance with GMPs. That's just from a federal perspective.

REP. STUPAK: If the government system broke down here because it was never inspected and if the private company that's making the profit here broke down, the American people are truly just at risk then. I mean, there's nothing we can do other than a re-overhaul of the FDA.

MR. ENGLAND: I believe that that is not an overstatement.

REP. STUPAK: Mr. Nielsen, you're trying to jump in there.

MR. NIELSEN: And coupled with that, as far as responsibility is, I do think there has to be a reevaluation of the good manufacturing practice regulations. It is not a new topic for the agency for a rewrite of the drug GMPs.

REP. STUPAK: Any idea the last time that was rewritten, Mr. Hubbard?

MR. HUBBARD: Two thousand three -- they're relatively new, but they're very general. They don't really deal with some of the problems that arise here.

REP. STUPAK: Dr. Crosse, we're focusing quite a bit on IT here with these questions I was asking. But yet on page 12 of your testimony, you talk about the foreign vendor registration verification program. And I was pressing the commissioner to try to give us an idea of when it's going to happen. And it says in your testimony, "FDA currently plans to award this contract in May '08." But yet you cite for an example, "The agency has not yet established the criteria it would use to determine the establishments would be visited for verification purposes to determine how many establishments it would verify annually."

Does it look like one of these things where the FDA is going to award a contract and yet not have the criteria before we even have the contract?

MS. CROSSE: It's not clear to us. This is something that's very new, and it was difficult for us to get very much information about it. Our understanding yesterday after we submitted this statement is that it's now been pushed off to June but that they do still intend to move forward in trying to establish some program. It's not clear to us what exactly is going to be done under this contract, whether they're going to perform on-site inspections of a certain proportion of facilities, how they're going to select those facilities, what's going to be involved in the verification, what information they're going to get beyond just is there a building there and do they manufacture drugs. It's really unclear at this point, and we were not able to get very many specifics from FDA about it.

REP. STUPAK: And I think Mr. Nielsen or Mr. England mentioned the shared establishment data service. That would have to be dovetailed into this also, would it not? I mean, FDA needs to know about it, but Customs needs to know what's coming in and what's coming in. Could you probably get the information quicker by going to Customs? At least they know what's coming into this country.

MS. CROSSE: Well, it's not clear how this backtracks to a particular facility that's manufacturing a drug with information that's coming in from Customs. Again, sometimes they have difficulties linking back in that way. And as I said in my statement, there's not yet agreement that this (said ?) system, the unique identifier that would be used with Customs is going to move forward because it requires the agreement of a large number of federal agencies, and they all have to fund the changes to their systems to make this work.

REP. STUPAK: My time's running out, and I think we'll probably go a second round because I enjoy this panel, and you have good suggestions.

But Dr. Cassell, if I may, on page 56 of the Science Board Report, there's a recommendation, and I pressed the FDA last time and never got a commitment so let me ask it this way. There's a recommendation at the FDA to develop a comprehensive plan that includes how and when the agency would respond to the recommendation. Has anyone from the FDA after you submitted the report got back with the Science Board and said here's what we're trying to do, here's our recommendations to implement? I mean, you gave them a blueprint on how to fix things. Have they worked with you to try to get it implemented or to say here's our priorities? What has happened after you submitted your report?

MS. CASSELL: To my knowledge, they have not gotten back to the Science Board. I'm only one member of the Science Board. They could have talked to others to share with us specifically how they would propose to implement the recommendations. I'm aware, however, that they have begun the review of ORA and NCTR that we recommended. And I am aware that, you know, a chief scientists has been appointed, although that was not in relationship to our recommendation but rather, it seems, the -- (inaudible) -- legislation that also recommended the chief scientific officer. Outside of those three things, I'm not aware of other activities that are ongoing.

REP. STUPAK: And as the chair of the Science Board, your Science Board members are available to help the FDA implement these recommendations, are they not?

