Best of the Blog: IN VIVO, April 2008

"Best of the Blog" is a monthly column highlighting the best of our free online content at www.windhover.com/blog. In April: Televancin Delayed by Grassley's Ketek Data Integrity Rule; Diabetes Drug Development and Regulatory Risk: Why the Guidance May Be Good News; and Mircera: Bad for Patents, Good for Patients?

Best of the Blog is a monthly column highlighting the best of our free online content at www.windhover.com/blog. In March, Windhover’s editorial staff posted 41 articles to the site, covering biopharma, device and diagnostics R&D, business development, regulatory, and commercial news. Last month we reported from our PSO and BIO-Windhover meetings, analyzed FDA’s personnel decisions, and even tried our hand at haiku. Here are a few of our favorite blog posts from March.

Televancin Delayed by Grassley’s Ketek Data Integrity Rule

FDA is adopting whole-heartedly at least one of Iowa Republican Senator Charles Grassley's new de facto rules for drug approval reviews: the agency is not going to risk its public credibility by continuing to consider for approval applications where there is even a hint of a data integrity problem.

That's one of the lessons of the Ketek investigation and one that Innoviva Inc. experienced painfully late last month. On March 3, Theravance explained more about the last-minute cancellation in the planned February 27 FDA advisory committee review for its injectable antibiotic, telavancin.

The delay stems from FDA's unwillingness to review the application after the removal of data from one study site. Theravance said that the agency asked the company to remove the data from the site on January 30, 27 days before the scheduled Anti-infective Drugs Advisory Committee review and 19 days after the agency first announced its intention to hold the advisory committee review of the drug.

Theravance maintains that the "removal of these data had no material impact on the overall efficacy and safety results or conclusions of the study previously reported, and we believed the site issue had been adequately addressed by the data removal."

In that case, the company was too focused on its own application and not paying attention to the overall environment and the pressure on FDA from Grassley's intense oversight--focused in particular on the agency's willingness to overlook some questionable data to keep an application on track for approval.

Grassley sent FDA a letter on December 19 in his continuing review of FDA's handling of the Sanofi telithromycin (Ketek) application that created a de facto standard: a sponsor cannot resolve a data integrity issue by just removing the results from the questioned center or investigator.

In his mid-December letter, Grassley made it very clear that he expects FDA to halt the approval process on applications if the agency finds any problems with data integrity. (See "Data Integrity Delays: Another Key Takeaway From Ketek," The RPM Report, January 2008 .) Grassley's letter, coming right before the Christmas holiday break, was probably ignored by much of the financial community. It was also overshadowed by Theravance's December 27 announcement that it was getting ready for an imminent advisory committee review.

FDA tried to work around questionable data before. It asked an advisory committee previously to review the Ketek application with some suspect data from a clinical investigator removed. Based on the heat it has taken from Grassley for that review, FDA was unlikely to repeat that process of a quick fix for the data in the case of another drug, especially another antibiotic.

Theravance says it is "committed to working with the FDA to resolve outstanding issues related" to the telavancin clinical trials for complicated skin and skin structure infections, the "ATLAS program." The company reports that FDA wants to "further evaluate study site monitoring and study conduct to ensure data integrity in the ATLAS Phase III program." The agency wants to look into monitoring at other sites and not just take the word of the contract research organization.

Other NDA sponsors would be well advised to pay more attention to all pending data integrity issues for products nearing the review stage. The agency's division of scientific investigations is clearly emboldened and carrying more weight within FDA from Grassley's attention (See "Investigating the Investigators: Another Headache for Drug Sponsors," The IN VIVO Blog, February 21, 2008.)

Theravance's follow-up statement, however, at least begins to peel back the cover from the mystery of the recent wave of meeting cancellations. For a while in February, it looked like FDA did not want to bring any products to advisory committees. The agency canceled three meetings last month (see "FDA, You’re a Heartbreaker," The IN VIVO Blog, February 26, 2008).–Cole Werble

Diabetes Drug Development and Regulatory Risk: Why the Guidance May Be Good News

The buzz among investors is that a new Food & Drug Administration draft guidance on diabetes drug development makes an already tough regulatory standard even tougher.

An article by Forbes summarizes the reaction, describing the guidance as proposing "tougher standards for how and when diabetes drugs will be tested for risks to the heart" in response to concerns raised by the rosiglitazone (Avandia) controversy. It comes complete with comments from Cleveland Clinic cardiologist and Avandia meta-analyzer Steve Nissen praising the guidance as a step in the right direction—a notion sure to reinforce the view that the standards must be very tough indeed.

