Via Suburban Guerilla, there's a link to the Dembot blog, where Andrew Baron posts an open letter to James C. Mullen, the chairman of Biogen, Inc. (the first link is just an excerpt of the second, which includes more detail).
Baron's father has multiple myeloma and is near death. Biogen Idec produces a drug called Tysabri (natalizumab) which might save Andrew's father's life.
In what can only be defined as a miracle in timing, a few days ago, one of his doctors who has been studying his tumor cells in the lab for years found an antibody with an exact match: Tysabri which is manufactured by your company, Biogen Idec. In the test tube, it attached to the antigens on the surface of the tumor 100%.
Tysabri is FDA-approved for use against multiple sclerosis and Crohn's disease, but not for cancer. Biogen refuses to allow the physicians to administer Tysabri in this case.
If this drug was rare, scarce, or if people were waiting in line to obtain it, we would not be expecting any privileges. But the drug is readily available, cheap and even sitting in our clinic’s pharmacy just 6 floors below us right now… . All we need is for you to just say “yes” to save his life.
Normally, a physician can prescribe a drug for any purpose at all - if not for the FDA-approved use, the use is called "off-label", and in the US (or at least most states), the only legal sanctions a physician might face for an off-label prescription would be in the liability/malpractice area. I take two prescription drugs, and both are for off-label applications (and seem to be working).
But apparently in this case, Biogen is able to legally restrict the use of the drug to only its FDA-approved uses. Since the drug is already sitting in the clinic's pharmacy, this is not an issue of physical property rights. It's an issue of intellectual property rights - licensing attached to the product, just like a software license, the MLB/NFL prohibitions on using their broadcasts for anything but home viewing, or the "FBI Warning" on DVDs and tapes. Biogen just says "no".
Now perhaps it'd be understandable if Baron's request was refused. Refusing a request from doctors at the Mayo Clinic is a little more perplexing. Lance Armstrong called Biogen and was told "no". Bill Clinton was told "no", as were Kerry, Kennedy and other Senators. The head of the FDA personally approved the use, and was still told "no" by Biogen.
You'd wonder why, after the requests of all those people, Biogen would still say "no". You might think it was because Biogen doesn't think Tysabri could ever be useful against cancer - but they're planning their own trials using the drug to treat multiple myeloma. It's hard to find a reason for Biogen's refusal. Perhaps there is some economic self-interest that Biogen feels is at stake, but you wouldn't think they'd allow someone to die over that, would you?
Why is this a big deal? There is a lot of commonality between the biochemistry of autoimmune/inflammatory diseases like MS, Crohn's disease, and aortic aneurysm and some forms of cancer. For example, the antibiotic doxycycline is used off-label to possibly reduce aneurysm growth, ameliorate MS, and perhaps as a prophylactic against colon cancer. All those uses are indicated by some lab reasearch, but none has been established as an effective treatment - the same as in the situation here.
Similarly, there are examples in the literature of compounds which can actually cure one condtion in mice, but are being investigated for use against other conditions which provide a much larger market. The same issue could arise over and over again if drug-makers are allowed to dictate how their products are used.
The bottom line is that allowing drug-makers to decide on medical treatments is no different than allowing insurance companies to make life-or-death decisions. In both cases, the self-interest of the companies is not necessarily the patient's best interests - those decisions are best left to someone whose interests do align with the patients. That would be the patient's physicians.
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One possible reason- liability
Some companies have gotten nailed big time for off-label use. Wyeth got hammered to the tune of $36 billion because some physicians prescribed phen-fen. Very, very few people were harmed by phen-fen but class action lawyers made out like bandits and it has had a profound impact on the way the company does business. If you were a pharmaceutical company facing those kinds of lawsuits with that much money at stake, you too would slam the brakes on any off label testing. Without going through clinical trials first, it is very risky for the company. Maybe they think their bottom line can't afford to take that kind of risk.
If they're planning their own trials, the best bet is to try to get the patient into one.
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I doubt it
Not when the head of the FDA approves the use. Biogen could ask for a liability waiver.
The patient had 24-48 hours to live - trials probably aren't an option.