MS. CASSELL: Well, I'm not chair of the Science Board but rather I was chair of the subcommittee that conducted the review.

REP. STUPAK: Right.

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REP. STUPAK: We'll go to a second round of questions, but go back to OCI on KeyTech, the OCIs were doing their job and they were asked to do their investigation and they were denied the opportunity, and they got frustrated, and basically are leaving the agency because they're not allowed to do their work in some cases. It's more of a structural thing.

And, you know, we were talking about issues of mandates of the FDA. We, this committee, or our Energy and Commerce Committee, we don't mean to micromanage the FDA on mandate lots of programs, but without quality leadership at the top of the FDA, we must resort to the mandates as a trigger, or a triage, or emergency patch to correct some of these most pressing issues. And that's why I was pressing the Commissioner today on BPA or on the discussion draft of the legislation we have floating because we want to move that quickly to try to give them the resources they need to do their job and to help reconfigure the FDA so we can get at this issue which is getting to be a growing problem.

Along those lines, on our legislation -- Mr. Hubbard's mentioned it, a couple of the others have mentioned it -- if you have some suggestions on things we should improve upon that draft, we are moving on that bill fairly quickly. So if you have anything further, please get with us.

Doctor Cassell, you indicated new drugs, new biologics, the genome, that active pharmaceutical ingredient, other things we're going to be relying upon, given the multitude of additional foreign firms. And you're going to see places like Thailand, Vietnam and Malaysia are expected to start making drugs and will likely export to the U.S. If we're grappling with the problem right now, and all these other countries come on line and new medical discoveries come on line, how are we ever going to be able to keep ahead of the curve?

MS. CASSELL: I agree. I think in some respects, it's almost mind-boggling when you think about the degree of the complexity of the products increasing, and especially in terms of safety issues as it relates to biologics. They're not as easily manufactured as you -- we all know and appreciate -- as small molecules.

So, I think, again, it goes back to assuring that we have the latest scientific evidence for the decisions that would be made; the best people making those decisions; the technologies in place to improve upon our inspections.

We mentioned in our testimony, I think -- and some of the discussion on the 29th of January, that the Department of Defense, Department of Homeland Security has invested millions of dollars in their information technology for doing data mining on a lot of different topics, particularly as it relates to biological weapons. And they've also developed very sophisticated methodologies for detection in the field of both chemicals and biologicals.

These same methodologies could be applied, I believe, to inspection, in terms of quality control, as far as potential chemical and biological contamination of our products. I don't know to what extent, you know, the FDA has tried to leverage those technologies and apply them, or bring them on-line.

But, I think we have to begin to apply newer, better technology, as well as just be sure that the individuals that are performing these functions are up to date in terms of what new science is available to help resolve a problem.

REP. STUPAK: In the last panel, we talked a little bit about this heparin and the altered drug. And I think Mr. Burgess brought up the fact that it was -- could have been for criminal or a deviant mind, but whether it's melamine or heparin, I don't think we see that. Is it really economic pressures? -- putting pressure on to find a cheaper substitute, as melamine, you know, as supposed to high protein, but it ended up --

Why would you alter a drug? Anyone care to speculate on that? I mean, I'm sure it's just not -- it's just not criminal. I mean --

MR. HUBBARD: They've got very good chemists over there. And the best example is, you know, pharmaceutical-grade glycerin is fairly pricey, and antifreeze you can get down at the dollar store. And so, you know, it tastes the same, looks the same -- it's just that one will kill you, and one's perfectly safe.

So, you know -- and people just don't care about where it ends up going. And, of course, a lot of children in Haiti, in Panama and other countries died because someone didn't care.

REP. STUPAK: I mean, I think also -- if I could, quickly, that, my understanding was that there was a problem with some of the pig intestines --

MR. NIELSEN: Pig stock, yeah.

REP. STUPAK: Right, the pig stock -- right.

MR. NEILSEN: So, they were running into a capacity problem --

REP. STUPAK: So, they were looking for alternatives.

