Pharma’s Cutting Edge

A few years back, as a consultant, I was asked by GTX to take a look at their unreleased Phase 2 ACAPODENE (toremifene citrate 80 mg) data and to make some recommendations and predictions for Phase 3.  I remember being very bullish on the prospects for this therapy and finding very little for the company to worry about.  They seemed appropriately restrained in their own optimism, so I wasn’t too concerned about them under-powering Phase 3 by assuming too much efficacy.  As it turns out, Phase 2 basically told the same story that GTx is now reporting from their top-line Phase 3 results that tested the drug in men with prostate cancer who’d undergone androgen deprivation therapy (ADT). 

Toremifene, you might know, is a SERM, like its kissing chemical cousin tamoxifen.  For years, the drug–marketed by Orion as Fareston–at lower doses has been used to treatment hormone-responsive postmenopausal breast cancer patients, as its antiestrogenic activity inhibits estrogen-driven cancer cell growth. 

Now, toremifene’s estrogen-like effects in bone and on lipid metabolism, which were always suspected of being a bit stronger than those of tamoxifen, are being exploited in men to inhibit excessive bone resorption and correct the dyslipidemia caused by ADT.  The data released by GTx suggest that the drug worked quite well in both respects, with a modest (~2x) early increase in the risk of VTE, a known risk of SERMs in women.  Data on hot flashes are pending, but you can expect to hear of an increased risk of hot flashes as well; I’m guessing 4x over placebo for the first year, with few med discontinuations due to them.  No news on stroke risk, which is good news.

This is potentially a very inspiring story for those of us who still feel positive about the value of this industry.  Were high-dose toremifene repurposed by a large company, we’d soon be reading criticisms about anticonsumer lifecycle management strategies and a persistent lack of innovation alongside the news of its clinical success (you know, to balance out any good feelings industry proponents might be having).  But that’s what is so great about this situation.  We won’t have to hear these criticisms alongside the good news, because GTx is a small company, largely backed by one guy (JR Hyde, of AutoZone notoriety) with deep pockets, who believed in his people (most notably Mitch Steiner and Marc Hanover) and their ability to bring this drug along without the help from big pharma.  That was gutsy, some might say crazy, but I think most Americans will appreciate the story.

That GTx are likely to have found an important new therapy without the need for medicinal chemistry to create something brand new is a beautiful example of how innovations should be judged by the value they offer and not by the mechanisms through which ideas become reality.  Should ACAPODENE make it to the market, it will be a triumph of ingenuity and entrepreneurial spirit.  We need more stories like this.  I’m sure patients with serious illness would agree.

I’ll update this story when we see further data and learn of regulatory progress.  I anticipate priority review at FDA.

Disclosures:  As indicated, I received consulting revenue from GTx several years ago; none since then.  I own no stock in their company.

In November 2007, Harris Interactive published their annual poll of Americans attitudes towards industrial regulation by government and the trustworthiness of industries.  I made the above chart using data from that poll.  It shows the percentage of people polled who believe that the referenced industry is generally trustworthy and honest.

As evidenced by the poll, despite being a nation supposedly undergirded by capitalist, free enterprise principles, we have a deep distrust of industry.  In 2007, 44% of us believed that none of 17 industries mentioned was generally honest and trustworthy.  Furthermore, our distrust of industry has been increasing.  In 2003, just 37% found none of the listed industries to be generally honest and trustworthy.  I’ll leave it to the politicial pundits to judge whether the current administration’s generally pro-industry policies are the cause of the recent, steady erosion of public trust (not that there was not a heck of a lot of trust to erode in 2003).

Let’s focus on our industry.  Pharmaceuticals, surprisingly–given the almost daily attacks in 2007 from Congress, insurers, presidential candidates, medical groups, and consumer advocates–fared relatively well in the public’s eyes.  Sure, the industry is trusted no more highly than car manufacturers or airlines, but it is more highly regarded than managed care providers and health insurers.  More than twice as many respondents trust pharma over managed care.  And pharma’s rep actually improved by four percentage points over 2006, one of only five industries to see an increase in its trustworthiness during that one year interval.

