Pharma’s Cutting Edge

Why am I posting a comment about pending legislation that seeks to limit liability to gun manufacturers? Simple. Because it would create a precedent if passed [Editor’s note:  an amended version of this Senate bill was passed into law in October 2005 (109-92)]. It would mark the first time in the history of the United States that Congress has deemed it necessary to protect an entire industry from civil liability. I’m not suggesting that the gun legislation automatically leads to protective legislation for the pharmaceutical industry in 2006–after all S.397 is fairly narrowly focused towards protections against claims of liability related to the abuse or criminal misuse of guns. It would do the pharmaceutical industry little good merely to substitute the word ‘pharmaceutical’ everywhere that ‘firearm’ appears in this legislation. However, should this gun liability legislation become law, it would serve as the signal that a legislative window has opened with room enough for pharma to shimmy through. Limited civil liability protection for pharma in 2006? Keep an eye on S.397 to see if it’s in the cards.

When John Jenkins (FDA Director of Office of New Drugs) testified to the Institute of Medicine this past week that: “I don’t know that we’re ready at this point to say we are going to completely change the paradigm and start asking for databases 10 times bigger than they have been,” he wasn’t suggesting that current safety database sizes were “adequate”. What he was suggesting is that: “There could be a lot of really unintended consequences to what sounds like an easy, good idea.” In other words, he is justifiably concerned that a knee-jerk reaction to highly publicized safety recalls of new drugs is going to create unintended health hazards, chief of which is delayed access to important new medicines.

So, is this a justified concern, or is it kowtowing to industry, as industry opponents are sure to claim? Here are some facts to consider. Safety database size is determined by several factors that are described in detail in ICH Guidance E1A and FDA Guidance on Pre-Marketing Risk Assessment. The most important factor is the minimum exposure size needed to detect an adverse event “signal”. A signal is usually regarded as a single event. A simple rule of thumb is that a single adverse event occurring with a frequency of 3/X, where X is the drug-exposed population, will be evidenced with chronic dosing 95% of the time. So, for instance, the minimum recommended chronic dosing (i.e. 6 months) exposure of 300 subjects in ICH E1A will essentially rule out a safety signal occurring with a frequency of 1/100 (1%) if said signal is not evidenced during the studies. This is the minimum requirement. Most safety databases resulting in approval of the most widely used drugs are much larger. In the Vioxx case, the original NDA contained exposure to rofecoxib of 1396 subjects treated for at least six months at any dose. So, this size was sufficient to rule out a safety signal occurring with a frequency of about 0.2% with 95% confidence. Read the rest of this entry »

The Associated Press has apparently joined the ranks of scare-tactitians like Public Citizen, who look for evidence of harm from new drugs simply to generate publicity for their cause. Any drug will do, so long as the scare-tactitian can use the story to create significant buzz.

These purveyors of shoddy pharmacoepidemiology, in this case Martha Mendoza of the AP, use the Freedom of Information Act to request Medwatch safety surveillance data from the U.S. FDA and then “analyze it” for signals suggesting harm. Ms. Mendoza used this tactic to implicate Ortho Evra, the first female contraceptive patch approved for marketing, in the deaths of “about a dozen” women among the reported 800,000 U.S. users in 2004. I’ll give her some credit, at least Ms. Mendoza went to the trouble of contacting the manufacturer, asking them to supply their side of the story. Public Citizen doesn’t usually afford drugmakers this courtesy. The article was obviously written with the intent of generating buzz by scaring women, and it seems to have at least accomplished its buzz goal.

Interpreting passively collected postmarketing safety surveillance data is difficult in the most capable hands. It is completely unreliable in untrained hands, such as those of Ms. Mendoza and the consultants she used for her story. But of course you won’t read that caveat in the lay press. Instead you’ll read conflicting “expert” opinions and the tragic tales of two young women who died while on the patch. Get used to this type of “expose.” Should FDA start making Medwatch serious adverse event reports readily available on its website in near real-time–as it is currently planning–it will trigger a deluge of shoddy drug-safety reporting like the AP’s Ortho Evra story. It won’t make for a better-informed public or safer drugs, but it will lead to confusion and further disaffection of patients from their caregivers.

In yesterday’s NEJM, Dr. Eric Topol once again climbs up on his dais to preach the anti-pharma gospel, this time with the example of nesiritide (Natrecor) as the basis for his sermon. Topol’s facts are largely indisputable, and his conclusions–save for the apparent allusion to a pharmaceutical-FDA conspiracy to dupe well-meaning clinicians–mostly reasonable. In short, Topol argues that nesiritide should not have been approved for clinical use on the basis of the surrogate measure of reduction in pulmonary artery pressure (PCWP), especially given evidence for worsened renal function. [He fails to mention, however, that the drug also reduced symptoms of CHF, and it appeared to do so better than nitroglycerine.] Furthermore, he continues, once concerns of increased mortality with nesiritide were raised (and later substantiated), promotion of the drug should have been restrained.

