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Over the past few weeks, the Food and Drug Administration has been criticized for some of the steps taken – and not taken – to combat Covid-19. High on the list was a decision to grant an Emergency Use Authorization to allow hospitals to provide a pair of decades-old malaria drugs, which were touted by President Trump, even though there is no evidence the medicines may be useful in patients stricken by the novel coronavirus. We spoke with Janet Woodcock, who heads the FDA Center for Drug Evaluation and Research, about this decision, as well as the steps her division is taking to maintain quality control standards at manufacturing plants and keeping advisory committee reviews on track. This is an edited version of our conversation.

Do you worry that hydroxychloroquine overuse threatens to undermine the standard FDA review process and the respect that the public has for that process?

Well, Plaquenil [the brand-name version] is an approved product that’s been around for 40 to 50 years and when clinicians started using it under certain circumstance and are still using it in all kinds of situations, even prevention. We approved the EUA [Emergency Use Authorization] for a Bayer drug that wasn’t approved in the U.S. and a couple of other hydroxychloroquine drugs during a time when there was tremendous demand and people with lupus and other autoimmune diseases were having trouble accessing the drug because of the demand.

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We were clear that an Emergency Use Authorization is not an FDA approval in any shape or form. We simply said it’s possible from the in vitro data this may have a beneficial effect and the benefits may outweigh the risks.

But you’re right. People see the Emergency Use Authorization and may misinterpret it, although the data we have shows there was widespread use of this for Covid-19 well before that.

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There’s this perception that the EUA was granted for political reasons, because we don’t have the benefit or risk information, and we don’t have trials for Covid-19, specifically. I’m wondering the extent to which that’s a concern. And how do you justify the EUA when you don’t have that information that we’d like to have?

Well, that’s what the EUA is for. We did an EUA for Peramivir if you recall for [H1N1] influenza [in 2009]. This was an approved drug, hydroxychloroquine, that is, that was being widely used off label. So if people want to misconstrue it as an FDA approval, they can, but that’s not what it is. It augmented supply. It was only directed toward hospitalized patients with Covid-19, where they could be monitored for any EKG abnormalities. But people, as you well know, will say what they say. It won’t affect the FDA approval standard and there are many robust trials going on for hydroxychloroquine and we’re going to find out whether it works or not in all the various areas in which it’s being used.

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If I asked whether you had second thoughts about the EUA, would you say ‘no?’

Given the circumstances, I would say we did the best we could.

Is there anything about the EUA that you would have done differently?

Well, I probably could have intervened to make it more orderly. I tried, but it was such a crisis situation. You’re asking about policy. The EUA is intended when there are interventions that are ‘needed’ in an emergency situation. And in this case, it allowed use of an unapproved manufacturer’s version of an approved drug. The Bayer drug wasn’t approved in the U.S. and we tested it. Otherwise, it could have been distributed although not by the government. It could have been distributed into the drug supply, but the EUA allowed the government to distribute it. … It applies to a couple of drugs. There was a big donation by Sandoz, which is approved in the U.S. and was put into the EUA, but only distributed to hospitalized patients for Covid-19. We were pretty clear about what was known and wasn’t known, that there were only some case reports and in vitro data.

Given ongoing quality concerns among some suppliers — there were reportedly quality control problems not long ago at the plant where the Bayer drug is made — is there anything you might have done differently? And how do you reassure the public that quality standards for manufacturing will be adhered to, regardless of an emergency situation?

Alright, well, the EUA was for a certain donation and we tested that and so did USP [the U.S. Pharmacopeia, an independent organization that publishes standards for manufacturing medicines]. So we’re confident that was adequate. And we didn’t just do standard testing. We did a lot of tests on it. As far as concerns for other products, we’re well aware of their histories and compliance status. We can put in additional steps and we do that all the time for shortages and for additional quality measures to make sure supply meets standards. Obviously, we’re not intending to let substandard, suboptimal products into the United States.

Obviously, the pandemic has delayed various things. What is the plan for reconvening advisory committee review meetings? And will you set priorities and how that will work?

Well, of course, we’re looking at doing remote or virtual ad comms. We’ve done some before. Right now, our virtual working is going quite well. Honestly, there are some complications if we have to do an adcomm, but we feel we can carry that out. But given the different pieces involved, we’re going to be judicious about whether we hold one or not. It’s a little harder to get a virtual adcomm together and have it function really well. But it can be done. … It will have to do with what questions we need advice on and how burning those questions are.

