Wednesday, April 28, 2010

Pharma Should Not Settle Off-Label Promotional Suits

Major headlines were made when it was announced that AstraZeneca Settles Case Over Marketing of a Drug For $520 Million. This is not the first and will not likely be the last off-label settlement by a drug company. The charges from the Justice Department , which the company denies, claim that Astra Zeneca (from Med Page Today) paid doctors for "ghostwritten journal articles that the named authors did not write and reported studies they did not conduct" and "to give promotional lectures to other health care professionals about unapproved and unaccepted uses" for their drug Seroquel (quetiapine) which is used to treat bipolar disorder. Though ghost written articles may not be the best way to promote your product, they are not illegal. In addition, paying physicians to speak about a product is an FDA approved way for drug companies to discuss their products with practicing providers. These activities were not the problem, its that (the Justice Department claims) they were off-label, not on label promotions.

I blogged about what is meant by labeling a while ago in a post called An Indication For Change. Briefly, a physician can prescribe any FDA approved drug for any reason they want. However, a drug company can only promote (sell) that drug for what the FDA says it can be used for. A great example would be Crestor. Back in November of 2008, I blogged about the results of the Jupiter trial (see Jupiter is Out, and the News is Good! ), which showed that in patients who had relatively normal cholesterol levels but high CRP levels, 20mg of Crestor reduced the risk of heart-related death, heart attacks and other serious cardiac problems by 44%. This was a large, randomized clinical trial with important information and the first real trial showing major benefit when a statin was used as primary prevention for heart disease in people with normal cholesterol levels. Despite the exciting news, the Crestor drug reps couldn't talk about it, even though the study was published, and the results were headlines in every major media outlet. This would have been considered off-label promotion. It wasn't until February 2010, when Crestor was approved for primary prevention of cardiovascular disease by the FDA.

I will admit that I do not write Seroquel, and told many of the AZ drug reps who tried to get me to use this drug, that Seroquel was not really a primary care drug, and they would be better off spending their time speaking with the psychiatrists. However, though I am certain one or two rogue drug reps probably bent the rules here and there, given the previous large settlements by other drug companies, I find it very hard to believe that AZ systematically promoted Seroquel for off-label use. As stated AZ denies these claims.

If this is indeed the case, then I believe AZ should fight the claims by the Justice Department, rather than just pay a fine. If you are really innocent, then you will try to prove your innocence at any cost.

As a physician, I understand what settling a case means. The vast majority of malpractice claims are settled. This is because doctors get nervous when their fate is left to a jury to decide between the rich doctor and the injured patient. For physicians, especially given the cost of litigation, it often makes more sense to settle, admitting no wrong, and get on with your practice then to prove your innocence. However, with pharma's deep pockets, cost should not be an issue. Every time a drug company settles a claim for off label promotion, it is saying to patients and physicians "we are not to be trusted." As part of their settlement, AZ will likely have to send "Dear Doctor" letters to all physicians essentially admitting guilt.

Interestingly, The Wall Street Journal is reporting in a post Whistleblower Twice Over: First Lilly, Now AstraZeneca, that the same person who reported AZ to the government (and will pocket $45 million) previously blew the whistle on Eli Lilly who settled a $1.4 billion for off label promotion (he pocketed up to $100 million for that). The fact that the same person blew the whistle on two companies for the same charge (in my mind) calls the entire off-label promotion scheme into question.

This will not be the last big settlement for off-label promotion. The government makes big bucks on these cases, and the drug companies just write a check when fined. If pharma really want to show physicians, patients and the public that it is just trying to make useful medications to help people and not trying to make a profit any way they can, they should fight these claims as hard as possible.

Sunday, April 18, 2010

Where have all the journalists gone? More bad reporting on Avandia

I thought journalists were supposed to be impartial, report multiple sides of the story, and only use facts. At least in the case of reporting on prescription medications, Avandia in particular, it seems those "rules" no longer apply.

Today the Wall Street Journal announced that the FDA Weights Halting Avandia Safety Study .
They are basing this report on a Letter written to Sen. Grassley on 3/30 by the FDA commissioner in response to Grassley's findings on the FDA's handling of Avandia. If I were a journalist (and I don't pretend to be one), after reading this letter, the headlines I might have suggested to my editor would have been:

FDA to Grassley: You Have to Wait Until July or
FDA seeks Big Gun in Institute of Medicine to Help with Avandia

Nowhere in the 5 page letter does it say ANYTHING about the FDA considering halting an ongoing study. Here is the particular section that the journalists from the Wall Street Journal are basing their headline on:

"I recognize that head to head safety trials can pose challenging ethical questions. On the one hand, such a trial, by its very nature, must be conducted in the face of a safety concern. One the other hand, if one therapy is clearly inferior to the other, then such a trial should not be conducted, because it would place one group of patients at unnecessary risk."

