Age-related macular degeneration (AMD) is a major cause of blindness and the wet form is the worst version. So it should be good news that the US FDA just announced its approval for a new biological treatment for it. The drug has shown remarkable effectiveness when injected into the eye, monthly. AMD is caused by the new growth of leaky blood vessels beneath the retina. The drug halts this neovascularization and even results in improvement of vision in a substantial fraction of those treated. It not only thus stops the relentless deterioration of vision that leads to blindness but can reverse its direction.
The drug is a fragment of another drug, Avastin, used to stop new vessel growth in colon cancer. Use for AMD was discovered by US ophthalmologist Philip Rosenfeld who had heard that Genentech, the maker of Avastin (and the new drug, Lucentis), had shown potential for the eye condition. Rosenfeld tried it and soon news was spreading. It is a remarkably inexpensive treatment because one vial of Avastin can be split into many eye doses. All good new, right?
Recently The Guardian exposed the machinations of Genentech in keeping this use of Avantis off the market in the UK:
A major drug company is blocking access to a medicine that is cheaply and effectively saving thousands of people from going blind because it wants to launch a more expensive product on the market.
Ophthalmologists around the world, on their own initiative, are injecting tiny quantities of a colon cancer drug called Avastin into the eyes of patients with wet macular degeneration, a common condition of older age that can lead to severely impaired eyesight and blindness. They report remarkable success at very low cost because one phial can be split and used for dozens of patients.
But Genentech, the company that invented Avastin, does not want it used in this way. Instead it is applying to license a fragment of Avastin, called Lucentis, which is packaged in the tiny quantities suitable for eyes at a higher cost. Speculation in the US suggests it could cost £1,000 per dose instead of less than £10. The company says Lucentis is specifically designed for eyes, with modifications over Avastin, and has been through 10 years of testing to prove it is safe.
Unless Avastin is approved in the UK by the National Institute for Clinical Excellence (Nice) it will not be universally available within the NHS. But because Genentech declines to apply for a licence for this use of Avastin, Nice cannot consider it. In spite of the growing drugs bill of the NHS, it will appraise, and probably approve, Lucentis next year. (Sarah Bosely, The Guardian)
Use of a colon cancer drug for AMD is "off label." To get its use for AMD approved by health insurance (including national health insurance) it needs regulatory approval. But the regulators won't approve it without a formal application from its maker, who now has no incentive to get it approved.
Prof Rosenfeld said the real issue was drug company profits. "This truly is a wonder drug," he said. "This shows both how good they [the drug companies] are and on the flip side, how greedy they are." He would like to see governments fund clinical trials of drugs such as Avastin in the public interest.
[snip]
About 20,000 people are diagnosed with age-related macular degeneration in the UK each year. "From the patient's point of view, if they have an eye condition that deteriorates very quickly, there is no question of waiting," said Professor Wong. "We're talking about days and weeks, rather than months. The question is should we do nothing and say there is no randomised controlled trial to prove Avastin is of value?" He called for primary care trusts to agree to pay for the planned phasing-in of new drugs for the condition.
What's the company's response?
Last night Genentech said its main concern over the use of Avastin to treat eye conditions was patient safety. "While there are some small, single-centre, uncontrolled studies of Avastin being performed, safety data on patients who are treated with Avastin off-label is not being collected in a standard or organised fashion," said a spokeswoman for the company.
Pharmaceutical firms say they need to launch drugs at high prices because of the hundreds of millions of pounds spent on developing them. Critics point out that the company's calculations also include the marketing budget.
Didn't they already do that when they launched Avastin? That development and its costs are over. This is a new market for an existing drug. But they can make that market much more profitable with the new version, which they took the trouble to test for safety.
Here's a bit of the FDA announcement:
"This approval is of great importance for the 155,000 Americans who are diagnosed each year with AMD, a common cause of severe and irreversible vision loss in older adults," said Dr. Andrew von Eschenbach, Acting Commissioner of Food and Drugs. "At a time when our elderly population is rapidly increasing, this product preserves quality of life for those affected by this disease, helping them to regain the ability to participate in everyday activities such as reading and driving." (FDA)
It sounds like it is the quality of life of Genentech investors that is really at issue here. We see which side the FDA is coming down on. We're not blind (yet).
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Not exactly. If you want to market an existing drug for a new indication, you have to formally prove that it's safe and effective for that indication. That's a new and separate development effort, with significant costs (especially in a case like this, where the route of administration is quite different).