Clearly, nesiritide was approved with a minimal amount of efficacy and safety (about 800 nesiritide-treated subjects in Phases 2 and 3 combined) data, and this re-submitted package was labeled to support use of the drug only in acute CHF decompensation setting. FDA determined that the data were sufficient to exclude a 50% increase in mortality with nesiritide with 95% confidence. Clues to clinicians’ attitudes surrounding a possible adverse effect of nesiritide on mortality at the time of FDA approval come from the FDA Advisory Committee discussion on the mortality question. [Author’s note: The highly complex discussion filled with scientific and clinical jargon and depply convoluted logic that follows in not for the faint-minded. Consider yourself warned.]

CHAIRMAN PACKER: Okay, fine. Let’s not talk about the philosophy of mortality. Let’s ask the Committee: are you concerned about the mortality data with nesiritide as it has been presented by the sponsor? Ileana, are you concerned?
DR. PINA: No.
CHAIRMAN PACKER: Is anyone concerned?
DR. KONSTAM: Well, I’d just like to comment on it. You know, I think that my reading of the data, you know, I would throw out the PRECEDENT study as I’ve said because I don’t think dobutamine is an appropriate comparator for this, and if you throw it out, you know, I think what we saw was that the upper boundary on mortality endpoint was 40 percent.
CHAIRMAN PACKER: If as randomized, it’s probably 50 percent.
DR. KONSTAM: Okay. So it’s 50 percent. Just to define are we worried or not worried, I mean, I’m a little bit worried. I’m a little bit worried. I think, you know, we’ve got to be a little bit worried if we cannot rule out a mortality effect smaller than a 50 percent increase. So I’m a little bit worried.
CHAIRMAN PACKER: Okay. Let’s just go through this quickly. We did this before. You’re not worried. You’re a little worried. You’re a lot worried. I don’t know how else to do this. Ileana, are you not worried, a little worried, a lot worried?
DR. PINA: I’m not worried.
CHAIRMAN PACKER: Okay. We’ll start with –
DR. KONSTAM: I’m a little worried.
DR. ARTMAN: I’m not worried.
DR. HIRSCH: Not worried.
DR. GRABOYS: A little worried.
CHAIRMAN PACKER: Tom, please. We –
DR. GRABOYS: Not worried, not worried.
CHAIRMAN PACKER: All right. Jeff?
DR. BORER: I’m a teeny little bit concerned so that I’d like to see data as they come out, but basically not worried.
DR. LINDENFELD: I’m just a little bit worried, just a little bit.
DR. NISSEN: I’m a little worried, too.
DR. D’AGGSTINO: Not worried.
CHAIRMAN PACKER: I’m a little worried. How did we count Jeff’s vote? I think you want your vote to count that you’re not worried, right? Okay. He’s a little worried. Are you a little worried?

Okay…that was fun. But the point is that the clinicians were willing to overlook a very serious safety signal because they were convinced of real efficacy, at least in the short-term. Therefore, they believed that the mortality signal was probably false. Well, we know now that the signal was real, and the drug should be restricted in its use to the acute CHF setting (as it was labeled). The fact that Scios and later J&J seemingly encouraged off-label use in the chronic-management setting is not at all surprising. Should they be condemned for such encouragement? If their encouragement breached the ethics of industry-clinician relations, then yes, they should. But if the companies practiced within ethical guidelines (such as those the AMA promulgates), then clinicians must shoulder blame for inappropriate use of drugs. No one twists a physician’s arm to prescribe, and no one forces a physician to seek reimbursement aggressively. The pharmaceutical industry and FDA make for convenient scapegoats, but clinicians who fail to consider and to communicate to patients fully the weight of evidence that supports (or does not support) their off-label use of a drug, must finally accept blame when something goes wrong.

This article in yesterday’s NY Times isn’t really news, but it’s part of a trend of quasi-editorial stories in the lay press that describe the growing expense of certain new therapies, particularly oncology therapies.

I report on this to prepare you early for the impact of the announcement to occur some time within the next 3 years that US and state governments will begin to consider cost-effectiveness in their equations for government-sponsored formulary and reimbursement coverage determinations for drugs and devices. We’ve seen CMS take some baby steps in this direction already (see my June Note on CMS’ draft guidance on drug coverage determination using health outcome measures), and it seems inevitable that much bolder steps will be taken, as government drug spending spirals out of control beginning with next year’s Part D rollout.

Neither pharma nor the big biopharms seems particularly prepared for the coming policy changes (are they in denial or just poor planners?). But because investors currently value biopharma at a substantial premium to pharma, and because biopharma is relatively more exposed to price-control policies (especially those focused initially on the most costly therapies), long-term investors in the former should be particularly concerned about a selective and fairly rapid de-valuation of the biopharma sector once cost-effectiveness supplants drug re-importation as the focus of drug-cost discussions in the legislature. I have little idea specifically when that will happen, but I’ll be sure to keep an eye on the signs of its imminent approach.