Advocacy: FL generic drugs

The converse of compounded medications.

In June, a Florida appellate court reversed an earlier judge's ruling that a branded drug could be substituted with a generic drug, without consulting the patient or their doctor, even if this drug was not on the original substitution list approved by the FL legislature.

What this means is that patient rights have been protected by not allowing substitutions of drugs that have not been specifically approved by our Legislature (which represents We, the People).

The legal basis for this ruling is that the appellate court felt that it would be unconstitutional for a judge to replace the laws set forth by our Legislature. Several years ago, the Florida Legislature approved a list of generic drugs that could be substituted for branded drugs. This was based on the FDA ratings of the equivalency of these generics to their branded counterparts.

Since the time of the Florida law, there have been many additional generic drugs added to the FDA's list. The original Florida judge simply extended generic drugs allowed for substitution to include those in the current FDA list. The appellate court then overruled this decision, by stating that FL laws approved by the Legislature cannot be trumped by the federal FDA list. if additional drugs are going to be added to the allowed substitution list, the FL Legislature would be doing this, not the FDA.

This decision is important to people with neurological diagnoses especially, since substituion with generic drugs can lead to fluctuations in medication levels. This could have dire consequences in conditions such as, epilepsy. Our aptly name journal, Neurology contains an article about the risks of changing to various generic medications, as opposed to remaining on the branded drug or, even, staying on the same generic drug (made by the same generic manufacturer). The reason for this is that the FDA allows each medications to be within a drug level range. This means that when you are taking a medication and it is switched around, you may not have the same response that you did to the original (either the branded drug or one type of generic).

To sum this issue up, while generics are good because they are less expensive and are similar to the branded drug, there may be more variation when changing from one generic to another to another (as is done by retail pharmacies as their arrangements with the makers of generics change based on pricing deals).

For more on this, see the article from Neurology (used with permission from the publishers):

http://www.neurologique.org/Generic_Topiramate.html

So, let's try for some real advocacy together: patients, carepartners and neurologists.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Going to the other side

Pharmaceuticals and devices: looking for answers.

[Since there have been a lot of questions: I am an MS specialist who sees a lot (~2000) of MS patients and what follows is an open-mided (hopefully) view of CCSVI.]

Well, with all this talk about pharmaceuticals, I thought (and with some prodding) that it was time for me to address CCSVI (Chronic cerebrospinal venous insufficiency). For those of you following the stock market, but ignoring the patient blogs, it is time for a serious discussion of this theory and how it may fit into MS diagnosis and treatment.

Analysts at Investor Village have even started discussing the role CCSVI will play in the MS "market." Before we go into the nitty gritty of CCSVI and unanswered questions, we need to take a step back and realize that this is not a case of "us vs. them." We (doctors,, patients and carepartners) are all in this together and we are working diligently to find out the cause and cure of MS.

An example of how heated these discussions are becoming is found in the following statement from another blog about an MS expert who raised doubts about the central role of CCSVI: "Doctors who downplay or dismiss this treatment should openly disclose their research grants from Big Pharma!" Don't forget that the device companies are going to profit from CCSVI procedures.

What is CCSVI?

Chronic Cerebrospinal Venous Insufficiency.

Huh?

Let's go through some definitions to clear things up:

[As an aside (not to be confused with CCSVI), most MS patients are very (unfortunately) familiar with cerebrospinal fluid (CSF) from lumbar punctures (spinal taps). CSF is constantly overturned (this is why neurologists can safely remove some CSF -- ~500 mL of CSF is made everyday and we have ~150 mL of CSF in our CNS (central nervous system) at any one time.

CSF is (hopefully and normally) clear, colorless fluid that drains into our venous system.]

If the veins are constricted then there may be reduced drainage of the bloodstream in the veins; this may cause reduced outflow of the blood and a greater iron (a component of blood) deposition in the brain, optic nerves, cervical and thoracic spinal cord.

Iron may irritate the CNS and cause an inflammatory reaction that, in turn, causes the bright spots (T2 hyperintensities) we see on MRIs.

I thought MS was autoimmune ... is it?

Well, there have been many theories of MS over the years and actually Jean-Marie Charcot discussed the treatment of MS with other types of metals, such as gold and silver.