From The Guardian's article, one might think Genetech could have simply filed a few extra forms or something to allow NICE to formally approve Avastin for AMD. Not so. Approval for a new indication normally requires randomized, double-blind, placebo-controlled trials proving that the drug works for the new indication. In a case like this, there would also need to be studies on the safety of injecting it into the eye. None of that would have been done when developing Avastin for colon cancer.
I'm not necessarily defending Genetech here; I don't have enough information to judge. I hope you'll agree that they're entitled to recoup the costs of development for AMD. Could they have done so with Avastin? I don't know. Is Lucentis just a cynical effort to game the system? Perhaps. But it's not nearly as clear cut as your post seems to suggest.
quetzal: I think the cost of a clinical trial is far less than the profits the will accrue here. They can also let a government agency bear the cost of the trial if they don't wish to. I don't think clinical trial costs are significant here. How much could it be? $10 million? $20 million? Profits from this will be much larger. Moreover, the basic biology and discovery of these drugs was done with public monies which Genentech paid nothing for.
Your point that the analysis could be considerably more nuanced and detailed is a fair one, but it is hard to imagine it would change the bottom line here. I suppose without doing it that will be an open question.
In other words, you've already made up your mind, and further information is unlikely to change your "bottom line." Thanks for making that clear.
And, no, I'm not defending Genentech either. I agree the whole affair has a bad smell about it. I'm merely echoing qetzal's point that it's a lot more nuanced than you make it out to be. For instance, you're wrong that development costs were over. Lucentin is a fragment of Avastin optimized to penetrate the vitreous humor. You can argue whether such a modification was needed or not for this indication, whether unmodified Avastin itself would have been good enough, and whether this is in fact in reality just a ploy to prevent the use of Avastin at much less cost. Add to that the requirements for more clinical trials, and it's not an insignificant expense. I also have no idea where you got the idea that the drug company could let a regulatory agency bear the cost of a trial if it wanted to. In the U.S. at least, drug companies bear the cost of such clinical trials. Finally, as in one of my previous comments, there aren't yet any good randomized studies to show that Avastin or Lucentis is better than presently existing treatments, either. Avastin may or may not be the "miracle" drug that its adherents make it out to be.
You appear to have fallen prey to the temptation of a simplistic and easy big pharma-bashing post. It may or may not be justified, but the information that you have presented does not allow me one to determine whether it is.
I agree. Last September, SG Cowen projected peak Lucentis sales at $600 million/year. And that's actually down from a previous estimate of $1.1 billion, because of expected competition from off-label use of Avastin!
No doubt the cost of developing Avastin for AMD would never have approached those numbers.
Just for fun though, let's play with some numbers from this article (selected arbitrarily after a Google search). Assume Lucentis will cost $1500/shot. $600 million/year at $1500/shot means 400,000 shots per year. According to the same article, AMD could be treated with Avastin for at most $100/shot. 400,000 shots per year at $100/shot = $40 million per year (peak sales).
I'm pretty sure $40 million/year (max) does not make it worth Genentech's time.
Does that justify charging patients/insurers/society $600 million/year for Lucentis, when they could get the same benefit from Avastin for only $40 million/year? No, but it helps show why it probably isn't worth Genentech's time to pursue Avastin for AMD.
Are you saying Genentech didn't discover Avastin & Lucentis? I tried to find an on-line referece for that, but couldn't. Or, are you talking about the more general work on anti-angiogenesis, VEGF inhibition, etc? I agree the vast majority of that basic science was publicly funded, but I don't see the relevance of that.
I think this is the real solution, except I don't even think Genentech should even get to decide. I see no reason that NIH couldn't sponsor the trials to prove that Avastin is safe & effective for AMD. I don't think Genentech could stop them.
Once that was proven, I see no fundamental reason that insurers (including Medicare) couldn't agree to reimburse Avastin for AMD. If there are some laws or regulations that currently prevent that, they should be changed. (Product liability would probably have to be addressed somehow.)
Even if Genentech is guilty of profiteering here, the real problem is that the system itself allows and even encourages it. Genentech won't pursue Avastin for AMD because the return isn't worth the investment (assuming the numbers above are roughly correct). Lucentis is only worthwhile for them because the system ensures minimal competition from Avastin.
It's not up to Genentech to change the system. It would be nice if they didn't take egregious advantage of it, but that's really another matter.