Though the next paragraph mentions that some experts believe that Avandia is inferior to Actos, the paragraph concludes that some experts, in particular the American College of Cardiology and the American Heart Association, have not come to these conclusions.

I implore you to read the entire letter, and read it in the context that the head of the FDA is writing this letter in response to a Senator who wrote a very public and scathing report on how their operation is run. The report does not read, "thank you senator, we were wrong and will consider stopping this dangerous trial." Rather, what the report actually says is that safety is important to the FDA, in 2005 they became aware of a questionable safety issue but decided it did not warrant going public, when it did (with pressure from Sen. Grassley) the FDA met in July 2007 and decided to keep Avandia on the market, there has been new, more robust data since 2007 which seems to indicate that Avandia is safe, and we have already planned (even before the Grassley report came out) to meet this July to review all the data again.

Read in its entirety, the FDA had already planned to review all of the Avandia data, including the TIDE study in July. The letter to Grassley, that the Wall Street Journal is reporting on, gives no indications that these plans have changed or that the FDA is now considering stopping an Avandia study. If anything, in a very subtle way, the FDA is telling Grassley why the study is needed.

Bad reporting on this subject is not new. In my post More Avandia Scare- Again, Unwarranted back in February, I wrote about New York Times piece that broke the story on the Grassely report. While I do believe the story was worth reporting, the Times failed to mention that everything in the report was from 2007. Both the Grassley report and the Times failed to mention that there was new data, specifically the RECORD trial (see For the RECORD, Avandia does not cause heart attacks, Avandia Vindicated, ) which seems to exhonerate Avandia from any heart risk. This is the real story, that a good diabetes drug continues to get bashed in the media, when a very well done study presented almost a year ago has shown in to be safe.

As referenced above, I believe the real story in the FDA commissioner's letter to Grassley is the fact that they are asking the Institute of Medicine to look into the matter. More importantly, they seem to indicate that the IOM's report will be ready by the July 2010 advisory board. My read on this is that the FDA, based on the scientific data available, feels that Avandia is actually a safe drug. However, given the scrutiny and political pressure they are under, likely believes that anything less than a "pull it from the market" recommendation from the July advisory committee will keep it under fire. Thus, they have brought the impartial and well respected IOM on board. The only reason I can think of for doing this is to back them up on a decision in favor of Avandia.

Here's something to think about:
Because of the media storm caused by Avandia, the FDA now requires any new diabetes drug to prove that it does not cause heart attacks before being approved (see Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III ). These criteria are not surprisingly pretty strict. Based on the results of the RECORD trial, Avandia has now met this new standard of cardiovascular safety, now required of all new diabetes drugs. How will the FDA be able to continue to say that there might be a risk, let alone pull the drug and stop a safety study, when Avandia has now met the FDA's rigid cardiovascular safety criteria?

Friday, April 16, 2010

Read "The Estrogen Dilemma" With Caution

There is a piece in the New York Times called "The Estrogen Dilemma" which many women will read with great interest. I would urge women to read this with great caution before jumping to any conclusions.
The article is a well written piece by journalist Cynthia Gorney, who discusses both the controversy of hormone replacement and possible benefit with memory and mood, simultaneously with her own personal medical history. I would imagine many women readers will identify with both Ms. Gorney's depression (since it is so common) and her struggle with the decision whether or not to stay on hormone replacement (since there is so much confusion around the issue).
The article pokes many holes in the landmark Women's Health Initiative (WHI). Prior to this study, many physicians, myself included, were prescribing hormone replacement to perimenopausal and post-menopausal women like candy. We did this because the data on the purported benefits seemed robust, and the data on risks seemed minimal. The WHI proved that making routine decisions without large, randomized clinical trials was not necessarily a good idea. The WHI showed that, at least in the population studied, the risks of hormone replacement (breast cancer) outweighed the benefits (heart attacks turned out to be a risk not a benefit). More importantly, many doctors stopped prescribing hormone replacement because alternatives to protect against heart attacks (statins, aspirin) and osteoporosis (bisphosphonates, calcium, vitamin D) existed and didn't carry the same risks. However, this doesn't mean that the risks/benefit ratio for hormone replacement applies to every women equally. Women who suffer from severe symptoms of menopause, especially with a low risk of breast cancer, would certainly have a risk/benefit ratio favoring hormone replacement.
Gorney's article suggests that perimenopausal mood issues such as depression, memory/attention, as well as prevention of Alzheimer's disease can all be linked to estrogen deficiency, and estrogen replacement just might be the solution. These facts coupled with very real holes in the WHI data regarding women in their late 40's and early 50's (who weren't in the study), suggests that hormone replacement may in fact be just what many women need.
However, the key is the lack of data. Though studies are underway, we do not know whether or not estrogen can help with perimenopausal mood disorders, or even if it does, whether it is any better than other treatment such as anti-depressants. In addition, though there is reason to believe that the dangers found in women in the WHI might not apply to younger women, we do not have data to prove that it is safe. Absence of evidence is not the same thing as evidence of absence (harm).

