Flu and the FDA: An Interview With Margaret A. Hamburg, MD

Margaret A. Hamburg, MD; Laurie Scudder, DNP, NP


January 23, 2013

Editorial Collaboration

Medscape &

Editor's Note:
The 2012-2013 influenza season is in full swing, with widespread influenza reported in all but 2 states, according to the Centers for Disease Control and Prevention (CDC) FluView report last issued in the second week of January. In comparison, no state reported widespread geographic influenza activity for the same week in 2012. The CDC continues to urge unvaccinated persons to be immunized, though reports of spot shortages of vaccine may make this difficult. Additionally, treatment with neuraminidase inhibitors oseltamivir (Tamiflu®) and zanamivir (Relenza®) is recommended as early as possible for any patient with confirmed or suspected influenza, particularly in those who are hospitalized; have severe, complicated, or progressive illness; or are at higher risk for influenza complications. This recommendation also is made potentially more difficult by shortages. Medscape spoke with Margaret A. Hamburg, MD, Commissioner of the US Food and Drug Administration (FDA), about the FDA's efforts to address shortages and other issues related to pharmacologic management of influenza.

Shortages or Not?

Medscape: Is the FDA concerned about shortages of influenza vaccine? What efforts are being made to address actual shortages and those resulting from uneven distribution? Should clinicians prioritize administration to high-risk groups or modify usual practice in any other way? If so, can you elaborate on any specific recommendations?

Dr. Hamburg: The issue of shortages is a very important one and very much on the minds of consumers and healthcare providers. We are receiving reports of spot shortages of the vaccine, though we know that there is still vaccine out there that needs to be accessed. People who want to be vaccinated still can be. We recommend that consumers use the online flu vaccine finder at flu.gov to determine where vaccine is available in their community. That really is very effective. Healthcare providers can contact their distributors directly, of course, or search for vaccine by using the influenza vaccine availability tracking system (IVATS). Combined, these systems are very valuable.

As for the overall supply, I think it is fundamentally good news that the FDA has now approved influenza vaccines from 7 manufacturers who have collectively produced over 140 million doses of this season's flu vaccine for the United States. In recent years we have seen an increase in the number of manufacturers, and the supply this year is actually about twice the size of what was available just a few years ago. Overall, that is very good news. In years when the flu season is less pronounced, some vaccine remains unused due to lesser demand. However, this year there is a very high demand that has come on suddenly. So, we are seeing some spot shortages and we hope that, with these additional tools to help find vaccine and a little persistence on the part of healthcare providers and consumers, everyone who wants to be vaccinated can be.

Medscape: Is there concern with any particular region of the country having less vaccine than others?

Dr. Hamburg: The reports have been more spot and not regional concerns.

Medscape: Oseltamivir shortages have also been reported, most notably of the oral suspension used for children. We have read reports of Canada releasing oseltamivir from its National Emergency Stockpile because of concerns about potential temporary shortages. Is this a concern in the United States? Can you address this issue, including guidance to clinicians and pharmacies regarding compounding oseltamivir if the suspension is unavailable?

Dr. Hamburg: Antiviral therapy for flu does have a very important role. The CDC recommends that it be begun within the first 2 days of symptoms, particularly for the most vulnerable patients, in order to derive the most benefit. Of course, that then does focus on the available supply. Overall, the product is available, but we are concerned that there are limits on the suspension version that is often prescribed for children. Some locations are experiencing intermittent temporary shortages of this oral suspension that we believe, unfortunately, will persist for the remainder of the flu season. We are working with the manufacturer, Genentech, to increase the supply. We also have put out information for healthcare professionals about the FDA-approved instructions, available on the label, for pharmacists on how to make a liquid form of Tamiflu from capsules if the oral suspension product is not available.

Medscape: It is not a new recommendation that pharmacies can compound oseltamivir when they need to, correct?

Dr. Hamburg: That is correct. When available, the commercially available oral suspension of Tamiflu should be used. But if it is not available, then the suspension can be appropriately prepared by pharmacists according to the directions on the current label.

Oseltamivir: Appropriate Use

Medscape: In December 2012, the FDA approved use of oseltamivir in infants as young as 2 weeks of age for treatment but not for chemoprophylaxis. Can you review specific issues with use of this agent in these very young children who cannot be immunized?

Dr. Hamburg: Tamiflu is the only available product for children in this age range. The CDC does not recommend flu vaccinations for persons younger than 6 months of age, so this is an important addition to the armamentarium to treat patients at those young ages with flu infection. It does need to be given appropriately, and the dosing really has to be calculated for each patient based on their exact weight -- and, of course, they do need the suspension formula. Families and healthcare professionals have to work together very closely, first to make sure that the drug is indicated, and then to ensure that the correct dose is administered to these children with the right dosing regimen. That is all clearly outlined in Tamiflu's label and prescribing information.

Medscape: The recommendation for use of oseltamivir in older children and adults is to treat presumptively. Even in the case of a negative rapid influenza diagnostic test (RIDT), a clinician who suspects flu should begin antiviral therapy. I presume that the same recommendation is probably even more true in these very young infants.

