Biosimilars And Gene Patents In This Week's News

According to a story by Bronwyn Mixter in this week’s Bloomberg’s BNA BioTech Watch, the FDA has received at least twenty-five IND’s for biosimilar development programs.  Some quick perspective on that is appropriate.  Twenty-five initial IND’s for the development of new small molecule drugs for cancer or autoimmune disease would face many years of clinical trials and long odds against approval (DiMasi et al estimated the approval rate at sixteen percent to nineteen percent).  However in this “a little brave” and “a little new” world of biosimilar development, clinical development programs are likely to be much shorter in duration than development programs for new drugs or innovator biologics, and the success rates are likely to be very high, as I indicated in my post of May 19^th, 2014.  The DiMasi study referenced above estimated the large molecule success rate at thirty-two percent; and, biosimilars are not only within that large molecule category, they are copies of drugs that have already been shown to be reasonably safe and effective.  So it is very likely that we will see filings for the approval of more than twenty biosimilars in the next three years.  It will be very interesting to watch the development of the biosimilar marketplace.

Novartis Hopes PARADIGM-HF Study Results Lead to Blockbuster Sales for Its LCZ696: Big Diseases and Pharmacoeconomics

In this week’s New England Journal of Medicine the most widely publicized article reported on the findings of the PARADIGM-HF study, which tested Novartis’s experimental drug LCZ696 against enalapril, a commonly used ACE inhibitor, in the treatment of heart failure (HF). The double-blind study randomized over 8,442 patients with moderate to severe HF to a regimen of the experimental drug plus standard therapy or of enalapril plus standard therapy.  The primary outcome was a composite of deaths from cardiovascular disease and first hospitalizations for HF. After 27 months, the trial was halted because an interim analysis showed a very large benefit for the experimental drug group. The LCZ696 patients had an approximately 20 percent reduction in the primary outcome (914 patients versus 1,117 patients in the enalapril group: “hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001”).  The experimental drug group also had comparably substantial and significant reductions in the risk of death from any cause and the risk of death from cardiovascular disease.  The results of the study have been reported on widely and it is clear that Novartis hopes LCZ696 will achieve blockbuster revenues.  For purposes of this post, I would like to focus on two of the study’s findings with obvious pharmacoeconomic ramifications for calculating the drug’s costs and benefits, which are the reductions in both hospitalizations and in deaths:

Over the duration of the trial, the numbers of patients who would need to have been treated to prevent one primary event and one death from cardiovascular causes were 21 and 32, respectively.

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Crystal Balls, Ebola, and Pharmaceutical Development in 2020

It is always safe to make predictions about what the future will be like in ten years, because if it turns out that you were wrong, the odds are no one will remember. If it turns out that you were right, you can seize the opportunity to remind everyone of your remarkable prescience. With that as prologue, I will start by revisiting a prediction I made sixteen years ago about a date still six years from now. In April of 1998, at a conference entitled NEXTMED:  The Future of Medicine, I made a prediction for the year 2020 (20/20 vision was a popular theme in the futurist business back then). Actually I made several predictions, but I have carefully selected the one which has the best chance of proving accurate. In my talk I included the Ebola virus as an example of the progress I foresaw in our ability to respond to future threats:

Immunology at the Rainbow’s End: A Push-Button Vaccine Machine

It is a few years off, but obviously the science of predicting protein structure from a gene sequence is moving rapidly; and, well within the time frame spanned by this talk, it will be a reality. At that point, the window will slam shut on the possibility of our being overrun by a third-world virus, another HIV or, worse, a more widespread and contagious Ebola. Within days of the first cases being picked up, a blood sample of a victim would be sufficient to do a full genomic analysis of the pathogen, the pathogen’s proteins would be fully analyzed both for their function and their antigenicity, the most antigenic regions would then be synthesized with an appropriate adjuvant, and a very effective vaccine would be coming off the production line a week or two later.