It seems to us that this is making a mountain out of a molehill—or perhaps, confusing a molehill (the FDA draft guidance) with the mountain (FDA’s authority to mandate post-marketing authorities).

Here (we think) is the section of the guidance raising concerns:

"Although a recommendation to demonstrate macrovascular risk reduction pre-marketing may delay availability of many effective antidiabetic drugs for a progressive disease that often requires multiple drug therapy, sponsors should conduct large outcomes trials before submission of marketing applications for drugs in development that show nonclinical or clinical evidence of increasing macrovascular risk. Therapies that have not demonstrated a deleterious effect on cardiovascular outcome during extensive pre-marketing evaluation may need further post-approval assessment for their effects on long-term macrovascular disease."

This is news?

FDA would certainly say it would never have approved a glucose-lowering drug with a clear signal of cardiovascular risk without demanding long-term safety trials. The agency’s critics may dispute that, citing Avandia itself as an example.

We'll leave that debate to others. The point is that whatever FDA might have done in 1999, does anyone really think the agency would approve such a drug today? That question may sound rhetorical, but it doesn’t have to be. Look not at Avandia, but at muraglitazar—the Bristol-Myers Squibb Co. diabetes drug that the agency declined to approve in 2005 after Dr. Nissen helpfully pointed out a cardiovascular safety signal in the Phase III trial database. (See "Shadow FDA? Researchers Are Taking Approval Matters into their Own Hands," The RPM Report, December 2005 (Also see "Shadow FDA? Researchers Are Taking Approval Matters into their Own Hands" - Pink Sheet, 1 Dec, 2005.).) The agency asked Bristol to do a long term study prior to approval, and Bristol opted to discontinue development.

FDA says Nissen’s outside review had no impact on its decision with muraglitazar, and we’ll let others debate that point as well. What the agency did, though, is not debatable—nor is the fact that in doing so it set a standard for requiring more than glucose reduction as an endpoint when a drug carries a significant cardiovascular risk signal.

In any event, if the bar for type 2 diabetes had been raised, it was raised then. Bristol certainly reached that conclusion, opting to partner its Phase III DPP4 inhibitor saxagliptin with AstraZeneca PLC to help share risk in light of the tough climate. [See Deal] (We’ve argued elsewhere that, while Bristol undeniably did very well financially in this deal, it may have been overestimating the regulatory risk based on its experience with muraglitazar—see "How Do Some of the Biggest Deals of the Year Measure Up Against Regulatory Realities?" The IN VIVO Blog, October 30, 2007.)

We would argue that, in fact, the diabetes guidance is a sign that the regulatory risk in type 2 diabetes is a bit lower than most investors might think.

First, lay to rest any idea that FDA put this guidance out in response to Avandia. Guidance development does not move that quickly at the agency—to say the least. In this case, FDA began drafting a diabetes drug development guideline in 1996, and presented a draft to an FDA advisory committee in 1998.

After that, the agency’s Endocrine & Metabolism Division veered off into related issues like diabetes claims for weight loss drugs, standards for diabetes prevention claims, and discussion of metabolic syndrome as a potential therapeutic indication. The new draft guidance references a different starting point: a 2004 FDA/National Institutes of Health forum on diabetes. In any event, the guidance is most definitely not, on the whole, a reaction to Avandia or even muraglitazar.

Then there is a misinterpretation of what FDA guidances do: they attempt to lay out the agency’s thinking on drug development—not change that thinking. In other words, the guidance tells you what the agency already thinks. By definition, it doesn’t raise the bar on its own.

That in turn is one reason why issuing the guidance probably lowers regulatory risk: at least sponsors can read for themselves what the agency’s thinking is—and can frame their submissions appropriately to address the issues the agency has identified.

And then there is what the guidance doesn’t do: back away from HbA1c as a fully validated surrogate endpoint. "For purposes of drug approval and labeling, final demonstration of efficacy should be based on reduction in HbA1c (i.e., HbA1c is the primary endpoint of choice, albeit a surrogate), which will support an indication of glycemic control," the agency says. That is nice and clear.

We suspect that the real issue here has nothing to do with the guidance, and everything to do with the fundamental changes underway in the regulation of drugs prompted by the new safety law enacted in 2007.