FDA has nothing to do with liability release
It has never prevented anybody from suing the company
Sure, but
what other liability would Biogen have other than an off-label use, which has now been blessed?
It's not their decision to administer it (if they'd allow it), it's requested by the patient (or his attorney-in-fact) and his physicians, and therefore presumably a well-informed decision, the drug is presumably pure (it's in the clinic, and they're liable for mfg defects no matter what), they're not claiming it's an appropriate use, and they could ask everyone involved to sign a liability waiver.
In fact were it not for the peculiarity of this drug that allowed Biogen to determine its use, there probably wouldn't have been anything they could have done to stop it.
Liability to stockholders (some issue of profitability or whatever) might be a different issue - but not one worth someone's life. And it's a pretty big stretch anyway.
Were it my father, they'd be facing a big wrongful death liability suit by denying the use of the drug, particularly if their own trials later prove its efficacy. That would lead me to think that there's a lot more money than a single possible settlement at stake here, and that's what Biogen's reason is. But I don't know that.
Damn, I just wrote a long post about this and lost it
The issue here is not just legal. We are not talking about a drug blocking a unique marker on this patient's cells. This is a drug that works by blocking an adhesion molecule (I can go into a long tangent on adhesion molecules, but you will all be bored to death) that is expressed on a large number of various cells in the body. There is little indication that this drug will help and not hurt in this particular case. This drug has been pulled off the market in the past for adverse interactions with immunomodulating drugs (guess what chemotherapy is) and causing progressive multifocal leukoencephalopathy (aggressive immune cell infiltration in the brain). The patient has 24-48 hours to live, cellular responses take hours in a culture dish and days in the organism. The drug is not a magic cure, there is not likely to be an improvement, but a very high likelihood of adverse effect and diminishment of quality of life (however short it is). It is a desperate attempt by a devastated family member (my heart goes out to him), and an extremely unethical move on the physician's part.
Commissioner of the FDA, Andrew C. von Eschenbach, has nothing to loose giving his approval, he probably did not even read the documents.
That's an entirely separate issue
Whether the drug works or not is certainly an interesting technical issue, but the facts here are that
a. Doctors at the Mayo Clinic see research pointing to the efficacy of this use
b. They recommend it with the patient's informed consent
c. Additionally, Biogen seems to think it's efficacious - I doubt they spend money on clinical trials in a shotgun manner or "just for fun".
That would seem to make it more likely to be successful than something like, say, laetrile. At least the assumption of success is based on something more than pseudo-science, if something less than scientific certainty.
So again, whether you think it'll work, whether Biogen thinks it'll work (and they seem to) - neither is an issue.
The issue is who decides if available resources are used in the treatment of someone's illness. I'd prefer it was my physician, rather than you, Biogen, or an insurance company.
Let me address this point by point
a. Doctors at Mayo Clinic (I don't mean all, just the resident/fellow/whoever who stained for the marker, and read a couple of abstracts) see an opportunity to publish. There are a only a handful papers that suggest that there might be some effect of anti-integrin a4 antibody in mouse models and in in vitro models. see PubMed
b. To give informed consent a patient needs to understand how the drug works, what researches are expecting to see, what are the possible adverse effects, etc. Since nobody understands what will happen in this case, there can not be informed consent.
c. It's a speculation about Biogen doing clinical trials with Natalizumab for multiple myeloma. They don't have it listed in their drug pipeline: http://www.biogenidec.com/site/pipeline...., which means they are not even doing IND-enabling research studies for this indication. Drug companies love putting stuff in their pipeline as soon as they can to keep investors happy.
Well ...
a. Motives don't necessarily make research valid or invalid. If that were the case, we'd throw most research out. But again, that doesn't have a lot of bearing on who decides - it's one factor in evaluating whether the decision is rational.
b. For a patient to understand how a drug works, researchers need to understand how a drug works. In a lot of cases, that understanding is a relatively recent phenomenon. For example, when my doctor asks me how I'm doing quitting smoking with the bupropion (Zyban, Wellbutrin) she prescribed, she invariably points out that "we don't really know how it works". Works pretty well though (Yes, I've read the speculation on the mechanism).
