Asthma Drugs Get Mixed Review From FDA Panel
15 CommentsBy Ed Silverman // December 11th, 2008 // 4:00 pm
A two-day meeting yields good news and bad news - Glaxo’s Serevent and Novartis’ Foradil both pose serious risks that outweigh their benefits for treating adults, adolescents and children with asthma, an FDA advisory committee decided. At the same time, Glaxo’s Advair and AstraZeneca’s Symbicort, both of which are much more widely used, have acceptable safety profiles for asthma patients.
The panel reportedly voted 27-0 that Advair benefits outweighed its risks, and the committee voted 23-3, with one member abstaining, in saying the benefits outweighed the risks in adolescents ages 12 to 17 years old. Advair, by the way, is Glaxo’s biggest-selling med.
The drugs are known as long-acting beta-agonists, or LABAs, and are used when asthma patients find their symptoms aren’t well-controlled by other drugs, such as inhaled corticosteroids. Advair actually contains both a long-acting ingredient and an inhaled corticosteroid.
FDA staffers had recommended approval be withdrawn for the LABAs for children younger than 18 years old, due to an increased risk of asthma-related deaths and attacks (back story here and here on FDA concerns and requests for more data).
UPDATE: Glaxo issued this statement: “We are confident that our proposed new labeling, medication guide and risk management plan would help physicians safely manage the appropriate use of Serevent in conjunction with an ICS…We are concerned that - if the FDA adopts the panel’s recommendation on Serevent - it is possible that Serevent would be severely restricted and deny patients needed treatment for optimal care of their asthma.”
Novartis and its partner, Schering-Plough, issued this statement: The drugmakers “strongly disagree with the Joint Advisory Committee’s view that the benefits of FORADIL do not outweigh its risks in patients using it according to current product labeling for the maintenance treatment of asthma. We believe this opinion is inconsistent with clinical evidence supporting the benefit/risk profile of FORADIL in patients not adequately controlled on other asthma-controller treatments.”
And AstraZeneca belatedly sent us this: Howard Hutchinson, M.D., Chief Medical Officer of AstraZeneca, said, “We are pleased that the joint advisory committees’ recommendation confirms our view on the positive benefit-risk profile of Symbicort,” says Howard Hutchinson, AZ’s chief medical officer.
ol cranky
As someone who has seen the data for these drugs as well as short acting beta agonists, I think our buddy Graham is so enamored of himself he’s not thinking clearly on these drugs.
The “problems” with the class is related to tachyphlaxis which, theoretically, should be a problem with both long and short acting beta agonists. In actual practice (use of drugs marketed here in the US) we’ve only actually seen a clinically significant issue with salmeterol. The SMART study was almost as confounded as insurance data is on the issue and just muddies the water more than it helps. Considering physicians were not required to treat patients in accordance with ATS guidelines (and, unfortunately, too many docs in practice bother to learn, let alone follow them) what the study ended up doing was conflated tachyphlaxis issues with poor treatment (probably due to a lack of physician understanding of asthma and how to properly treat the condition). Patients using LABAs should be on daily steroids (not only because they help attenuate tachyphylaxis but because LABAs are not second line treatment) and docs who choose to use LABAs for their patients should have them diary symptoms and peak flows for at least 2, 12-week cycles. One usually sees signs of tachyphylaxis to salmeterol by week 8 - 10 of a second 12-week cycle - patients will describe a noticeable decreased duration of effect in which they pretty much note feeling OK one minute and then really tight rather suddenly. Those patients should get a prednisone burst and discontinue to use of salmeterol to get them back to baseline. I have to be honest, I haven’t even heard anecdotes of similar issues with formoterol. . .you would expect it just as you’d expect to hear a lot about it form albuterol and yet you don’t. If a LABA appears to be necessary for a patient who doesn’t tolerate salmeterol, consider conversion to formoterol (in the US you’d really have to convert the patient to symbicort to stand for steroid and LABA because the delivery device for foradil is craptastic at best). Even though they are the same class of drug, there are significant differences between salmeterol and formoterol and it’s unlikely the patient will start exacerbating due to tachyphylaxis with use of formoterol even if they do not tolerate salemeterol. In truth, salmeterol is a good drug for those who don’t have tachyphylaxis issues and for whom it is appropriately prescribed. Physicians need to spend the time to learn about asthma, how to maximize therapy, identifying factors that are signs of decreased stability and educate their patients. Unfortunately, too many docs (usually PCPs) seem to be too tired, distracted, arrogant and/or lazy to do so.
