Archive for Lifecycle

Drug approval double-header in today’s NEJM

August 29, 2007 at 10:35 pm · Filed under Lifecycle, FDA, Drug Safety, Legislation

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’.

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Some lessons from the Plavix patent challenge

October 16, 2006 at 4:27 pm · Filed under Lifecycle, Generics, Legislation

Drug makers continue to battle in Court for the rights to sell (Apotex) or prevent the sale (BMS, Sanofi-Aventis) of a generic version of the blockbuster blood-thinner Plavix.  Meanwhile, the FTC vows to keep fighting the kind of settlement deals BMS and Apotex tried to reach before a group of state Attorneys General gave it the thumbs-down and despite FTC’s highly publicized failure earlier this year to derail a settlement between Schering-Plough and two generics manufacturers.

When faced with such important and potentially confusing matters concerning patent challenges to innovators’ drugs, I turn to my colleague Greg Glass, editor of the Paragraph Four Report and an occasional guest author at Pharma’s Cutting Edge, for the big picture.  Greg hasn’t let us down.  Below he gives us the skinny on the some take-home lessons from the Case That Brought Down a Pharma CEO.   

FJC

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Over the summer, as many of you know, the deal between Apotex and Sanofi-Aventis/Bristol-Myers fell apart, and Apotex launched its generic product.  To label these events as “highly unusual” would be an understatement, and they are so bizarre that I cannot help myself but to discuss them.  While many things have been brought out from under the shadows, it is clear that there is some important information we still do not know, and can these events be applied to pending and future settlements? First, let’s review some key facts from this past summer, some of which the press reported.  Follow me on this as this gets a bit detailed…• On June 26, the U.S. Supreme Court denies the request of the Federal Trade Commission to review the Schering-Plough case, which rejected its position that a brand can’t pay a generic to settle a PIV case, among other things.• The next day, U.S. Senators introduce a bill that would prohibit a Paragraph IV (“PIV”) patent case settlement if the generic company receives anything of value and postpones marketing of its product.

• On July 20, the FTC testifies before Congress about the problems of PIV settlements though it admits that legislating settlement terms (and removing payments to generic companies) would be “challenging.”

• In late July, Attorneys General from several states reject the Plavix settlement.

• On July 27, agents from the federal government raid the office of Peter Dolan, CEO of Bristol-Myers, seeking evidence of anti-competitive behavior in the Plavix deal.

• On July 31, the FTC had yet to approve or reject the settlement, so it expired, allowing Apotex to launch. 

• On August 4, Medco Health Solutions mentions that it expects to get a generic clopidogrel in stock in August.• A few days later, Apotex launches “at-risk” though we later learn that most, if not all of, the risk had been bartered away by BMS as well as its right to file an immediate injunction.  Apotex CEO Barry Sherman reportedly negotiated such terms because he figured the FTC would never accept such a deal.  (One must assume he was gleeful.)

• After the injunction is considered, the Court in New York sides with the brands, mildly suggesting that Apotex may not have that great of a case after all.  However, the Court does not go as far as making Apotex remove product that is on the market.• On September 12, Peter Dolan is removed as CEO; presumably because he did not keep the BMS Board informed of the deal every step of the way and allowed an executive to negotiate, by himself, with Barry Sherman. As you have undoubtedly noticed, the connected dots start with the Schering-Plough case which is seemingly unrelated.  However, I am not a huge believer in coincidences when it comes to politics, and it raises the first question.What is the current FTC position on settlements? It appears that the FTC is still taking the position that any payment to a generic company, along with a “delay” in the launch of a generic product is a per se violation of antitrust law.  It took the same position to Court and lost (see Schering-Plough). Now it appears to be using the legislative process to promote its position.

If the agreement was such a clear violation of antitrust law, why didn’t the FTC reject it? Because it couldn’t, in all good conscience, given the results in Schering-Plough. In this situation, FTC could wait it out, knowing that the deal would expire at the end of July if it didn’t act.