Similarly, there's a huge Canadian population study that indicates patients with abdominal aortic aneurysms (AAA) who take ACE inhibitors are significantly less likely to experience an aneurysm rupture (i.e. - die) than patients taking other blood pressure meds or no BP meds.
The effect is, in at least one paper, thought to be possibly related to MMP supression, but there isn't even real certainty that MMP levels are related to aneurysm growth or stability (it certainly seems very likely, but I haven't seen an article that flat out states it - most see it as a tentative conclusion).
So you're suggesting that if I have an AAA, my taking an ACE inhibitor is misinformed, because no one, including me, understands how the drug works? Or I shouldn't refuse a calcium channel blocker because there's only one small study that shows an increased risk of rupture with those, and nobody knows that mechanism either?
I don't think that's a real argument either. A lot of (most?) medical decisions come down to a evaluation of probabilities or a best guess or "try this and see if it works", and not certain knowledge.
c. This link, which is in the original post ("their own trials" - maybe easy to miss) is from the Boston Globe and has the headline Biogen Idec testing Tysabri as a cancer treatment
I did miss your link, sorry
For you point b - informed consent issue does not apply. This is between you and your physician, you are not participating in the clinical trial or a research study nor are you directly involved with the company producing the drug. The physician takes it upon themselves to prescribe off label use, and you take the risk of trusting your physician. In your case, you and your physician are running your own little experiment
Main mechanisms of actions for Bupropion are well known, it is also understood why it works for smoking cessation.
MMP (Which MMPs? There are a several of them. The quick search I did, suggests that we are talking about MMP-9) are absolutely involved in angiogenesis, any type of wound healing, tissue stability and remodeling - not really that unknown to researcher, but may be to the physicians. There is solid data that some ACE inhibitors (specifically lisinopril) does inhibit MMP9. This most likely accounts for some anti-fibrotic (see fibrosis) effects of ACE inhibitors. But MMP and their involvement in tissue remodeling is not a simple matter, there are many more players in that game. You take you chances with the best available information.
MMP-9 mostly, MMP-2 and
as you indicate, lots of others - other MMPs and non-MMPs as well. There are also some indications that MMP-9 isn't relevant and some other action is responsible - again, as you indicate, it isn't a simple matter. All of the studies have been fairly small, or in rodents, and it's likely that AAAs have multiple causes.
I was responding to "a patient needs to understand how the drug works, what researches are expecting to see, what are the possible adverse effects, etc.". My doctor and I certainly are running an experiment (at my instigation), it seems to be working, and that's the privilege or right I wouldn't want to lose. But I wouldn't go so far as to say either of us (or anyone) completely understands how the drugs work, or even if they do for certain.
Your experiment does not require you to sign
an informed consent form - you are the instigator of the experiment. If your physician was running a study or trial that involved Institutional Review Process and patient recruitment, this physician would be required to provide informed consent that I described.
Have you and your physician ever considered mast cell stabilizers?*
*I am not a physician, just a cell biologist**
**I am not affiliated in any way, shape or form with Biogen or Elan
Looks like I lost a reply too
Anyway, what I talked my doctor into (which was fairly easy) was bupropion for smoking cessation, an ACE inhibitor (I have moderately elevated BP, but bad white-coat hypertension, so that was easy to get prescribed), and doxycycline (which is one focus of research - either as an MMP-9 inhibitor or some other mechanism). Plus multi-vitamins for copper availability and lowering homocysteines, both of which might enhance matrix repair. She threw in low dose aspirin, which may also help.
Those were the best research indications, I thought, as well as the lowest side-effect meds, and available in generics.
I've had one ultrasound after starting that - 6 months - and no change in aneurysm size. If that holds for 2 or 3 years, I'll be more convinced all that's working.
I just did a quick look at mast cells (and I'm not a cell biologist). It looks like there are indications of mast cell involvement. I didn't find any therapeutic recommendations, and most of the research was in mice. I did find some indications that doxycycline might also inhibit the impact of mast cells. There was also one article that indicated chymases produced by mast cells could replace angiotensin conversion enzyme in the production of angiotensin II. The connections seem to overlap a lot, making it difficult to isolate exact mechanisms.
I'll have to look into it more - kind of late now.