Drug Safety and FDA Approval Times: It Is MUCH More Complicated Than the HEALTH AFFAIRS Study or the FORBES Response

In my blog post of March 26, 2014, I commented on a New England Journal of Medicine article authored by Darrow, Avorn, and Kesselheim that focused on the serious safety issues arising from the FDA’s accelerated drug approval programs for “breakthrough” drugs.  It is clear that the expedited approval of drugs based on surrogate endpoints can result in marketing approval for drugs with questionable risk/benefit ratios.  However, in the past week a different controversy has arisen over the relationship between drug safety and FDA approval times, sparked by an article in Health Affairs by Cassie Frank and others entitled Era Of Faster FDA Drug Approval Has Also Seen Increased Black-Box Warnings And Market Withdrawals.  The Frank article prompted a response from John R. Graham in Forbes with a title that evidences his disagreement with Frank’s group: Faster FDA Approvals Have Not Caused More Drug Safety Problems.  So who is right?  Actually, my answer is “Neither article sheds much light on the FDA role in drug safety.” It is complicated, like so many problems in pharmaceutical policy.

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Ebola Biologic Stirs Bioethics Discussion

I was quoted (and my expertise inaccurately described) in the San Diego Union-Tribune’s article about the ethical issues raised by the experimental ZMapp biologic for the treatment of persons infected by the Ebola virus.  I am not a specialist in bioethics, which is the description provided for me in the article, and only claim to know something about the ethical issues that are raised in drug development.  The otherwise reasonably well-written story is here. There has been a fair amount written about the ethical issues in this situation, where there are very limited amounts of a drug that has only animal data supporting its safety and efficacy.  The New York Times article by Andrew Pollock is here. Arthur Caplan, who has moved to NYU since his infamous involvement in the tragic Jesse Gelsinger gene therapy death at the University of Pennsylvania, is quoted at the very end of Pollock’s article.  Caplan expresses concern about the appropriate allocation of resources to therapy research versus public health in the expanding Ebola epidemic.  He may be correct that expenditures for drug research and development will do little for the current outbreak, but that is largely irrelevant.  I doubt that the development and scale-up of Mapp Biopharmaceutical’s biologic is diverting significant resources from the public health measures that Caplan favors.

Norway Leads the Way in Biosimilars: The NOR-SWITCH Study!

On July 24, 2014, Novartis announced that the FDA had accepted for filing the first application seeking marketing approval in the U.S. for a biosimilar version of filgrastim (Neupogen).  In my May 19, 2014, post “A Few Thoughts About Biosimilars” I discussed the problem of driving down the price of these somewhat cheaper, but still very expensive, drugs.  Biosimilars have been available in Europe for some time but none have been approved yet in the U.S.  In this post I will discuss a different but related problem in biosimilars development, which is built into the Biologics Price Competition and Innovation Act (BPCIA).  

Pradaxa and Drug Safety: Product Liability Played a Role

This week’s post is about the problem of product liability in pharmaceutical policy, an issue that I have not discussed since my first posts on this blog in February.  Boerhinger-Ingelheim’s drug Pradaxa (dabigatran) is a “thrombin inhibitor,” an anticoagulant drug used to prevent strokes and embolisms in patients with atrial fibrillation or other conditions that put them at high risk for stroke. One of the principal selling points of Pradaxa and other direct thrombin inhibitors is that their recommended use does not monitoring patient’s blood levels of the drug, unlike the much older drug Coumadin (warfarin) which is used for the same purpose but has a different mechanism of action and requires individual dosing and monitoring. Pradaxa has been the subject of very interesting news this past week, initiated by an article by Deborah Cohen, M.D. in the British Medical Journal (BMJ) entitled: Concerns over data in key dabigatran trial.  Accompanying the article was a feature editorial with the even more attention-grabbing title: Dabigatran: how the drug company withheld important analyses