"Even if Genentech is guilty of profiteering here, the real problem is that the system itself allows and even encourages it... It's not up to Genentech to change the system."
Yeah, but who bought the politicians to ensure the system was designed to encourage profiteering? The best way to change the system is to expose the problems, and it looks to me that Revere is just trying to do that.
Besides, Big Pharma has itself to blame for any kneejerk bashing -- so maybe it is up to Genentech & co to change the system.
P.S. Some of my previous comments assume that Avastin really would be equivalent to Lucentis. As Orac points out, this may not be the case. I don't claim to know. I just wanted to address what could be done if it is true.
Orac: "In other words, you've already made up your mind, and further information is unlikely to change your "bottom line." Thanks for making that clear."
No, I said it's hard to imagine (and qetzal's f/u comment gives some reasons why) but maybe that's a failure in my imagination.
If Genentech wants to make and develop Lucentis to compete with Avastin that's fine. But they shouldn't be obstructing deployment of Avastin so they can make out like a bandit on its competition. You could argue that they are under no obligation to help with a competitor and I think that's a fair criticism of my post because it implies a drug company shouldn't act like a drug company. But then you can't accuse me of reflex drug company bashing, because drug company bashing is accusing them of acting like drug companies, not, as they claim to be, legitimate businesses whose primary goal is the public welfare. For Genentech, a drug is just a dollar's way of making another dollar. If that is what I am accused of saying, I plead guilty.
You agree the whole thing has a bad smell. And I acknowledged I could have made this a more nuanced presentation but thought that was overkill. You obviously think that Genentech might have an argument that my simplistic post ignored. And what might that be?
I don't believe I said the regulatory agency should pay for a clinical trial. One of the main suggestions for regulatory reform is that trials be done by a national institute for the purpose, not drug companies whose record in the clinical trial area has not been sterling. Iin any event, I purposely said a government agency because in fact nothing prevents such a trial from taking place if it is the public interest. NIH funds many intervention trials.
It seems to me the only relevant piece of missing information here is whether Avastin truly works and is safe for treating AMD. Since the trials haven't been done (and this was part of the point of the post, because if they had been done there would be no issue) I could hardly provide you with that information. If we knew this then we could ask if Lucentis was better and whether it is worth the cost. Nobody has developed this information sufficiently for regulatory purposes for this use. Genentech has no incentive to do so, but could have done so. Instead they did a trial for a much more expensive (and profitable) alternative.
You can argue that we expect drug companies to act like that, and in fact qetzal does make that point, which I don't dispute. Is that drug company bashing?
To summarize, you believe my post was crude and simplistic because I don't know that Avastin really works. And I don't know that because neither Genentech nor anyone else has done a Randomized Clincal Trial (RCT). (BTW, how many surgical procedures you do daily have had RCTs? Just asking). But Genentech has done an RCT for a much more expensive competitor they wish to market that would compete with the ophthalmologic use of Avastin. qetzal essentially says, "What do you expect?":
But for me it's not another matter. This is just what I expect, but your response is this is unfair?
Am I missing something here?
Name wrote:
The only part of this that I agree with is that exposing problems is a good step towards correcting them. Which is why I took the time to explain where I think the real problem lies in this case.
The rest is just nonsense. If you believe Big Pharma (including Genentech?) is buying off the politicians, why would you expect them to change the system? Do you similarly think bank robbers should be responsible for putting themselves in jail?
If you agree there's a problem that needs correcting, perhaps you should consider offering solutions. Unsupported accusations and kneejerk Big Pharma bashing solve anything.
Revere:
Look at what you originally wrote:
That's not only biased against Genentech, it's inaccurate. Genentech isn't keeping Avastin off the market for AMD in the UK. It's choosing not to perform the studies that would be required for approval. If the UK health authorities want to approve (& pay for) Avastin for AMD, why don't they just do it? How could Genentech stop them?
It's not Genentech's fault that there's no incentive for them to develop Avastin for AMD. It's unfair for you to blame Genentech for a problem that they're not responsible for.
It may be fair to say they're morally wrong to take advantage of the situation by developing Lucentis.
Orac & Qetzal,
Thanks for turning my stomach on this lovely sunday morning.
"If you agree there's a problem that needs correcting, perhaps you should consider offering solutions. Unsupported accusations and kneejerk Big Pharma bashing solve anything."
EVERYONE sees the problems and the solutions are multitudinous and completely stifled by clinicians and politicians that pharma bought off. Unsupported accusations? Do you not think the track record has been FIRMLY established?
