Pharma’s Cutting Edge

It’s been a while coming, but 2006 has finally seen the introduction of legislation to the U.S. Senate that, if passed, would create a statutory pathway for FDA review and approval of genuine generic biologic drugs.  The Act, which the sponsors have asked be called “Access to Life-Saving Medicines Act,” was read into Congress yesterday.  The Senate version has No. S.4016 and has been referred to the Senate Health, Education, Pensions and Labor Committee (Chaired by Sen. Enzi ) for review and debate.

The U.S. generic manufacturers trade association, the GPhA, immediately announced its strong support for the legislation, while PhRMA and BIO, the innovators’ trade groups remained silent.  It’s likely that GPhA personnel played a prominent role in crafting this legislation, which has been speculated to have been in the works for over a year.

The text of the Senate bill is still at the printing office, but Rep. Waxman, who will be sponsoring the unnumbered House version, published the bill’s text on his website.  As there is a reasonable chance that the version that will eventually emerge from Committee will conserve some elements of the bill as published, and as there is also a chance that a competing bill (supported by innovators) will soon be introduced, I’ve decided to devote some of my time outlining it here.  For those of you would would like to read the official summary, Rep. Waxman has published that as well.

Just a bit of background for readers who may not regularly read my blog (have a look at the generics category for related posts).  This new bill is intended to amend the Public Health Service Act.  Biologic drug products are regulated primarily by Sec. 262 of the PHS Act.  “Traditional” small-molecule drug products are not regulated by the PHS Act, but rather are covered by the Food, Drug and Cosmetics Act.  Of particular importance to this discussion is Sec. 505 subsection (b) and Sec. 505 subsection (j) of FDCA, which provide for the major pathways by which new drugs gain introduction to the U.S. market. 

Although an accelerated development/approval pathway that relies on predecessor biologic drugs per se is not found within Sec. 505 (b) or (j) of FDCA, Sec. 505 (b)(2) does provide for accelerated development/approval of new drugs that rely on another sponsor’s investigations, when the original sponsor’s patent(s) and marketing exclusivity have expired.  FDA has published a draft guidance (2001) for how and when such investigations may be used to gain marketing approval for a new drug.  As one of the examples for types of applications that would be covered in 505(b)(2), FDA wrote the following:

Naturally derived or recombinant active ingredient. An application for a drug product containing an active ingredient(s) derived from animal or botanical sources or recombinant technology [my emphasis] where clinical investigations are necessary to show that the active ingredient is the same as an active ingredient in a listed drug.

Time does not permit me to review the debate–and lawsuits–that have surrounded FDA’s application of 505(b)(2) provisions.  Suffice to say, that innovators have generally opposed use of this pathway and that generic manufacturers have generally supported it.  No surprise there.  Nevertheless, prior to 2006 quite a few drugs, including several peptides and four recombinantly made proteins, have been approved using the 505(b)(2) pathway.  Read the rest of this entry »

I always look forward to getting Wired in the mail each month.  It’s one of my few guilty pleasures–a magazine ostensibly devoted to technology and science that is actually a slightly more sophisticated version of Stuff.  Not that there’s anything wrong with that…Freddy likes his gadgets.

So you can imagine how disappointing it was for me to open the plastic sheath protecting October’s Wired (not yet linked online) to find a pic of a big mouth about to pop a tablet below the caption:  “The Thin Pill: How Big Pharma turned fat into a disease–and then invented a drug to cure it.”  I deflated like a stuck party balloon.

Prepared for the worst sort of pharma bashing, I opened up to the article and read carefully.  Turns out the story, by Wired’s Deputy Editor Thomas Goetz, is actually a mostly balanced discussion of the evolution and debate surrounding the metabolic syndrome, not sensationalistic at all. 

Well, Goetz does take his hyperbolic shots at pharma:  “Drug firms owe their prodigious success to doing one thing exceptionally well. R&D? No–marketing.”  But for the most part, Goetz restrains his anti-industry rhetoric and provides a reasonably complete and, again, balanced view of the scientific, regulatory and commercial issues surrounding obesity and the medical community’s efforts to treat it.

