The Year in Multiple Sclerosis – 2013

What have we learned this year about MS? Two new medicines. 20 years of modern care. MS is no longer a dread disease. The FDA is working against us.

20 Year Anniversary of Betaseron

The more mature among us will recall 1993 with the landmark release of the first disease modifying treatment for MS. Prior to this, doctors choose to use chemotherapy (cyclophosphamide and hair loss), or older immunosuppressive drugs (azathioprine, cyclosporine), or lots of steroids to treat MS. MS was rapidly disabling.

Twenty year follow up of the patients in this trial (98% ascertainment) showed an astonishing and still marvelous effect. Those people who waited 2-3 years to start treatment with Betaseron (the first interferon-beta for MS) are not only more disabled, but twice as likely TO DIE from MS. The government will not let this information be discussed by the pharma companies because they did not approve the study (more on FDA censorship below and at another time). So both patients and doctors are unaware of this important finding. An old dogma is that MS does not shorten lives (which is wrong). MS is more deadly than breast cancer. MS patients are three times as likely to die as their peers. Why? Disability kills. More respiratory infections.

So we can be thankful that interferon-beta makes MS better by 50%. In fact at first symptom the initiation treatment protects the majority of patients from a relapse of disease for over 7 years.

Why don’t you hear about this?

The FDA is censoring that from promotion by Pharma as well. So the mission of FDA is protect us. They are failing us by penalizing the dissemination of information by Pharma. Yes censorship exists in America, and the Department of Justice and Food and Drug Administration are in bed together to extract billions in fines from Pharma for overstepping  “claims of efficacy”. This results in more government lawyers, less money for research and education, less dissemination of scientific knowledge, and less innovation and drug development by Pharma.

Early MS treatment is the standard

An enlightening study performed by a worldwide MS consortium demonstrated for the first time that in specialty practices, there is a group of first symptom patients who does far worse than the others. Who are these unfortunate souls? They are the ones who choose not to be treated at the first symptom. They fare even worse than the really severe MS patients on treatment. The moral of the story is hard to swallow for many newly diagnosed first symptom patients.

Choosing Wisely er Unwisely: How The American Academy of Neurology (AAN) Betrayed People with MS and Their Doctors

A year long saga has been ongoing with a stealth attack of the insurance industry on MS treatment. MS has become the most expensive disease yet to treat (surpassing cancer), because of the nature of the medications, cost of the research and development, and the longer and more productive lives which people with MS are having due to favorable responses to treatment.

The American Board of Internal Medicine has an initiative called “Choosing Wisely” where committees try to identify cost-saving practices. Well when it came the time for AAN to offer suggestions the board empaneled a small committee of neurologists. This committee claimed to have used a Delphi process (expert input and development of opinion) to construct a series of recommendations to save money. The head of the committee was Annette Langer-Gould, a physician employed in a partially administrative capacity by the largest HMO in the world, Kaiser Permanente, widely known for it’s penny-pinching denials and heavy-handed healthcare policies. Without input of a single other specialist in her field, this doctor crafted a treatment guideline for MS that anyone with progressive features should not be treated. She claimed there was no evidence of benefit in treating people with progressive MS (with or without relapses) with interferon-beta or glatiramer acetate. There are in fact many trials showing the same benefits of treating higher disability people with MS as those with lower disability, on relapse and MRI. This astonishingly unscholarly work got published in a prestigious journal. Furthermore, she claimed to have consulted the largest community of neurologists in the world. She never did. When we cried foul, her defense was “you know I am right and nothing works.” We were astonished how our society could have put such an ignoramus into such an important role, and we complained both to AAN and the journal Neurology. Then the CYA-fest began. The Editor of Neurology claimed “she didn’t really commit fraud because she just made a mistake.” The other members of the committee defended themselves by saying “she was the expert.”

It will take years to repair the message “you shouldn’t treat MS” and opens the doors to insurance companies to increase the difficulty and expense of being treated, even though decades of solid scientific study show the benefits. I suspect in the next year your insurer will start to examine if you have disability and haven’t had new MRI and relapse (that is you are being treated effectively) that you should not be entitled to therapy because they want to call you progressive MS.

This is an antiquated and useless term other than for retrospective shorthand purposes. Hopefully, we can reverse the damage. I expect insurance companies will take liberties with MS patients, as they are taking people of one treatment to save a few hundred dollars a month, even though they are doing well to try to make them take another that is not as well supported or convenient because they can get it a little cheaper.

Lifestyle is a big thing

I touched on this in the last blog. Vitamin D supplements, stop salty and greasy food, stop tobacco. Eat tuna and salmon. Exercise.

Aubagio (teriflunomide) for MS

This new pill came to market a year ago. It is very similar to an existing medication for rheumatoid arthritis. I wasn’t sure if it would be better. I have become convinced it has less blood and liver abnormalities than it’s parent drug leflunomide. We are learning how to use it. While the company made a bold move initially of pricing it less than the other drugs, insurance companies were not kind to them. So they then raised the price back up to where other drugs were and offered discounts in negotiation. The biggest obstacle to it’s use is that it has a high liability for birth defects if a developing baby is exposed, and this is even more difficult, because the medication lasts for many many months after stopping it, unless a complicated regimen to extract the medication from the body is done. This has limited the use of this medication also to essentially infertile women (and couples) or post-menopausal couples, or those with absolute bullet proof contraceptive use. I cannot take the time to educate for hours a fertile woman on all the issues to assure that they understanding the risks to a baby and how to use. Concern for minor transient hair thinning is present, and most young women do not view this enthusiastically. It is a well tolerated medication, but does not distinguish itself in efficacy, although it works for patients with progressive MS and is simple after monthly blood and liver tests the first six months.

Tecfidera (BG-12, dimethylfumarate)

This medication was long awaited and proved even more popular than the “Wow” it was given a couple years ago when the medication’s efficacy data was presented. Tecfidera was released in April and quickly became a market leader despite some major missteps in handling it by the most experienced MS company in the world BiogenIdec. Biogen changed the manner in which the drug is started by trying to economize on the smaller capsules and make people take bigger capsules right away. This resulted in a much greater rate of serious side effects (and hospitalizations and serious nausea and vomiting). There was even a death caused by it. Furthermore, Biogen published a disingenuous response to a scientific report demonstrating that dimethylfumarate causes PML, a devastating brain infection caused usually by Tysabri. They went around trying to convince physicians it was different from the form of the drug which caused PML. This was all scientific disinformation designed to obfuscate. The FDA failed to properly disclose to physicians and patients when approving the drug that this, as well as other serious infections (one called Kaposi’s sarcoma) had occurred with dimethylfumarate. Also, no mention was made of the rare cancers that occurred. These risks are fortunately small, one in many thousands. However, all in all this is a good drug, and will likely continue to be used in MS in people who tolerate it. I am thankful that Biogen has brought it to market.

