TCS Daily

Needed From the FDA: Not Perfection, Just Consistency

By Henry I. Miller - March 9, 2007 12:00 AM

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."



Well done article
FDA needs to be aggressive watchdog.

I took the notorious zyprexa from Eli Lilly which caused my diabetes.

The 'black box' warning came to late for me.

I agree, good article
I'm sorry to hear you were affected. My dad is dead and effects from Vioxx are now suspected.

As a stockholder in one of the companies involved with Tysabri, I followed the story quite closely. One thing that seems to escape attention is the fact that PML was diagnosed ONLY in patients who were using a combination therapy consisting of Tysabri AND Avonex (a Biogen MS drug). NOT ONE patient on Tysabri monotherapy has yet developed PML.

You never said the best policy for the FDA?

Get rid of it. What does the FDA know or do that these suppliers know or do? Our society is regulating itself to death and that seems to be exceptionally true for HIGH RISK medications and the like.

The FDA can not know what my risk tolerance is let alone that of tens of millions of people in various stages of these terrible conditions.

billott1 wants to abolish the FDA altogether. I would say that the least that should be considered is to decentralize. Have the FDA provide a seal of approval that may be used as a guideline by state regulators if they so choose. Obviously, state regulators would have no control over interstate commerce. Still, in a more paternalist state it would at least be plenty obvious to people that if they need to order their pills from a more permissive state (I bet there would be at least one), they are consciously taking a risk that their government considers unacceptable. The paternalist state might even put on a big public service announcement campaigns against Dangerous Pills from Nevada (or whichever state first succumbs to the temptation of becoming a national hub for mail-order pharmacies.)

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