If you've been staying up to date with our COVID-19 blog series, you should have a general overview of what governments both in the US and overseas are doing to help in the fight against the Coronavirus. Regulatory agencies around the globe are relaxing some of their typical requirements to get products on the market and available to consumers as quickly as possible. At first glance this sounds like a great solution, but what kind of risks does this pose for agencies such as the FDA? I sat down with RQMIS President Barry Sands to explore risk management during COVID-19 and its effects on patients as well as industry.
B: Different types of products (food, cosmetics, devices, drugs, tissue, etc.) are regulated by the FDA and they have the ultimate minimum requirement of ensuring the safety of those products before they can be sold to the general public. But there is a subset of these products, such as medical devices, pharmaceuticals, and vaccines, that the law requires the FDA to also ensure the effectiveness of the product. That judgement of how much evidence is enough to support the claims of safety and effectiveness (i.e. objective evidence, both preclinical and clinical) is a judgement call by the Agency . And in the normal course of review there is this struggle to understand how much of that objective evidence is required for FDA to be able to sit back and say: “This product is safe and effective or not safe and effective” – and this gauge of how much evidence is needed is hopefully driven principally by risk.
B: Whenever we look at a product and its objective evidence, we know that any given product has certain inherent risks. No matter how well you design this product it will still continue to possess a certain degree of residual risk. It’s just like if you get in your car today and you start driving down the interstate, even though you may drive the speed limit and take precautions there is still an inherent risk that somebody may hit you, or that you may take your eye off the road and get into an accident – thus there is an inherent risk to that decision to drive your car. But yet, we all still get in our cars and we all still drive 65 mph or faster down the interstate to get to another location and we deem that benefit of getting to that destination is a higher benefit than the risk of not driving from point A to point B. So in essence, the FDA is in that same position of looking at let’s say, a total knee replacement, and making a decision as to “is there enough preclinical data” and “is there enough clinical evidence” for the agency to agree that the product is safe and the benefits outweigh the risk. Now, even given an environment without a pandemic, different individuals will come up with different requirements as to what is needed to determine the safety and effectiveness of a product and oftentimes the agency will solicit input from industry, academia, and so forth – but ultimately the agency has to come to a conclusion of what that body of evidence is.
B: Sometimes industry doesn’t like it because it can be an undue burden if there is more information being requested than is necessary. And then of course the general public doesn’t want the agency to ask for very little information because then they run a higher risk of approving a device or medicine to be placed on the market where it turns out to be unsafe and/or ineffective. And unfortunately, in both cases we have examples to demonstrate those extremes of risk management in decision making in terms of the regulatory approval process. But the bottom line is that the FDA or other competent authorities overseas have to make that call. Hopefully it’s not too burdensome or too restrictive, and on the flipside hopefully it’s not too loose and relaxed such that ineffective or unsafe products reach the market.
B: So, you now overlay that process of determining what body of evidence is required under normal circumstances and then add the complexity of a public health crisis like the current pandemic we’re experiencing, and you get three key aspects (from a public health standpoint) that the FDA needs to consider very seriously during their preapproval process and those are:
B: Clearly healthcare providers are the highest concern and their role and skillsets are critical in treating and helping patients that already have the virus. And of course, you don’t want to lose those individuals. So, we start talking about Patient Protective Equipment, or PPEs, used to protect them from contracting the virus. These are all medical devices and FDA has to look at how readily available those are on the market and how they can be best placed on the market to protect these groups of people.
B: First, the government should be taking measures to build up inventories of these approved PPEs so that they’re available at such a time when a pandemic does occur. With regards to medical products that are specific to a virus one cannot build inventories of approved products (diagnostic kits, pharmaceuticals, vaccines) because the type of virus is unknown until it appears (the reason we call it Novel). With regard to the premarket review of these virus specific medical products, in this case specific to COVID-19, on top of the standard review process you quickly get a situation where the product clearance or approval process is subjected to achieving a balance of quickly diagnosing, treating, and preventing the virus to reassure the public that their government is addressing the crisis without approving an unsafe or ineffective medical product. The pressures on the FDA are enormous to approve products quickly but the Agency recognizes their legal obligation to only approve medical products that are safe and effective based on objective, scientific evidence. The FDA understands better than most that if they don’t approve these virus specific medical products that the public’s anxiety can go through the roof. This level of anxiety can slam the breaks on consumer activity and destroy the economic health of the economy. On the other hand, clearing/approving an unsafe/ineffective medical product can further the spread of the virus or cause serious harm or death to consumers.