Will we get Lemtrada (CAMPATH, alemtuzumab) or not?

So we end up in December. The FDA is on the “Naughty” list this year yet again for it’s handling of the biggest game-changing medication ever for MS. They managed to find a panel of physicians who were unbiased to review the research data to decide about approval for MS. Unfortunately, these were the most ignorant group of physicians ever assembled to review an MS drug application. 20 years of research data. Thousands of patient years. Absolute unbelievable ignorance. They voted the trials were inadequate and poorly designed (not a single expert believes this). The medication was twice as effective as Rebif, a standard of care medication. It was so much better than Rebif anyway you would have thought that Rebif was an inactive medication. Yet they voted it should be approved (they were not following the rules). We’ll see if there is someone wise enough at FDA to clean this mess up. This after the poor company waited TWO YEARS for the FDA to address the application. Another reason drugs cost too much…the FDA is slow. Not understaffed, just really really slow and lazy about following its own rules.

We really really need alemtuzumab. Just like you need a chainsaw when a big tree falls in your yard. This is the drug for the heavy lifting in MS which we have needed for years. It ACTUALLY MAKES PEOPLE BETTER FOR YEARS. More about this when the drug nears approval.

Well I wish you a very happy 2014. I am dreading January and the abuse which insurers heap on us physicians with unnecessary paperwork, trying to kick patients off of treatment a few weeks so they can make more money off of sick people.

Dr. Samuel F. Hunter, M.D., Ph.D. practices at Brain and Nerve Neurology in Franklin, Tennessee, and directs the advanced Neurosciences Institute (http://neurosci.us) and the NeuroNexus Neurology Education and Research Center (http://neuronexus.org). Follow him on twitter at NeuroNexus1. He conducts research in part sponsored by pharmaceutical companies, of which he is a great fan, as well as critic and iconoclast.

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The biggest MS meeting in the world

Well, it’s been a busy year, but I have saved up some topics for the blog.

ECTRIMS 2013 was a plethora of presentations, many of which were not unexpected, and a few that were a surprise.

Lifestyle issues in MS continue to increase in importance for the health and management of the severity of MS. 

ITS THE SALT STUPID

Most surprising is the first clinical paper supporting earlier animal studies in EAE (and suspicions in related autoimmune diseases), namely that  sodium intake is a key regulator of the aggressiveness of the inflammatory response in MS.

Mauricio Farez, MD, from the Institute for Neurological Research, Buenos Aires, Argentina presented an MRI and clinical study of individuals with results stratified to dietary sodium intake.     Exacerbation rate was threefold higher with moderate and fourfold higher with high sodium intake relative to a low sodium diet. Individuals with high sodium intake had on average 8 more lesions and more than threefold risk of new lesions on MRI.

Sodium intake is an astonishingly important and heretofore unappreciated environmental risk factor for the severity of MS, and a very attractive approach in the adjunctive therapy of the disease. It may also explain the increasing prevalence of MS in populations with a Western diet. Even if repeat studies show a much smaller effect, the insights which such a mechanism offer into control of the disease have implications for every physician who sees multiple sclerosis.

Other lifestyle issues continue to be reviewed. Vitamin D3 deficiency is now recognized as a fundamental cause and exacerbating factor of MS. Tobacco use has been seen also to be an important factor in the cause and severity of MS.

GELINYA IS REALLY GOOD

Many presentations on existing therapies and investigational agents nearing approval continue to support the  previously recognized efficacy of these MS immunotherapies.

Gelinya (fingolimod) long-term studies support a robust, long-term, treatment effect on slowing and preventing brain atrophy, as well as enduring suppression of relapse rate and protection against   disability in a 5 year follow study from the original TRANSFORMS and FREEDOMS cohorts.

Important data regarding the transition of patients from Tysabri (natalizumab) to Gelinya (fingolimod) was presented by several groups, making this transition a straightforward and palatable option for the management of PML risk for the majority of MS patients.

LEMTRADA IS EVEN BETTER

CAMPATH (the old name) or likely to be called Lemtrada (alemtuzumab), which is recently approved in Europe, and likely to have approval imminently in the USA, represents the most potent and effective therapy yet seen for multiple sclerosis, has robust effects at three years, with an expectation of improvement (not simply slowed progression) with 45% improved and 25% stable in disability at 3 years. The effect clearly continues beyond the treatment cycle years into the year where fewer patients receive a cycle. A new endpoint, 12 month sustained reduction in disability, was introduced which 27% of the subjects met.

We are on pins and needles waiting on new medications for MS!

SFH Headshot

Most people know me as a huge cheering fan, but sometimes critical, of the pharmaceutical industry. Yes, I am a fan of capitalism and all the great innovations it produces for us. However, they are regulated by the government, which is in the habit of making us wait a long time. Nevertheless,  this has been the most eventful period of development of new medications for MS, and we are waiting for some tremendous advances.

Three new and completely different medications are likely to be approved within the next year.

First up any day now: teriflunomide “Aubagio” is a daily pill which is closely related to an established and widely used drug for rheumatoid arthritis known as leflunomide “Arava.” In fact it is essentially the same (leflunomide becomes teriflunomide in the body). This medication has undergone extensive testing in MS, and at generally lower doses than in rheumatoid arthritis, with less other immunosuppressive medications, produces a satisfactory decrease in disability, relapse, and MRI activity. It is not spectacular, but it is fairly simple. It will be marketed by Genzyme which is owned by Sanofi. The upside it works, the downside is that it is complicated to use in women who become pregnant, and immediate action is required to get the drug out of the body to reduce the risk of birth defects; about 1/2 of children exposed in the first two months of pregnancy have multiple minor defects (these are not usually serious). It is also important to monitor for depressed white blood cells “neutropenia” which is an established and not rare complication of the drug. Liver complications are much less significant. Serious infections were not a problem at the doses used in the trials. Unfortunately, a significant fraction of patients become allergic to the drug (as many as 10-15%) and cannot take it further. Some hair loss can also occur.

