The drug shortage dilemma: Prevention
USAGE OF EXPIRED DRUGS: When paramedics ran out of a critical drug used to treat irregular heartbeats, the Bend Fire Department in Central Oregon resorted to using expired medications. Medications are only guaranteed to work as intended until their expiration date. When stored properly, most expired drugs won’t be harmful to patients but will become less effective with time, according to medical professionals and according to the Associated Press, Oregon health officials began allowing ambulances to carry expired drugs, and southern Nevada has extended the expiration dates for drugs in short supply. Arizona has stopped penalizing ambulance crews for running out of mandated medications.
THE PROGRESS: While there are still drug shortages in affect, the United States government and the FDA has begun to play an active role in trying to help the drug shortage problem. New acts signed into law by Barack Obama will speed up the review process of new drugs that could be used in the place of others not currently available. The act will also increase the communication between the drug manufacturing companies and the FDA so that the FDA is ready to help these companies avoid shortages. Furthermore, the FDA has begun to import drugs from abroad that were not yet available in the United States. With these continued efforts it is hoped that the drug shortages will begin to lower. (Source: www.cnn.com)
PRESCRIPTION USER FEE ACT: The Prescription User Fee Act was first passed in 1992 and has been renewed several times and was renewed most recently this year in the hopes that it would help to alleviate the drug shortage problem in the United States. The act allows the Food and Drug Administration to collect fees from companies that produce particular drugs and biological products in the hopes that it will speed up reviews of new drugs and therapies. In 2012 the act was renewed for another five years and an early warning system for possible drug shortages was also added to the legislation. Under the early warning system, manufacturing companies will have to notify the FDA at least six months before discontinuing a drug or if there are any foreseeable disruptions in the manufacturing process that might make a particular drug be in short supply. Hopefully with warning the FDA will be able to prevent a drug shortage by either helping the company rectify the issue or finding another source of the drug. (Source: www.ama-assn.org)
Real Admiral, Sandra Kweder, M.D., Deputy Director of FDA Office of New Drugs, discusses the current drug shortage problem and what is being done to help the issue.
What is the current situation with the drug shortage problem?
Dr. Kweder: The current situation is that we are in the midst of what we see as a crisis of drug shortages in this country. We have been in the thick of this for about three years now. The drugs that are in shortage change on an almost daily basis, but the volume really isn’t changing; it’s pretty constant.
This is a really loaded question but, why is this problem happening? What’s behind it?
Dr. Kweder: There are a lot of people who are trying to understand why this is happening now and a lot of people smarter than me who’ve looked at things like economic factors, the industry that makes drugs, as well as pricing for generics and Medicare. From our perspective at FDA what we see is the problem rooted in the manufacturing sector. Really drugs go in to shortage because companies have difficulty making them pure and simple.
Why are they having difficulty?
Dr. Kweder: Again that’s something that remains a question, but what we see when we look at why and as we work with companies is they are mostly having problems with maintaining quality of the production of these drugs themselves. There are a variety of reasons for that. One of the things that is pretty clear is that most of the drugs that have been in storage, not all of them but most of them are in the generic sector, they’re often older drugs. The majority of these drugs are sterile injectables and sterile injectables require very specific, meticulous, controlled manufacturing systems. When plants and production facilities are not well maintained and updated they start to break down. That’s what we’re seeing with that sector of the market today.
Can you talk about the quality issue with the product?
Dr. Kweder: The cause of quality issues with the products that we have seen is the kinds of things that are serious concerns to doctors and patients. So for example, we have seen fungus growing in IV bags, we’ve seen bacterial contamination, antitoxin contamination. We have examples of metal shards in IV solution and with glass shards in IV solution; we have precipitate forming in the IV bags or the vials for injection, in one case because the actual active ingredient in the product was reacting to the rubber stopper in the vile. Those are the kind of things that when we say quality problems are some of the most concerning. We have other examples that are on a more systemic nature in companies where they are getting reports of adverse effects with their products related to quality and they have no system for following up to figure out whether or not this is a continuous problem; they just have nothing in place. Those raised big red flags, and those are the kinds of products that I as a physician do not want my patients getting and I as a patient would never want to be put in position of receiving.
I wonder why in the last few years it seems like those issues are more common than maybe what they were up here, though we didn’t have a drug shortage.