MR. NIELSEN: So, it wouldn't surprise me that, under that pressure, that there -- that there was some intent to find something to put it in there.

REP. STUPAK: I think --

MR. NIELSEN: In fact, I'll just quickly, the APIs that FDA approves --

REP. STUPAK: Right.

MR. NIELSEN: -- when everything goes into a source -- inspection and finds an API facility to be fined, the value of their product on the world market doubles overnight. So, right, now you've got the incentive. You've got a cushion between guys who -- people who are not approved, and people who are. And it's a lot cheaper sometimes to buy the product than it is to make it.

REP. STUPAK: So, instead of using the pig intestines here in heparin and I use something else, do I have to get FDA approval to make heparin in this manner or method? Or can I just say, oh, no, this is okay, because the end result is it's still heparin?

MR. HUBBARD: You're supposed to get FDA approval but, believe me --

REP. STUPAK: But, they don't.

MR. HUBBARD: -- you wouldn't get it for that. (Laughs.)

REP. STUPAK: Right. Is that common -- I mean, that we make substitutions to a formula that we use?

MR. HUBBARD: No, you can't do that. You have to at least -- well, it depends on the severity of the change. If it's a very great change, you have to get FDA approval. If it's a minor change, you have to at least tell FDA so that they can object.

MR. ENGLAND: I mean, one of the things to keep in mind, even on the counterfeit API, like the carbamezapine --

REP. STUPAK: Right.

MR. ENGLAND: -- it has to pass the test. Even if it's nominal, it has to pass the identity test at least. And so, it has -- it's going to have to look like that, or else at least the safeguard at the end user, or the finished-dose manufacturer will detect it.

REP. STUPAK: Okay.

Mr. England, you mentioned the import alerts. In fact, as we were -- this panel was seated, we've had three import alerts just come out from the FDA on some foods and other issues here. You're not a big fan of it. They don't work, you said. Explain that a little bit further.

MR. ENGLAND: Well, there's a couple of things to --

REP. STUPAK: And what shall we do in --

MR. ENGLAND: Right. And what solutions, perhaps, there might be.

I mean, as far as -- as far as them not working, I think that's an IT issue. I think that there was evidence last year where products that were -- that should've been subject to a number of different seafood alerts, a reporter rather quickly found 200-some-odd shipments that had gotten through the system and never been tested by the FDA, had never been stopped, even though they were subject to the criteria.

You know, and so when Carl was asked in the press as to whether or not that surprised them, of course the answer is, no. I mean, there's been holes in that system forever. So putting up an import alert is not an answer. It certainly is a piece, and it certainly does put information out there.

I think another aspect of it is that I'm not so sure that FDA has the authority that it exercises sometimes in these countrywide alerts. And so, you know, if Congress wants FDA to have that, they -- that's something that they may want to consider clarifying.

But in many respects, the import alert is supposed to be just guidance to the field. And it really ends up acting as a regulation. And I think that's where the agency begins to run into some particular -- potential liability. They've been challenged a number of times, and I don't think they've -- I don't think FDA's won yet, when they've been challenged on an import alert, as to whether it's legitimate.

I mean, to fix that -- those -- some of those problems, I think FDA -- in fact, Bill Hubbard, when he was -- when he was in the agency and -- along with us, we went through a process of trying to establish what we called an "an attention without physical examination rule," that basically described these are the -- are the kinds of evidence FDA might really on to issue an import alert. Here's the kinds of evidence we might rely -- might seek in order to overcome it.

And at least you created a regulatory regime to manage it, and then your guidance could be your alerts that are just applying the reg. But there is -- the number of those kinds of situations, both IT and, I think, also the way that the authority is structured, that the agency is vulnerable and it's not as effective.

REP. STUPAK: Let me just -- and anyone can jump in on this one -- but maybe Mr. Hubbard, more directly at you.

