90% Of Preclinical Cancer Research Is Not Reproducable

Oh my:

In their Comment article 'Raise standards for preclinical cancer research', C. Glenn Begley and Lee Ellis (Nature 483, 531–533; 2012) refer to scientists at Amgen who were able to reproduce findings in only 11% of 53 published papers. Several correspondents have asked for details of these studies, which were not provided in the article.

The Amgen scientists approached the papers' original authors to discuss findings and sometimes borrowed materials to repeat the experiments. In some cases, those authors required them to sign an agreement that they would not disclose their findings about specific papers. Begley and Ellis were therefore not free to identify the irreproducible papers — a fact that the Comment should have mentioned.

Nature, like most journals, requires authors of research papers to make their data available on request. In this less formal Comment, we chose not to enforce this requirement so that Begley and Ellis could abide by the legal agreements.

The scientists at Amgen could not have implemented their study had they reserved the right to reveal the outcome for individual papers. The Comment highlights important systemic problems in preclinical cancer research, which we felt appropriate to communicate to our readers, even though the authors could not disclose the studies in question.

"Safety And Efficency"

For all those who think that the FDA will help solve ME/CFS, that the pharmaceutical industry will help solve ME/CFS, that "we, the patients" should lobby the FDA and doctors to help the pharmaceutical industry:
You are deluded.



BBC Panorama - "Paxil Study 329"


(Via 1 Boring Old Man)

Translational Medicine Has Failed

1 Boring Old Man (emphasis mine):

One reason that I suggest you read the whole article is that in his thinking, the perspectives of the pharmaceutical industry, psychiatry, and the NIMH are discussed as if they are the same thing. For example, he discusses academic research and pharmaceutical research as if they are in synergy with different strengths and weaknesses, an unbroken chain:
…
Here’s the thing about that argument – I can’t think of any examples. The drugs that have characterized the post-DSM-III era are all me-too drugs developed by pharma. What the academics have done is sign on to the industry’s papers as KOLs, involve themselves as sites for drug trials, and traveled around on speaker’s bureaus. If the academics are doing what he described, I missed it. Dr. Hyman, Fibiger, and Insel should be in a better position than I am to know about such things – but I think that this scheme, at least over the last quarter century, is more their shared delusion fantasy than some hard reality.

So while it seems a cynical thing to say, I can’t think of any accomplishments by the Translational Medicine era to mention other than to produce a lot of articles and a few new journals. So how could it be stalled? It never took flight in the first place except as a monotonous rhetorical device and a name for a bunch of centers that haven’t produced very much. The Translational Medicine rallying cry "from bench to bedside" has lacked in productivity from the bench side of the equation.

It seems "Translational Medicine" is nothing but a fancy buzzword to get funds for research, and to hide the fact by how much medical science has been stalled in the last couple of decades…

Marvellous

David Healy:

Companies don’t engage in conspiracies, we are being told, they are masters of the cock-up, and if given a choice of feet to shoot themselves in will opt for both feet.

Truly marvellous.

If Pharma made cars…

David Healy:

If Pharma made cars..

Companies are legally obliged to answer the question “Can cars kill?” with a “Yes”. They can usually evade this by answering instead the question “Will this car kill me?” or “Did it kill him?” with a “No – absolutely not – if things went wrong it was the Dr’s fault”. But ultimately they depend on their professors (who are carefully managed independent contractors under no legal obligation) to deliver the message “Cars Cannot Kill”.

If Philip Morris made drugs..

If Philip Morris made medicines, all available drugs would come with prominent Black Box warnings that this product can kill consistent with the traditional medical view that Every Drug is a Poison, and the Art of Medicine lies in finding the right dose.

There would be a ban on all advertising including Direct to Consumer Adverts. The use of drugs for children would be severely restricted, and exceptional rather than common.

As company products are available over-the-counter rather than on prescription-only, doctors would be openly skeptical of the claimed benefits and would fully support ongoing research to demonstrate the risks. Somewhat more puritanically perhaps some doctors might be expected to attempt to get Philip Morris sponsorship of university activities banned.
…

Psychiatry Kills – Just Say No

David Healy:

Patients with psychosis, just as they were 100 years ago, are now 4 times more likely to be dead after 5 years of treatment than the rest of us. Patients with schizophrenia are 11 times more likely to be dead – this is much worse than 100 years ago.