One of the key changes in the law: FDA now has the authority to mandate post-marketing studies—and to levy fines for companies that fail to follow through. That means that the wink-wink Phase IV system in place for many years, under which sponsors of products like Avandia agreed to post-marketing commitments as a condition for approval and then failed to complete the trials, is over. Those commitments were typically "negotiated" in the final weeks before an approval deadline, under circumstances that encouraged sponsors to agree to anything FDA requested—and which even FDA recognized seldom led to useful data to resolve legitimate scientific questions.

In other words, if FDA was really worried about a safety question, it would demand more data prior to approval.

Those days are over. Now FDA and sponsors have to agree on realistic, real-world post-marketing studies. For sponsors, that means recognizing that commitments to develop long-term outcomes data in diabetes are indeed commitments.

And for FDA, that means the agency can have the confidence to approve a new anti-diabetic without demanding long-term outcomes data up front.—Michael McCaughan

Mircera: Bad for Patents, Good for Patients?

Anyone following the heated Amgen Inc.-Roche battle over Roche's Mircera might be interested in some court documents posted today--notably Roche's license agreement for a proposed launch of its drug in the US, and Amgen's counter-brief. (Hat-tip to our friends at Bear Stearns...er...JP Morgan...for this one.)

What, you say? Didn't Judge Young rule last October that Roche infringed Amgen's patents--the latest of several of EPO victories for Amgen over the decades?

Well, yes he did. But although Amgen won the patent battle, it apparently hasn't yet won the public interest battle. The Judge basically isn't sure whether blocking Mircera from the US entirely, as Amgen is seeking via an injunction, would best serve American patients (or their government's wallets). So he left open the possibility, in a hearing two weeks ago, that Roche may launch the drug nevertheless.

There are conditions: Roche must pay Amgen a 22.5% royalty on US sales (as Roche had already said it was willing to do); it must price Mircera to the Medicare program with an average selling price the same or less than that of Epogen; it must provide evidence of clinical usage and the real world dosage of Mircera to allow a dose conversion factor to be calculated; and it must fund an independent monitor to account for royalty payments. Lastly, patients switched to the Roche drug must be allowed to access the product at the same price going forward regardless of the outcome of future legislation.

Fine, says Roche in its posting, we'll adhere to all that. And we think it's great that patients are offered choice, and a better treatment option--especially, it says, rubbing it in, "given the FDA’s recent re-examination of serious safety issues associated with Amgen’s ESA products." Amgen's behaved rottenly, the document continues (yes, we're paraphrasing somewhat), so any harm that may come to it following a potential modification of this injunction in Roche's favor should be ignored. Hail billions of dollars of savings to the U.S Treasury!

Amgen isn't used to this kind of post-victory set-back. And it could probably do without it, given everything else going on--not least ODAC's not-so-bad-but-not-great-either decisions on restricting ESA usage in chemotherapy-induced-anemia patients, etc. (See "FDA’s Careful Reading of the EPO Market," The IN VIVO Blog, March 11, 2008.) The Big Biotech comes back with just the points one would expect in a briefing support document (filed, with Roche's, ahead of a potential ruling early next month over whether Mircera will indeed be allowed this conditional entry).

Innovative drugs like ours have enhanced economic growth and reduced medical expenditures, Amgen says. Letting Roche in would create an unwelcome precedent, suggesting that even valid and infringed patents don't fully protect innovative drugs. Woe betide the end of private sector investment in drug R&D, etc.

Now, though we do hear that Amgen's IP-protection tactics have perhaps over-aggressively exploited quirks in IP law, and while we do feel, like Roche, that Amgen's monopoly has perhaps overstayed its welcome, the US biotech does have a couple of points here. If patents are judged to have been infringed, the infringer should be banned until the patents expire--that principle underpins the industry, right? And we also tend to agree with Amgen's point that "with all due respect, determining the appropriate amount Medicare should pay for biopharmaceutical products and medical treatments is not the province of this Court."

We're not lawyers and perhaps we missed the point. Though if we may toot our own horns for a second, we predicted nearly two years ago that Roche would be willing--or required--to agree to cut prices as a condition for market. (See "A CERA-ous Challenge to Amgen’s EPO Franchise?" The RPM Report, June 2006 (Also see "A CERA-ous Challenge to Amgen's EPO Franchise?" - Pink Sheet, 1 Jun, 2006.).)

Still, the battle was over whether Roche infringed Amgen's patents. Turns out it did (whatever you think about how Amgen extended and protected those patents). Bringing issues of drug costs and patient choice into the court-room mix may be well-intentioned, but may also backfire big time if it dilutes the power of patents.—Melanie Senior