Bottom Line: Medicine has to be individualized. Every therapy and test, including screening tests like PSA's and mammograms, have risks and benefits. Balancing those risks and benefits is important, and is not the same for every patient. Age, individual risk for disease, personal preference, and symptoms are all important factors. Estrogen may have an important role in mood disorders and memory for women, and may be safe if started in the late 40's and early 50's, but we simply don't know for sure. Estrogen, especially when given with progesterone is definitely linked to breast cancer, and given later in life, increases the risk for heart attacks. If you are a perimenopausal women that identifies with Ms. Gorney, and you think that estrogen replacement may be the miracle cure you are looking for, proceed with caution. Weigh all the available data, risks and benefits before jumping to conclusions from a very well written and emotionally impactful article. Your physician can be very helpful in guiding this decision.

Wednesday, April 14, 2010

FDA Announces End for CFC-Propelled Inhalers

As reported in Med Page Today, the FDA Announces End for CFC-Propelled Inhalers. Of the seven inhalers with deadlines for removal, only three are still being made:

Flunisolide (Aerobid Inhaler System) on June 30, 2011
Albuterol and ipratropium combination (Combivent Inhalation Aerosol) on Dec. 31, 2013
Pirbuterol (Maxair Autohaler) on Dec. 31, 2013

The reason for this is because CFC's are harmful for the environment, and the newer inahlers have to be replaced with a different, more environmentally friendly propellant called hydroflouroalkane or HFA. I have blogged about this previosuly (please see Asthma inhalers and More on Asthma Inhalers ).

According to the FDA, "patients using the inhalers scheduled to be phased out should talk to their health care professional about switching to one of several alternative treatments currently available. Until then, patients should continue using their current inhaler medication."

What you should do:
1. Albuterol If you are taking albuterol, please see my earlier posts. I still have patients that have their very old albuterol canisters, which are probably no longer effective. An important thing to know is that there is no longer any generic albuterol. More importanly, if your physician writes a prescription for albuterol, the pharmacist will likely give you ProAir, which may or may not be what your insurance prefers and/or what is least expensive for you. This is because many of the chain pharmacies are getting a kick back from the makers of ProAir. Make sure your provider writes for the correct inhaler. All things being equal (same co-pay for patients), I recommend Ventolin HFA (because it is the only one with a dose counter) or Xopenex HFA, because of diminished side effects. NEW INFORMATION: GSK, makers of Ventolin HFA sell a $9 inhaler, regardless of your insurance. Though the inhaler has fewer puffs in it, if you are using your inhaler that frequently, then your asthma is not under good control, and you should be on a different controller medication. Ask your doctor for Ventolin HFA 60 (they have to write the 60 part).

2. Maxair- Some patients love this drug, but it's going away. Before January 2014, get another albuterol. See above and previous posts for advice.

3. Aerobid- I didn't even realize they still made this medication. It is no more effective then other similar medications, probably less effective, possibly more side effects, and it tastes nasty. If you are on this medication, switch ASAP to another inhaled steroid. Good alternatives include Flovent, Pulmicort, Asmanex, and Alvesco.

4. Combivent- This will likely affect patients the most, since few patients are on Maxair or Aerobid, and there are far more COPD patients than asthmatics. It is very likely that before January, 2014, the makers of Combivent with come out with a Combivent HFA. However, there are reasons to consider switching now. Please see older posts Good News for COPD , Bad news for COPD: Why this meta-analysis should be believed (and the Avandia one should not) , and UPLIFTing News for COPD

Briefly, a few studies have come out which make me very concerned about using Combivent. One study published in the Annals of Internal Medicine studied a VA population and found that patients taking ipratropium had significantly higher death rate of about 11%. A second study was a meta-analysis published in JAMA that analysed date from 14,783 patients with COPD and found that patients taking either ipratropium or tiotropium (Spiriva) or both had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). Though combined, these studies might cause safety concerns with the entire class of anti-cholinergic inhalers, the UPLIFT trial, a long-term, large randomized controlled trial (4 years, almost 6000 patients) which unfortunately failed to show that Spiriva could decrease that rate of lung function decline, did show about 10% relatively fewer deaths. Thus, though anti-cholinergic medicines may cause some harm, it appears that this is likely mainly for the short acting ipratropium and not for the long acting tiotropium. I would therefore recommend that COPD patients talk to their doctors about stopping their Combivent now and switch to a different controller medication (Advair, Symbicort, Spiriva) and/or switch to albuterol alone as a rescure medication.