Dr. Kweder: We’re trying to understand why there has been a change. As we see the change, the real slope in the curve probably started around 2006-2007 and it’s really unclear. One of the things that the ASPE (Assistant Secretary for Planning and Evaluation) report did show was 2007 seems to be a banner year for sudden surge in generics, in products turning generic. So there seems to have been at that point in time a real increase in the generic market, so that plants were operating more and more continuously. If you have a plant and the American public is counting on you to make an important product, one of the things that you need to be able to do is make sure that you have built into your operating schedule enough downtime for idle capacity time in order to institute important repairs, routine maintenance, and really maintaining meticulously quality. That is especially important in facilities that manufacture sterile injectable products. These facilities are amazing to see; every little tiny step needs to be meticulously controlled and it takes time to do that kind of upkeep. If you’re in production mode all of the time, when are you going to do that? That’s one of the things that we’ve seen. Now, is that the cause? It’s certainly an association that we're seeing.
What are some of the drugs that are experiencing the most shortages now?
Dr. Kweder: It’s been interesting to watch, we’ve seen shortages seem to affect certain sectors of the market in succession. For about a year and a half one of the biggest clinical errors that were affected was oncology. It stands to reason because cancer treatments are most often intravenous; they’re sterile injectable products. There seems to be in some of the biggest producers of the sterile injectables we’re having for cancer are having problems. That seems to have abated somewhat and things have improved. We’ve been able to identify alternate sources of product by working with alternate companies to increase production. Antimicrobials also have been pretty heavily affected, but that seems to have been in smaller periods of time. I would say currently one of the biggest areas where I’ve seen problems is with anesthetic drugs; drugs used in operating rooms and emergency rooms, including some of the parental intravenous pain products.
What is the FDA’s role in remedying this problem?
Dr. Kweder: Our role is to do as much as we can to understand when there is a problem or even more importantly a potential problem so that we can try to prevent shortages in the first place; that is number one. If we can’t prevent the shortage we take many steps to try and mitigate the shortage by working with other companies and helping the original company that may be having a production problem resolve that so they can resume business as usual. So our work comes in several stages, and in order to do that we need companies to tell us when they’re running in to difficulties. Getting companies to do that has been something that we’ve spent a lot of time building relationships with the industry over the past five years to do. So if you’re a company and you think you’re going to have a little problem on the production line, you are not required to tell FDA about that. There’s no regulation that requires that except in very narrow circumstances and your instinct is probably not to call FDA. It’s kind of not intuitive that that’s what a company would want to do, but as we’ve built relationships with these companies through our drug shortage program they’ve begun to do that because they know that the public is counting on their production of a particular product. So, they’ve learned that if they contact us we may be able to help them not go in to a shortage in the first place, and if there is going to be a shortage, help them get out of it; so early notification has been key. The one question is, well what can we do to help a company address a problem they’re having? One thing we can do is they may call us and tell us that they foresee a problem getting raw materials. They have an application and it’s becoming critical and if they can’t get that raw material they’re going to have to stop production. However, they have an application in house with FDA in the generic drugs office where they applied six months ago to be able to utilize an alternative supplier from another part of the world for that active ingredient and it’s sitting in the queue in the back lot. If we know that we will immediately pull that application and put it to the front of the queue and it will get addressed expeditiously so there may never be a shortage. So that’s a simple example. The other thing that we can do is if they tell us, look we’re having problems and whatever the problem is we think we’re going to have to do x, y, and z we may be down for a while. FDA knows who all the alternate manufacturers are who have the other parts of the market and we will go to them and ask if they have the capacity to increase their production and how much lead time do they need in order to increase production. Often if they can they will. What they want to know is how long do I need to do this for and I’ll say we’ll keep you posted. And we’ll look at what the market is and how much they need to make to be able to supply the market readily. That’s another example of something that we can do.
So it sounds like it’s just good communication.
Dr. Kweder: Communication is critical, but we also need other companies who are willing to step in and help and we’ve had great success with that. All of these companies have their own challenges and they’ve been really good about stepping in when asked if they can, but they can’t always do it. For example, some of them can’t produce certain products; they don’t have an approved application to produce it or they don’t have the appropriate facility to do it. A good example of that would be a cytotoxic agent. Chemotherapy agents have to be made on a really separate part of the plant and you can’t make other products on those production lines. So a company that isn’t in the cytotoxic business can’t step in and help produce cancer drugs probably, at least not easily and without a lot of lead time and investment in equipment. The other things that we’ve been able to do is we work with our regulatory counterparts in other countries to see if there are alternative sources of product that we could import. Sometimes U.S. companies make product here for shipment overseas that for whatever reason they’ve never bothered to have approved here, but they have it approved in another country and it’s essentially the same. We will look at what the inspections for that have been and they might be able to ramp up production of that product. Or we look to alternative suppliers of product in other countries and we allow temporary importation of that product until the producer here can come back on line.