All in all this good. It is an immunosuppressive medication which hits rapidly dividing cells, and whether long term there is more risk is not clear. MS patients generally have less of these complications due to the factor they do not take multiple immunosuppressive medications like RA patients.

I think Genzyme/Sanofi has a challenge. If they price it too high, it won’t be used, and leflunomide is still out there and is essentially the same drug (really, for practical purposes it is the same drug). If you want to know more about this drug, go to the prescribing information for Arava/leflunomide. The active metabolite, which is discussed at length, is teriflunomide.

Up second by 1st qtr 2012 is a real game changing drug. Alemtuzumab/”Lemtrada”, formerly known as CAMPATH. Also being marketed by Genzyme/Sanofi and copromoted with Bayer Healthcare. This is the most powerful drug ever seen in MS. It also has some significant medical risks, but the vast majority of people treated do not have a major complication. This a bioengineered targeted “magic bullet” monoclonal antibody for which TWO Nobel prizes have already been awarded. It has been researched in MS for over 20 years and the therapy was invented by the brilliant professor Alastair Compston at Cambridge University. I think he deserves a Nobel as well. It will save the lives of many, many people with worse than average MS.

Alemtuzumab basically makes the immune system reboot by wiping clean a great fraction of the immune cells “lymphocytes” which are the dysfunctional, misbehaving cells causing MS. It induces wonderful remissions after two once-yearly treatments (IV 5 days the first and 3 days the second). It stomped a very good MS medication (high dose interferon-beta or Rebif). Most people do not need further MS treatment for years. Mild-moderate infections, mostly minor nuisance infections (yeast, ringworm, shingles) can occur in the months following treatment, but the immune system is amazingly intact.

The down side–people feel run down a few weeks after the annual cycle. A large amount of surveillance blood testing is needed because a large fraction (25%) will develop some kind of thyroid problem, usually overactive (hyperthyroid). A few percent have this severely and feel bad for an extended period of time and need  radiation therapy (radioiodine) to treat a severely overactive thyroid. A few percent also can get a temporary bleeding disorder called acute ITP, which if detected early on a blood test is simple to treat with prednisone. Both of these illnesses, and a few milder and rarer ones occur, because the immune systems of people with MS are capable of generating immune cells which react against many of the bodies organs. About 1/3 of MS patients develop thyroid disease in their lifetime anyway.

So trading severe MS for an annoying minor thyroid problem is a good deal. Moreover, alemtuzumab is the first medication which reliably IMPROVES disability in MS patients.

Our clinic has been a leading center in research worldwide in this treatment. It seems to work for even the most severe MS.

Last of all, coming 3rd qtr 2013,  there is the medication with a sexy name “BG-12” (doesn’t have a brand name yet), but is dimethylfumarate, owned by the little engine er company that could, Biogenidec, the powerhouse of MS research. This drug is a simple chemical, used for decades for psoriasis in Germany, which seems to have two fascinating properties- it trips the sensor cells use to tell they are being stressed by oxygen, and this turns on the systems (nrf2) which quelch damage from oxygen and chemicals, which helps in MS because the inflammation is doing this harm. An added bonus is it throws the circuit breaker on the inflammation by blocking a powerful inflammation inducing signal (NFkappaB). So, this is a completely new class of drug. The closest thing to it, believe it or not, is broccoli (mostly the sprouts), which contains a chemical called sulfurophane, which also does this. You don’t want to have to eat enough broccoli (pounds a day).

The data on dimethylfumarate evoked a “WOW” last fall at the ECTRIMS meeting, and again at AAN this spring, where it stomped Copaxone, besting it by another 50%. This drug seems to have very little toxicity (none), except it causes a bellyache which doesn’t go away in about 10% of people, and those folks can’t take it. There is occasionally some nuisance flushing which decreases with aspirin. We don’t have more than about 3 years of data though. That said, it looks pretty safe. The only other drawback..it will be a twice a day pill.

Having been involved from early in the development of this dimethylfumarate, I like this drug very much. It could fundamentally change how we treat MS, provided the manufacturer prices it appropriately and the long term data continues to look safe.

All these medications will have a role. Alemtuzumab will have the biggest impact as it adds a nuclear weapon to our arsenal, literally making it the last medication someone may ever need. It is not a cure, but the closest we will see in the next 10 years. Patients and doctors will have to swallow hard and accept the risks in order to get the benefits, but the vast majority will get off without anything more than inconvenience.

The other pills will have to see both longterm risk, and how the manufacturers price them. Hopefully, they will not make the mistake drug giant Novartis made pricing their products in the stratosphere, which made it impossible for people to get them in many cases.

The existing medications will be used. For a substantial number of people they are safe, reliable, and already doing the job.

People with MS are going to be switching treatments more, and their paths and options are going to be more individual.

Samuel F. Hunter, M.D., Ph.D. is a neurologist specializing in neuroimmunology and neuroimaging, and has a remarkably broad background in pharmacology, image analysis, medicine, and neurosciences. He directs the Advanced Neurosciences Institute, Novel Pharmaceutics Institute, and NeuroNexus Center for research and education in Franklin, Tennessee, a suburb of Nashville. He participates and directs a multiple sclerosis clinic and many research trials for multiple sclerosis and its related conditions. He consults or performs contract research and consults for many pharmaceutical companies. Dr. Hunter has previously been a consultant for many pharmaceutical companies.

Copyright 2012, Dr. Samuel F. Hunter

Why do new medications cost so much?

In response to a reader’s request, I will address the cost of medications for MS. She asked specifically about Obamacare causing this, but the issue is much bigger and more complex.

What do you pay for when you buy a brand name medication? Why do they go up in price so dramatically? How can we get them cheaper?

To provide a definitive “white paper” to explain all this would be hundreds of pages. If you will permit me, I will instead outline for you in a more understandable fashion, although you must give me the leeway to make some statements which are not explained in more detail.

