For the past several months, the FDA has been widely criticized by Congress and others for not doing more to crack down on the New England Compounding Center, the now-bankrupt pharmacy tied to a nationwide outbreak of fungal meningitis that has led to 53 deaths (see this). Since the scandal broke, the FDA has argued various court rulings limited its authority, although critics maintain the agency has, in fact, been able to pursue violators, notably compounders that effectively mass produce medicines without individual patient prescriptions and ship out of state. Since early January, the FDA has responded to the pressure by inspecting 44 compounders (read here) and issued 31 reports (look here) detailing a host of violations, and follow-up actions are expected. Clearly, the agency is devoting more resources to a problem that has caused one of the worst public health crises in decades, and agency officials acknowledge that more could have been done sooner to thwart the NECCs around the country. We spoke with Janet Woodcock, who heads the FDA Center for Drug Evaluation and Research, and Howard Sklamberg, who heads CDER's Office of Compliance, about the issues...
Pharmalot: What are you finding so far at the (44) pharmacies you’ve been inspecting?
Sklamberg – Those are in a couple of categories. A majority, about 30, are inspections we did that are based on a risk model. One of the issues with compounding is because firms don’t have to register with us we don’t know right now the universe of firms out there and what they produce. We have fragmentary information about firms, based on past interactions with firms, based on reports of illnesses and other events, recalls and things of that nature. So we identified about 30 firms to inspect.
Pharmalot: If you don’t know what they’re doing, how do you know which ones to inspect?
Sklamberg: We looked at the information we have.
Woodcock: The ones that rose to the top…
Sklamberg: We wanted to identify firms that are high risk, so that would include a few categories and combinations of factors. Their history – firms that have a history of problems that we observed, adverse events and products they produce. We looked at firms that produce riskier products, such as sterile injectables. And then as far as what firms are producing. We researched the Internet. The inspections are still ongoing. And then there are an additional set of firms that we found out problems during the course of these couple of months and we inspected those as well.
Pharmalot: There seems to be a lot of confusion and debate about the FDA’s authority. When I talk to people who say they know FDA law, what I continue to hear back is that FDA really does have –and has had the authority – to do more about compounding. And I know the FDA has said ‘No, we really don’t because of a couple of different court rulings and we need this straightened out.’ What is different today that stopped you from doing this two, three or five years ago? You’ve had the ability since January 1 to inspect however many pharmacies. Why hasn’t the agency done the same sort of thing in the past?
Sklamberg: First, I think the way to answer that is to provide a little bit of background about what the agency did in the past. The legal landscape as you mentioned is complicated…. I could find five people who would have five different interpretations (of court rulings concerning FDA authority over compounders)…. The statute we have now divides the world into two categories – traditional compounding pharmacies – it doesn’t use the word traditional - and have a venerable history and perform a valuable function, starting with the mortar and pestle years ago, and providing drugs for people with individualized needs. It could be different dosages required, different concentration for special needs. And then there are basically manufacturers. So you have this middle category that grew up over the last couple of decades, which is basically what has been happening in hospital pharmacies. And if you go into a hospital pharmacy, you’re going to get sterile injectable drugs and they have to basically take a certain drug and put it in an IV bag. …. That had been done, historically, by hospitals and now it’s being done by a whole bunch of firms.
So the dispute, where people have differing opinions, is what legal category do those firms fit in? Some of the firms might say ‘We are a compounding pharmacy, even though we don’t get prescriptions for individual patients and even though we sell across the country in large volumes of products. And that’s illegal to you.’ The problem with that is if those folks are operating under that legal regime and they’re regulated by states, the state law governing it, is not made for mass production of pharmaceuticals around the country… What happened is that we as did inspections over roughly the last 10 years, we would do inspections based largely on reports of problems. We’d go to a firm and we would encounter resistance from firms who would dispute what legal category they’re in. Just as a statistic – the agency as a whole since 2002, occasionally we would have to get administrative warrants. So when a firm tells us they restrict our ability to inspect. They say you can’t inspect or can’t look at certain records or can’t do a full, complete inspection. We have to go to court and get an order from a judge, the Justice Department has to get an order from a judge. Since 2002, half of all the administrative warrants FDA has gotten across all product areas – from foods, devices, drugs – were from compounding pharmacies, which is truly astonishing. The universe of warrants we got in that period is roughly 25 or 26 something like that, since 2002.