Patients with schizophrenia are 10 times more likely to be dead at the end of the first year of treatment than they were 100 years ago. There is no other illness in medicine where such a statement could be made.

Death in the early years of schizophrenia does not come from heart attacks or strokes – it comes from suicide. In their first year of treatment, patients with schizophrenia are over a hundred times more likely to commit suicide than the rest of us.

This is shocking. When I have written about the social function of psychology, I seriously underestimated what harm these psycho*s from the psychiatry department are doing.

Drugs To Take, Drugs To Avoid?

I was thinking in general what I would take and what I wouldn't take with regards to pharmaceuticals. There are a few (hypothetical) situations were I would definitely take pharmaceuticals/medications, vaccines and treatments in general:

• Anti-retrovirals, when faced with an persistent (and clearly identified) infection that causes problems
• Same with antibiotics for bacterial infections
• Same with anti-fungals for fungal infections
• Depending on the cancer – and carefully considering the options – I would be willing to take anti-cancer
• I will take any recommended vaccines against deadly child disease like the usual suspects (MMR, Polio, and the like)
• I would take vaccines against "new" diseases if there is an outbreak (or real risk of an outbreak) in my country, and if the disease has severe health outcomes (e.g. SARS)
• I would take insulin if I had type 1 diabetes (T1DM)

On the other hand, there a few instances where I would definitely not take stuff from pharma or other kinds of treatments:

• I will not take heart disease or vascular medication, especially "preventive" disasters like statins (I'm already fatigued from dairy, I don't need pharma to help with that. And anyway what is wrong with trying out Paleo?)
• I will not take any medicals against diabetes, hypertension, obesity or the like (do Paleo instead, duh!)
• I will not take vaccines against the latest hyped virus (e.g. a repeat of the bird flu disaster)
• I will not take anti-depressives (cf. David Healy)

Furthermore I would try to avoid some forms of surgery (e.g. prostate cancer surgery, which seems to be a result of overhyping prostate cancer – not every "cancer" poses a danger). As a child I was subjected to a unnecessary tonsillectomy which by all means did more harm than good – were I a parent today, I would say no to such surgeries (and in addition the doctor suggesting this would run the risk of needing surgery himself).

But then there quite a few "gray areas". The influenza vaccine? If I knew.

That all got me thinking, would it possible to have a sort of guidance for this? Well, I came up with this, were I would more readly trust pharma:

• The disease needs to have clearly defined adverse outcomes (e.g. like HIV/AIDS), so doctors can not substitute the reality of a disease with their narrative
• The disease has to affect clearly many who are diagnosed with it, and not be some "risk number"
• The drug has to have clearly visible efficiency (e.g. like insulin for T1DM), that does not does not rely on statistical analysis to show efficiency (e.g. definitely not like statins)

So if it is a disease that clearly kills or maims many, and if the treatment does not have to rely on statistical manipulations analysis to show that it does something, then yes, I would take that treatment. In all other cases I'd be careful. Patient discretion is advised.

When Patients Do Lobby-Work For Pharma

David Healy:

… Quite innocently some decades ago a network was set up by Silvio Garattini among others to investigate rare diseases. This later gave rise to Eurordis, an organization to speak on behalf of patients with rare diseases.

An organization of patients and by patients and for patients sounds like a wonderful thing but far from being a sanetocracy it has turned out to be an insanetocracy.

As it happens as of 2011 Eurordis took funds from 38 different pharmaceutical companies. These only amounted however to 22% of their income. Financial conflicts are not really the issue – they could survive without the money. It’s something else that keeps them tied to the Corporation. This is the patient group for whom pharmaceutical solutions are a lifeline. They are more committed to the interests of the pharmaceutical industry than are any of the employees of any of the pharmaceutical companies.

They can be absolutely depended upon to read the runes right and come out with a strong industry position, making it possible for industry representatives to sound relatively accommodating to others in contrast …

The ME/CFS community should take notice – especially those lobbying for Ampligen – not to become unpaid pharma shills.

Fuck That.

David Healy - Time to abandon evidence based medicine?