What have you done to ramp up for the expected requests for approvals for drugs being tested to fight Covid-19?

The hard part of this is [happening] now and we’re dealing with it. We have over 70 [different drug development] programs that we’re overseeing and we’ve had to turn around those protocols, let them proceed, manufacturing reviews. There are a number of manufacturers in this space who are scaling up at risk in the hope they will succeed and have an effective therapy. So we’re giving them advice. My point is that, before we get a successful therapy, we’re probably going to have done a lot of work in advance, similar to what we do for extremely promising drugs in other areas.

Led by the Office of New Drugs, we have a multi-disciplinary team across multiple divisions which is dealing with all the Covid applications, and similarly with pharmaceutical quality. They’re crashing on all these manufacturing alterations that are needed. Many of them are related to the supply chain for existing drugs, but some of them are related to scaling up for potential therapies [for Covid].

How are you maintaining the balance between approval standards and addressing the need for pandemic products? There’s been lot of talk about this issue.

It’s as critical as any time that we have effective therapies and this time is no different than any other time we have any other life-threatening disease, except it affects a whole lot more people.

As usual, you’ll have studies in very ill people that have mortality endpoints and we have a certain way of dealing with that, that’s a hard endpoint. And even a little change in mortality is really important. And the benefit-risk [ratio] is very clear versus pre-exposure prophylactics that healthy people will take, say health care workers, to prevent them from acquiring the virus. That’s a whole different circumstance, where most of the people, even if they’ve gotten the virus, may not get very sick. And so, the benefit-risk [ratio] there is different and you have to ask different questions. I don’t think any of this is new territory.

How soon can plant inspections — domestic and foreign — resume? And how do you compensate for missed inspections?

Well, we have authority where we can request information in lieu of or in advance of an inspection and we’ve been using that authority already in a number of cases. In some cases, other agencies have been into a facility and were able to get information from other inspectorates. But as this goes on, this becomes less likely because no one is traveling. It feels like forever, but it’s only been a relatively short time. For PDUFA and GDUFA [review dates for brand and generic drugs], we try to get the inspections done real early because we have to do them regardless of whether or not we’re going to approve the drug. We don’t put it off until the last minute. So we haven’t a lot that went missing, yet. But the ones coming up in the summer, we wouldn’t have done an inspection yet, at least in many cases. It depends on how long this goes on.

Do you still think allowing IPCA Laboratories to supply hydroxychloroquine was the right decision? (Last month, the FDA took the unusual step of lifting an import ban that was placed on the company in 2015 due to poor manufacturing practices).

We knew that at the time. It wasn’t like we were without information. We took all the factors into the account.

Would you make the same decision today?

Yes, however, accepting a single donation … people are completely confused about this. It’s not allowing people to mass produce and import under their own recognizance. … That’s where GMPs  [good manufacturing practices] are extremely important. You need to make something over and over again in a reliable manner.

Is there anything that you could see FDA doing to ensure standards are maintained in order to dial back the criticism of the past few weeks?

I’ve been dealing with concerns and criticisms for 30 years. You can’t please everyone. The EUA has nothing to do with our approval standards. We have adequate standards to deal with Covid-19.  Efficacy is going to be more important than ever so that we have an effective treatment. So we’re not going to back off on effectiveness. And the amount of drift that’s tolerated depends on the population you’re trying to treat, whether you’re trying to do a prevention study or treating critically ill people.

… We’ve had very similar standards for a very long time. All people want to do is speculate that our standards are going up, down or sideways. … Where you have a mortal illness like for some people, it’s more important than ever that anything we give them works. It’s not just hydroxychloroquine. We’re seeing patients given all kinds of things because they have nothing else and you’re seeing people going down the tubes. We’ve got to do rigorous science and find out what works and we can build on that to decrease the mortality and morbidity from this illness. And it has nothing to with regulatory. It’s an imperative for society.

  • Hydroxycholoquine has been prescribed millions of times to lupus patients, with the risks well-established and understood.

    It hasn’t become more dangerous just because Trump oversold it.

    Doctors on the frontline, with limited alternatives, are using it.

    There is no evidence that any med works for the virus. So do nothing? The cardiac risks are long-established and well-understood and the medicine has been safely prescribed for decades.