Badger, hopefully we can continue this discussion
when I have a bit more time to tell you about mast cells (and other tissue repair), and why I think they might be important to consider outside of ACE. They are rather complex, and multiple mechanisms and programs are at play.
That would be cool
I actually didn't plan to get off on this tangent, but obviously I have reason to be interested.
Sorry to burst your bubble but...
...class action lawsuits have had a devastating effect on R&D. The propensity of people to sue even when they aren't injured has made many companies risk averse. No one is taking any chances anymore.
I'm sure that a lot of patients will suffer for it but with increased calls for rigor and zero side effects comes caution to the point of strangulation. And there is no indication of how far is too far. No drug is perfect. They all involve risks but the country has been screaming for risk free drugs for years now and handing down very punitive verdicts. Many companies have been forced to withdraw their drugs from market. It's very expensive and has lead to a lot of downsizing and outsourcing. But consumers aren't thinking about that. They want what they want when they want it and sometimes when they get it, they sue.
A company can't be too careful these days. The phen-fen thing was started by a report from the Mayo clinic on a handful of patients who had heart valve problems but later were found to have recovered over time. The company didn't package the drugs together. Using them together was off-label usage. Physicians prescribed them together. But it was the company, not the physicians that got socked with the $36 billion price tag. It's a cautionary tale and I am not in the least little bit surprised that it has come back to haunt us. I feel really bad for the patient in this case and his family but there was going to be a day of reckoning sooner or later over the lawsuit industry.
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I'd like to see something to back that up
because open-heart surgery is outside my definition of "recovered over time".
The rest of the story linked is interesting, because it doesn't seem to line up with what you're claiming (it appears the woman profiled was taking only Wyeth's Redux, not the fen-phen combination). I haven't been able to find anything that says that Wyeth set aside more than $21B (which is still a lot of money around our house), not $36B, and nothing that supports your narrative.
And I still fail to see any liability issues in the case I cited. If you want to discuss the liability issue, it would make more sense to do it in terms of a situation where it's relevant.
Wrong target
Andrew Baron is being given the runaround by his father's physicians and the Mayo Clinic. They are the ones with the power and the ability to administer treatment, not BioGen and not the head of the FDA.
Both Federal law and Minnesota state law recognize the responsibility of a physician to treat a patient in dire circumstances with the best available methods regardless of formal indications or restrictions. Little paperwork is involved and only verbal prior approval from the chair of the institutional human research committee is required. This approach to treatment is called "Emergency Use" and here is an example of the protocol.
There are major mitigating considerations here however. If the clinical situation is as dire as reported, then tartu's analysis is almost assuredly correct and this treatment will not effect a cure. Severe adverse consequences have been seen with the drug Tysabri, as tartu noted, and the drug was taken off the market under FDA direction. It took BioGen two years and much money to get it back on the market, but FDA insisted on a regime that sharply restricts the drug's use. Neither the CEO of BioGen nor the head of the FDA can suspend those rules; it requires a process that consumes many months to do that.
The power lies with the treating physician and the hospital administration, and that is where the holdup is. To the extent they have directed Mr. Baron elsewhere to seek "approval" they are misinforming him. The power - and the responsibility for any outcome - rest with them alone and they are apparently unwilling to assume that.
This is not a case of corporate greed on the part of Big Pharma, or a matter of a cold-hearted CEO. It is a far more complex issue for which there is only one solution and that would be boldness on the part of the treating physicians and institution. Unfortunately, and I speak here with extensive first-hand knowledge, the Mayo Clinic culture discourages boldness. As a culture, they are extremely risk-adverse.
Another option that
avoidsobviates the need for the Emergency Use approach, not that I would have any first-hand knowledge of it but so I've heard, is to make a diagnosis of a disease for which Tysabri is approved and freely available - such as MS, the symptoms for which are often vague and all but imperceptable. Under current restrictions an MRI is required but this is only a formality. If treatment is unsuccessful and the patient expires from his MM, no harm is done. If the patient recovers, oh happy day, it will then be discovered that the diagnosis of MS was incorrect; misdiagnoses happen all the time and in this case no harm no foul.The only problem would be if the patient shows signs of recovery from MM but suffers harmful complications from the administration of Tysabri - quite possible, considering the drug's history. This is the risk the hospital and the doctors are unwilling to assume, and where they will be looking for legal reassurance. Unfortunately, in cases like this no ironclad reassurances can be given.