First, let it be said that I am a great admirer of the pharmaceutical industry and capitalism in general. No other industry has performed for humanity in this way. The fact that you have at your disposal thousands of very cheap medications is due to enormous investments in scientific research and plain hard work to show these drugs work. These costs are mostly manpower and factories. Once feared conditions are now routine – hypertension, diabetes, arthritis, ulcers, pneumonia, cardiac disease, and many types of cancer. Moreover, you are likely to get these medications at pennies on the dollar of what they originally cost.

The current cost to bring a new medication to market is about $1 billion, give or take a few hundred million. Why so much? Manpower, safety testing, and almost all government regulation. All major companies require extremely rigorous testing with thousands of people over many years, and all this data is carefully collected in a rigid setting using somewhat expensive and out of date methods (required by the governments). And it takes 7-10 years to get to market. About 50% of drugs which enter phase III testing will fail for safety or efficacy. To get approval, there must be both. So more or less a new drug has to clear several billion dollars of revenue. What amazes me is that so many companies will place enormous amounts of capital at risk. Very few blockbuster profits have been made, but the system produces continual innovation. In a large number of cases, the brand name drugs are superior to, or have no comparable drug, in the generic market place.

How do drugs become generic? Patent law specifies a monopoly on a new product (an involved process on it’s own) for a minimum of 17 years, and in some cases 20 years. So after this time, other companies are free to try to produce their own versions. Since many drugs are chemicals which can be made in large bulk and packaged using available technologies, there is a huge economy to competition and scale.This results in pharmacies giving them away to get you and come in and shop for milk , cheese, and butter, and over the counter cough and cold remedies, which make much more money.

So why are brand name drugs expensive – we said monopoly is one reason, but that money in large part goes to reward the risks and investment taken to produce the drug. About 1/3 of revenues go into production costs, 1/3 back into research and development, and 1/3 marketing/distribution/profits. Sounds reasonable? Well why then does the cost keep going up? There is the problem.

Any good business charges what the market will bear. But is healthcare really a market? Yes and no. Insurers and consumers have influence by choosing products, but if products are limited, or if they are quite different, these are not as powerful. Moreover, a large part of the cost is borne by a third party – insurance, or ultimately governmental funding. So only a percentage is passed on to the consumer.

How do drug companies increase profits? Well, they can either sell more drug, or raise the price. Market is limited and there is competition. They sell more drug by providing incentives to patients to use their product, e.g. copay rebates. These rebates may expire. Insurance companies may force someone to change products.

How does increasing the price help? Well in some cases they get many times more money from the insurance than from the consumer. Some companies like Bayer (Betaseron), have adopted this strategy to provide a 100% rebate of copay to the consumer. Other companies like Pfizer/Serono (Rebif) try to get insurance companies to do the work for them and sell their drug to the pharmacy/insurance at a lower cost and don’t provide the consumer assistance.

What about people on Medicare Part D, TRICARE, Medicaid? Well, the manufacturer is not permitted by the government to give you assistance unless you meet some economic criteria (near poverty). The insurer wants to, but the government calls it a “kickback” (corrupt practice).

So what was behind the recent run up in drug prices? In 1993, when Betaseron came to market it cost about $17000 a year. Now that drug is $47000 a year. Did costs go up? No. The same factories have been making the drug for 20 years. But new drugs came to market, and when they did they needed to recover their costs of development, and had some advantages, and no competition, so they set their prices higher. What happened then? Well, those companies with older products were able to raise their prices because now the market would bear it.

The most dramatic examples have occurred when the US government instituted Medicare Part D prescription coverage. Previously, many of these patients were given subsidized or free drug. Since now the government would foot the bill, this is the greatest bonanza a company would hope for, and because the government was promising with one hand to help pharma, and the other hand to beat them if they did not control costs, Pharma took the initiative and dramatically raised costs for fear in the future government would not permit them to do so.

The other major recent event was the advent in late 2010 of a new and improved therapy known as Gilenya by giant Novartis. Novartis priced this drug at a highly criticized and outlandish cost of nearly $50,000, and subsequently jacked it up even higher. Why? they only have 6 years to recover the costs of a 20 year research program, and the drug is twice as good as many of the drugs on the market. This was nearly twice the cost of the other drugs. So everyone else raised their drug prices too.

One last factor driving costs is that the patent on Copaxone is expiring in 2013, and three other companies are lined up to knock it off. It is a very cheap to make, 1960s technology, and TEVA pharmaceuticals has been wildly profitable due to the recent increased revenues, low production costs, and captive market, since unlike interferon-beta, no glatiramer products compete in the market. The actions of TEVA can only be described as nonadmirable and most would consider it an abuse. At the same time, they started provided much less assistance. Most of my colleagues have interpreted it as greed, pure and simple, the worst of capitalism. TEVA also embarked on a landmark course of suing other companies to stop them from doing what is legally permitted. Ironically, in the past, TEVA has usually been the one knocking off other drugs and getting sued. Both US Food and Drug Administration and the European counterpart have stated that Copaxone can be simply knocked off as a generic drug. TEVA has unfortunately suffered a major failure in drug development of laquinimod (another subject to blog about).

So my advice is that if Rebif is costing you too much, go talk to Bayer about Betaseron. You’ll likely get a better deal. Bayer has been rebating everyone’s copay and the other companies don’t do this.

Beginning 2013, the advent of multiple competing versions of generic glatiramer acetate (Copaxone) will mean you will have pressure to use this drug instead of Rebif, Betaseron, Extavia, Avonex, Gilenya, and Tysabri, since the cost will be much lower. Patients new to MS will be required to do glatiramer and “fail” regardless of whether your doctor thinks this is right for you.

I am of the opinion that Copaxone (glatiramer) does not work well for many MS patients, so I do not relish this development. I do however have faith that our capitalistic system will continue to perform for people with chronic disease. However, the excesses which occur along the way will likely result in more regulations, which will simply be passed on to the consumer and taxpayer.

Obamacare? Well it is the government taking over healthcare. How well do you think that is going to work?

Samuel F. Hunter, M.D., Ph.D. is a neurologist specializing in neuroimmunology and neuroimaging, and has a remarkably broad background in pharmacology, image analysis, medicine, and neurosciences. He directs the Advanced Neurosciences Institute, Novel Pharmaceutics Institute, and NeuroNexus Center for research and education in Franklin, Tennessee, a suburb of Nashville. He participates and directs a multiple sclerosis clinic and many research trials for multiple sclerosis and its related conditions. He consults or performs contract research and consults for many pharmaceutical companies. Dr. Hunter works for many pharmaceutical companies, does research for them, and patient education under their auspices.