• You can't trust trial data
• You can't trust reviews (not even Cochrane Reviews)
• Real significant problems (e.g. increased suicides on Prozac) can be "statistically not significant"
• Data is hidden
• Evidence vs. Evident: Large controlled trials are needed to weed out the drugs that don't work – drugs that "really" work show their effects in small trials. If you need 10,000 people to show an effect, something is fishy.
• If alcohol were a novel substance, a (hypothetical) trial could be made that would show that alcohol works as an anti-depressant drug
• In this (hypothetical) "alcohol as anti-depressant drug" example, one could even get alcohol as drug to be included in the NICE-guidelines
• One (hypothetical) 6 week (!) trial alone (!) could "prove" that the economy would save lots of money by putting people on alcohol for depression
• And this (hypothetical) one 6 week trial would be enough "prove" that doctors would insist that patients should take this drug for life(!), because the condition is life-long
• If a drug causes symptoms (e.g. more suicides), which the disease can also produce, then a control trial can not answer that question for you
• Clinical trials are not the answer:
  1. If both the illness & the drug cause a problem
  2. If the clinical population is heterogenous (if the underlying condition is unknown)
  3. If the researchers don't know what they are doing
  4. Clinical trials cannot provide patient level answers
  5. Clinical trials do not reveal cause and effect
• Doctors will defend prescription drugs – and hereby delay investigation into adverse effects by 15 or more years

And all that is not even including the carnage done by quacks…

Fuck that.

We have all these amazing medical, technological and scientific advances, which should put us in a position to fight diseases in a way that would make all the Pasteurs and all the Enders' and all the Salks and all the Sabins of past times green with envy. Where is the evolution in medicine? Why does it seem to me that we are stuck in a dead end?

The medical profession does well with clearly defined illness – say HIV/AIDS – that, if left untreated, lead to clearly measurable, visible adverse outcomes. But things like depression? MS? T2DM? In all likelihood, the treatment may lead to worse outcomes than if the illness is left untreated.

And this hits me at the moment. My doctor is willing to try out medication for my ME/CFS and therefore I'm currently looking into what agonist drugs are available to stimulate the alfa 2A receptor which is shown to be involved in at least subgroup of patients. Besides

• the almost total lack of scientific interest in ME/CFS by the medical commuity that leads to a situation where every person with ME/CFS is going from one "personal drug trial" to the next because guiding trial data is non-existent,
• besides not having any certainty whatsoever what actually the pathology is in my case (besides some personal indication that the alfa 2A receptor might be involved for me as well),
• besides not knowing if a stimulation with an Ad2A agonist is actually the right thing to do, if it is the Ad2A in my case,
• and besides not knowing what the actual (vs. claimed) spectrum of adverse reactions of these drugs is,

besides that I am totally at loss whether the supposed alfa 2a agonists actually do what the pharmaceutical industry claims they do.

Should I give Guanfacine a try? Or rather Tizanidine? Maybe Xylazine? What about Lofexidine?  Is Brimonidine only for occular hypertension?

I know, let's play guinea pig! And if one doesn't work, or makes me awful, then we try the next! Oh boy, what fun.

I feel like I might go to a pharmacists, and at gun point take any random medication and try that – and not be worse off…

But it sure is nice to see a psychologist like David Healy sharing his good insight into the problems of his profession and giving his best to address them properly.

(Health) Research Expenditures

Labrigger on (health) research expenditures.

Cervantes on the Medical-Pharmaceutical-Industry

Cervantes on the Medical-Pharmaceutical-Industry:

The Senate finance committee has found that [the Medtronic corporation] paid -- get this, it's not a typo or an extra zero -- hundreds of millions of dollars to doctors to pretend to be the authors of articles they drafted, edited and approved praising its product InFuse. Senator Max Baucus says, "Medical journal articles should convey an accurate picture of the risks and benefits of drugs and medical devices, but patients are at serious risk when companies distort the facts the way Medtronic has." Indeed. The editors of Spine Journal weigh in: "If surgeons had known that the lead authors of the 13 original studies on InFuse had received payments ranging from $1.7 million to $64 million [sic!] from Medtronic and that its marketing employees were co-authors and co-editors, would they have been as eager to use InFuse on their patients?"

That's all well and good but BMJ fails to name the names of those "physicians." They are all cruising along with high powered appointments and continuing to publish.

Hobbesianism in the pharmaceutical Industry

Ben Goldacre:

Question: Do you think there are any pharmaceutical companies that stand out in terms of transparency of trial results? And at the other end of the scale, are there any companies that consistently fail to publish negative trials?

Ben Goldacre: No. I have no reason to believe that any one is any better than the other. If you have bad regulations, incoherently enforced, then everybody does what they have to do, to succeed in the marketplace.

