Living With MS

Discussing all aspects of Multiple Sclerosis, various treatments, including accurate information regarding Tysabri.

Saturday, March 10, 2007

My Tysabri Diary...

Now HERE is patient advocacy at it's finest!

Needed From the FDA: Not Perfection, Just Consistency

FDA regulators need to balance patients' access to therapies with ensuring the safety of drugs. The consequences of poor decisions can be grim: Promote access at the expense of safety, and a dangerous product can cause incalculable harm; over-emphasize safety at the expense of access, and patients suffer from the absence of life-saving, life-enhancing medications.

In recent decisions on the post-approval risk management of two drugs, Tysabri and Rituxan, FDA regulators have failed to be internally consistent - and thereby sowed confusion among patients, physicians and drugmakers.

In late 2004, Tysabri became only the sixth medication approved -- and the first in several years -- for the treatment of multiple sclerosis, a common and debilitating (and often heart-breaking) autoimmune disease that affects the central nervous system. The drug's testing in clinical trials yielded impressive results -- the frequency of clinical relapses reduced by more than half - and induced the FDA to grant accelerated approval.

In early 2005, however, with several thousand patients already being treated with Tysabri, it was discovered that three had contracted progressive multifocal leukoencephalopathy (PML), a rare and often fatal neurological disorder caused by a virus. (Because the drug suppresses certain components of the immune response, regulators, clinicians and the product's developers had from the beginning been sensitive to the possibility of infections as a side effect.) Immediately -- some would say prematurely -- the manufacturers voluntarily halted production and distribution and withdrew Tysabri from the market.

An uproar ensued. Self-appointed "safety watchdogs" cited Tysabri as yet another case of an allegedly harmful, inadequately tested product finding its way onto the market. Conversely, MS patients and neurologists were bitterly disappointed at being deprived of what for some was an almost miraculous therapy -- and of the ability to make their own informed decisions about options for treatment. After the analysis of new safety data, an FDA advisory committee recommended Tysabri's return to the market with revised labeling.

However, the FDA went far beyond modifying the labeling to contain more prominent warnings to reflect new knowledge of the drug's side effects (which would, in my view, have been sufficient) and insisted instead on a baroque risk management action plan (RiskMAP) that imposes onerous restrictions on the use of Tysabri. These include limited distribution and additional education and monitoring requirements for patients, prescribers, pharmacies and infusion centers.

RiskMAPs were originally conceived by the FDA as a fail-safe for the small number of products that offer unique benefits but also carry atypical and significant risks. Less intrusive elements of these plans might include special labeling and more intensive education about product use and precautions, but the FDA adopted far more obtrusive restrictions and requirements such as mandatory enrollment in patient registries, controlled distribution, and prescribed behavior (such as the use of two kinds of contraception in the case of one drug) by patients.

Other products subject to such regimes include Accutane, used to treat severe recalcitrant nodular acne; and Thalomid, for multiple myeloma and the cutaneous manifestations of leprosy. Like Tysabri, both drugs provide unique and significant benefits to their users that are not offered by other medications but have severe, rare side effects. Accutane and Thalomid are known potent teratogens - substances capable of interfering with the normal development of a fetus and causing birth defects or the loss of a pregnancy or other complications - and therefore must be avoided by women who are or who may become pregnant. But the exhaustive (and exhausting) list of requirements for physicians, pharmacists and patients makes one wonder whether the next FDA safety innovation will be a mandatory live-in nanny to monitor patients' compliance with the RiskMAP.

The RiskMAPs for all three drugs are excessively restrictive, seemingly more appropriate for weapons-grade plutonium than a pharmaceutical. Although health practitioners and patients certainly need complete and accurate information about a product's potential risks, regulators should enable patients and physicians to make informed decisions within an expanding universe of therapies, not create an obstacle course between the sick and their medications.

Patients, physicians, pharmacists and drugmakers conform to the RiskMAPs because they have no choice: The FDA is the only game in town, and playing along is the only way that all these stakeholders can variously receive, prescribe, dispense and manufacture the medications.

And that brings us to Rituxan, a treatment for rheumatoid arthritis and certain kinds of lymphomas. Like Tysabri, it acts by suppressing elements of the immune system and also has been linked to PML; there have been 23 confirmed cases of PML in patients receiving Rituxan for the approved indication of non-Hodgkin's lymphoma and, most recently, two in patients being treated experimentally for systemic lupus erythematosus ("lupus").