You mentioned that a drug company doesn’t have to tell you if they foresee a drug shortage, do you think they should have to tell you?
Dr. Kweder: Today certain companies are required to tell FDA. If they make a product that is to treat a serious and life threatening condition they are required to report potential for a shortage to FDA. That’s new and that is a law that was passed by the Congress just this past summer, and that is really going to help us greatly. Since late 2011 we’ve seen a great increase in the number of companies reporting to us voluntarily. That occurred because of an executive order issued by President Obama encouraging that and it’s been great. We’ve seen a six fold increase in reports to us about potential shortages, but now the new law requires companies to do that.
The FDA cannot force a company to make a medication?
Dr. Kweder: That’s right. We cannot force anyone to make anything.
So how does reducing profit margins on certain drugs effect the shortage situation?
Dr. Kweder: You would think that if it was reduced profit margins what you would see are companies just ceasing production, but we have had very few shortages related to companies stopping production; well below ten percent. Usually when those occur there’s somebody else behind them ready to start production.
We’re talking to pharmacists about this problem and some of them say it’s just taking a lot of their time, a lot of their money, and one even compared it to a third world country. What’s your response to that?
Dr. Kweder: This is extremely difficult. It’s difficult for us but the difficulties for FDA pale in comparison to the experience of people taking care of patients. Whether it’s clinicians who have to choose an alternative medicine or a patient who feels like they have to take a therapy that may not be as effective as what the doctor originally prescribed. The logistics for pharmacists can be a nightmare. I’ve talked to pharmacists who are pharmacists in healthcare facilities and they have up to several people working full time just to monitor where they’re going to get a supply of critical medications. That is just unheard of.
Is there any way to estimate how many people in the last five years are affected by this shortage?
Dr. Kweder: We don’t have numbers on that but we probably should try and calculate that. My best estimate would be that it has to be hundreds of thousands to that of millions. You just look at the drugs that have been affected; some of the most commonly used medications in oncology, in anesthesia, and in medicine in general have been affected by this.
So what is the next step for the FDA in solving this problem?
Dr. Kweder: We are looking at every option we can possibly try and see what role we can have to try and address the problem. What we have seen is that a lot of the companies that have had major problems, where they’ve actually closed plants, are rebuilding those plants or revamping existing plants. We think that’s a step in the right direction and when they are doing it we are working with those companies to make sure that we’re in communication about what the plans are for quality control in the twenty-first century. Our mantra in this has been that what needs to happen is the quality has to not only be built into the facilities, it has to be part of the culture in these companies. That quality starts at the top and people have to be held accountable for quality. There are companies in other sectors of the pharmaceutical industry and many other industries in this country where quality is job one. Absolutely in every aspect of the pharmaceutical industry, particularly for these medicines that patients rely on, there can’t be any other way. That’s what we think is the long term solution. We’re not going to fix it overnight, but the industry remains healthy and we think that things will start to move in a positive direction.
The Prescription Drug User Fee Act, what is that?
Dr. Kweder: Yes, the Prescription Drug User Fee Act is in its fifth round of existence. It gets renewed every five years where Congress passes legislation that allows FDA to collect fees for certain activities. In exchange FDA commits to certain conditions such as timelines of product reviews and implementation of specific programs. The industry has requirements as well. As part of the Prescription Drug User Fee Act this year there were the requirements for companies to report where shortages or potential shortages came from. A unique element is also the Generic Drug User Fee Act which was passed in 2012 and is new. For the first time FDA will be able to collect user fees for reviews of generic drug applications. The first order of business that FDA has under the Generic Drug User Fee Act is to eliminate the backlog of generic drug applications and supplements. If you remember I said that sometimes companies have supplemental applications to change a manufacturing procedure, site, or supplier. Those come into the generic drugs office and right now there’s a backlog of almost two years to get those reviewed. If we know that a particular application can prevent or address a shortage we pull that immediately and put it to the front of the queue, but the goal is to not have to do that, to have that backlog gone. So if there’s any role that FDA has in these shortages from being slow on reviewing these applications that will be eliminated.