If iron is deposited in the CNS then inflammatory cells can attack this iron and this can cause damage; the iron may also have direct toxic effects on the CNS. So, is this a form of autoimmunity? Well, the iron is part of the a person's own blood and if the immune system attacks the iron, can't this be called autoimmune?

The question is not one of terminology, but of whether the observation that people with MS have narrowing of the veins draining the venous system leading to the CNS can actually undergo a balloon venoplasty to open up the venous constriction to allow a better venous outflow back to the heart (thus allowing the iron to be cleared out).

What came first: the chicken or the egg?

Even if venous constriction led to the development of MS early on, how do we know that opening up the veins will help resolve the MS? It may have no effect or it may only stop newer plaques (and damage) from forming, without actually clearing up old damage (this may also depend on whether the prior damage was permanent or not).

Before we even discuss the newer papers coming out, let's look at:

J Neurol Neurosurg Psychiatry. 2009 April; 80(4): 392–399.

The first concern I have is in the Background section of the abstract. Most people with MS know that CDMS is a category from the Schumacher and Poser criteria, and is Clinically Definite MS and not Clinically Defined MS. Although it may seem like I am focusing on minor terminology issues, it is important in that it reveals how much the Italian team needs even more support from more mainstream MS neurologists (this is a call to arms for my fellow neurologists to join the efforts of my friends in Buffalo and Detroit) [on page 313 of Walsh and Hoyt's clinical neuro-ophthalmology,

the phrase "clinically defined MS" does appear, but it is not used

synonymously with CDMS].

So, let's help:

1. It is possible that the previous findings will not pan out

in larger, well controlled studies (this is always true, as

with the disappointment surrounding Genentech and

Biogen Idec's Rituximab and BioMS and Eli Lilly's

Dirucotide or MBP8298). This is why we do big

(expensive) confirmatory studies.

2. These findings could be true in the Italian population

studied by Dr. Zamboni, but not generalizable to the

worldwide MS population.

3. Although healthy controls were looked at, it is possible

that there will be similar findings in other people with

non-MS autoimmune disorders.

4. If these findings are not associated with other

autoimmune disorders of the body, it may be associated

with other inflammatory diagnoses that affect the CNS,

such as: neuro-Behcet's, neuro-lupus, and neuromyelitis

optica (NMO or Devic's disease).

5. Even if the association with MS holds up, CCSVI and

MS may be caused by a third factor (MS may not be a

direct cause of CCSVI).

6. CCSVI may be caused by MS, instead of vice versa.

Chronic inflammation and neuro-degeneration may

cause the veins to constrict.

7. In the Canadian TV show on CCSVI, Dr. Zamboni's

patients seemed to describe progressive MS. It would

not be surprising, then, if they did not have relapses in

follow-up. What about people with relapsing-remitting

MS (RRMS)?

8. Even if venous constriction is responsible for MS, why

do some people have more brain vs. optic nerve vs.

brainstem vs. cervical spinal cord vs. thoracic spinal

cord? Are we going to see an association between the

type of venous constriction and the type of MS. The

4 patterns of CCSVI reminds us of the 4 pathological

types of MS.

9. Do people with CCSVI have more headaches than

people without? If the venous system is backed up,

we would expect the increased pressure to create

headaches (think about the Monro-Kellie hypothesis).

10. I am especially interested in the spinal cord lesions

and CCSVI.

At ECTRIMS 2008, I presented the following poster:

http://www.mindcull.com/search.php?q=kantor&

conferenceYear=ECTRIMS+2008+-+Multiple+

Sclerosis&society=none

Perhaps CCSVI explains why we found a predilection for

MS at certain spinal levels.

11. CCSVI may explain MS in some patients, and not in

others -- so can we develop a predictor (like the

biomarkers we are looking for) of response.

This is important, as venoplasty is not without risk

(cerebral angioplasty carries a risk of stroke and

hemorrhage).

12. Even if you can treat MS by opening up the veins

draining from the CNS, is balloon venoplasty enough?

What are the rates of re-stenosis? Are we going to need

stents? What are the chances that these procedures will

need to be repeated? Will we have to wait for new

symptoms to repeat the venoplasty?

As you can see, there are a lot of unanswered questions.

This is why we need more research; the Canadians have

started us off by announcing that they will fund CCSVI

research, but this is only for Canadian institutions.