I'm not a big fan of PDUFA, where you -- use a user fee to get your drugs approved, with the new drug applications. But from a practical point of view, PDUFA has worked. I mean, you've given them money; the drugs are approved by such-and-such a timeline. And I'm not talking about the safety or efficacy of it but, I mean, we met those timelines given the resources.

And I know Mr. Burgess kept bringing up the tobacco issue. Again, they'll be given the resources. If given the resources, you know, with a clearly-defined mission, can the FDA -- and the Dingell bill -- Dingell/Pallone/Stupak bill -- the one we have out there, we have a registration fee that's going to be probably size-relative to fund this program -- can the FDA do the job if given the resources in a focused area --

MR. HUBBARD: Oh, I can --

REP. STUPAK: -- s in PDUFA, or a tobacco regulation, wherever it might be, as long as resources are there and they can -- can they attract the science people that we need to do the job in this country?

MR. HUBBARD: I think, absolutely. I think the programs that have been well-funded at FDA work well. You don't hear the criticisms about them. And the programs that are not funded well are the ones that everyone's screaming about.

The one problem with PDUFA is that it says to the OMB and the appropriators, there's a lot of new money flowing into FDA, so we can cut back on appropriations. And those cutbacks have occurred in places like imports and food safety, not in the Drug Review Program. So it's had a negative consequence, I'm afraid, in that sense.

REP. STUPAK: Sure. And in that sense -- like the new money coming into the FDA in the last budget, that's really from MDUFA and PDUFA fees. There's really not that much new money to take care of these shortfalls, and that's what we've got to guard against.

But it seems like the 71 million (dollars) we've been talking about to do the proper inspections is probably a small amount, and we can attract the science and the inspectors we need, provided we have a dedicated funding source, because I don't want to see an example like this panel has pointed out, where Homeland Security had the 650 inspectors -- got them right away right after 9/11, got them trained, and within two or three years they're all gone because there was not a dedicated funding source.

That's seems the -- Dr. Cassell, do you want to jump in on that?

MS. CASSELL: I think you're right to be concerned about that. I, like Mr. Hubbard, though, believe that given the resources -- with emphasis upon the right people, not just warm bodies, I think they can absolutely do the job.

The other thing that I would just encourage us all to think about again, though, is to encourage putting in place this external peer review, if you will, process because, to me, that would also help ensure accountability. And in the long-run -- I know it's just one more committee for FDA to deal with -- but if you look at -- at the NIH, if you look at CDC now that they have these external review committees in place, the peer pressure does play an important role in keeping things on track.

REP. STUPAK: My time is up.

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REP. STUPAK: If I can jump in just for a minute. You know, I sat through the '98 hearing when GAO testified again about the IT system. And it's been 10 years. Why is IT here such a problem to get our hands around?

I mean, it's not just FDA, it seems like IT just seems to be a problem that the government can't get its hands around, especially this one. We got, I think, seven different databases we're dealing with with the FDA on food and drug safety. Why has this been a insurmountable task that we can't seem to get to?

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REP. STUPAK: Mr. Melancon? No?

Well, thank you to this panel. It's always a very, very good panel. We enjoy it, and that's why I'd just like members just to go on and ask the questions.

I mentioned the three recalls, just while this panel was impaneled. We had, from China, snow fungus, which is mushrooms; from Vietnam, ginger; and from China, dried lilly bulbs. Those were the three recalls just came -- or alerts that just came in.

MR. NIELSEN: Not my clients. (Laughs.)

REP. STUPAK: Just thought I'd give you a heads-up. Just trying to figure out what do we do with dry lilly bulbs.

But, anyway, that concludes all questioning. I want to thank our witnesses for coming today, and your testimony. And thank you again.

And, Dr. Cassell, be sure you tell your committee, thank you very much for their work and expertise.

I ask unanimous consent that the hearing record will remain open for 30 days for additional questions for the record. Without objection, the record will remain open. I ask unanimous consent that the contents of our document binder be entered into record. Without objection, documents will be entered into the record.

That concludes our hearing. Without objection, this meeting of the subcommittee is adjourned.

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