Copyright 2012, Dr. Samuel F. Hunter

Doctors quitting neurology

I learned this week that another valued colleague has “retired” due to the stress of office practice brought on by insurers and government. He went to take a part-time VA job. His patients are scrambling to find someone to provide their care. The sick ones are learning that nobody is eager to help them.

Why do we have this state of affairs? In 1996 the government took over the pay scales for Medicare, Medicaid, and Tricare. For several years, they kept the system as it was set up to provide a fair reimbursement that was tied to the cost of care. However, Congress required that they pay the doctors less whenever the cost of the program grows. Since more and more people are going onto Medicare all the time, the cost of the program has grown. Each year Congress has had to act to prevent what are now draconian cuts in pay (over 30%) mandated by the law, and laws have been passed to keep the rates stable or increase 1%. The situation has resulted in the current payments being 25% below 2000 levels, and well below the cost of providing the care. YES I SAID THE GOVERNMENT PAY SCALE IS BELOW THE COST OF PROVIDING THE CARE (By about 25%). Furthermore, it is illegal to collect more, without leaving the Medicare system entirely, and having the patient sign a contract. In that case, we have to leave Medicare at least TWO YEARS, and if a patient were to see us, the patient cannot submit the claim to Medicare for reimbursement (Patient gets no money from the government for the care).

This is the madness we are dealing with. Every 4-6 months. Due to Congress (president gets the blame also for lack of leadership).

Right now we are told that next month we will be paid more than 30% less for the same work. Since this is about half the cost of caring, this it like saying the government will shut us down in a month. And we put up with this crazy scenario multiple times a year.

So our cost to provide a complex visit may be $200, and we are allowed to charge $160, get paid $140 by the insurer, and they patient has to pay $20, that means $40 has to come from someone else. I am told by my wife that her hair salon visit can run over $200.

In a strange quirk, the system pays the doctor less for every additional minute spent with a patient. This means if I spend 45″ with each patient (often required for a complex case), I get paid half as much per minute as doing simple work which could be done in 15″.  This means doctors either have to lose money taking care of ill people, or refuse to take care of them.

The government has also tweaked the numbers from the originally fair system in 1996 in order to cheat the system further. For example, if you have a procedure with an expensive piece of equipment which requires specialized personnel, the rate is supposed to take into account the cost of maintaining the equipment and how often it is used. So they just adjust the numbers from using it 10% of the time to 90% of the time and pay us less. The other result of the 1996 law, is that they have the last say in setting the rate. We cannot sue, appeal, or have any means to correct the insanity. We can of course write a letter. Wow.

This problem is made worse by several additional factors beyond our control. First, the government in many cases prevents us from collecting the balance. If someone who is poor on Medicaid and Medicare, we are preventing from charging them for anything. This means if the doctor will not accept their insurance, we either give them the care for free or do not see them. In our state and many others, it is ILLEGAL to charge people with Medicaid, so even if someone else wants to pay from them to see the doctor, they cannot do it. This is healthcare prison of course. Did you know that the ObamaCare plan will extend this to most Americans?

Only because the government set these rates, all the insurers now demand them as well. So where does it come from? Nowhere in many cases. Large institutions have market power to negotiate better rates.

So how do some doctors cope? Some quit, especially older good ones. Others have stopped seeing Medicare patients. Some overuse tests which help cover the overhead.

Others do poorer quality care. I have colleagues who see a complex case in less than 10 minutes, don’t review any of the history or records, and shove the patient out the door with a half-baked opinion and fraudulent documentation of what was done during the encounter. They make a lot of money like this. They are called “productive”. This care is unacceptable. These doctors seem to experience little reprisal for this dismal care, indeed, they make a lot of money doing this,  and I have many patients who recount the behavior to me in disbelief. The experienced consumer of health care, who is the chronically ill person, can easily distinguish these doctors. They ask me what should be done about them. I always ask, “did you report what happened to the hospital/medical board/etc?” They never do, and the bad care continues, and the doctor continues to be paid well for doing this bad job.

Other doctors order unnecessary tests. Some practices do multiple tests on everyone like a mill. Usually they are treating the poorest patients on Medicaid. The system pays them and they see many patients and order many tests it is quite profitable. But they will not care for the sicker patients.

Doctors can’t insist on more money from government or insurers. Doctors are BY LAW prevented from negotiating as a group with insurers. We would go to jail. We are not permitted to strike. We always will see someone in an emergency.

How will the system change? Good care is always available, but it will cost you. The good experienced doctors will be inaccessible to people on Medicare, Medicaid, TRICARE, and many of the more profitable insurance companies (United, CIGNA, Aetna). You are going to see more nurses, get lots of mediocre care if you do not act more choosey, and pay more out of your pocket for good care. Why? the government and the insurers are pocketing the savings of paying less than the cost of the care.

The younger generation of doctors is not as committed as the older one. I have interviewed many of these folks and many want to take home a paycheck, work half-time, and have no responsibility. They don’t want to work for the outcomes and feel just as entitled as the patients to good treatment. It is not going to be pretty when they enter the new Obamacare era.

You can change it by insisting that Congress fix the Medicare system properly.

Are You Ready for your Specialist to Lose 18 percent of Medicare Pay?

October 11, 2011

For the first time, the congressional advisory committee MedPAC has recommended that Congress should cut Medicare payments to physicians in exchange for ending the Medicare Sustainable Growth Rate (SGR) formula.

If these recommendations are passed by Congress, as a specialist, we will lose approximately six percent of your Medicare payments each year for the next three years. After that your pay will be frozen for another seven years.

This recommendation threatens the very core of neurology—the direct face-to-face time with patients—yet protects reimbursement for non-specialty physicians.

This means effectively that a specialist, with 8 years of graduate medical training, will be paid less than a nurse with less than two years graduate training. This “solution” is unacceptable, which is why we need all AAN members to send a message to Capitol Hill today.

This means that specialists would STOP TAKING MEDICARE ALTOGETHER.

Tell your representatives to reject MedPAC’s outrageous proposal.

Contact Your Legislator!

http://www.usa.gov/Contact/Elected.shtml

Vitamin D: what is important?

