Will J&J Do the Right Study?
By this question, I am really asking whether Scios/JandJ truly want to know whether the drug is safe. At this point, I don't consider this an issue for the FDA. Let's ask the CEO, do you want to know? Do you really want to know?
Maybe I should ask this way...
You do want to know with a high degree of confidence that your drug doesn't hurt people, don't you?
If the answer is yes, as it should be, it's simple. Put aside $20-40 million right now, today. Declare to your customers that you want to show everyone that you care, that you want to prove the safety of the drug beyond doubt. It may seem like a lot of money, but even if such a move slows sales by $200 million a year, and it takes two years to find the answer, it still is less than $250 million a year for two years for a company with $40 billion sales per year. That is like you or me spending a few thousand to make sure that people won't be hurt by the drug (i.e., killed).
If the supporters of JandJ are right, this investment will yield incredible increase in sales. The amazing thing is that Scios/JandJ knew about these data raising concerns about safety by 2001. We'd know whether it was safe or not by now if they had done the right thing then.
Talk about this with doctors, patients and anyone else who is interested. Maybe that will convince them to do the study now, and do it quickly, instead of just starting slowly and letting it drag on for 4 or 5 years, getting the answer as the patent expires!
Interesting Spin by J and J
Amazing to watch "damage control" in action. In response to the publication of our study in Circulation, Scios/J&J have enlisted the help of some of the smartest people in the field (I hope). Their responses focus on the fact that we included data from doses higher than are the recommended starting doses. This is true.
We included all the data that they used to get the drug approved by the FDA. I re-read the transcript of their public meetings from 1999 and 2001. I can't find one point where a representative of Scios asked the FDA to ignore any of these studies. Scios used all the studies to support their view that the drug was safe and effective.
So now they don't want some of these studies to be included in this independent safety analysis.
The company can't have it both ways. If you want to use all the data to get your drug approved (as you should), then you can't back away from most of your data for convenience, as they are doing now.
Bottom line: the drug probably has significant risk, and until they complete an appropriate mortality trial, nesiritide should not be used until a combination of diuretics and nitroglycerin prove inadequate.
Will Doctors Pay Attention?
Hopefully, at least a few will. For over 2 years, I have heard consistent comments from my peers finding fault with my view that nesiritide (Natrecor tm) could be dangerous. Now there is a publication in the pre-eminent cardiology journal, Circulation, based on our work. (you can read the report in the NY Times, Detroit News or at Forbes.com) Of course, it really is not something for which I deserve the bulk of the credit. So I want to thank those who allowed this observation to be made.
First, thanks to Scios/J&J. They did the studies that identified the risk of worsening kidney function, the harbinger of marked increased risk. Without them, I could not even have asked the question of whether the brief improvement in symptoms that nesiritide produces are worth the possibility that risk of death may be increased so markedly in the subsequent weeks and months. This is not "tongue-in-cheek" stuff. They did the initial studies very carefully. It's just that for some reason they did not do the appropriate follow-up studies.
Second, the investigators and patients, without whom the studies could not have been done.
Third, the FDA, for making so much information available for anyone with any curiosity to find. We all find things to do to fill our time, that's easy. But spending an extra hour or two looking up the information about a medicine on the FDA website does not seem to be all than much for a patient to expect a doctor to do. (Why not offer your doctor to pay cash and collect the insurance payment yourself for the next three visits in return for your doctor looking up all the relevant information about the medicines you are taking?)
Finally, there are several of my peers who have been supportive of my efforts. The guidance and encouragement have been invaluable. You know who you are.
Now, we need to get the definitive studies started. If we do that now, perhaps we'll know how, when and in whom to use nesiritide by 2007 or 2008.
Danger Appears Associated with Nesiritide
Today at 4pm, the results of an important study will be posted on the website of the medical journal Circulation, the official journal of the American Heart Association.
This study shows a troubling association between the use of nesiritide (NatrecorTM) and worsening kidney function. It is well recognized in the medical community that worsening kidney function typically means there is a higher risk of death subsequently. I can't prove that is the case for nesiritide, especially since the manufacturer of this medicine has refused to let me ask any questions based on their data. (I asked several tims in the past.) But they have known about this possibility since 1999, it seems to me, and certainly since 2001. In late 2003, they acknowledged it in a press release.
Perhaps the publication of this manuscript will provide some momentum to force the company to acknowleged that this risk is important to people getting the medicine and even fund an appropriate trial to prove its significance (or perhaps prove that the association we report is a statistical fluke). None of their on-going studies address this concern, though they assert they do.
By 4pm today, just follow this link to see the manuscript, and hopefully become part of the concern that forces the right thing to be done. Understand, I do not believe this drug should be pulled from the market. It can have potent effects when a person is critically ill with no other option. But it's safety is not equivalent to the old drugs, including nitroglycerin, milrinone or simply diuretics. Those should be used first.
Read the paper from Circulation, the official journal of the American Heart Association before using nesiritide for the treatment of acutely decompensated heart failure.
Am I Naive?
I suppose I am. After all, perhaps I should expect people to be angry with me.
A fortune 500 company is selling a medicine that is touted by many of my peers as a breakthrough medicine. While it does not generate enough money to affect the bottom line, and therefore, any problems with the drug are unlikely to affect the stock value, there are many people whose livelihood relates to the use of this medicine. If information is revealed that casts doubt on the safety of a medicine, sales are likely to be affected in a way that could impact many people working for this big pharmaceutical company. Many doctors may feel obligated to publically acknowledge that their strong endorsement for the past 2-3 years may have been premature.
So when I started my investigation of this medicine, my goal was pretty simple: get a clinical trial performed to determine whether the data that suggested the possibility of risk was right or wrong. Merely because there was no proof of danger does not mean a drug is safe if no one ever looks to see if there is danger. We should be smart enough to realize that.
Yet several events are starting to make me a bit nervous about the events that could soon unfold. First, I was told (though it is hearsay) that part of a company sponsored teleconference within the past year or so included a discussion focused on defining my goals. Here is evidence I was definitely naive. I figured they would take me at my word, that I wanted to prod them into doing a definitive study. (They say they are doing a study that will answer the question of safety, but in fact, the current study evaluates the effect of the drug in a group of patients that are different than the ones that appear to be at risk.) More recently, a colleague told me that an employee of the company stated very clearly that there were ramifications to what was being done, that is, things that would happen as a result of the studies we are publishing this Spring.
It's hard to imagine that I could do much to stop a company of this size with these resources. So I suppose I'll need to continue with my naive view and hope that an ethical pharmaceutical company will follow the data, not merely consider the business of health as a business that relates to their own financial health.
Getting Ready
In the next week or two, a scientific paper will be published on line (and in print soon after) in a leading cardiology journal. This journal is the preeminent cardiology journal, and I am very proud that it's the journal where the results of my work with talented colleagues over the last 2.5 years will be published. The journal is so impressed by the importance of this research that there will be an editorial about it.
Now I am not permitted to say where this article will be published or reveal the contents, but if you were to look back over the entries in this blog since November, you will probably be able to guess. The research indicates that a drug that is commonly used appears likely to have some risk; risk previously not appreciated and risk that is quite relevant.
Last week at the American College of Cardiology meeting, a colleague told me that the manufacturer of this medicine is preparing a statement/press release in response to this paper. I'm not sure what it may say, but I am confident that if I focus the discussions on the data, all will work out smoothly.
I'm ready for anything. After all, what could a multibillion dollar company possibly do to me that would be damaging? Especially when they have projected this medicine to reach one billion dollars in annual sales?
The data will be the story. That's where the focus must remain.