But unlike Tysabri, Rituxan has never been subject to a RiskMAP. And in spite of the new cases of PML in patients with lupus - and the fact that Rituxan also is under consideration for treatment of MS - the FDA was content merely to update the package insert for Rituxan.

Multiple sclerosis patients on Tysabri are right to feel discriminated against. While they and their healthcare providers must navigate a veritable RiskMAP maze to obtain and maintain access to their approved medication, patients taking Rituxan - which carries a similar risk of PML - need not.

I am not arguing here that Rituxan should be subject to a more restrictive RiskMAP or that Tysabri deserves a less restrictive one (although I favor the latter) -- merely that the FDA's inconsistency sends mixed signals and creates uncertainty, the bane of patients, physicians and drug companies alike. Are some medications more worthy of patient and physician discretion than others even if they carry the same risk? Are some patients more deserving than others of the right to make their own decisions about risk and benefit?

Even under ideal circumstances, the regulation of drugs involves complex risk-benefit calculations performed with incomplete and evolving data. We cannot expect perfection from our regulators, but we can demand sufficient consistency to make the process transparent to patients, health practitioners and drug developers.

Dr. Miller, a physician and a fellow at the Hoover Institution and Competitive Enterprise Institute, headed the FDA's Office of Biotechnology from 1989 to 1993. His most recent book is "The Frankenfood Myth."

Yaaaaaaaaaay Dr. Miller (he deserves a BIG Woooooohooooooo!)


Love, Lauren
A very proud member of


  • At 9:28 PM, Blogger chris m. said…

    Hi Lauren: I was looking through back issues of the Canadian Medical Association Journal and went to their archives for articles on MS (see below):

    It seems that no-one has written about Tysabri as a treatment for MS in the CMAJ and as you know it is now available in Canada (I saw that you mentioned that someone you are in contact with was going to be treated in Vancouver).

    FYI - Elladoessquamish

  • At 5:03 PM, Blogger Lauren said…

    Hi there Chris, thanks so much for bringing this to my attention.

    I wrote an eletter/article to the CMAJ website as follows (let's hope someone there jumps on my suggestion asap):

    Considering the fact that Tysabri, a monoclonal antibody, with superior efficacy of 68%, is currently being administered in Canada, it is apparent that your website is woefully out of date as it doesn't even mention Tysabri.
    See: 4 October 2006 Health Canada Grants Approval of TYSABRI(TM) (natalizumab) for the Treatment of Multiple Sclerosis Following Priority Review
    Also, see the New England Journal of Medicine:
    A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
    Authors: Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators.
    Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
    BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinic
    al relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. ( number, NCT00027300.)

    By the CMAJ failing to update it's website, the CMAJ is performing a terrible disservice to MS patients by allowing the uninformed MS patient to suffer avoidable relapses, accumulating disabilities, and disease progression.

    Please update your website as soon as possible.

    Sincerely, Lauren Roberts (MS patient for 31 years and current Tysabri patient as well)"

  • At 2:30 PM, Anonymous Patq said…

    So glad, Lauren to "meet you" on the Tysabri web site and finding you subsequently here. Having made the decision to see another neurologist I have calmed down significantly and looke forward to sharing my experience with the new group a month from now with all of you. I thank you again for your help and your positive attitute.

    Whether the new dx of SPMS is correct or not, my goal is to find a team that chooses to listen and treat me with a minimum level of respect. My phsyciatrist is a wonderful man who I trust and am considering asking him to add a letter to my file at the new facility, in order to fill out the picture of my credibility on my history that has not been provided by the neuro. Any thoughts anyone?

  • At 4:19 PM, Blogger Lauren said…

    Hi there Pat!

    Congratulations on becoming your own patient advocate and seeking a 2nd opinion (new neuro)!

    Just remember there are TWO categories of SPMS; 1) with relapses (which is what I am and thus eligible for Tysabri); and 2) without relapses (ineligible for Tysabri).

    I think Trevis' group is great, they are a terrific bunch of MS'ers over there!

    As far as your psyche dr. writing a letter to your new team in order to compliment your "missing" MS history, I think anything that helps the patient (plus you trust him) is a good thing! Oh geez, I sound like Martha Stewart again (laughing at myself - lol).

    Take care Pat and good luck!

    (((hugs))) Lauren :)


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