Recent research has led to the dramatic conclusion that a relative deficiency of vitamin D causes risk for many illnesses. Many of these diseases are increasing, and scientists have noted that they are much more frequent in people with lower Vitamin D levels, actually the pre-hormone 25-hydroxy-D.

Vitamin D is important in the absorption from food and retention of calcium in bones. However, many people are unfamiliar with other functions of this vitamin/hormone. It also is important in stimulating and calming certain immune cells, and fighting infection. In fact, immune cells use vitamin D activation to turn on production of infection-fighting natural antibiotic molecules. People who are vitamin D deficient are also susceptible to both common mild respiratory illness (cold, bronchitis), as well as severe infections such as tuberculosis, mononucleosis, and influenza. Vitamin D levels less than 30 are also strongly associated with osteoporosis (weak bones) and risk of fractures, especially in older people. Bone density (DEXA) tests are used to diagnose osteoporosis. A T-score of more than 1.5 is a significant risk of fracture. Smaller people, especially women, Caucasians, and those going through early menopause usually suffer from osteoporosis. This can lead to painful or disabling hip or back fractures. It seems to have been a dogma that you can get too much vitamin D, and this has always led to conservative recommendations. However, the concerns are now being overcome that the far greater problem is lack of adequate vitamin D. Exceedingly high doses of vitamin D, such as are used in rat poison, are far beyond those generally consumed by people.

Many people are aware of the need in children in order to prevent a deforming bone illness called rickets. Rickets was virtually eliminated in North America by adding small amounts of vitamin D to milk, and in Europe by laws requiring children to play outside in the summer without clothes (really!).

Vitamin D comes from two sources, sunshine and diet. People who live in the sun daily throughout the year do not need vitamin D supplementation. Since very few of us are lifeguards or work in fields year round, most of us need to take care to get enough of the “sunshine vitamin.” We were always told that we needed to drink milk to get vitamin D. Unfortunately, the amount required is much greater than we consume. To barely get enough vitamin D to live (800 U), one has to drink 8 glasses. Fish is an excellent source, and 3 oz of tuna has 200 U. However, it takes quite an effort to obtain enough vitamin D from diet.

Most vitamin D comes from exposure of our skin to the sun (the same ultraviolet irradiation which can cause sunburn and skin cancers). A 30 min full body exposure to noontime summer sun triggers the release of 20,000 units. Judicious use of sunshine with protecting the skin is an important way to assure enough vitamin D. However, most of us choose to stay indoors most of the year and protect our skin from the sun with clothing and sunscreen.

The exact benefits and needs for Vitamin D in people are still unclear. Vitamin D metabolism, genetics, and needs are an active area of research, and the following recommendations are based on expert opinion, and not as much on proof from research.

Vitamin D deficiency has also been implicated in susceptibility to cancer, influenza, fibromyalgia, multiple sclerosis, systemic lupus, and rheumatoid arthritis. Dr. Edward Giovanucci of Harvard School of public health fells that certain cancers and immune dysfunction are strongly associated with vitamin D deficiency. He found prostate cancer and low blood levels of vitamin D (specifically, of proteins produced as vitamin D is metabolized). The more unlucky men had variations in genes involved in vitamin D processing and were more than twice as likely to develop aggressive, deadly prostate cancers. Moreover, more than two-thirds of the nearly 15,000 men in his study were deficient in the vitamin. Populations with adequate vitamin D levels have about half the risk of colon cancer as people who don’t get enough. Other cancers have been linked to lower vitamin D levels, too, particularly those of the digestive tract. People who live in the North (or the South in the Southern Hemisphere), are more susceptible to these cancers. Dark skinned people are likewise at greater risk, as a given amount of sun produces only half as much vitamin D in dark-skinned people.

Traditionally, 800 units per day from the diet were recommended, but we now know that 5000 U are required by adults (1,000 U/day for every 25 pounds weight in children). Many doctors recommend 2000 units a day, or more. However, recent evidence that even these supplements are inadequate for most of the year for nearly half of people. Doses of 10,000 units a day have been proven safe. Why? Because the “vitamin” is not the active hormone form of vitamin D. We use up the vitamin in our body by 50% every two weeks when we stop getting it from sun. It undergoes two stages of activation to do its job in the body, and this is closely regulated. The widely used calcium and vitamin D supplements are helpful, but likely not adequate to meet the new recommendations. Vitamin D supplements of high potency (1000-5000 units per capsule) are recommended to meet these new recommendations. If vitamin D (usually sold as D3) is taken in larger doses without calcium, it can be taken in any reasonable fashion, daily or weekly. Currently, capsules with 5,000 IU are widely available. One must check carefully the bottle when purchasing vitamin D, as it comes in sizes from 400 to 5,000 units per capsule.

A research trial published in 2010 showed children taking 1,200 U D3 daily in winter were 42% less likely to get infected with seasonal flu.

Judicious sunshine exposure, year round if possible, is recommended, for a total of 40 minutes within one week of full body (as practical) sunshine exposure. It is not necessary to tan, get hot, or burn, and the sun is effective even during early or late parts of the day, and even on overcast days. It is important to expose as much skin as possible and not to burn. Tanning beds do not have the right type of UV light, but still damage the skin.

 As a neurologist, this has greatly affected how I practice, as it has been seen that multiple sclerosis, a fairly common and serious disabling illness is strongly associated with low vitamin D levels. Not each person has low levels, and those with higher levels are usually less severely affected. People affected with MS have lowered vitamin D levels (as measured by 25-HO-vitamin D), than others in the population, and people with very high vitamin D levels seem to almost never get multiple sclerosis. A genetic cause of this vitamin D deficiency is likely, and people with MS may “waste” vitamin D. Most people which we see with MS are vitamin D deficient when we test them. Similar findings are present for rheumatoid arthritis and Crohn’s disease, other immune diseases which share the same risks.

The target level of 25-hydroxy-vitamin D in the blood is more than 60 ng/dl. This is twice the currently recommended level for bone health. It is possible but difficult to take too much vitamin D. A toxic level of vitamin D is usually 200 or over (150 is the upper limit to avoid toxicity). Excess vitamin D results in too much calcium in the blood with tiredness and fatigue, and can predispose to kidney stones. We recommend vitamin D levels be checked in the late winter/early spring (March) as they are lowest at this time. The level should be checked any time there is a suspicion of too much vitamin D.