When we inspect Pfizer, there’s no dispute whether it’s a full cause inspection or what your authority is or whether we can inspect the scope. They might disagree with the results of the inspection or what actions we take, but it’s the same basic set of rules. Here, what we find with these firms is there is a dispute as to even whether we can inspect and get in the door to look at their records, whether GMP would apply to them. So they’re saying ‘Why in the world are you talking to us about GMPs when we’re not a drug manufacturer?’
Pharmalot: So these 44 (compounders) that you have inspected, are you inspecting them against GMP standards?
Sklamberg: We’re inspecting them to GMP standards, though we have to evaluate after the inspections are over before we take any enforcement action and which legal category they’re going to go into. But what I’m explaining is that the history and how these inspections have gone the last 10 years is totally different from the way typical drug inspections have gone.
Woodcock: This is no way to regulate an industry. Sure, we could have gone out and done more inspections like this and battled each one in court. But there’s 28,000 compounding pharmacies of any type and we don’t know who’s who, because they don’t send us anything or tell us. So how would we regulate that industry when we go there and have to get a warrant from a judge to walk in the door? You could say we could battle in court and get in the firm but what about the other 27,999? We have to have a scheme – these firms we regulate or we don’t.
Sklamberg: To effectively regulate anyone, you need to know who they are, what they do and what rules apply before you even get to how well you do the inspection, how well you do the enforcement..
Pharmalot: Did you need warrants for the 44 that you visited this year?
Sklamberg: We have encountered some pushback. Since the fall, two warrants.
Pharmalot: I would imagine some of these firms are less likely to push back because of the publicity over NECC..
Sklamberg: Yes, that’s true. But just to give you an example. We got a warrant on a firm called Wedgewood. I think it was January. So just think about that. We had all this stuff going on since the fall and the spotlight on it, a tragedy and we had hearings. And we’re still getting resistance.
Pharmalot: A cynic would say 18 months ago or 36 months ago, theoretically, the agency could have gone to three dozen other compounders and knocked on their doors and decided to say we want to inspect and look at GMP issues, which you’ve started to do this year. You could have done that, right?
Sklamberg: Mmm-hmm..(nods yes). I would say when we were inspecting… We did inspections that were reactive in the past. We faced this legal environment where we were arguing over the very basic ground rules and the very basic ability to do the inspections. We were dealing with a landscape that shifted legally during this period a whole bunch of times. There were a series of court decisions that changed. And as we were, in fact, working on those inspections and the oversight of those particular firms, the firms themselves, even aside from warrants, were pushing back on our authority... We had a judicial ruling quite recently that took a bite out of our authority in respect to Franck’s.
Woodcock: In Franck’s, it was polio in ponies and blindness, right? Two different outbreaks – there was harm. A lot of ponies died. They were traced to this pharmacy in Florida and it was regulated by the Florida authorities. And yes we still lost some of our authority (back story here).
Pharmalot: As a result of these 44, what will occur with the next 44? So far you’re getting a chance to inspect and issues on inspection reports. What’s the next step? Will you take enforcement actions? Are you confident you can do that based on what’s transpired?
Sklamberg: We are, as we get inspection results in, we are in fact evaluating for appropriate enforcement and compliance action. We will do what’s appropriate using the authorities that we have. I can’t predict how the firms will react. I can’t predict how the courts will react. We are going to try to use the tools that we have. There have also been some recalls during this period. An important is that we have partnerships with the states.
… The total number of people in CDER is .. about 3,200… you think of the multiple there. The way we’re able to do it with respect to drug manufacturers - and do it well - is through risk models. With the Innovation Act that passed, we’re ramping up our risk models to get more and more information where we have to inspect more often and where we have to inspect less often. You can’t do that well when you don’t have the information. You can make educated guesses and you can obviously react, but you can’t really have a well thought out program that’s going to target the riskiest firms.
Pharmalot: And where are you with that one compounder that forced you to get a warrant?
Sklamberg: .. I don’t want to talk about specifics.
Pharmalot: What I’m wondering is that if you could do that now, you could have done it before. If it could have been done before, what’s prevented the agency from continuing on that course?
Woodcock: We could get totally tied up in lawsuits and we would have to stop inspecting the drug industry. And that would be great, for some people. Any time we have to go to court, we have to get warrants, we have to do all these things. It isn’t to say we weren’t doing it before. It was done for cause. During those 10 years, we were getting court rulings partly because we were active in that space. So nothing would prevent us from having ongoing reactive programs.