So, why did the settlement fall apart? This is a great question which we may not fully know the answer. Clearly, this appears to be more about politics and money than anything else and appears to have been used to make a point about the broader issue of drug pricing.  The FTC, some states attorneys general, and some senators can now boast (to senior citizens voters) that they are fighting to get less expensive drugs to market.  It is an election year.  The fact that some states rejected the agreement also makes you wonder if their decision was entirely independent of the FTC.Are other settlements at risk for falling apart?  Lately, we have seen many PIV settlements, but these are not likely at risk though there are similarities between these settlements and the Plavix agreement.  Barr Labs had the right idea when it settled Adderall XR® in August by announcing that it would reach the market with a generic before the challenged patent expires. Though this was also true for Plavix, it frames the issue to negate the “generic was delayed” argument.  It may also help to toss in other items like cross licenses and co-promotion deals to make the PIV case a smaller part of a larger transaction.  Remember that how these settlements are portrayed and positioned may be important than what terms they contain.  Frankly, the Plavix settlement terms really weren’t that much different than most others and somehow those other agreements were deemed “okay” while the Plavix settlement was “bad.”So, the FTC is giving up on its position.  Right? Well, not really. During its testimony in front of the Senate, the FTC admitted that it was looking at other settlements which suggests that they might bring the same argument again, in the hopes of winning in a different circuit, thus increasing the odds of the Supreme Court hearing the case as there would then be a conflict in the circuits if the FTC position prevailed.  One would expect it to wait until a case can surface in the 9th Circuit which may be more sympathetic to the broader issue of access to generic medicines.  So, it may not be giving up. Will the Senate bill, dictating terms of settlement agreements, become a law? I don’t know, but I sure hope not. Though the drug industry is highly regulated, last time I checked, the U.S. operated on a sort-of free market system.  One of the last things we need is for elected legislators to be a de facto part of the negotiations between two companies trying to settle a private patent dispute.  If this is fair game, what’s next?

How should a company approach a settlement of a Paragraph IV case?  If you believe the accounts of what happened to Peter Dolan, the safest approach would be to have all executives involved, copy the Board on everything, and never let an executive negotiate alone. Of course, the more people involved, the more likely the chances for a leak of a pending settlement. 

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Waxman, Schumer, Clinton, Leahy, Stabenow introduce generic biologics legislation

September 30, 2006 at 1:22 pm · Filed under Lifecycle, Technology, Generics, Healthcare delivery, Legislation

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 »

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GSK’s recent pricing deals

September 20, 2006 at 9:10 am · Filed under Lifecycle, Sales and Marketing, Health Econ

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?

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Drug Industry Raises Concerns Over Potential Changes To Patent System

August 24, 2006 at 11:40 am · Filed under Lifecycle

I’m not sure I’ve commented on this issue previously, so I thought now would be a good time, as legislation has now been proposed, and presumably there will be some debate in Congress.

The issue of bringing US inventorship criteria more in line with the rest of the world has been around for some time. In most of the world, inventorship is determined in part by first-to-file status. In the US, by contrast, inventors do not have to be first to file a patent application, but they must be first to conceive of the invention and they must be diligent in reducing the invention to practice. Practically speaking, the US system places a substantial burden on inventors to document their inventions (i.e. the ideas) and their reduction to practice (i.e. activities and observations supporting the ideas) prior to filing an application. This burden is shared by anyone that desires US patent protection, which is to say nearly everyone in our industry, because the US is the largest single market for drugs and devices. If you work in drug discovery you know this burden first-hand all too well. Switching to a first-to-file system would not eliminate the need to document experimental details and new ideas, but it would reduce the burden on scientists by eliminating some administrative tasks that serve only to meet current US patent requirements (e.g. the need to have lab notebooks signed on a regular basis).

The article suggests that the pharmaceutical industry is against this change to the US system, but it doesn’t explain why. At first blush, it seems that everyone would be well served by a European-like inventorship determination, because it would reduce work that doesn’t contribute directly to innovation (i.e. it would boost innovation productivity). But remember that patent life is a fixed period that begins with filing of the final patent application. Effective patent life (i.e. actual time for patent protection of a marketed product) is determined by the date of patent filing, the time between filing and product launch, and the time of generic entry into the market. As we all know, there is a relatively long time between initial discovery of a potential therapeutic and its realization as a product, often a decade or more. Under the U.S. patent system, companies are now able to maximize effective patent life by waiting to file their first patent applications, while protecting themselves by documenting the inventions and their reduction to practice internally.

In a first-to-file system this type of strategic patent filing isn’t possible. Companies practically cannot wait to file in a first-to-file system, since the filing itself represents the only acceptable way to assert inventor status. All else being equal, the result is that effective patent life for drugs in the US would be reduced relative to the current system. Exactly how much it would be reduced in an individual firm can be estimated by using internal data. Calculate the time interval between the dates of first filings for successfully marketed products and the dates the inventions were first documented in the lab (in the lab notebook). This interval is the maximum reduction in effective patent life that would be expected from a change in inventorship criteria. Actual effective patent life reduction would be less than this, and may be estimated subtrating the amount equal to administrative tasks (i.e. preparation of the filing) plus the time interval between the idea and the filing filing (approximated as the time between the provisional and final patent applications). The calculation looks like this: Effective Patent Life Reduction = (Date of actual first final patent filing-Date invention first conceived)-(Time to prepare patent applications+(Date of final patent application-Date of provisional patent application)).

The life science industry won’t be alone in opposing this legislation, but they will be in the minority. Few industries use patents to appropriate their inventions as much as the innovative life science industry, and fewer still have the long development times “enjoyed” by the drug industry. In particular, industries such as software and consumer electronics strongly favor the first-to-file criterion. Look for spirited debate in Congress–assuming legislation reaches the point of debate–fueled by intensive lobbying activity behind the scenes.

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