Pharma’s Cutting Edge

The New England Journal of Medicine: This Week’s Table of Contents

The NEJM must consider this week’s Perspectives concerning rosiglitazone and follow-on biologics of great public importance–they’ve made them both freely available, along with accompanying correspondence on Cliff Rosen’s rosiglitazone Perspective from FDA, GSK (Dr. Krall), and from Rosen himself. 

Also, in the current issue, and also fully available for free, is correspondence refuting the association of rosi with MI.  Michael Bracken from Yale calls attention to lack of concordance between the Peto odds reported by Nissen and both the risk and common odds ratios.  I previously discussed why the common odds ratio was more a appropriate method to use than the risk ratio, but I didn’t discuss Peto vs. common ORs, because, well, because I didn’t.  It’s an adavnatge of being my own editor.  The fairly esoteric discussion necessary to explicate this letter fully leaves me bored just thinking about it, let alone motivated to write about it.  However, if a dear reader feels compelled to comment on odds ratio esoterica, by all means doon’t let my lack of enthusiasm for doing so myself stop you.

First up is Dr. Rosen and dear old rosi.  Rose chaired the recent FDA advisory committee hearing, in which the panel recommended, nearly unanimously, that FDA not remove rosi from the market.

The basic plot of the rosiglitazone story quickly became obvious to the advisory committee: a new “wonder drug,” approved prematurely and for the wrong reasons by a weakened and underfunded government agency subjected to pressure from industry, had caused undue harm to patients.

Off to a rousing start.  Here’s more:

These data suggest that we urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary end points. This is not a radical proposal: 20 years ago, the FDA shifted its primary efficacy end point for osteoporosis drugs from bone mineral density (a reasonable surrogate for the risk of fracture) to fractures themselves. Without a regulatory sea change with regard to diabetes drugs, we are certain to be in the same position 5 years from now that we are in now: we will again find ourselves in possession of a new wonder drug that is designed to treat a devastating chronic disease but that may do more harm than good.

Hmmm…Will FDA notice that Dr. Rosen forgot (benefit of the doubt) to mention that hyperglycemia is not only a surrogate marker of disease but also a condition worthy of treatment itself?  You guessed it…Slam.  FDA is nothing if not keenly observant.  Well, that and the fact that they write the rules governing approval of antihyperglycemia drugs in the U.S. helps.  Thus quote FDA:

All drugs currently approved for the treatment of diabetes are indicated to improve glycemic control. Reductions in glycated hemoglobin levels directly reflect improved glycemic control, leading to a lessening of hyperglycemic symptoms, including polydipsia, polyuria, and blurred vision. In this respect, the FDA views a reduction in the level of glycated hemoglobin as a well-validated surrogate for a beneficial effect on the immediate clinical consequences of diabetes.

Dr. Rosen’s oversight aside, his underlying observation, that for chronic-use drugs FDA must demand of sponsors more thoroughly defined safety profiles prior to marketing than they have been., is spot on  If the U.S. had a highly effective postmarketing surveillance program in place, I might feel differently, but, inexcusably, the U.S. is a long way from this goal.  Until then, large safety studies pre-marketing should be de rigeur for chronic-use drugs intended for large treatment populations.

The follow-on biologics Perspective is by Richard Frank of Harvard. 

The prospect of the loss of patent protection for tens of billions of dollars’ worth of biopharmaceuticals increases the urgency of the need for a regulatory policy that promotes price competition and preserves the safety and efficacy standards that Americans expect from prescription drugs. In my opinion, the Hatch–Waxman framework is not sufficient to cover both relatively simple biopharmaceuticals and very large and complex molecules—a new regulatory framework is needed. Because of the need for complex, situation-specific judgments, the FDA should be granted a great deal of discretion. The conflicting goals of bolstering price competition in biopharmaceutical markets and preserving the incentives for innovation call for a nuanced policy that must be based on the best current science and key features of the economics of biopharmaceutical markets — not on the impassioned claims of the interested parties.