But let’s face it, despite the public not quite equating pharma with tobacco yet, it’s not the place to work it once was.  Back when I got into the business of pharma R&D in the mid-1990’s, it seemed like everyone was celebrating its achievements.  Wall Street loved us because of our lofty equity valuations based on robust growth prospects; politicians lauded us an example of US-led innovation success, and health advocates praised us for bringing much needed advancements to medical care in many previously underserved areas of medicine (think of SSRIs for depression as an example).  What happened to our rep since then holds many lessons for industry leaders, some of which I’ve offered in posts since I began blogging a few years ago.

Today, instead of offering some advice to a select few industry leaders who will never read nor heed it anyway, I thought instead that I would speak directly to the thousands of you who, like me, make no claims to and have no aspirations for such positions of power and responsibility.   

Call it viral PR.  Call it standing up for yourself.  However you think of it doesn’t matter.  What’s important is that each of us has a responsibility to make ourselves a part of the response to attacks on our work.   

We want to believe that we work in an industry whose R&D efforts are genuine, with lofty goals that include the alleviation of human suffering and improvements in the quality and span of life.  We want to believe that we help to market and sell our wares at the highest prices local markets can bear, because our R&D efforts are worthy of substantial at-risk investments that depend on the promise of generous financial returns.  We want to believe that all of our co-workers feel as we do. 

We are sickened by comparisons between pharma and tobacco or insurance companies.  We understand why many people mistrust us, but we hate it.  We don’t have thick skin, as PhRMA’s head Billy Tauzin, recently said in a WSJ interview.  We have the same delicate skin as everyone else in the healthcare professions who head to work each day feeling like they are making a positive impact on their local communities and maybe the rest of the world.

We, each of us, must defend our work if we believe in it.  It’s okay, no…it’s important, to be openly critical of specific policies espoused by our political leaders if we believe they are misguided.   But we must also resist denigrating our own well-intentioned efforts to fit in with conventional thinking.  Respond when people attack your work, and start by questioning their assumptions.

When asked how you justify spending valuable R&D funds on “me-too” drugs, first state that the term “me-too” is derisive and you don’t appreciate it.  Never use it yourself.  In other industries, we don’t think of follow-on innovations as “me-too;” we think of them as welcome competition that lower prices and offer more choices (of features, for example).  In pharma, such innovations are generally critically important to offering patients choices that increase the chances of finding a drug that works as intended without adverse effects.  Eventually, when the US government becomes the single largest direct negotiator of drug prices, follow-ons will also become more important as money-savers for consumers.  Sure, there will always be certain examples of follow-ons that proved to be of no incremental benefit (a couple of stereoselective enantioners come to mind), but these will be exceptions to the general rule.

After you’ve addressed faulty assumptions, dispel grand conspiracy theories that are used by industry enemies to paint pharma with the broad brushstroke of “evil-doers”.  People love a good conspiracy theory, and they are apt to assume that a grand conspiracy is the correct explanation for bad behavior evidenced by pharma (yes, like every financially motivated business, pharma has experienced its fair share of bad behavior).  Explain to them that a grand conspiracy isn’t necessary for a company’s bad behavior, even large-scale bad behavior.  It takes only a handful of bad actors in powerful positions to drive a large corporation to the dark side.  Look at Enron as a shining example.  Explain that you and the people in your circle of fellow researchers/marketers etc. are well-intentioned.  Explain that, for the most part, important decisions you have been involved with making came down on the side of doing the right thing, even when the right thing and the most highly profitable thing were not the same.  Admit that in your particular industry there is always a need to balance priorities between the need to get the most important drugs into the hands of the people who need them most and the need to sustain the expensive R&D engine that invents those drugs.  And admit that some individuals let greed be an equal priority.

After you’ve dispelled some faulty assumptions and grand conspiracies, don’t be afraid to tell people about achievements of a personal nature for which you can take pride.  Remember, keep it personal:  “I worked on a 50-person project team that helped to develop a follow-on drug for heart disease.  Because we knew that there was a similar drug already approved, we conducted a very large study measuring the effect of this drug compared with standard therapies to prevent deaths.  We coordinated the activities of over 100 clinical investigators and their patients from 17 different countries in this study.  It cost us over 100 million dollars to conduct it.  The good news was that it worked.  There were nearly a third fewer deaths seen after just five years of study.  Now, about a million people around the world use this drug every day.”  That same story with a different outcome, a failed trial, can be even more compelling to a skeptical audience.  Be as proud of your failed efforts as you are of your successful efforts.