B: As a regulator, politics are not supposed to enter into the decision process. The FDA is supposed to be looking at objective evidence and rendering a decision as to whether something is safe and effective, or again in the European standpoint the Notified Bodies and competent authorities in the regulatory review process are supposed to be rendering decisions based on objective evidence, science and engineering. However, when you get into a situation like we have today where you’re tremendously struggling to determine the level of infection that you have in the country because you don’t really have good testing based on objective evidence or sufficient quantities of tests, or you flood the market with numerous tests that have not undergone any level of 3rd party review you can create significant anxiety. Combine that with the need to restart the economy and you can have a real nightmare on your hands. Bottomline, the regulatory review process can become so influenced by political pressure that you open the market and the consumer to unproven diagnostic tests and off label use of unproven pharmaceuticals. With this environment you are significantly increasing the risk to the consumer and to the business environment in general.
B: Some of the influence is not bad. Not devious types of political influence like exchanging money for a reviewer to get something approved faster, but the natural friction that can be caused when you recognize, especially in a situation like we have today where you should do everything you can to reassure the public that you understand what’s going on, that you’re addressing it in an objective way based on science and facts but also to convey confidence in the public that you’re addressing it in a very pragmatic way. When you’re in that type of situation there is going to be a natural pushback from the non-scientists in the government to push the FDA to make quicker decisions.
I would argue that this is normal, but what of course needs to occur is that very well-considered balance between allowing a product to go to market quicker to reassure the public that the government and private industry are on top of the situation and doing everything possible to address it, while not releasing product that is not safe or is not effective in doing what it is intended to do. This is the risk management process that FDA must go through internally to balance benefit over risk.
B: Yes. Today you can release and begin selling a diagnostic test for COVID-19 without FDA approval, but with the understanding that within two weeks of marketing the product that you need to submit an Emergency Use Authorization (EUA) to the FDA to get approved for emergency use. That is a HUGE risk for the FDA because the product is hitting the market without any agency oversight. Normally you would have to submit a 510(k) or PMA to the agency which could take 3-12 months depending on the amount of evidence you need to submit.
B: They may have to recall the product because their body of evidence, now that the FDA is looking at it, is not compelling. The motivation to be less risk-averse is because when you’re blind to how high of an infection rate you have or how quickly it’s spreading, that also is a huge risk for the general population. The FDA is now relying much more heavily on industry to do their job. Most companies know the body of evidence they need to produce to convince the FDA that their diagnostic test is effective. So now what the government is saying is that, at least initially, they are going to trust industry to develop that body of evidence and trust them that it’s adequate so that they can go ahead and hit the market quicker.
B: Of course, the risk to the individual is much higher with medicines because if FDA decides to reduce the objective evidence used in their assessment of a medicine after it’s on the market, you could be distributing a drug that is not actually safe and/or effective. And for a drug or therapeutic, the impact to the patient can be huge. The way to talk about medicines is in two categories:
Oftentimes you can study a drug, get it approved for a certain condition, and then realize it can be useful to treat other conditions as well. From a public health standpoint, you want to look for these kinds of drugs because it allows the agency to react the quickest. If today I came up with an active ingredient that I thought was tremendously effective, I probably have a 4-5 year process in front of me before I can prove it to the agency. Whereas if I take a drug like an approved drug to treat malaria, we can say that we KNOW it’s safe in this particular population that has malaria, and IF it has a mechanism of action that COULD treat COVID-19 (or its symptoms) we should use it to treat COVID-19. This use must be based on some degree of scientific evidence. It may not rise to the standard of a new drug but there are prospective study based data that points (not confirms) to its potential benefit for the off label use. This approach to off label use can give the FDA and the public a glimmer of hope.
B: If they just blindly say “use it” – that’s really elevating the risk profile to the patients themselves. Doctors are the ultimate ones who have to make the decision to give it to their patients. They may have a patient with the virus and let’s say there’s an 80% chance they’ll go through 60 days of feeling very sick and miserable but ultimately they’ll recover - do they now add to the complexity of that patient’s case and give them a drug in which they really don’t have any objective evidence to say it MIGHT work and they don’t know what the safety profile of the drug is in this particular population? That is a very difficult risk assessment to take and I think what you see playing out in the press is this debate where one side says “Okay, I’m watching people die, there is no drug available that’s approved for this virus, but I have a glimmer of hope here and do I basically suggest to a doctor to do nothing or use this drug that has a glimmer of hope, which MAY complicate the patient’s condition and we’re not 100% sure that it will even be effective?”.
So, I think that the agency is having their judgement of risk influenced by the government’s desire to convey to the general public that they have a possible solution to the virus. And therein lies that risk assessment that the FDA has to face on a daily basis that is getting influenced by politics. For anything the government does to try to work as a group and to do what’s best for the public good or public health, in times of crisis there is always going to be that sense of needing to do something, versus making sure what we do is actually helpful and not harmful to the public health. The risk management processes across the globe are undeniably getting influenced by politics.
All we can truly hope for is that we don’t go so far out on the limb that the limb snaps.