The message is to strongly consider supplementation with vitamin D3 5,000 U a day in adults, and as above for children, to assure any ill effects of a deficiency are avoided as much as possible. Great care should be used in obtaining sufficient sun exposure so as to avoid sunburn, which predisposes to skin cancer. Attention to children obtaining sufficient vitamin D may lead to preventing many serious infections and immune illness, as well as assuring strong bones and less fractures later in life.

Dr. Samuel F. Hunter, M.D., Ph.D. practices at Brain and Nerve Neurology in Franklin, Tennessee, and directs the advanced Neurosciences Institute (http://neurosci.us) and the NeuroNexus Neurology Education and Research Center (http://neuronexus.org). Follow him on twitter at NeuroNexus1.

Goodbye cladribine – the rise and fall of a promising treatment for MS

SFH Headshot

Last week Merck KGaA (not the same company as Merck in the USA), the parent company of EMD Serono in the USA, made a decision to halt development of oral cladribine for multiple sclerosis, and withdraw it from the market in Russia and Australia where it had recently been approved. Cladribine had recently been denied approval by both the US FDA and the European Union regulatory agency.

This step backwards for progress in multiple sclerosis cries out for us to analyze and scrutinize the missteps of pharmaceutical companies and regulators. We have lost a tremendous amount of time and resources in the development of a promising therapy for multiple sclerosis.

Why give up? Merck KGa cites discussions with US and European regulators which indicated that ongoing clinical trials would not produce sufficient data to address regulatory concerns (interpret this as safety), more trials would be required (interpret this as expensive) and given the appearance of several new competitors for this market within 1-2 years. The cost of the program thus far – 600 million Euros or about 800 million US dollars.

So how did this go wrong? You will have to hear a long story. Drug development is an expensive and long process, and cladribine is no exception.

Cladribine (2-chlorodeoxyadenosine) was designed in the 1980s by a brilliant Scripps-trained biochemist using information arising from an understanding the genetic defects of severe combined immunodeficiency syndrome, better known as “bubble boy syndrome.” These rare and unfortunate children have a genetic defect in purine metabolism (adenosine deaminase deficiency) from birth which results in an accumulation of certain building blocks of DNA (purines) within key immune cells (lymphocytes), resulting in the death of these cells and severe defects in the immunity which they provide. The biochemist designed cladribine to temporarily cause a similar condition which would kill a large number of lymphocytes in a normal person.

Cladribine was conceived as a “magic bullet” drug and first used to treat cancers of lymphoid tissue, with great benefit for hairy cell leukemia. See more information (http://en.wikipedia.org/wiki/Cladribine ).

When this drug was approved for hairy cell leukemia in 1994, Dr. Jack Sipe, a neurologist at Scripps Clinic in San Diego, proposed it be used for MS to reduce harmful immune cells and preserve those which are required to fight more common infections. Dr. Sipe performed several research trials with the injectable drug in the 1990s with the drug in severely affected MS patients with benefit.

A few concerns had arisen during this research. First, a death occurred in the small trial at Scripps from severe liver failure. I remember this being reported about 1995 at the big neurology meeting. Subsequently, when Dr. Sipe published the treatment data regarding cladribine, no mention was made of any death. Colleagues asked “what happened to the dead guy?” Sipe’s defense was that experts had looked the case over and decided the death was unrelated. Few were convinced. However, work proceeded with a larger multicenter international trial which was still small by modern comparisons. Dr. George Rice and colleagues found that in more serious MS, clinical benefit could not be demonstrated, but benefit on MRI was outstanding, and the work published in 2000 (http://www.neurology.org/content/54/5/1145.abstract ). Dr. Sipe also published a small study of relapsing MS showing clinical benefit (http://msj.sagepub.com/content/1/6/343.abstract ).

 This work ultimately led Serono (a swiss-italian company), working with IVAX, to acquire the rights to oral development of the drug for MS. Serono was experienced at MS drug development having developed and marketed Rebif (an injectable interferon-beta) and marketed Novantrone (a chemotherapy for MS). The development program with oral cladribine led to completion of a placebo-controlled trial and presentation of the data at American Academy of Neurology in May 2009, in Seattle. Cladribine required only a few oral doses to obtain effective control of MS with very few side effects.

http://www.scripps.edu/newsandviews/e_20090601/MS.html                           http://www.wabash.edu/news/displaystory.cfm?news_ID=7982

 In 2006 a vice president for Serono U.S.A. had consulted with me informally to get my input on the development program (as I have a very broad expertise, I usually enjoy such chances to voice my opinion). He indicated that Serono expected to obtain the approval for the drug with no problem due to its outstanding efficacy and safety in the preliminary (phase II) trials. Furthermore, he boasted they would get approval for the oral drug partially by using the prior preliminary trials (some with marginal efficacy) with intravenous formulations. I thought this reflected a bit of overconfidence. This was coming on the heels of withdrawal of Tysabri (natalizumab) from the US market for concerns for a 1:1000 complication of rare brain infection (PML). Indeed the US FDA granted “fast-track” status to oral cladribine development which guarantees a “rapid” evaluation of submitted data for priority drugs (“rapid” to FDA means 6 months). Shortly thereafter Serono was bought by Merck KgaA (also known as Merck Darmstadt).

As usual several phase III trials (for regulatory approcal) were designed, but one was started earlier and designed with a placebo control (CLARITY), and finished in early 2009. Serono as usual kept a tight lid on information about the drug. A colleague at Wake Forest University, Dr. Doug Jeffries shared his concerns with me on several occasions about cladribine, as several reports from the leukemia literature indicated a risk of new malignancies after treatment with cladribine, and one summary “meta-analysis” put this risk at twofold.

When I saw the CLARITY research data in May 2009 I was immediately troubled. First, cladribine had not been tested in a type of patient which would use a new, toxic, or risky drug in practice. They used relatively young, mild and early cohort of MS patients instead. Second, cladribine was highly effective at suppressing MS relapses (58% reduction in relapse)and MRI evident new lesions (more than 95% reduction). But however and finally, one in 200 of the young people with MS who were treated with cladribine developed malignancies (no cancers in the placebo patients), and there was a death from infection, and numerous cases of shingles, as well as profound reduction in lymphocytes. It was clear to me that there was serious concern. Furthermore, a very rare cancer (choriocarcinoma) occurred in the trial.