I'm so glad I got out of that business. Sleeping at night is a wonderful ability.
qetzal: I'll concede I made some inferences here, and while traumatized suggests why the inferences are justified), they are just inferences. I agree with Orac that it smells bad and together with other behavior of Big Pharma (and I am including Genentech in that group although one can argue about size criteria if so inclined) I made the inference which I did not nail down tightly in the post. All true.
This is a blog, but that's not an excuse for unfair or unsupported statements. I am not conceding what I have said is either unfair or unsupported but clealry there is room for argument, which I welcome. Because it's a blog post it is not supported in the same fashion as a legal brief or an academic paper. I have sketched some of the reasons I think it both supportable and fair.
I am not blaming Genentech for a situation they are not responsible for. The situation is that they can make much more money if they develop and market a drug which may or may not be better (or sufficiently better) than Avastin and they are doing it in a way that makes it difficult for Avastin to be used for AMD in the UK and in the US. The US and UK governments could remedy that.
Your comment is correct that it is not Genentech's responsibility to make sure Avastin is available for that purpose. I don't disagree. I only wish, then, that the nature of their business was portrayed for what it is, just a way to make a buck. Then they could dispense with the high minded rhetoric they use to justify what are, by any measure, obscene profits.
We know Big Pharma has been active pressuring the US gov. to protect their so-called property rights in ways that harm public health, especially in developing countries. For that reason I have no spontaneous sympathy for them nor any tendency to give them the benefit of the doubt. If that is what you mean by a "knee jerk" reaction, I am guilty.
Just to point out a common misconception.
To my knowledge, no health insurer (at least in the US), uses FDA approved indications to guide their coverage of various drugs.
Most use the US Pharmacopia manual, which lists off-label use with varing levels of support and evidence. Certainly, some drug companies may require Class I (double blind) evidence whereas others may accept Class III or IV (retrospective studies, community usage), but none I'm aware of (including Medicare & Medicaid) limits the usuage to FDA approved purposes.
There are some real issues with Multiple Dose Vials of injected opthalmic medicines -- for instance, the risk of infection (in an already weakened eye), is much higher. That being said, a single dose vial of Avastin would require that Genetech would go through the entire approval process (hypothetical -- getting a 0.5mg SDV approved when minimum approved dosage is 20mg would be a problem).
Now, whether or not the difference in pricing, ~2400 / dose, is worth it, I think most of us can say NO -- certainly from a public health perspective. Currently however, Genetech's responsibility is to charge as much as they can to maxamise their profits -- even if they give a significant amount away through patient assistant programs. If we don't like this, we should change the regulatory structure (patents, FDA process, etc)around big pharma, rather than blaming the execs who are doing their job to the shareholders.
"I am not blaming Genentech for a situation they are not responsible for. The situation is that they can make much more money if they develop and market a drug which may or may not be better (or sufficiently better) than Avastin and they are doing it in a way that makes it difficult for Avastin to be used for AMD in the UK and in the US."[emphasis added]
Sorry, I still don't see the basis for the last part of that statement. What is Genentech doing that makes it more difficult to use Avastin for AMD in the UK and in the US? How are they "obstructing deployment of Avastin so they can make out like a bandit on its competition?" (Other than not pursuing it themselves, of course.)
This is where I think you are unfairly blaming Genentech. I'm not trying to be contrary. I honestly don't see a basis for this claim. Please explain?
I think this is an important point to clear up. Let's assume that Avastin is, in fact, a very effective treatment for AMD that could cost as little as $20-100/month. Surely the best outcome to patients and society is to make it as widely available for AMD as we can. If Genentech is actively impeding that, as you suggest, then by all means let's try to do something about it.
But if, as I claim, Genentech is not the real problem in this situation, it's quite counterproductive to continue blaming them, because it distracts from addressing the real problem.
BTW, I appreciate your reasoned replies. I certainly don't object to you being skeptical of big pharma's motives, and yes, I think it's fair to include Genentech in big pharma (by size and sales, anyway). Pharma is clearly in business to make money, and I agree their statements about serving the public welfare are really just puffery. Pharma is clearly not above influencing the political process for their own benefit. Unfortunately, I don't think traumatized's approach of saying "Big Pharma is so evil, it nauseates me!" will solve anything.