I guess that’s enough pontificating for today.  I leave it you to contemplate other ways to infect people with your enthusiasm for your job, assuming you still have some left.

PharmaGossip: More on ENHANCE - the case of the shifting endpoint

The controversy has arisen from Merck/Schering-Plough’s failure to date to publish or present in full data from a trial that started in 2002 and was completed in April 2006. While the joint venture put the delay down to technical difficulties – notably, the need to examine more than 40,000 scans of the arterial intima-media thickness (IMT) of patients’ carotid and femoral arteries collected from 18 multinational study sites – some observers inevitably concluded that the companies had something to hide.

As PharmaGossip indicates the New York Times is fueling a controversy over Zetia that now has spilled over into Congress.  Initially, the story simply concerned delay in publishing results from ENHANCE, a Phase 3 study of 700 subjects with a genetic form of hypercholesterolemia, which was completed in April 2006.  Merck and Schering-Plough chalked up the delay to complicated logisitics analyzing 40,000 IMT scans.  Now, the Times is implying that the Merck/Schering-Plough alliance might have purposely delayed publication of studies, including ENHANCE, that might contain information indicating a liver toxicity problem with Zetia. 

By way of full disclosure, I have no personal financial relationships with either Merck or Schering-Plough, but my employer might.  I’ll also state that I have been medicated with statins for many years and began using Zetia shortly after its U.S. launch.  I’ve personally had no problems with the drug and continue using it at its maximal recommended dose daily in combination with a statin at its maximal recommended dose.  It has effectively reduced my LDL-cholesterol by around 20% over statins alone.

Published data on Zetia is plentiful, although more is always welcome.  The reports of a complete lack of public results from the ENHANCE study, however, are correct.  There are no data, published or simply posted in the PhRMA’s clinical study results registry, from ENHANCE (search ZETIA with and without the registered trademark symbol if you look for it on the PhRMA results website).  Should Merck/S-P eventually be proven to have purposely delayed publication of this study or to have attempted to rig publication in favor of Zetia by changing the pre-specified primary endpoint, then shame on them.  Those responsible will deserve punishment and public embarassment.  If, though, the logisitical nightmare of coordinating the reading and interpretations of the tens of thousands of IMT scans are to blame for a conclusive efficacy read-out, then it’s reasonable to expect Merck/S-P to delay both a peer-reviewed publication and any public release of safety and secondary endpoint results as well, so as not to provide a false impression of the benefit to risk ratio in this study population.

I think I can speak for most people who use and prescribe Zetia when I say that we would love for Merck and Schering-Plough to study hard outcomes (MI, death, stroke) with the combination of Zetia and maximal doses of statins versus statins alone in high-risk patients.  In the meantime, we rely on reductions in LDL-cholesterol as an unproven surrogate marker for the particular mechanism of action of Zetia (reduced intestinal cholesterol absorption), hoping that reduction in LDL-C with Zetia will offer benefits similar to those of statins alone.  The ENHANCE study will offer little additional evidence of efficacy, or lack thereof, to the majority of Zetia users who more closely resemble me than the subjects studied in ENHANCE.  Whether Zetia reduces or leaves unchanged carotid IMT compared with statins alone will not change my decision to use the drug in the hope that it is reducing my risk of MI.  Likewise, the drug has not adversely affected my liver, so I will not stop using it if ENHANCE shows that some patients with heterozygous familial hypercholesterolemia experience liver damage while using it.  Only if ZETIA increases IMT significantly in this population would I think consider stopping it.

I, like many people at high risk for heart disease, need help keeping my LDL-C in a safe range, and Zetia plus statins is the only reasonable choice for me at the moment.  Clearly, people in my position need more choices.  We could benefit from more information on the long-term effects of Zetia too.  But the results from ENHANCE and other “hidden” Zetia data (that have been reviewed by regulators) are unlikely to be of any consequence for all but a small percentage of Zetia users.