ol cranky
oh yeah, and how about learning about pulmonary function tests? you have no idea how many docs don’t even bother using spirometry - even occasionally - to assess their patients (and even fewer who know how to read them)
Sierra Night Tide
I have severe asthma and two of the medicine the FDA wants to ban is on the list. I am asking that anyone that has or has known someone with a lung disorder please contact the FDA and let them know that all Americans with any disorder or disease be allowed to continue living life best they can with the current medicines available and not to ban them. Banning even one of the medicines I take can reduce my daily life by as much as 50%
http://www.fda.gov/comments.html
Justice in Michigan
This question - As I understand it, Advair is not only Glaxo’s best selling drug, but is the second best selling drug in the world, second only to Lipitor.
Is it really possible that there are that many people - of whatever age - who suffer from asthma, COPD, chronic bronchitis, or related conditions?
I would be interested in any informed views on this. Thank you.
laurie
Once again Advair is a drug that is overprescribed. It should be reserved for those who’s asthma is not controlled by any other method. Instead it’s used as a “first in” drug by many GP’s and pediatricians, hence the “blockbuster” status.
ol cranky
Justice:
Asthma was under diagnosed by GPs for a long time and then was suddenly over diagnosed however asthma is a huge public health problem that has been steadily growing over the past 15 - 20 years. COPD diagnosis include both chronic bronchitis and emphysema - the majority of cases are due to smoking, so it’s not surprising that there is a fairly high rate of COPD in the US population (alpha-1 anti-trypsin deficiency is a genetic cause of COPD that found in the hispanic/latino population, so there may also be an increase in those patients associated with increase in the number of people in that demographic).
The utility of LABAs in patients with moderate - severe asthma is undisputed but it is probably overprescribed in the population with mild asthma. This is due to the aforementioned lack of knowledge by those providers who diagnose & treat the majority of asthma cases: the GPs. I’m unconvinced of the utility of LABA in the majority of COPD patients since most of those patients aren’t significantly “reversible” (show an increase in FEV1 post administration) with beta-agonists as the majority of their obstruction is fixed.
Sierra I’m a little confused by your statement that 2 of the medicines you are taking to treat your asthma are on the potential ban list. The asthma meds to be banned are the LABAs not the steroids paired with them on the combination product. Nobody should be taking two different LABA, there is no clinically justifiable reason to be using both (and it’s a potential disaster waiting to happen).
I hope you may think that banning salmeterol or formoterol which would lead to the discontinuation of advair and symbicort would be a net loss of two drugs you need. In truth, both fluticasone (flovent) and budesonide (pulmicort) which are the steroid component of these combination products will continue to remain available even if the LABA/combination products are withdrawn. This being said, while I do think that the black box warning for the class is not really applicable to formoterol, I do think that salmeterol is a safe ad useful product when prescribed and used in accordance to ATS treatment guidelines and a physician who really understands obstructive lung disorders.
Dingle
Justice, over 25MM people suffer from asthma in the US. To complete the Lipitor analogy, cholesterol is more than 2x prevalent, but obviously asymptomatic so not much urgency/interest to treat from people. Lipitor also isn’t the market leader. Advair is far and away the preferred agent in treating asthma. So, that explains why it is the 2nd highest selling agent to Lipitor (not sure if that is true though).
Justice in Michigan
Re: best-selling drugs, the 2006 list can be found at:
http://depth-first.com/demo/20070725/ten-best-selling-drugs-worldwide-with-structures.html
Dingle is probably right that has changed. Advair was #3 then, just behind Nexium. I believe it has moved up. In any event, we’re talking about $6 bil, so it is certainly very near the top.
Appreciation to OC for his detailed discussion.
ol cranky
Another thing to understand in the sales of a drug to treat asthma vs those for a statin is competition. Even after there was a noticeable increase in the incidence and prevalence of asthma, companies were not keen to jump in and put money into drug development for respiratory conditions. Part of this was due to the fact that development of a topical agent (orally inhaled) to treat and control symptoms is made excessively difficult because it involves delivery devices (exacerbated by a lack of interest in drug deposition vs what comes from the actuator by the FDA). Comparative studies with orally inhaled products are damn near impossible - this is truly a shame since, if they were easier to do, AZ would have not only had an opportunity for symbicort to take market share away from advair, we would have have a real opportunity to do a large scale, real-world comparison of the safety of formoterol to salmeterol and get more information on the tachyphylaxis issue (including pharmacogenetics of the 5′ UTR polymorphisms) from a long-term head to head of advair vs symbicort.