Couldn’t have said it better.  To Senators Hatch, Waxman, Clinton et al. get on the ball.  Time is a wastin’ and the world is a waitin’.

In Milestone, FDA Pushes Genetic Tests Tied to Drug - WSJ.com

Kudos to Anna Wilde Matthews, from the Wall Street Journal (Subscr. Req.), who has done a superb job documenting some of the practical difficulties of implementing genetic predictors of therapeutic response in clinical practice.  Here’s a snippet from her piece:

Some specialists say testing hasn’t been proved to reduce the risks of the drug. They fear patients who don’t get the tests and run into trouble will sue doctors, citing the drug’s label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don’t. The insurers say they need more evidence about the benefits.  “It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label,” said University of Washington professor Ann Wittkowsky in an interview before the FDA’s decision. “It is fascinating science, but it is not yet ready for prime time.” Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has “substantial” evidence to support the new label and hopes it will improve safety by informing doctors.

Dr. Lesko’s hope for a benefit of the genetic predictors is commendable; it shows he’s open to supporting new ways of improving the safety of potentially dangerous drugs.  It’s also irrelevant to prescribers and insurers who need evidence of actual benefit, not just the hope of benefit, to guide their practices.  Before FDA supports the widespread use of such theranostics, it must require theranostics vendors, or in some cases drug manufacturers, to perform the clinical studies needed to support their use.

In the absence of such studies, doctors prescribing warfarin should not deviate from their current empirical dosing practices using measurement of INR to gauge response.  The one exception to this recommendation is a high suspicion of genetic predisposition to atypical warfarin pharmacokinetics based on a suggestive family or personal history.  In such cases, the prior probability of a positive test might warrant its use prior to dosing.

Data on genetic predictors:

Common virus may contribute to obesity in some people

Last September, I noted that the epidemiology of modern obesity (in the last couple decades) strongly suggests transmissible or pervasive environmental factors–more persavive even than junk food and sedentary behavior–at work in its etiology.  Now, Magdalena Pasarica, M.D., Ph.D., of the Pennington Biomedical Research Center and her colleagues are reporting at the American Chemical Society meeting that adenovirus-36 (Ad-36), a common form of this common human-infecting virus, is capable of differentiating adult human stem cells into fat:

In the current study, Pasarica and her associates obtained adult stem cells from fatty tissue from a broad cross-section of patients who had undergone liposuction. Half of the stem cells were exposed to Ad-36 and the other half were not exposed to the virus.  After about a week of growth in tissue culture, most of the virus-infected adult stem cells developed into fat cells, whereas the non-infected stem cells did not, the researchers say.  Funded by the National Institutes of Health (NIH), Dr. Dhurandhar’s group recently identified a gene in the Ad-36 virus that appears to be involved in causing fat accumulation observed in infected animals. That gene, called E4Orfl, is now emerging as a promising target for future human therapies, such as vaccines and anti-viral medicines, aimed at preventing or inhibiting the obesity virus, she says.

About 30% of obese people are infected with Ad-36, compared with 11% of nonobese people.  While this evidence doesn’t prove an etiologic link between Ad-36 and obesity–that ultimately requires evidence that eradication of the virus or its effectors ameliorates obesity–it is a necessary step up the proof ladder.  Personally, I’m thinking that environmental factors that alter the gut microbiome (antibiotics? environmental pollutants?), increasing the efficiency of intestinal energy absorption, are more likely culprits than adenovirus, but then again, multiple etiologic agents are likely contributing.