Avastin Distribution Change - Open Letter

I read today’s WSJ Health Blog on Avastin thinking that Genentech had appeased eye specialists by maintaining distribution of Avastin to compounding pharmacies, but after reading the above open letter, I’m confused about Genentech’s actions in the recent past and about what it’s planning to do in the near future.  Take a look and let me know if you share in my confusion.

The decision we communicated [to cease Avastin distribution to compounding pharmacies] was not made lightly. In fact, it was guided by our company’s strong commitment to take actions that are scientifically and clinically sound and in the best long-term interest of patients, while at the same time adhering to government regulations and remaining mindful of the retinal community’s views.

The above open-letter snippet suggests that Genentech was motivated by their concerns around the safety of Avastin formulated for intravenous delivery being delivered ocularly.  They make this explicit later:

Genentech’s decision was not motivated by a desire for increased profits. We did not and do not expect that this change in policy toward compounding pharmacies will lead to any increase in LUCENTIS® (ranibizumab injection) sales. Further, we expect Avastin to be available and that physicians will continue to prescribe it for ocular indications.

So far, so good.  Genentech is making a logical argument.  Essentially it’s saying that, like Hippocrates himself, Genentech aims to first do no harm.  Fair enough, although I think it’s disingenuous of a for-profit company to imply that an important decision can be divorced from a business case, but I’ll leave that for a future discussion.

Then we get the news that FDA had inspected Genentech’s manufacturing facilities (just when, relative to the company’s compounding-pharmacy decision, we’re not told), and Genentech reacted:

…[W]e destroyed four batches of Avastin deemed unsuitable for use in the eye due to a higher visual inspection standard. (These lots would have been entirely suitable for its approved use as an intravenous cancer medication.) The action resulted in the loss of more than 350,000 vials of Avastin with a market value of more than $200 million.

Now I’m lost.  Why would Genentech have to destroy $200 million of Avastin stock intended for use as a cancer therapy (albeit used off-label for other uses, included ocular uses) to appease FDA inspectors?  Is Genentech saying that FDA mandated that Genentech produce a product capable of withstanding the same visual-inspection standards required of ocular drugs and that Genentech relented to this mandate without fighting it?  Is that what Genentech is saying?  Okay, let’s say that’s it for arguments sake.  What happens next?

The letter implies that sometime after this self-imposed drug destruction, Genentech made its compounding pharmacy decision and soon after that met with key opinion leaders to revisit the decision (N.B. no mention was made of FDA’s involvement at this KOL meeting).  Genentech communicates publicly after this KOL meeting that it will continue to supply Avastin to compounders until at least January 2008 and maybe longer if FDA approves. 

In contrast to what was earlier implied by the juxtaposition of the FDA manufacturing/packaging audit and destruction of drug, this latter sequence of events suggests that Genentech’s Avastin destruction was voluntary, not FDA imposed.  Why else would Genentech be able to decide unilaterally to continue supplying Avastin to compounding pharmacies–without FDA approval to do so–beyond November, the original date of its distribution cessation?  If FDA had ordered destruction of Avastin they would have also, it would seem, had to approve continuation of its supply to compounding pharmacies.  Yet, no mention is made of such approval.  Indeed, Genentech states that it will continue shipment of drug to compounding pharmacies after January only with FDA approval, again suggesting that FDA is having some say in how Avastin is distributed (or packaged for distribution to compounding pharmacies).

So, I’m left with a bunch of questions that leave me wondering what really happened here and what is going to happen come February 2008:

What did FDA actually find during its audit and what specifically prompted the destruction of a large amount of Avastin intended for use in oncology?  Was the destruction voluntary or FDA-mandated? What alternatives to destroying the drug were considered?

What changes to manufacturing/packaging were made following destruction of the drug, and how will such changes affect distribution to compounding pharmacies? 

Is an FDA ruling on manufacturing/packaging changes both necessary (as implied in the open letter) and sufficient for Genentech to extend distribution of Avastin to compounding pharmacies beyond January 2008?

Is Genentech planning to change the cost of Avastin for compounding pharmacies?  Will there be distinct ocular-specific and oncology-specific formulation/packaging?

When we get some answers to these questions, I’ll post an update.

Disclosure:  I have no equity or other financial stake in Genentech or its direct competitors.

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.