It is a very sad time, and my sympathies go out to the patient and his loved ones. But the blame such as it is for failure to treat lies not with BioGen or FDA but with the clinicians. They are the ones who need to be pressed, and if they decide that the treatment risk far outweighs the gain then that will be the best available medical judgement and it really is not anyone else's place to second-guess.
You would have saved a lot of time
had you read the links.
From the letter linked:
and
It seems unlikely the head of the FDA would be talking to Biogen about it if the scenario you pose (based purely on speculation) were true.
Restricted prescription use due to FDA
http://www.tysabri.com/
http://www.tysabri.com/tysbProject/tysb....
It seems they have it on the shelf
in the pharmacy, so I'd assume they've qualified for that.
I could only guess that "patients enrolled" is related to diagnosis and Biogen's approval. And "developed with the help of the [FDA]" is a lot different than "administered or enforced by the FDA" in terms of who decides.
I have some time, and I can read
Andrew Baron is in error about who to hold responsible, and I did make the assumption that it is a result of being mislead. Considering the circumstances, I'll stick with being non-judgmental about his motivations here.
The reason those restrictions are in place is that they are part and parcel of the regulatory filing approval terms that restrict the drug's use. Those terms, covering prescribed use for MS and Crohns as well as the clinical trial for MM, are the result of prolonged, multi-year negotiations between FDA and BioGen.
From a legal construct, the terms are BioGen's. From a practical standpoint, however, the restrictions are imposed by FDA; they would not approve the filings unless the restrictions were included.
Baron is correct in his assessment that there is no shortcut around those restrictions. Neither BioGen nor FDA can shortcircuit the approval process for either expanding applications - not possible without evidence of both safety and efficacy - or as an exception to the terms of the clinical trial, a can of worms that neither of them want to open and that would by law take many months at least to conclude.
B: It seems unlikely the head of the FDA would be talking to Biogen about it if the scenario you pose (based purely on speculation) were true.
It is entirely likely. Both Andrew Baron and his father are seriously connected within the Democratic Party, and it appears that the next president will be a Democrat. If you were the head of FDA and wanted to keep your job, would you under pressure from all the big Democratic power brokers be likely write a meaningless letter to BioGen to show that you'd done everything possible? Doesn't change anything from a practical standpoint but politically you can call back those pressuring you and say "Look, I've done all I can do" and shift the blame to BioGen. But BioGen can't do anything unilateral to change the restrictions either, and so there it sits.
I'm not writing here from speculation, badger; I made a very nice living over 30 years in part by designing and managing clinical trials as well as shepherding marketing applications through FDA. I'm well aware of the processes, their limitations and their restrictions. The only way this patient gets this drug is if the treating physicians and institution have the courage to give it to him. Blaming BioGen will not mitigate that fact.
But once again
Baron says:
That would seem to imply that von Eschenbach can grant special approval, but that Biogen is ignoring it.
It's a helluva system where a physician or institution has to "have the courage" to use a drug that's been approved by the FDA (even with "conditions", which don't seem especially relevant in a terminal case) for human use. It's also a little cavalier to talk about "courage" without knowing specifically what the consequences might be (and I don't, so I'll speculate).
It appears that to get the drug for other patients with approved conditions - which Mayo Clinic certainly has - the clinic has to qualify for a program administered by Biogen, where presumably Biogen can disqualify them for cause. In that case, it isn't courage but weighing the life of one patient against the quality of life of perhaps hundreds of patients. Which would make the position of the physicians and clinic fairly clear, and also indicate that in the end it's still Biogen standing in the way.
There's no doubt from the list of names in the letter that the Barons are well-connected - how much worse off does that make a patient who isn't?
I stand by my comment
Fen-phen was not Redux.
The suit began when heart valve problems were observed in some obese patients on the drug combination.
The initial amount continued to climb and had reached $36 billion last time I checked with someone who still works for the company.
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