So, what’s up with that cover title or its internal cousin: “75 million Americans have something called metabolic syndrome.  How Big Pharma turned obesity into a disease–then invented drugs to cure it.”? 

Goetz’ article doesn’t discuss how “Big Pharma” medicalized obesity.  He does point out that it’s in Pharma’s interests to have obesity recognized as a serious health problem by regulators and third-party payers.  But, if anything, Goetz accurately describes the vigorous scientific debate surrounding metabolic syndrome and the medicalization of obesity, and appears to conclude by a preponderance of opinion presented, that obesity really IS a serious medical problem in dire need of treatment with…DRUGS. 

The article also doesn’t provide any claims by Pharma or any else that the industry has invented or is on the verge of inventing drugs to cure obesity.  Rather, in a small sidebar and a brief backgrounder on rimonabant (Acomplia, Sanofi-Aventis), Goetz illustrates the challenges faced by industry as it tries to discover and develop safe and effective drug treatments for obesity and its many serious sequelae.

Let’s summarize.  Wired’s cover indicates that it holds within an expose, revealing that Pharma has essentially invented a medical condition and, since it has itself invented the disease, was able to cure it and reap vast rewards.  What Wired’s story actually contains, however, is a mostly balanced depiction of the medical community’s scientific debate over the metabolic syndrome and, more generally, obesity and its complications.  It also mentions that recognition of obesity as a serious medical condition (or disease) with serious health and economic consequences will benefit Pharma as it tries to develop new drugs to combat it.

Am I crazy, or is Wired using the current Pharma-bashing craze as a way to move product off its shelves?  If I’m sane (and the eery voices in my head assure me that I’m just fine) Big Pharma has become Anna Nicole-Smith, it’s become Michael Jackson, it’s, gulp, Paris Hilton!  Big pharma’s reputation is apparently so sullied among the general populace that newsstand magazines feel comfortable exploiting it the way some supermarket checkout rags exploit pics of clouds that look like demons or an anorectic starlet’s beach jog.

Let’s face it, Pharma works for Dr. Evil in the public’s eyes.  If Pharma wants to re-capture its once decent public rep, it will not be enough for it to break with Evil.  No, denouncing Evil won’t be nearly enough.  Pharma must destroy it.

I was thrilled to learn of the Journal of Negative Results in BioMedicine in Wednesday’s Science Journal, Sharon Begley’s regular column in the Wall Street Journal.  How cool is it, how overdue is it, that a peer-reviewed journal is dedicated to publishing negative studies.

The peer review will help keep out the poorly designed studies, so the public will be left with a repository of reliably negative results, balancing out the attention-grabbing (and usually positive) content of the currently top-ranked biomedical journals.  Let’s support this effort.  Short of the push for universal open access to all published research–I’m still holding my breath–I can’t think of an effort in the publishing world more important to the advancement of scientific knowledge.  Congrats and thanks to BioMed Central for publishing this journal.

If you read the WSJ article, you’ll also see mention of the Journal of Spurious Correlations.  Unfortunately, it’s dedicated to the social sciences, so us biomedical science nerds won’t be reading much of this one.  That’s too bad, but I hold out hope that a publisher will start a journal for clinical-science spurious correlations, which they can title…um…The Journal of Observational Studies.  Just kidding!   Well-designed observational studies can be of value if interpreted and used properly (see for some examples: Concato et al and Benson et al in NEJM 2000). 

The inaugural issue of the Clinical Journal of Spurious Correlations could re-publish some of the literature’s classical oops of observational studies.  Here are a few of my favorites:

Postmenopausal Estrogen and Progestin Use and the Risk of Cardiovascular Disease (NEJM 1996).  The classic spurious correlation between use of estrogen/progestin hormone replacement therapy and the risk of coronary heart disease courtesy of the Nurse’s Health Study.  The authors were well aware of potential biases affecting this study, including confounding by indication.  Neverthless, these findings contributed in a big way to recommendations made by key physician groups, notably the American College of Physicians, that nearly all postmenopausal women should be offered postmenopausal hormone replacement.  The eventual overthrow of this view by randomized trials–HERS and WHI–has opened many eyes to the dangers of relying on observational clinical studies as sufficient evidence to support practice guidelines.