Dan: Thanks for the clarifications. I did have the misconception that FDA approval was usually a prerequisite for reimbursement, so I stand corrected. I think the situation in the UK with the NHS is different.
qetzal: Yes, you make a good point. I yield on it. I am suspicious by nature when it comes to Big Pharma because I have seen a great deal of incredibly bad stuff, which makes it easy to believe much else. Whether Genentech has really acted badly in this instance does remain something to show and I feel chastened on that score.
This is a bit off-topic, but I want to address a point made by John R. Insurance companies most certainly do use FDA indications when making decisions about coverage for prescription medication. At least, they do so when thay think it is to their advantage. A case in point: two mid-sized HMOs have refused to cover the use of methylphenidate to potentiate the effect of antidepressants. There are dozens of papers on the subject, and the usage is promoted in several textbooks.
Now, I cannot say exactly why they made the decision they did, but I can say what they say about it. They say explicitly that they do not cover it because it is not an approved indication.
Joseph,
I certainly can't dispute that some insurance companies use that as their justification -- but I would be surprised if that reasoning permeated their entire formulary. I should have been clearer in indicating that FDA approval for a certain use is not the only (or even most significant) criteria used.
Quite often, FDA approval for a specific use is seen as a defacto proxy that a drug is no longer considered experimental, and thus approval is automatic. But many drugs are approved for uses by insurance companies where the FDA has not approved them.
There is a large grey area between "experimental" and "covered" use. For instance, the FDA approved use for naproxen (Anaprox) is fairly limited -- it is not approved for relief of migraines, as a fever reducer, etc., but I know of no insurance companies that limit it to osteoarthritis, rheumatoid arthritis, and acute gout. The line where a specific use passes from "experimental" to normal use can be fraught with arguments.
Finally, in the US drug approval for a specific use can be sought by anyone -- not just the drug company. Claritin was moved to an OTC drug due to an application by Kaiser and United Health Care -- the drug company would have preferred that it stay prescription (at least initially).
I should have noted (before I'm corrected) that OTC naproxen (Aleve) is approved for treatment of migraines and fever. Its prescription counterpart is not.
Approval for a specific use is most often a marketing gimmick of some sort. Although in the last 10-20 years it is becomming more important as issues such as pediatric dosing have become more recongized.
I keep wondering if some legislative protocol would help off-labeling of drugs. Does anyone know if this has been attempted. I'm fairly ignorant in this area.
I want to address a common misconception here. Off label use of drugs is NOT necessarily a 'bad thing' that requires any kind of intervention.
As an example, methotrexate is a drug that has been around for years. In fact I have no idea what its 'on label' indication is, if it has one, but it was originally used as a chemotherapy drug for various cancers.
Methotrexate's most common and most important use now is as a treatment for rheumatoid arthritis. Its value for this was discovered serendipitously and it has never been approved by the FDA for this use (FDA approval defines what the 'indication' for the drug is), but there are a host of studies showing is it effective, and indeed it is now the standard of care for RA.
As another example, there's a drug called gabapentin that was approved by the FDA for control of seizures. Turns out that its a crummy seizure med, but pretty good for some kinds of nerve pain, for which it is now most commonly used.
The point is that 'off-label' use can be a legitimate and important use of a medication. If a drug could only be used for a disease when specifically approved by the FDA for that disease, we would lose a host of very valuable, and in many cases cheaper, treatments.
Steve: You are certainly right that many off-label uses are valuable (although gabapentin is a pretty good anticonvulsant, too). The point of the off-label discussion was its importance for reimbursement via insurance or the NHS in the UK.
April 8, 2009
I have read this thread dated 2006 and I am, today, going to receive my first injection of Avantis. I have not been able to get more recent studies or comments regarding Avantis. I will continue this thread as my results (over three injections) become "transparent".
stuart gilman
I had my first injection of avantis nine daysago. I notice significant improvement in my left eye (wet amd). There is no black spot in the central portion of my vision but I do not see detail. What I see is blurred but I see, whereas I did not see anything before in the central portion of my vision. I have two treatments left, six weeks apart. I am both optimistic and depressed, since so much of the literature is negative and still speaks of amd leading to blindness.
stuart gilman
My comment is addressed to Stuart Gilman: I note that you have begun treatment with Avastin as of April 2009. My wife had her first treatment today. Please leave a comment, reporting on how it is going after your second and third treatments.
I will report on how it is working for my wife.
Milt Poulos
I agree, Wet AMD is hard to face. It's nice to see you taking positives out of it.