Thursday, April 8, 2010

FDA too focused on risks compared to benefits when approving drugs

In my opinion, the pendulum has swung to far in the safety direction when it comes to approving new drugs. Over a decade ago, the reverse was true and medications like Vioxx and Rezulin were approved and prescribed too quickly without either additional studies required before approval or closer follow up after approval. Though a more vigillant approach to safety was certainly needed, now there are many drugs that may never get approval because it appears that the FDA is concerned about virtually any risk at all.

Today, as reported best by Medpage in Panel Votes Against New PDE4 Inhibitor for COPD, despite prior discussions in favor of the drug, the FDA decided not to approve roflumilast (Daxas), a phosphodiesterase 4 (PDE4) inhibitor, for treatment of chronic obstructive pulmonary disease (COPD). Now, I will admit after seeing some of this data, that I was not overly impressed with Daxas. It would never be my "go to" drug for COPD, because we have so many better options such as inhaled corticosteroid/LABA combinations (Advair, Symbicort) and long acting anti-cholinergic agents (Spriva). However, there are still many patients with COPD who take both drugs as well as additional short acting inhalers, and are quite symptomatic. In addition, prior to either of these medications being available, one of the primary treatments for COPD was theophyline, one of the original PDE inhibitors. It had a far worse side effect profile than Daxas (seizures, blood levels needing to be monitored), but was the mainstay of therapy. In fact, there are many doctors still prescribing theophyline today for their COPD; mainly in those patients who can't take or are still symptomatic on the aforementioned inhalers.

Looking at the Daxas data, roflumilast resulted in a significantly greater change in prebronchodilator FEV1, improving it by 48 mL over the course of the study (P<0.0001). This amount of improvement would be minimal for a healthy person or even an asthmatic, but for a patient with COPD, this could be the difference of being able to walk up the stairs or having to live on the first floor. In addition, the number needed to treat to prevent once exacerbation was significant, between 3 and 5. In other words, even though this was not the best medication in the world for COPD, it was certainly beneficial, and would have an important role for patients not well controlled on standard therapy.

Safety concerns were certainly real. A total of 218 cancer/tumor events were reported in 208 patients -- 60% of whom were in the roflumilast group,and 40% of whom were in the placebo group. However, even though there were more cancers in the roflumilast group, many believe these cancers were not caused by the drug because most of the tumors were identified months after treatment, which would be too soon for the drug to have a causative effect. The most common side effect was nausea and diarrhea, and this was the most common reason that the 14% of patients stopped taking the drug. There seemed to be a signal for psychiatric conditions, including suicidality, but again, it is unclear that the drug actually caused this.

Every drug has risks and benefits. My guess is that aspirin would not be approved by the FDA today, since it has an increased risk of GI bleeding, other medications can relieve pain, and the benefit of heart attack and stroke prevention is controversial. The key is to balance these risks and side effects. If there are safer, more effective and similar drugs, then there is no reason to approve a new one. However, in many cases, it is better to have a drug with some known risks associated with it available to patients who have failed other therapies, then to not have the drug available at all. The FDA could have easily approved the Daxas and recommend it for patients who were still symptomatic on more standard therapy. Now, physicians will not have this medication in their tool kit for the select few patients who might actually benefit from the drug.

I believe that because the FDA has come under so much scrutiny regarding drug safety, it has made decisions where risk and benefits were not balanced appropriately. Because of the Avandia scare (which has since been proven to be unwarranted see For the RECORD, Avandia does not cause heart attacks), it is now difficult for any new diabetes drug to be approved. I also recently mentioned how unwarranted safety concerns by the FDA will likely harm far more asthma patients then help (see FDA Blows it on LABA Safety ). When safety or the need to get new drugs on the market is such a major driving force, patients are harmed, regardless of which direction the pendulum is swinging. The safety folks seem to be in the driver's seat and may be harming patients by not giving them access to needed medications. It is time for the FDA to start taking a more balanced approach to approving medications.