Of what reminds me that, that "everybody does what they have to do, to succeed in the marketplace"?

"That which is now to be expropriated is no longer the labourer working for himself, but the capitalist exploiting many labourers. This expropriation is accomplished by the action of the immanent laws of capitalistic production itself, by the centralisation of capital. One capitalist always kills many."
-- Karl Marx on the primitive accumulation of capital

"Je ein Kapitalist schlägt viele tot."
-- Karl Marx über die ursprüngliche Akkumulation

Yes, the "expropriation of many capitalists by few capitalists", everybody has to do what he has to do to succeed – aka Hobbesianism.

“Actually, it’s worse than you know…”

The life of frauds and whistleblowers in the medical sciences:

…
I travelled to Telford last month to hear Wilmshurst give a lecture to the Royal Statistical Society on libel and other barriers to exposing research misconduct. It took me back to 1996 when we invited him to come to the BMJ and give a talk—behind closed doors—to our staff and advisers and colleagues from the Lancet. He reeled off case after case of misconduct, many of them involving prominent people. The audience listed intently, but I was unsure of the reaction. Might somebody leap up and say “How dare you accuse x of misconduct. He is one of the great men of British medicine”? In fact in my memory the reaction was the opposite. People said things like “Actually, it’s worse than you know…”
…
Now 16 years later Wilmshurst has a longer and updated list, and somebody in the audience asked if he thought things are getting better or worse. He thinks probably worse: he’s had seven whistleblowers contact him in the last two months.
…

Lot's and lot's and lot's of anecdotes and case studies, but when will there be more research as to causes and mechanisms, and when will there be real consequences to prevent this in the future?

Perhaps strangely it was his first story that best captured the corruption that Wilmshurst has been fighting all his professional life. It was the early 80s at St Thomas’ Hospital in London, and Wilmshurst was doing research into amrinone, a new drug for heart failure manufactured by Sterling Winthrop, a company since taken over. The drug was supposed to increase myocardial contractility, but Wilmshurst found that it didn’t. Worse, it had serious side effects. Wilmshurst and his boss prepared to publish, but Sterling Winthrop, the manufacturers of the drug, threatened legal action. The company also asked if Wilmshurst and his boss would be willing to meet with their experts. They agreed. The message was that St Thomas’ was getting very different results from everybody else and that their lab would be discredited if they were to publish.

And by the way, the next person who ignores the countless lifes of patients that have been endangered by medical fraud and says "Well, but science is self correcting" will be diagnosed with a mental disorder, pumped full of fraudulently tested pharmaceuticals and put into a lunatic asylum for the rest of his life.

One of the things that seems to make Wilmshurst so cheerful is the black humour of his stories. Many of them involve doctors who are guilty of misdemeanours but who sit in judgement on others. He told the story of Peter Richards who decided to bury the fact that Clive Handler, a doctor, at Northwick Park Hospital, was found guilty of using NHS research funds to subsidise his private practice at a time when Richards was medical director of the hospital and chair of the professional conduct committee of the GMC. Previously he had been dean of St Mary’s Medical School, prorector for medical education at Imperial College, and chair of the Council of Deans of UK Medical School and Faculties. When Handler eventually appeared before the GMC, the GMC’s lawyers ask that Richards stand down from chairing the committee. As Wilmshurst said, it’s as if a judge at the Old Bailey were to say “I’ll have to excuse myself from hearing this case as I helped the accused bury the body.” After having to stand down from this committee Richards continued to chair other conduct committees. Wilmshurst told several stories of doctors who had been found guilty of research misconduct but gone on to be deans and others in charge of researchers.

Like we have independent investigation, prosecution and courts for criminal cases, we need a similar criminal law with similar independent institutions for medical fraud.

CFS, the cash cow that keeps on giving!

Not enough that we have Simon Wessely making a living out of treating CFS patients the right way (wink, wink), not enough that we have the CDC having their hand on CFS research money, not enough that we have the NCI having their hand on CFS research money, not enough that we have a lot of good friends like Harvey Alter, Judy Mikovits, Michael Maes and Kenny De Meirleir, no, we have a good old friend with Hemispherx having their hands on CFS research money!

http://www.thestreet.com/story/11730475/1/hemispherx-atm-withdrawals-raise-a-red-flag.html
…
Hemispherx used a Friday night SEC filing to disclose the sale of 10.9 million shares of stock at an average price of 92 cents per share. After expenses and commissions, Hemispherx net $9.5 million from the sale.

