Pharma’s Cutting Edge

S. Sen. Grassley: Secures independent review of FDA approvals based on narrow health benefits - FierceBiotech

In his letter to the GAO, Sen. Grassley asks for an investigation into FDA’s use of surrogates for product approval and whether FDA has appropriately followed up drugs approved initially based on surrogate markers.  He cites recent examples of Avandia and Vytorin as cases where the system hasn’t worked as intended.

Is he right?

Avandia was aproved on the basis of a surrogate marker, HbA1c, but the marker is a surrogate for the effects of chronic hyperglycemia on the body.  It is not a proven surrogate for the outcome of heart disease, as Sen. Grassley implies. 

The effects of chronic hyperglycemia in patients with Type 2 diabetes that are well established include heightened risks of diabetic microvascular disease, which is associated with diabetic nephropathy, retinopathy, and neuropathy and their sequelae.  There is decent evidence that reduction in chronic hyperglycemia reduces the risk of these serious health outcomes.

There is also reasonable evidence for associations of chronic hyperglycemia with other diabetes sequelae that relate to microangiopathies.  The evidence for an independent effect of chronic hyperglycemia in Type 2 diabetes on macrovascular diseases, which include heart disease, is much weaker.  Therefore, to say that FDA failed in its duties by approving a drug based on its effects on hyperglycemia alone is disingenuous. 

On the other hand, I’ve long supported large premarketing simple safety studies for drugs to be used chronically in large populations (see here, for example), so if Sen. Grassley’s intention is to try to make such studies a requirement, I support him.  I just don’t support his implication that FDA shouldn’t have relied on reduction in HbA1c as a demonstration of efficacy.  It was then and is now an adequate surrogate endpoint for many of the detrimental effects of chronic hyperglycemia due to Type 2 diabetes.

The other chosen example, Vytorin, is another poor one to use against the choice of a surrogate to claim eficacy.  As I’ve explained in an earlier post, the ENHANCE study did not establish the lack of efficacy of Vytorin or Zetia, as Sen. Grassley implies.  It merely demonstrated that in a highly selected population of patients with atypical hypercholesterolemia, the use of Zetia with statin failed to reduce progression of carotid intimal thickness, itself an unproven surrogate measure for the outcome of cardiovascular death or disability.  Genuine cardiovascular outcomes studies with this class of drug are underway.

Was Sen. Grassley wrong to imply that makers of drugs used to lower LDL-C or raise HDL-C should be required to do hard outcomes studies prior to approval?  Yes and no.  For the statin class, there’s little doubt that using LDL-C as a surrogate is justified, given the benefits on heart disease risk reduction shown with several class members, at least in patients with established heart disease at baseline.

For other classes of drugs, including the class containing Zetia/Vytorin, I think he’s mostly right, with one exception.  There are some diseases independently associated with high cholesterol in the blood that are amenable to treatment with drugs that lower blood cholesterol.  However, these conditions are rare and typically affect only those patients with very high lipid levels.  So, generaly speaking, I agree with the implication and with the sentiment.  Drugs used to lower LDL-C that will be used primarily by people like me who hope to reduce their risk of heart disease should be studied rigorously in the premarket setting, and such study should include evaluation of their effects on disease outcomes, rather than unproven surrogates (both LDL-C and CIMT, in the case of Zetia/Vytorin).

Phase 2 Gemini Study Top-line Results Described

This morning Alnylam presented top-line results from its Phase 2 POC study of anti-RSV RNAi therapy, known as ALN-RSV01, demonstrating an effect of the therapy in experimental upper respiratory RSV infection.

The intent of thes study was to determine whether relatively high doses of ALNRSV-01 delivered intranasally to experimentally infected healthy volunteers could reduce local viral load.  The volunteers were given two doses of the drug (one per day) prior to being nasally inoculated with roughly 10,000 viral particles (much higher than the typical natural infection load).  Then they were given further treatments of ALN-RSV01 or a matching placebo for an additional three days after inoculation; all told volunteers were quarantined for 12 days (yikes).  In order to ensure a reasonable rate of infection, potential volunteers were screened for anti-RSV antibodies.  Those with clinically relevant titers of antibodies were excluded from the study, necessitating the screening of 1,000 people to enroll 88 (double yikes). 

The rate of infection (primary endpoint, by plaque assay), viral load measures, and clinical symptoms were assessed.  In a nutshell, the therapy reduced the rate of viral infection by a number of measures and the primary endpoint was met.  Trends were seen in viral load measures but not in symptoms, which were modest in any case. 

This was a robust demonstration that RNAi delivered locally (and prophylactically) can reduce (but not eliminate) viral infection.  In that respect, it is valuable as a proof of concept in humans for topically delivered RNAi acting against viral cells directly at the site of inoculation.  I don’t think it should be construed as a proper POC of systemically delivered RNAi under any circumstances, nor for topically delivered RNAi directed against endogenous gene expression.  So, RNAi is still in its infancy, clinically speaking, but it’s showing signs of life. 

Investors on the conference call were interested in what this study might mean for the future of this particular therapy.  I think Alnylam’s management were appropriately circumspect when addressing the issue.  If I were an investor (I’m not), I’d be relieved that this important first hurdle has been cleared, but I’d also have to admit to myself that this therapy is still a long way from proving itself in naturally infected kids and fragile adults with RSV pneumonia.  Alnylam mentioned that the next Phase 2 will be a study of adults with naturally occurring RSV infection, presumably upper respiratory infection.  In that setting, ALN-RSV01 won’t be given a headstart over the virus–treatment won’t begin until clinical symptoms have appeared–and effects on symptoms would be helpful to guide future studies and gain investor confidence.  So, like any other drug, we’ll have to see.  But at least now there’s a decent reason to watch.

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.

After I had fnished reading the recent Supreme Court decision in Riegel v. Medtronic and some news reports describing the supposed implications of the decision for pharma, I was confused.  Were the implications for pharma product liability cases broad and profound or narrow and limited?  Certainly, the upcoming Wyeth Supreme Court case will have its own implications for pharma, but, in the meantime, I turned to my colleague Greg Glass, editor/owner of the Paragraph Four Report, to lend his opinion to the Court’s Medtronic decision.  Here’s what he said:

As for the [Medtronic]  case, you have to read it very narrowly. It appears that the gist of the lawsuit was that the plaintiff did not have much to go on in suing Medtronic. The product [apparently] was contraindicated for the use for which it was administered to the poor guy, and the balloon was filled to 10 atmospheres, rather than the maximum [recommended] pressure of 8.  So, it appears that there was not much product liability theory to go on. ([The situation would have been different] if the facts instead were that the product was used for its intended use and the balloon ruptured at 4 atmospheres).

So, the plaintiff, being “creative,” asserted the product failed to meet certain design and manufacturing standards.

The point of the law [MDA], and the FDCA for that matter, was to create a uniform approval and safety standard. For example, what would happen if Texas passed a law that required new drugs to have three controlled studies before the product could be sold in Texas? So, the idea is to have one set of rules — federal law — to control these things.

[Following this ruling], you can still sue under state laws in state courts for product liability cases — but those laws can’t create higher manufacturing and approval standards than what federal law creates. Federal courts are harder to get into and usually don’t hear the standard product liability cases.

That seems pretty clear to me.  If the device doesn’t work as it’s supposed to, according to the FDA, plaintiffs still have the opportunity to sue in state court under product liability laws.  But if the device is pushed beyond its recognized (labeled) limits, as the facts supported in this case, plaintiffs can’t sue in state court using a state law that creates a tougher standard for the product than the FDA recognizes.

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.