    • I think we can all agree that hydroxychloroquine is a life-line for patients with lupus. But to say the cardiac risks are well-established is something I am compelled to push back on. For example, hydroxychloroquine was only added to the ‘known risk of torsades’ list at CredibleMeds in October 2019. Before a Brazilian study was done within the last few months, we didn’t have data that QT interval prolongation is dose-related. The last and most important thing I take issue with is the idea that because these drugs are old we know everything about them. That is patently false and in fact the oppposite. The amount of data required for a new drug to be approved today (e.g., efficacy, safety, metabolism, etc.) is much more than was required when these drugs were approved. There are a number of ‘old drugs’ on the market (e.g., codeine) that might not get FDA approval based on current standards. This includes issues like drug interactions. This is my turf – I’m a pharmacist who was busy last month writing drug interaction content for chloroquine and hydroxychloroquine. It was challenging because there are very few clinical trials evaluating drug interactions with either of them. My final point is that the clinical data for these drugs is often many decades old… usually available only in dusty books in the basement of medical libraries… which are all closed.

    • I agree! Every drug has side effects! This drug has been around for many years and used on patients with very difficult medical problems! I am tired of the attacks on using this drug especially if can keep some Covid-19 patients from entering the cytoxic storm! Does anybody have anything better? I suspect a lot of these attacks on the use of this drug is political!!!

  • I agree with Dean W, and want to add that the FDA requiring US trials for drugs that are already approved and used in the EU / Japan (with reliable manufacturers), is preposterous and counter-productive to the health of Americans. The FDA must learn to accept already-performed reliable trials and drugs approved in reliable nations. As it is now, with old, outdated FDA rules, Americans incur years of needless delays in availability of treatments. The FDA shows more flexibility in this time of Covid-19, but this path must be continued so Americans are not under-served.

    • Dean W:

      There are biosimilars that have been approved in Europe but they are not marketed in US because of collusion between Pharma and US legislators who are elected by the people but sleep with the companies who whose motive is greed over need. It is what it is.

  • The evasiveness in Dr. Woodcocks wording indicates the FDA budged to presidential HCQ pressure. As we now know that both Covid-19 and HCQ cause serious CVD complications, this drug is contra-indicated. There are many other rheumatoid arthritis drugs with incredible results in moderate / severe ventilated Covid patients (Actemra a.o.). And there is Mesoblast’s RYONCIL (brandnew drug remestemcel-L, tested on compassionate use, 2 intravenous treatments in 2-4 days, with whopping 83% survival rate, as per news Apr 24). That is where FDA focus should be. Any pressure from a non-expert (such as Trump) who also blurts out unfathomable intravenous use of surface sanitizers (???) – should be fully ignored. The FDA should only deal with experts. Period.

    • There are biosimilars that have been approved in Europe but they are not marketed in US because of collusion between Pharma and US legislators who are elected by the people but sleep with the companies who whose motive is greed over need. It is what it is.

  • Dr. Woodcock has been a reliable authority about drug efficacy and safety for decades. From her comments here, I sense regrets re the chloroquine/hydroxychloroquine EUA. I agree with her. I was a pharmacist/medical writer in the 2009 pandemic and I’m still one. The difference in clarity from FDA then vs. now is startling. I think there is still time for FDA to clarify the message. The states still need advice from the agencies funded for that mission. I would encourage FDA officials to continue to do what they did before – inform us of details we paid them to provide. If they can’t do it, then say so.

    I’m bothered how obtuse Woodcock is about the rationale for authorizing the chloroquine and hydroxychloroquine EUAs. She implies it was to address needs of patients with lupus and RA, but I don’t see how the EUAs directly addresses the acute need of ~1.5 million Americans. If there are still shortages (as FDA shortage page says there are as if April 2), the feds need to tell us the plan moving forward. They also could help create a pathway to provide these drugs to the folks who need them for lupus, RA, and other rare diseases. None of this is clarified in this interview.

    We now have information from 3 different data sources in Brazil, France, and the US suggesting that chloroquine and hydroxychloroquine have clinically significant cardiac risks in the setting of COVID-19. I was able to review the topline numbers from those studies. Today, FDA also warned us about this risk and said they have a safety signal about it. Usually a safety alert justifies the action it takes by presenting data. But this alert shared nothing. No data. Why is there no data?

    • The FDA warning is for *home use* for COVID-19.

      All drugs have benefits and risks. When getting it in hospital, the treating clinicians can keep a better eye on its risks.

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