You said this stock sale was stealthy. Why?
…
An FDA advisory panel is scheduled to review the chronic fatigue syndrome drug Ampligen on Dec. 20. Presumably, a positive panel vote will push Hemispherx shares much higher than where they trade today. Yet, Hemispherx is rushing to raise money now. That's not a good sign.

Maybe Hemispherx wants to raise a small amount of money now and then plans to raise more money later, hopefully at a higher share price if the Ampligen panel votes to recommend approval.
…
Ha! That's funny. The FDA rejected Ampligen as a chronic fatigue syndrome therapy in late 2009. Yet for the past three years, Hemispherx has done nothing to advance Ampligen, including refusing to run a new clinical trial that FDA asked for. Hemispherx has plenty of cash to develop Ampligen. The problem is that management is hoarding cash to pay its outrageously high salaries, not to spend on Ampligen.

How much does Hemispherx CEO Bill Carter earn?

Carter was paid $1 million in salary in 2011. With bonuses, stock options and other perks, his total compensation for the year was $1.5 million. Carter's salary alone has doubled since 2009 -- the year that Ampligen was rejected.
…

I can hardly believe that!

It must be a lie!

Surely the invisible hand of the free markets will intervene! Let us all pray to the invisible hand of the free markets! Capitalism, in whom I trust, praised be your name, blessed be your trickle-down-economy!

The Big Pharma Conspiracy

Ben Goldacre at his best:

When the paper describing this situation was published in Jama, Lif, the Danish pharmaceutical industry association, responded by announcing, in the Journal of the Danish Medical Association, that it was "both shaken and enraged about the criticism, that could not be recognised". It demanded an investigation of the scientists, though it failed to say by whom or of what. Lif then wrote to the Danish Committee on Scientific Dishonesty, accusing the Cochrane researchers of scientific misconduct. We can't see the letter, but the researchers say the allegations were extremely serious – they were accused of deliberately distorting the data – but vague, and without documents or evidence to back them up.

Nonetheless, the investigation went on for a year. Peter Gøtzsche, director of the Cochrane Centre, told the British Medical Journal that only Lif's third letter, 10 months into this process, made specific allegations that could be investigated by the committee. Two months after that, the charges were dismissed. The Cochrane researchers had done nothing wrong. But before they were cleared, Lif copied the letters alleging scientific dishonesty to the hospital where four of them worked, and to the management organisation running that hospital, and sent similar letters to the Danish medical association, the ministry of health, the ministry of science and so on. Gøtzsche and his colleagues felt "intimidated and harassed" by Lif's behaviour. Lif continued to insist that the researchers were guilty of misconduct even after the investigation was completed.

Reported average costs for clinical trials per drug: $22.4 million

And estimated median, net, corporate cost to develop a new drug: $56 million.

Our own estimate of pharmaceutical R&D is often misquoted as an average of $43 million per new drug, which commentators reject as being absurd. However, we make clear this estimate for the year 2000 does not include the cost of discovery (because it varies greatly and no one has accurate figures), nor the "cost of capital" (for reasons explained in our article which can be read here). Our estimate is the net cost to major companies after taxpayers cover about 50% of their R&D expenses. We use the median cost because the average cost gets inflated by a few costly R&D projects.
In sum, we estimate that the median, net, corporate cost to develop a new drug, based on the confidential cost data that companies reported to their policy research center at Tufts University, is $56 million in 2011, plus the unknown company costs of discovery and the artificial estimate of profits foregone, if you think it should be added. We also show that R&D costs for in-house new active ingredients are much higher, and costs for me-too variations are much lower than this single figure.
Our estimate is almost double the only solid corporate report of R&D costs, which can be found in audited tax returns from the late 1990s. Here companies reported average costs for clinical trials per drug of only $22.4 million. Not $224 million but $22.4 million
...
if the Forbes figures and business arguments are correct, then nearly all of the global pharmaceutical companies listed in their article would have gone bankrupt between 1997 and 2011.

So much for the claims that "a new drug costs over a billion dollars".

(via denialism)

When Science is marketed...