Dr. Kweder: What the Generic Drug User Fee Act does is for the first time it allows FDA to collect user fees from the industry for certain activities related to generic drug applications. It gives FDA enormous resources for staffing in order to serve that sector of the manufacturing community and the public. What is seen as FDA’s first order of business under that act is to eliminate the backlog of generic drug applications. So now when companies tell us that they may have a shortage on their hands, we look to see if there are any applications in that queue of generic drugs that we could pull to review quickly and help prevent or address a shortage; that won’t be necessary any more. Those will already be being addressed and not an issue at all. If there’s any role for FDA in slowing down the ability to prevent a shortage or address it, that won’t be operative any longer under this act.
Where do you see this problem being five years from now?
Dr. Kweder: It’s very hard to predict. We didn’t get into this situation overnight and we’re not going to get out of it overnight, but I see the work of the industry, particularly the generics industry, to build new facilities and to begin to take quality more seriously as a really positive sign. There’s a lot of attention on it in the medical community and I think people have to keep up that tension; keep up the pressure. Americans count on and deserve high quality medications that they can obtain reliably. Who would have ever thought we would be in this position and I think that the public has a right to be dismayed and outraged and needs to keep the pressure on everyone involved, including us, to address it.
What is your personal involvement in the drug shortage?
Dr. Kweder: My personal involvement is for the past year I have been the lead for our center for drugs, and for the agency on drug shortages I’ve been the person kind of at the top of the center who helps bridge all of the dozens of people in the center for drugs who are working on drug shortages. It’s not just our drug shortage program staff who is the coordinators, but people in almost every office in the center, scientific, regulatory, and enforcement, have some role in trying to address this problem.
The makers of the drugs, wouldn’t it behoove them to just make bigger and newer facilities because their profits would increase?
Dr. Kweder: Sometimes people ask, ‘well why don’t these companies just go out and build new facilities?’ I think it’s complicated, particularly for a sterile injectable facility. I don’t know if you’ve even been in one, but they are amazing facilities; the requirements for sterility alone are incredible to see. There are people walking around in white space suits in these facilities because they can’t wear their regular clothes in to work; they have to change and shower. Every piece of equipment and plant for sterile injectables for the most part is custom made. You don’t just order them from a catalog they have to be custom made, custom designed. Even things like the air supply to the facility require special components that you don’t need in other kinds of manufacturing facilities. They take years to build and just the permitting situation alone probably takes a year to get. So they’re not easy; they’re huge investments.
What does the future look like?
Dr. Kweder: One of the things we look at very carefully is where the most critical shortage is and they don’t seem to affect any segment of the population more than others, which is very interesting. One might think that it’s mostly elderly patients because they have more health problems, and I suppose that to some extent that is the case. However, we have had crises in shortages for pediatric cancer treatments for example. Methotrexate in 2011, that was a shortage that was transient and we were able to address that very quickly with the help of multiple companies stepping up to the plate to really address a critical problem, and it’s no longer in shortage. We see patients undergoing elective procedures in the operating room who have to have their surgeries delayed because the anesthetic agents are in short supply. Emergency rooms who have to operate differently because the usual sedatives that they use and feel most comfortable and safe are in shortage, so they have to substitute something else that requires them to completely change how they monitor patients in the emergency room. So there is no segment of our population that is untouched by this.
Tell me how many drugs right now are in shortage.
Dr. Kweder: We’re usually operating in the range of around one hundred fifty to two hundred drugs at any given time; it changes almost on a daily basis. Fortunately most shortages get resolved, which is the good news. Sometimes drugs come back in to shortage for a variety of reasons, but most shortages do get resolved. We are monitoring this continuously and we work with not just the industry but with professional organizations, including the American Society of Healthcare Systems Pharmacies. They have a web page; we have a web page, so we talk almost daily. We work with physician organizations, professional organizations, other pharmacy organizations, and we are in contact with pharmacists on the ground in this country every single day. We learn a lot from them about how what we do ultimately plays out in their community so that we can improve our communications and the way we work with companies to get information out to them.
For more Information on drug shortages go to the ASHP website http://www.ashp.org/shortages or the FDA website at www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm
FOR MORE INFORMATION, PLEASE CONTACT:
FDA Office of Public Affairs
Drug Shortages Notification and Updates:
Joseph M. Hill
Director, Federal Legislative Affairs
American Society of Health-System Pharmacists
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