However, the doctors working with the company immediately went on the offensive about the malignancy issue. When Dr. Daniel Kantor raised this question in the public presentation in September 2009 at ECTRIMS in Dusseldorf, it was clear that the investigators speaking on behalf of the trial were going to maintain that malignancies occurring in different tissues were a non-issue. The investigators (including the distinguished Dr. Gavin Giovannoni in London and Stuart Cook in New Jersey) repeatedly and publicly ignored the existing literature on this risk, and effectively snubbed those physicians with scientific questions on how to address this issue. Moreover, it appeared that the trial was inadequately planned for careful follow up of this issue, so a clear answer was unlikely to be quickly obtained. The results were published in January 2011(http://msj.sagepub.com/content/early/2011/01/11/1352458510391344.abstract )

When two of my colleagues (Dr. Jack Burks, Dr. Daniel Kantor) voiced our opinions when solicited by journalists regarding the potential of cladribine, we included our concerns about the malignancy risk, as well as whether other risks would be apparent subsequently which would alter the decisions to treat people at early stages of MS with cladribine.

I had fresh in my mind lessons learned from a previous MS therapy, mitoxantrone (Novantrone, also for a time a Serono product), which came to the US market in 2000. When mitoxantrone became available (and it was outstandingly effective for MS), doctors raised the questions of malignancy risk and heart failure (a known risk). We were firmly told by the companies marketing Novantrone that these were not a problem and were rare. In 1999 the most experienced doctor in this world with this therapy, the brilliant Dr. Christian Confavreaux, gave a talk in a scientific forum at Consortium of Multiple Sclerosis Centers and told us he has treated 800 patients and seen leukemia once and two cases of heart failure (both in patients receiving more than recommended doses). This turned out to be a gross underestimate of these problems.

By 2005 the FDA had to issue an advisory recommending closer monitoring because of the many heart failure cases. Reports in 2005-2007 from clinics like mine indicated the heart failure risk was nearly 5% and leukemia risk around 1%. Despite the fact many investigators reported to Serono cases of leukemia, to my knowledge, Serono never publicly admitted to the magnitude malignancy issue. A small, company sponsored follow up study of people getting Novantrone reported far less than 1%.

When pharmawire.com reported my comments regarding cladrine and those of my colleagues (http://www.ft.com/cms/s/2/363484d8-332a-11de-9316-00144feabdc0.html ), I was told through the grapevine that colleagues at EMD Serono were not happy with me, but nothing direct was said to me. Since I was not involved directly in this program, I had no conflicts of interest.

Representatives of Serono (“scientific liaisons”) were trained to include statements such as “the cancers couldn’t be related because they were all in different organs.” Such messages were very disingenuous, and I felt meant to mislead doctors with less expertise in the field, since immunosuppressive agents like cladribine present a theoretical risk of increasing all types of cancer, and that multiple scientific reports on the issue were available. However, the drum beating by the marketing division was successful indicating that most US neurologists couldn’t wait to prescribe cladribine for US patients with MS.

First, FDA rejected the cladribine application in late 2009 as “incomplete.” I believe (but don’t know) that this was due to the attempt to include prior trials done by the international group and Scripps in the application for regulatory purposes. Subsequently, the “complete” application was submitted to FDA in early 2010.

The concerns about risks of cladribine did not go away. Cladribine (planned to be marketed first under the name Mylinax and subsequently as Movectro) was perceived in 2009 to be on track to be the first oral drug for MS to market by 2010, but the slow steady pace of drug maker giant Novartis got fingolimod (Gilenya) approved easily, with an overwhelming amount of comprehensive research data and on the market by mid 2010.

The FDA effectively withdrew the fast track designation (officially it was “extended”) for cladribine in 2010, issued a letter in early 2011, which was kept quiet initially, but was subsequently in March reported as a request for more analysis or more trials. The European Union regulators denied the application in September 2010, and repeated with a denial of appeal in early 2011, again citing concerns about a lack of data about risks.

So where are we now? I was hoping FDA would approve the drug for refractory MS with careful monitoring and post-marketing data acquisition. This would have allowed doctors to use it for those patients to whom it was best suited—aggressive multiple sclerosis. More data is coming. Much of the problems which I have discussed here are due to a lack of data. The rush to market, a financial imperative, requires some revenue stream to support the further research. Both the European Community and US regulators are going to deny that to cladribine. This effectively makes the drug inaccessible to MS patients. Essentially Merck is throwing in the towel. I have no ill will towards this company, just wish they wouldn’t be such pansies. They had lots of good advice which they didn’t follow. I guess they want the tax deduction this year for calling the clinical trials a loss on the books.

Did they push regulators too hard without the wealth of data required for approval (a la Novartis’ success)? I will bet so. Were there more complications which have not yet been told about? That is also likely. Are the regulators throwing out the baby with the bath water? Almost certainly. You can’t require a company with a product in full development to double an investment without some kind of revenue stream from the product.

However, the patent for cladribine was just granted last year. It has about 14 years to run (Patent 7713947 Issued on May 11, 2010. Estimated Expiration Date: December 20, 2025). Hopefully some other enterprising company will pick up the ball and license it from Merck KgaA and get it approved. MS patients need all the options they can get for fighting MS. Doctors want to know what the risks are in order that appropriate patients can be selected for each drug.

Meanwhile, regarding future topics…some really exciting drugs are coming. Did you know that MS is more deadly than breast cancer? We will also lament our current regulatory and healthcare system and the state of pharma further. We will talk about these in coming posts.

Samuel F. Hunter, M.D., Ph.D. is a neurologist specializing in neuroimmunology and neuroimaging, and has a remarkably broad background in pharmacology, image analysis, medicine, and neurosciences. He directs the Advanced Neurosciences Institute, Novel Pharmaceutics Institute, and NeuroNexus Center for research and education in Franklin, Tennessee, a suburb of Nashville. He participates and directs a multiple sclerosis clinic and many research trials for multiple sclerosis and its related conditions. He consults or performs contract research and consults for many pharmaceutical companies. Dr. Hunter has previously been a consultant for EMD Serono and its marketing partner in the USA, Pfizer.

Copyright 2011, Dr. Samuel F. Hunter