Sklamberg: There is, realistically with the government, limited resources. We made this a top if not the top priority for the drug inspection program over the last few months. Those folks from around the country who are doing this and were trained specifically for this, are not doing a whole bunch of other things. And while they’re doing this can I assure you they’re not missing something else? So the agency can always choose to target a specific thing as opposed to something else. And when we go through this process and have the resistance and have people having us get warrants and challenge our legal authority, it’s a bigger resource expenditure and bigger opportunity cost for the agency.
Pharmalot: Is that the reason the agency didn’t go the next step with NECC?
Sklamberg: I would say NECC has a long history and I don’t want to talk about that.
Woodcock: I was here in the late ‘90’s… we did a huge amount of work and set up a program. We went for five years and there was a court case, a court ruling that said we couldn’t do it that way, or something like that. And we had to go back and said okay we set up a program that would be a regulatory program and wouldn’t just be reactive… When we get a court case that set us back because it said we couldn’t do it that way, how are we going to do it? So sure, we could go after individual ones here and there, but we couldn’t predict… what the next outbreak might be. We’ve had incidents since the NECC and we didn’t know these folks would have products that were contaminated… .. In the late ‘90s, we got ourselves, got staff and put together a program and thought about the guidances and standards that would apply and had meetings. And then in 2003, we got this court ruling, which I never did fully understand but it said that we couldn’t do it that way… It was the advertising provision and said the whole thing went down or maybe or maybe not… but then we had two different courts in the country with two different statutory interpretations of the same thing. So we did try to set up programs.
Sklamberg: The backdrop is not only did the law vary, but it shifted over this period in different parts of the country and the state laws vary. And we didn’t have the inventory and the knowledge of what the firms were making. So you put this together and you can’t make an intelligent program. You can react. But you can’t make an intelligent program.
Pharmalot: So if we distinguish between the comprehensive or holistic approach from a reactive approach…. You’re saying it was hard to make that sweeping effort to pick up problems?
Sklamberg: The law says the agency can take action when there’s adulterated product or unsanitary products. The whole reason GMPs developed in the first place is if you wait til that point, its usually too late. So what that’s going to legally require is you find out you go to Ed Silverman’s firm and find the product its adulterated. You gotta test. If that test is going to show something in there by that time, it’s a good chance someone is already sick, which is why GMP’s developed in the first place, so we can have a prophylactic set of rules that would prevent that from happening. You’re right. The agency can do reactive inspections to be lucky enough to find the adulterated product before it hurts somebody.
Pharmalot: Using that logic, the agency could have used this high-risk approach a few years ago, which its doing this year. You’re saying it’s not necessarily comprehensive, but so far, the agency has captured a few dozen problems.
Woodcock: These all have to be registered by the states. They’re state pharmacies. So the states have a responsbiliity.
Sklamberg: One thing Congress tells us in the Innovation Act, we want you to inspect based on risk. We want you to consider additional information when you inspect. We want you to target your resources toward high-risk firms. We can put together a very basic model for compounding, but it’s going to rely on information we obtain reactively from firms. Firms we’ve inspected in the past, from other web sites. From other fragments. From people reporting harm. But we don’t have information without legislation to develop an intelligent comprehensive risk model we would need to develop a compounding inspection program.
Pharmalot: What’s the basic information you want?
Woodcock: Are they making a prescription for you or are they making a 6,000 vial lot and shipping them all over the United States.
Pharmalot: Are you using that metric now? What are you using?
Sklamberg: We take an estimate but when we go into some of these firms, we don’t know what we’re going to find. We may find a firm is 100 percent prescriptions or we may find it’s zero. We may find they’re making a whole bunch of sterile injectables and some stuff that may not be on their web site. We may find that they’re not. We may find they have an up-to-date clean room. We may find out they’re not.
Pharmalot: So which high-risk factors have you been able to identify this year?
Sklamberg: We are using the information we have to do our best estimate of those factors. High volume. Types of products. Another factor we don’t have is that compounding pharmacies don’t have to report adverse events or harm. Pfizer reports harm, so we’re able to look at a facility at a large firm, we’re able to say this firm has this pattern of adverse events, and this firm makes this products and has a history of its facilities and develop a risk model based on that.