• What will we do here in the U.S.?
• Who is going to donate research funds?

Are you?

If you are interested in us conducting trials regarding

CCSVI, let us know and help us make it happen.

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Risky compounds

As we approach the magic date of January 22nd 2010, the MS community waits in anticipation whether the first oral drug with MS in its label, will be approved by the FDA.

No, I am not discussing EMDSerono's Cladribine, Novartis' Fingolimod, Teva Neuroscience's Laquinimod, Sano-Aventis' Teriflunomide or Biogen-Idec's BG00012; the first drug with MS in its label will be Acorda's (ACOR) Fampridine-SR.

So, what can we do to help transition smoothly to this new compound?

1. I have already discussed the need for patients to show up on the FDA PDUFA date

2. Neurologists who can make it, should show up too. I am seriously considering making the trip.

What else can we do once the drug (what will it be called in the end? It didn't get approved in the Fall and we know that it will not be called Amaya anymore [see my prior blog on naming])?

As I have discussed in the past, there are clear advantages to the approval of Fampridine-SR over Compounded 4-Aminopyridine (hopefully the FDA will not demand lower dose trials prior to approving Fampridine-SR). I would like to demonstrate this to everyone by compiling patient experience with Compounded 4-Aminopyridine.

So, please email: neurologique@gmail.com and tell us:

1. The side-effect you had on the compounded medication (especially, seizure, confusion, headache and stomach problems).

2. What dose you were on when you had the side-effect.

3. How long you had been on the compounded medication.

4. Whether you had recently received a new bottle when the side effect happened.

4. Which compounding pharmacy you used.

Your answers will help us convince everyone that we should be switching to Fampridine-SR once it is approved.

Remember, safety comes first.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Just like the 1930s: Welcome to the age of rationing

Back to the Future II:

There have been a lot of recent references to the Great Depression (the state of the Economy) and to the Vietnam War (the War in Iraq).

Recent Screening for Breast Cancer recommendations raise issues of balancing what amount of the population needs to be screened (or treated) for every one person found to have breast cancer.

The U.S. Preventive Services Task Force (USPSTF) recommendations (http://www.ahrq.gov/clinic/3rduspstf/Breastcancer/) have raised an outcry from patient groups, nonprofits, medical groups etc.

Rationing is not new to the American public -- the Great Depression, World War II etc., but now we are learning that we are not only going to ration commodities, but health itself. This is separate than the idea of health insurance, this is truly about health care. Too often, these topics are discussed interchangeably; For example, may people discuss the right to health care, but then they extrapolate from this a right to health insurance. Currently everyone already has a right to health care -- you are not allowed to be turned away from an Emergency Department, regardless of your insurance situation, and nobody is allowed to impinge on your health -- but this is not the same as saying that someone has a right for their hospital costs to be paid for by others -- just as there is no right to have others pay for your Pursuit of Happiness.

These new Breast Cancer guidelines are just the tip of the iceberg in terms of what we will be facing shortly. Panels will revisit older guidelines and recommendations in order to determine the best way of saving money and resources for the entire population by limiting access to specialized (expensive testing). The goal of the Health Care resolutions in Congress are to expand access -- so more people will have access to less care.

The committee's recommendations take into account the large amount of false-positive results from mammograms and the subsequent testing (such as needle aspiration biopsies) that some women need to be exposed to, but this does not take into account the emotional relief many women face after having a negative mammogram. Which is worse: Having a false positive result or being frightened for 10 years that you may have breat cancer that has not been screened for by a routine mammogram?

The Task Force argues that the recommendations wil not necessarily translate into insurance plans denying routine mammograms for women in their 40s; this is difficult to believe, as Susan Pisano, spokeswoman for American Health Insurance Plans stated that "[m]ost of our member companies look at [the task force's guidelines] as the standard." She continued, "[b]ut if you are in your 40s and have a discussion about risk and benefits and your doctor gives you a referral slip, then that generally is going to be covered." I think that most doctors and patients will find this hard to believe when so many of us already face denials for medically indicated imaging studies (that are not even for screening but for crucial diagnosis and treatment).