In today’s NEJM, Jerry Avorn is once again given the editorial spotlight to wax sardonic at the expense of drug manufacturers:

Fast-forward to 2007, when the same company sought FDA approval for etoricoxib (Arcoxia), a new drug in the same class. Merck had initially proposed — and the agency had approved — a study comparing etoricoxib with diclofenac, an NSAID that many worried carried its own cardiac risk. Several years and millions of dollars later, Merck presented the FDA with trial evidence that etoricoxib caused roughly the same number of cardiac events as diclofenac. But this time, the FDA allowed its sharpest internal critic, David Graham, to present data to the advisory committee on the implications of approving another cyclooxygenase-2 inhibitor with potentially dangerous cardiac side effects. Had the company used a more appropriate comparator, naproxen, Graham and the others argued, the increased cardiovascular risk would have been clear. The committee voted overwhelmingly against approval. If diclofenac also presented a cardiac risk, the committee agreed, then the FDA should not approve a new product with no proven advantage that might confer the same hazard.  Not only did this decision fly in the face of the original study design, it was also a sharp departure from the conventional FDA view that a new drug in an established class need not be any safer or more effective than its predecessors. The committee’s vote was so lopsided that the agency, still embarrassed at having missed the risk of myocardial infarction associated with rofecoxib during 5 years of widespread use, could not but agree with its recommendation.

I’m guessing FDA didn’t cite embarassment in its non-approval letter to Merck.  I’m also guessing that no one in power at FDA regards its view that any new drug need be no safer than a predecessor as “conventional”.  Rather, I’m fairly certain that they regard it as the letter of U.S. federal law.  I’m sure I’ve posted relevant content from the Food Drug and Cosmetic Act previously, but here it is again.  The Act states that approval is granted for a new drug aplication unles one of the following criteria is met:

(d) If the Secretary finds, after due notice to the applicant in accordance with subsection (c) and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b), do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under such conditions; or (5) evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; or (6) the application failed to contain the patent information prescribed by subsection (b); or (7) based on a fair evaluation of all material facts, such labeling is false or misleading in any particular; he shall issue an order refusing to approve the application. If, after such notice and opportunity for hearing, the Secretary finds that clauses (1) through (6) do not apply, he shall issue an order approving the application. As used in this subsection and subsection (e), the term ‘‘substantial evidence’’ means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.

You’ll notice that the law makes no mention of evidence of superiority to predecessor drugs. In the Arcoxia case, FDA did not act out of embarassment, nor did it have to skirt the law to deny approval of Arcoxia, as Avorn suggests.  There were several legitimate–that is, legal–grounds for nonapproval.

Ophthotech Raises $36 Million; In-Licenses Two Compounds for Macular Degeneration

The Ophthotech Board will consist of: Henry Simon (SV Life Sciences and former Chairman of the Board of Eyetech Pharmaceuticals, Inc. (”Eyetech”), Axel Bolte (HBM BioVentures), Thomas Dyrberg, M.D., Ph.D. (Novo A/S), David R. Guyer, M.D. (former CEO and co-founder of Eyetech, who will also serve as Ophthotech’s Chairman of the Board), and Samir Patel, M.D. (President and CEO of Ophthotech and former co-founder of Eyetech). The management team consists of former senior Eyetech personnel led by Chief Executive Officer, Samir Patel, M.D. Eyetech developed and commercialized Macugen, the first anti-VEGF therapy for the eye.

Eyetech, formerly an independent biotech with an aptamer targeting VEGF (pegaptinib, Macugen) that is used to treat wet AMD, was acquired by OSI Pharmaceuticals not long ago.  The acquisition price was below the IPO price (details here).  It was a new therapeutic area for OSI, and it didn’t work out.  Despite the assistance from Pfizer’s ophthalmic salesforce, Macugen couldn’t stand up to pressure from Genentech’s anti-VEGF monoclonal antibodies, Lucentis and Avastin.  OSI is now divesting its eye business. As part of the divestiture, OSI has licensed its apatemer targeting PDGF (a related angiogenic peptide) to newly formed Ophthotech.  Ophthotech has also licensed development and marketing rights to Archemix’s aptamer targeting the C5 component of complement (an inflammation factor).  As you’ll read, Ophthotech is staffed largely by former Eyetech execs.  It’s a chance for them to do it all over again.  Perhaps this time around they will not sell out the early public-market investors by dumping the firm below its IPO price, while reserving a tidy sum for themselves.