To achieve the 98 percent efficacy claim, Merck excluded from analysis anyone who “violated” the study protocol. In other words, all real-world problems that arose were excluded from analysis. Problems like girls who refused to take a second or third shot after they became sick and (correctly or incorrectly) blamed the vaccine. Or doctors who incorrectly gave the vaccine to someone who shouldn’t have received it. While it’s worth knowing how effective the vaccine is when it’s used exactly as it should be, for a public-health decision, it’s not as relevant as its real-world effectiveness.

To Merck’s credit, they reported that when all women in the study were analyzed, the vaccine’s efficacy dropped to 44 percent. Still, 44 percent might be considered a smashing success when you’re talking about saving lives. Except for one thing: the numbers get worse. The 44 percent benefit included only those women with the two specific cancer-causing HPV strains found in the vaccine. But when the researchers looked at negative cervical changes from any causes, they found that changes occurred in unvaccinated women at a rate of 1.5 events per 100 person-years, while vaccinated women had 1.3 events—dropping the benefit to 17 percent.

Moreover, most of the cervical changes tracked by the researchers weren’t even indicative of cervical cancer in the first place. Most were innocent cellular abnormalities that either disappear entirely on their own, or never progress to cancer. In fact, when they looked more closely at advanced cervical changes most likely to progress to cancer versus more innocent changes that go away spontaneously, it was the innocent changes that accounted for the decline.

Whether Gardasil will reduce cervical cancer deaths in real-world conditions has simply never been answered. It might—but that would take a long-term study, and one that should be done before it’s widely promoted.

…

So how did the HPV vaccine become a multi-billion-dollar winner for Merck? Well you might not be surprised to hear that the company happily lavished money on doctors, professional societies, and over 100 legislators. Of course, there is no tie between the recipients of this largesse and their promotion of the vaccine, say beneficiaries like presidential candidate and current Texas governor Rick Perry. In 2007, Perry signed an executive decree mandating that all girls in Texas receive the vaccine. The $28,500 Perry received was minor compared to his other connection to Merck: Perry’s chief of staff, Mike Toomey, became a lobbyist for Merck, championing the HPV vaccine. Once in that position, announced his plans to raise over $50 million for Perry’s presidential campaign.

And always take your Statins!

In the past, the F.D.A. advisers have been concerned that over-the counter versions of statins could not be used safely, that some patients who did not need the drugs would take them.
I’d be worried about that too.  It’s much better to have doctors prescribe cholesterol-lowering drugs to people who don’t need them.

Since high cholesterol is a symptomless condition, consumers would not know whether the drug was working without having their cholesterol checked periodically.
Don’t be silly … of course consumers will know if the Lipitor is working.  They’ll wake up in the morning and say, “Holy crap, my muscles and joints are killing me!  It must be the … the … Honey, what’s the name of that stuff I’ve been taking?”

Fat Head at his/its best.

23 new drug applications in the US in 2008

Consider two numbers: 800,000 and 21.

The first is the number of medical research papers that were published in 2008. The second is the number of new drugs that were approved by the Food and Drug Administration last year.
…
And before anyone jumps to pin the blame on the F.D.A., it’s important to note that it’s not just new drug approvals that have declined — new drug applications have, too. Last year the F.D.A. received just 23.

Here are the conditions treated for those 23 drugs:

•  Diabetes Mellitus Type II (about 25 million people in the US)
•  Breast Cancer (1.35 million people in the US)
•  Rheumatoid Arthritis, Juvenile Idiopathic Arthritis (about 1 million people in the US)
•  Prostate Cancer (965,000 people in the US)
•  Schizophrenia (430,000 people in the US)
•  Allergic Conjunctivitis (425,000 people in the US)
•  Osteoporosis (416,000 people in the US)
•  Gout (385,000 people in the US)
•  Multiple Sclerosis (384,000 people in the US)
•  Cervical Dystonia, Blepharospasm, Glabellar Lines (about 30,000 people in the US)
•  Dupuytren’s Contracture (21,100 people in the US have this)
•  Gaucher Disease (10,600 people in the US)
•  Reduction of Excess Abdominal Fat in HIV-Infected Patients with Lipodystrophy (5000 people in the US)
•  NAGS Deficiency Hyperammonemia (320 patients per year diagnosed)
•  Pompe disease (90 patients in the US have this)

•  Contraception
•  Prevention of Thromboembolism in Atrial Fibrillation
•  Varicose Vein
•  Pneumonia, Skin and Structure Infection
•  Postcoital Contraception