Systemic agents are also notoriously hard to develop (I think Merck had at least 13 leukotriene antagonists make to early clinical trials and fail due to prior to singulair, which is really a drug to treat allergies).
Up until the SMART study, GSK had the best designed and executed clinical trials for developing drugs for asthma - they were the FDA darling for good reason. They were also the only company to really be willing to put money & support into drug development for asthma. AZ, on the other hand, had good products but wasted some exceptional talent and was notorious for pissing off the FDA at the direction of the powers based in Lund.
Despite the huge potential of the market, companies tend to shy away from asthma/COPD drug development and those of us with hard core and hands on understanding of the disorders and the industry have been dispersed across (or run screaming from) the industry.
Justice in Michigan
Thanks again, Ol Cranky,
Allow me to ask a “case study” question, no medical advice assumed, but rather to get a sense of how you or others would view threshhold for rx’ing Advair (understanding there is always more to know about any particular pt.).
65-year old woman. Shows slightly depressed results in pulmondary function tests which normalize with Advair. Pt. herself is unaware of any symptoms at all. She is very active, including physically, experiences no shortness of breath, wheezing, etc. Zilch on everyday sx. She is a former smoker - quit twenty years ago.
What she has experienced over the past few winters are two or three UR infections that tend to evolve weeks of hacking cough with wheezing - in other words, an apparent chronic brochitis triggered by these infections. In those periods, she obviously does have sx.
Understanding there is always more to know, is this a pt. more appropriately to be rx’d Advair year-round, or targeted to those periods when she first has a UR infection of the sort that has led to such symptommatic periods in the past.
Or, not at all.
Thanks.
ol cranky
If she has “slightly depressed PFTs” and occasional LR (not UR) infections in the Winter, she sounds like a pretty mild COPDer. Since she’s generally asymptomatic except for occasional exacerbation of bronchitis she’s not a target patient for a LABA at all so Advair would not be an appropriate addition to her drug regimen. To be honest, the description makes her sound like someone who could be well managed with just ipratropium (first line tx for COPD) as needed and antibiotics during exacerbation of the bronchitis. I’m not even sure an inhaled steroid would be warranted either (if so, you could start them about 8 weeks prior to start of Winter and discontinue them in the Spring to cover the short periods during which she seems to experience symptoms on a daily basis).
I don’t see how you can justify prescribing LABAs for someone who doesn’t require rescue albuterol at least couple of times/day. To prescribe them for anyone who doesn’t need to use a bronchodilator on a daily basis is even worse.
Justice in Michigan
Thanks, OC. This person owns Albuterol, but essentially never uses it.
I think the notion of rx’ing Advair year-round (yes, this is a real person) was that it would somehow “slow progression.” However, as I understand it, the only evidence we have of slowed progression is the TORCH study, people with advanced disease using the highest dose.
Personally, it seemed dubious to me that the combined risk of a LABA and chronic steroid use would outweigh that seemingly hypothetical benefit for someone like this. But I’m no doc.
Salmon
OC
I am not current with pulmonary diseases at all but your comment about AZ “pissing off the FDA at the direction of the powers based in Lund” struck me. In my experience it’s not just AZ but this is common with a number of the EU based companies. If they don’t have a good US presence and are run mainly from the home office the common attitude seems to be why the h*** should we bother to pay attention to what the FDA advises. We’ll do what we want to do and they better just accept it. Then they scream bloody murder when the NA letter comes back telling them that the studies were deficient in exactly the way they were advised several years before.
This of course also holds for US companies, but at least they have the sense not to indicate so it strongly straight to the reviewers faces.
Opinions are my own.
ol cranky
Justice:
The big question is whether she used the albuterol on at least a daily basis (preferably more than once/day) prior to being prescribed the Advair. It’s been a really long time since I worked on drugs for asthma or COPD but, if I recall correctly, the analysis that showed advair slowed the natural progression of COPD was done as a post-hoc analysis. The study was not powered for this analysis and I’m not sure if the differences in the decrease in FEV1 were clinically significant (something can be statistically significant but not clinically significant). Any actual utility (risk:benefit ratio) to our friend would really depend on what her actual clinical status was (and her response to the medication).
Justice in Michigan
Thanks, OC. Yes, your understanding of the TORCH study accords with mine. In any event, fyi, she may have used albuterol on a daily basis when she was a few weeks into one of the bronchitis episodes - probably for a week or so - but not more. If she did, it was more because it was rx’d than because it was sorely needed.