Ventricular depolarizations (VPDs) and mortality post-MI.  Several observational studies indicated that VPDs post-MI were correlated with the rate of mortality, a significant increase in risk of death was suggested.  The CAST trial, preliminary results of which were published hastily in 1989, was designed to test the hypothesis that suppressing VPDs post-MI would reduce mortality.  As many of you no doubt know, CAST, a randomized controlled trial, demonstrated that suppression of VPD with anti-arrhythmia drugs post-MI increased mortality substantially (2.5x to 3.5x).  Two big take-homes from CAST were that biomarkers are not disease surrogates unless thoroughly validated, and correlation not only does not establish causation it can be downright misleading.

Coffee and Cancer of the Pancreas (NEJM 1981).  An oldy but goody.  Three or more cups of day increased the risk of pancreatic cancer by nearly three-fold over no coffee consumption.  But the study wasn’t designed to examine the risk of pancreatic cancer with coffee consumption!  It was an exploratory analysis.  This study has since been widely taught as an example of the dangers of clinical-study fishing expeditions, particularly risky in observational studies.

Reserpine and breast cancer.  In the mid-1970’s a series of smallish case-control studies showed what appeared to a modestly increased irsk of breast cancer from use of reserpine (a plant-derived indole alkaloid, which at the time was one of very few choices for treating outpatient hypertension).  It wasn’t until nearly a decade later that the association was regarded as erroneous by opinion leaders (see, for example, Horwitz and Feinstein 1985).  The reason for the erroneous association:  exclusion bias.  Most of the studies demonstrating a relationship between reserpine and breast had excluded patients with a history of cardiovascular disease.  Since these exclusions weren’t equally balanced among cases and controls, it led to a spurious correlation.  Although by the mid-80’s the erroneous conclusions were widely appreciated, I can tell you from personal experience that reserpine jaundice remained in the eyes of practitioners familiar with the early literature long afterwards.

As Andrew Jack of the Financial Times (FT.com) first reported Sunday, GSK has apparently reached agreement with two EU countries’ to flexibly price its new medicines based on their demonstrated cost-effectiveness.  The agreements were further elaborated upon in an article Monday by Ben Hirschler of the Scotsman.  Details of the agreements weren’t disclosed, nor were the identities of the countries, although France is speculated as being one.

I’m very curious about the details of these agreements.  Certainly, there is great potential benefit to a pharmaceutical company if it can reach agreement prior to marketing on a pricing scheme that allows for near-automatic increases in reimbursed price based on demonstrated value.  It’s a clear departure from current reference-pricing schemes that set a price based on the perceived value of a drug (relative to its reference group) at the time of launch, with little room for value-based price changes thereafter. 

But there is a potential downside as well, should the drug’s value not live up to its promise.  Under the scheme as described, GSK would have to reduce its prices in these circumstances. 

Agreements as described raise a host of implementation questions.  I assume that the initial drug price in these schemes would be determined as it is today–a reference-based price determined via negotiation.  What I am not at all sure of is how prices would be adjusted for future demonstrations of value (or lack thereof).  How would a country enforce its agreed to pricing adjustments if they are unfavorable to the manufaturer?  Wouldn’t a manufacturer put up a hell of a fight before it subjected its drugs to price deflation?  What if a manufacturer simply refused to cut a drug’s price, or the health system refused to increase its reimbursement, each citing scientific arguments supporting its decision?  Would each disputed pricing adjustment end up in court, or is there an arbitration scheme built in?  How would demonstrated safety or tolerability issues be reflected in the price; would quality-of-life be used to determine price revisions?  What all these questions boil down to is this:  How will value be determined, who will determine it and how will it be reflected in price?

Imagine designing a clinical study where patients at high risk of getting diabetes will be instructed in ways to improve their diet and exercise regimens and will be randomly assigned to receive one of two drugs or placebo on top of those recommendations.