Welcome to a Brave New World.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Falls and MS

Patient questions are coming in:

Question:

Dr. Kantor, I have a question. When someone without MS breaks a leg or pulls a muscle, they go thru therapy, etc. and eventually heal and can walk perfectly again. Is it different for someone with MS?

I recently fell down stairs and severely pulled my tendon on my left calf muscle. I have MS and before this accident, I was walking fine without assistance. Now I am in a wheelchair, use a walker to get to the bathroom.

Is there any need to notify my neurologist, about this. Is this going to be a permanent injury because I have MS? Or will it take twice as long to heal than a non-MS person?

I'm very scared that I won't ever get back to walking normal again.

Please help me understand. Thanks

Answer:

I hope your leg feels better soon.

I encourage you to speak to your neurologist (she knows your situation best). But, to answer your question: People with MS may take longer to heal, especially since there may be other reasons for the problems with walking, besides the fall (i.e. the MS itself). Also, please remember that -- just like MS -- everyone's tendon damage may be different (you commented that it was "severe").

Without knowing your individual situation, there is no reason to think that you won't be up and walking like you did before the injury -- it just may take longer than most people. Also, please make sure to talk with your neurologist and with your primary care physician to make sure there isn't a different reason for the walking difficulty (or an actual fracture).

The question of whether trauma may worsen MS or cause a relapse (flair or exacerbation) is up for grabs, and it seems like we have a new theory every 10 years, or so.

A big question is, why did you fall in the first place -- and what can you do to prevent it in the future.

We all hope you feel better.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

NPR - Correction

Open Letter to Dr. Zorba (NPR - National Public Radio):

--

Dear Dr. Zorba Paster,

As an MS specialist, I was disturbed to hear your recent comments to a caller with bruising from her subcutaneous injections (11/08/09).

Based on your queries to her, you are not familiar with the injection system used in MS.

Instead of stating to her that you were not familiar with these injections (which is not unexpected), and instead of recommending that she speak to her neurologist and training nurse, you made dangerous suggestions such as using the specific autoinjector at a 45 degree angle (this is not really feasible with the specific type of autoinjector).

While you are clearly knowledgable about some medical issues, no one expects you to be an expert on all things and I would implore you to protect the safety of your callers by demonstrating more humility.

I do think that you should consider a retraction (as this makes your knowledgable listeners supect of all your answers). I would be more than happy to be given the opportunity of explaining these issues on the air.

Thank you,

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Looking forward to collaborations

2010 is around the corner; what can we look forward to?

Let's focus on the hot topic -- Fampridine-SR or Amaya:

In the past, we have clarified that Amaya is (unfortunately) not FDA approved yet (there seems to be a lot of confusion about this fact) as the PDUFA (prescription drug user fee act) date has been pushed off to January 22, 2010 (3 months from the original October 22, 2010 PDUFA date).

The reason for this is that Acorda (ACOR) wanted to work with the FDA on the development of an appropriate risk evaluation and mitigation strategy (REMS).

Hopefully, though, this deferment will give Acorda and the FDA time to reach an agreement regarding approving Amaya prior to the need for a lower dose (5 mg) study. [Interestingly in my patients on compounded 4-aminopyridine had more headaches on 5 mg, when I used to titrate it, as opposed to on 10 mg.]

So, what can we as the MS community to help the FDA along in approving Amaya? This is needed because, despite what patients and neurologists know -- i.e. that it helps people function better, the FDA is in no rush to approve this drug.

The MS community mobilized itself in trying to get Tysabri (natalizumab) re-released in 2006, by descending on the FDA hearing etc..

Where is that same community now?

Where is Sanofi-Aventis (SNY) in all this?

Sanofi-Aventis could benefit the MS community by helping the FDA understand to approve a medication that could improve neurological functioning. This may sound like a surprising challenge -- after all they are developing a competitive product (Nerispirdine, which affects both potassium and sodium channels); this would allow Sanofi-Aventis an reentry into the MS market (Aventis and its relationship with Teva on Copaxone or glatiramer acetate), it would help patients and it would be a nice way to show that Sanofi-Aventis is committed to MS.

So, even though it is an (eventually) competitive product, it would be free de facto advertising (like this blog) for Sanofi-Aventis and wouldn't hurt them because they are going to be facing the same challenges when they are ready to face the FDA.

As always, collaboration is key.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org