Pharmaceutical Pricing-- The Story That Just Keeps Going

After last week’s foray into patents and pharmaceutical policy, which is perhaps the most technical and specialized area of pharmaceutical policy, I will return to the never-ending story of pharmaceutical prices and the controversy over Sovaldi, Gilead's break-through Hepatitis C drug.  Sovaldi has a "sticker price" of $84,000 for a 12-week course of treatment, at the end of which 90% or more of patients would be expected to be cured. Since Sovaldi is a pill that is given once a day, the 12-weeks of treatment means that there are 84 daily doses. The math is easy, even if the price, unlike the pill, is hard to swallow--$1,000 per pill. The drug has been a huge financial success for Gilead, which reported $2.274 billion in sales in just the first quarter of 2014.   However, the backlash has been equally huge.  In a rare display of bipartisanship in Washington, Senator Ron Wyden (D.-Ore), the Chair of the Senate Finance Committee and Senator Chuck Grassley (R.-Iowa), the Ranking Member of the Finance Committee, sent a demand for information concerning the development costs of Sovaldi and Gilead’s pricing decision.  However, even more than the investigation by two senior senators, the impetus for today’s post came from the blog RxObserver, which featured a post entitled Sovaldi: A Poster Child for Predatory Pricing [sic].  Before discussing the epithet “predatory pricing,” the perspective of RxObserver requires a bit of explanation.  RxObserver is a site that primarily provides the views of pharmaceutical benefit managers (PBMs), or as the blog itself states its purpose: “the Clearinghouse of the Future for Pharmacy Benefits.” It is, in general, a very high-quality blog, with an editorial staff composed primarily of well-recognized academic and government experts in health care policy.  I regularly read it and find it useful, although I was taken aback by that “predatory” epithet.   Download PDF

The Good, the Bad, and the Ugly: Developments in the Intersection of Patents and Pharmaceutical Policy

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This week I am focusing on patent law, which is one of the more arcane and technical areas of pharmaceutical policy. A recent major decision by the Court of Appeals for the Federal Circuit (CAFC) in Bristol-Myers Squibb v. Teva Pharmaceuticals (BMS v. Teva) is rather remarkable in the degree to which it departs from prior decisions on the patentability of small molecules as the active ingredients in drugs. Chris Holman, a leading scholar in the intersection of intellectual property and the biotechnology and pharmaceutical industries, wrote a great article a few years ago arguing that a significant degree of unpredictability in patent law would substantially depress pharmaceutical innovation. Holman argues persuasively that the uncertainty as to whether or not a patent claim to a drug's active ingredient would be enforceable is, in essence, an additional cost burden on pharmaceutical research and development, and that this increasing cost burden is responsible for a decrease in the output of pharmaceutical research. Holman pointed to a long period of stagnation in the number of new drugs approved as evidence of the decreased output of pharmaceutical research. He uses two examples of Eli Lilly patents that had been invalidated as evidence of the unpredictability of patent law. Holman's analysis of the unpredictability problem centered on three different ways in which uncertainty is created:

the proliferation of loosely defined standards rather than bright line rules; unpredictability associated with long-delayed clarification of critical and identifiable ambiguities in patent law; and perhaps worst of all, unpredictability that occurs when courts adopt a new interpretation of legal doctrine and apply it retroactively, to the detriment of the investment-backed expectations of patent owners.

The End May Not Be Near But The Future Is Not Looking Very Good

I have always been an optimist about the future of biotechnology and the future contribution of the life-sciences industry to health and healthcare. There have been a fair number of market cycles since I first began studying the biotechnology industry in 1984. When venture capital was tight or the window for initial public offerings slammed shut, I was always confident that those downturns in financing were temporary. Sooner or later the level of investments in early-stage biotech would rebound and the public markets would again be open to biotech companies with significant products in later stage development. My optimism that the markets would recover rested on my faith in the long-term rationality of the investment markets, both public and private. As long as basic research continued to provide the foundation for significant commercial opportunities, sooner or later profit-seeking investors would seize on those opportunities. It is the "as long as basic research" part of that premise that causes me to be concerned.