Now, imagine that you believe that one of those drugs, a thiazolidinedione, will prevent over 20% of study subjects from developing diabetes during three years of follow-up.  You also believe that it will cause modest weight gain in most users, it will cause some patients to develop edema and very few to develop CHF.  Finally, you know almost for certain that no “hard outcomes” (i.e. microvascular or macrovascular diseases related to dysglycemia) treatment effects will be seen, given the low risk of such events at baseline. 

You design the study and pitch it to those in charge of the money (executives at Sanofi-Aventis, GlaxoSmithKline and King Pharmaceuticals and the Canadian Institutes of Health, to be specific).  What do you tell them will be the advantages of funding such a study? 

If you are Salim Yusuf or Hertzel Gerstein of McMaster University this scenario was probably close to reality.  If anything, Profs. Yusuf and Gerstein might have pitched a much greater reduction in incident diabetes with rosiglitazone, one of the two drugs included in the DREAM study, published late last week in advanced online versions of the Lancet and the NEJM (the other drug was the ACE inhibitor ramipril).  [see dream-rosi;  dreamlanceteditorial;  dream-ramipril; dreamnejmeditorial]  GSK sells rosiglitazone as Avandia. 

I’m actually having trouble imagining how the good doctors convinced GSK to co-fund this large study.  Surely, everyone involved must have imagined how even a spectacular reduction in incident diabetes would be received by the academic medical community, regulators and third-party payers. 

Well…the results were spectacular.  Rosiglitazone clearly and convincingly reduced the rate of incident diabetes by nearly two-thirds in high-risk patients, compared with lifestyle instruction alone.  So, how were they received?  In short, the study results are not going to win over any skeptics.  Here’s the party line from Jaakko Tuomilehto and Nicholas Wareham, from the  Department of Public Health, University of Helsinki and MRC Epidemiology Unit, Elsie Widdowson Laboratory, Cambridge, respectively.  The U.S. concensus is unlikely to differ very much.

Overall, despite the impressive risk reduction for progression to diabetes, the lack of data on long-term benefits and side-effects, and the high cost of therapy, mean that health-care funders are unlikely to see rosiglitazone as an appropriate agent for individuals with impaired glucose regulation but low absolute cardiovascular risk. Unfortunately, the greater benefits in higher risk individuals would have to be balanced against the likely increased risk of heart failure.

Surely, the above sentiments are no surprise to the investigators.  Surely, they are of no surprise to GSK. 

You might reasonably wonder why, then, this study was conducted, given that the “success” of rosiglitazone was unlikely to alter treatment practices, even if the “benefits” of therapy, as evidenced by the primary endpoint of incident diabetes (and death), was clear and convincing. 

Well, I for one am interested in the effects of TZDs on beta cell function and would like to see whether long-term treatment in this population can delay or prevent microvascular complications and progression of atherosclerosis.  These questions might be addressed by additional analyses and further study during the next phase of the DREAM trial.  In particular, we’re likely to get a good sense of the effects of rosi on atherosclerotic plaque progression, thanks to a subset of subjects who had annual carotid ultrasonography.  I’m less sanguine about the ability of the study to answer these other important questions.

Preventing diabetes with anything but lifestyle intervention is going to be a tough sell for any company that attempts it.  An ideal preventive would dramatically reduce the risk of developing not just progression of dysglycemia but also the vascular complications related to such progression.  Short of this demonstration, which might be too much to ask of any single drug-development program, a drug therapy would have to reduce the risk of developing diabetes to an extent greater than that achievable by intensive lifestyle modification alone (i.e. by more than 50-60% compared with routine lifestyle instruction), with evidence of superior adherence to therapy and minimally increased risk helping to make the case.  Perhaps these hurdles are more than any single drug can deliver.  Or perhaps not.

If the theory that diabetes progresses via gradual impairment of beta cells is correct, it is arguably realistic to think that a drug with prescriber-friendly characteristics is within our sights.  Perhaps long-acting exenatide or the emerging DPP-IV inhibitors will be the first such drugs.  We won’t know until the studies are done.  Can you imagine how those studies will be pitched?