Dr. Hamburg: One certainly cannot depend on an RIDT in that setting. The healthcare provider is critical to making the appropriate diagnosis and treatment recommendation, working closely with the parents of the child in question. Our role is to be able to provide the best possible information about how to use the product and the dosing. I should note that the smaller doses needed for an infant will require a significantly smaller dispenser than that currently copackaged with Tamiflu. Pharmacists must provide the proper dispenser when filling a prescription so that parents can measure and administer the correct dose to their children. Parents, hopefully, will understand that and have been correctly educated by their healthcare provider and instructed to confirm with the pharmacist that they have been given the correct dispenser for their child.

Medscape: A January 2012 Cochrane review raised concerns about oseltamivir, alleging that the manufacturer has not provided access to a substantial amount of data on the drug. These concerns were reiterated by other experts. In a response, the manufacturer noted that data from all sponsored trials have been published or are available on its Website. Has the FDA required any continuing study of this agent, particularly in young children? Have there been reports to MedWatch that have raised any concern?

Dr. Hamburg: There has been considerable experience over time with the broader use of these antiviral drugs for the treatment of influenza, and the benefits have really been well documented. We are confident in our review of the data and conclusion that Tamiflu is beneficial in decreasing the risk for flu infection in certain populations and in decreasing severity of the symptoms of the flu in infected patients. Treatment is certainly part of the recommendations that the CDC is making very clearly in the midst of this year's flu season. First, we encourage people to talk with their healthcare professional about the best course of treatment for them so that they are only taking the medication if it is appropriate. That will help to reduce any unnecessary complications or adverse events. We also, of course, routinely monitor adverse events as part of our adverse event reporting system and other mechanisms of ongoing postmarket surveillance. That is very important in terms of our understanding both the patterns of the adverse events and the types of adverse events in any given flu season. We, of course, look at that information over time and will continue our routine monitoring of adverse event reports with these drugs. With the broadened indication for use, this reporting is of great interest to us, and we will be looking very closely at any adverse event reports that might come in in that very young pediatric population. We will continue through various venues to make information available about adverse events. And let me take this occasion to remind healthcare professionals and patients that they should report any potential adverse events associated with Tamiflu's use to us through our MedWatch program. That is extremely valuable information and part of what we use to help ensure that we fully understand the safety and value of these products.

Medscape: On the basis of the experience of past years, I would presume that the FDA would anticipate a peak in reporting simply because of the sheer number of patients being treated this year.

Dr. Hamburg: Absolutely. We do see cycles in adverse event reporting. We saw a large increase in the number of adverse event reports because of the tremendous increase in the usage of Tamiflu back in 2009 during the pandemic period. The pattern of adverse events during that period did not suggest anything markedly different from any other flu season. We are tracking adverse events during this flu season, and, again, we have not seen any emerging new trends or concerns.

Medscape: Do you have any concluding statements for our readers?

Dr. Hamburg: It is important to note that we are working closely with our colleagues at the CDC to track this year's flu season and to address concerns about spot shortages or other concerns that might emerge related to adverse events. I think it is also important to note that in response to the increased demand for antiviral therapy, and Tamiflu in particular, we have been working with Genentech. They were just enabled to release 2 million more doses of Tamiflu, which is a good product but had the old label that did not include the newer indications for how to make the suspension product. We are very pleased that Tamiflu is now entering into the marketplace, and we are working with the company, pharmacists, and other healthcare providers to make sure that everybody can get access to the information about how to appropriately make the suspension product if needed. That information is also available on the manufacturer's Website.

While this is more for the future than for this year's flu season, it is extremely encouraging that late last year we approved 4 new vaccine products. In late November, we approved a cell-based vaccine, Flucelvax®, which holds promise because it reduces the preparation time for new vaccines and takes us a step away from our dependence on the older, egg-based vaccine manufacturing technology. That has vulnerabilities in terms of requiring access to eggs, potential contamination, and potential inability to actually generate viral incubation in those eggs if the flu strain kills the egg. This product will be an important contributor in future flu seasons. Just this month, we approved the first recombinant technology flu vaccine, Flublok®. Again, that holds a great deal of promise in terms of really moving to the next-generation flu vaccines that are built on recombinant technologies that are new in the influenza area, though we have had a lot of experience with them in other areas of vaccination, such as hepatitis B vaccines.

I think these new techniques will decrease some of the time involved in flu vaccine manufacturing and increase the viability of the flu vaccine manufacturing process. We have also recently approved 2 quadrivalent vaccines. That is important because these products include 2 strains of influenza A and 2 strains of influenza B; the trivalent products currently in use include just 1 strain of B. These new products will provide broader protection to the public.

Medscape: Do you anticipate that these new products will be commercially available by the next flu season?

Dr. Hamburg: One never knows with flu vaccine manufacturing, and that is one of the challenges. However, we see no barriers to production next year. We will be working closely with the companies if any problems arise in terms of manufacturing capabilities. We think that these will be important additions to the vaccines that are available in the US marketplace.