Stealth Comparative Effectiveness in U.S.

Are you sitting down?

The FDA is practicing stealth comparative effectiveness.

Or at least that's one of the claims to come out of a lively panel discussion that attempted to grade the regulatory agenda of the new leadership at FDA during the first day of The Pink Sheet's annual FDA/CMS Summit.

The discussion was sparked some provocative data released by the Director of the Office of New Drugs, John Jenkins, during his status report on new drug approvals. (You think he only took industry to task for submitting incomplete applications? Guess again.)

In an effort to silence critics who charge the FDA is becoming more conservative, approving fewer drugs because of its safety first initiatives, Jenkins and his team parsed applications data for the past 17 years, looking at the percentage of new molecular entities approved on first action during five-year increments. Here's what they found: NMEs with priority review did pretty well; in the most recent period, 68% of the compounds won approval, up from 58% in the previous time period. But for standard NME applications, the story was far different: 70% of the medicines were not approved on first action.

Calling this failure rate "a huge burden on the system," Jenkins challenged the drug industry to do some more navel gazing. "The industry needs to ask itself why the failure rate [for standard NMEs] is so high," he says.

It's not like execs haven't been asking that question. Perhaps the only issue causing more hand-wringing than comparative effectiveness is the lack of R&D productivity in the industry. That's why folks at Lilly, for instance, are aiming to expand their highly publicized Chorus experiment, which aims to identify earlier--and more cheaply--whether new compounds even have a shot at becoming viable medicines.

Mary Pendergast, the former deputy FDA commisioner and now President of Pendergast Consulting looked at Jenkins' data and came up with one possible answer that takes some heat off the industry. Maybe one reason it's so much harder to get the second, third, fourth, and fifth drugs in a class approved these days stems from FDA's desire to see superiority data. "What we are seeing--and should be paying attention to--is [the emergence of] stealth comparative effectiveness," she claims.

Note that current laws stipulate explicitly that FDA does not have a mandate to practice comparative effectiveness. But in Pendergast's view, the emphasis on superiority data "is a tiny loophole that the FDA is driving a truck through."

Better that than a camel through the eye of a needle, eh?

Image courtesy of flickrer (cup)cake_eater used with permision through a creative commons license.

Who's Waving Red Flags at FDA?

FDA’s top drug reviewer John Jenkins wants to put to rest what he says is a commonly held misperception among sponsors: You can’t always blame the Office of Surveillance & Epidemiology for putting the brakes on an application due to safety concerns.

Sometimes, Jenkins says, it’s drug reviewers in his Office of New Drugs that flag a risky product that was otherwise cleared by OSE.

Given that OSE’s primary focus in reviewing a new drug application is the product’s safety profile, it’s understandable that the office would get most of the blame for holding up a product over concerns about risk. But Jenkins says that’s too simplistic a view of the review process.

“There’s the perception in the outside world that OND is always overruling OSE in a way that may be viewed as less focused on safety,” Jenkins says. “But there are cases where the OND perspective is more conservative on the safety issue than the feedback we’re getting from our OSE colleagues.”

“I hear occasionally of situations where my staff tell me that they’re taking a more safety-focused or conservative” course “than what they think they’re getting back in the recommendation from their OSE colleagues,” Jenkins says. “It’s not...unilateral in its direction of differences of opinion….It goes both ways.”

Jenkins talked about drug safety during a wide-ranging roundtable discussion with The RPM Report. For a complete transcript of the interview—which also included OSE director Gerald Dal Pan and Office of Medical Policy director Bob Temple—click here. (If you are not already a subscriber, you can sign up for a free trial to read the story.)

Jenkins’ comments were made in the context of a new memorandum of agreement that gives FDA’s drug safety office an “equal voice” in making decisions about significant safety issues. We blogged about that here, and we’ve put together a more extensive analysis of what it all means for drug sponsors in the latest issue of The RPM Report.

FDA officials think all the attention on the perceived differences on drug safety between OND and OSE is largely overblown. Still the very public disagreements on how to handle the cardiovascular signal seen with GlaxoSmithKline’s Avandia certainly haven't dispelled the notion. “The highly publicized differences of opinion are the exception, they’re not the rule,” Jenkins says.

Perhaps not. But one thing is clear: Based on Jenkins' assessment of the drug review process, if you think that convincing drug safety officials that your products is safe is enough, you probably need to think again.

REMS to the Rescue? Why FDA's Drug Safety Tools May Mean More Approvals This Year

The statistics aren't encouraging: fewer new drugs approved by FDA so far this year than last--and last year was arguably the worst year all time for the innovative industry.

But we are boldly predicting a big finish to the year, in part for an unlikely reason: FDA's new mandatory post-marketing safety tools that allow it to compel labeling changes, Phase IV studies, and--most significantly--Risk Evaluation & Mitigation Strategies.

The REMS authorities kicked in in March, and we’re learning a bit more about how FDA is using its new tools. And while there was much nervous anticipation as industry braced for FDA to start wielding its new (now mandatory!) risk management tools, the reality has been pretty positive.

There have been a lot of required post-marketing studies, and relatively few full-fledged REMS programs for new molecular entities. In fact, it looks like REMS is turning out to be a way to revive applications that once looked dead (or at least terminally “approvable”).

FDA has applied the new drug safety tools to three new molecular entities so far this year--CV Therapeutics/Astellas’ Lexiscan, UCB’s Cimzia, and GSK/Adolor's Entereg. And in every case the sponsor has been thrilled to have a product to market at all. (Read about some of the early experiences with REMS here.)

That's just the tip of the iceberg.

A REMS is definitely in the works for GSK’s platelet growth stimulator Promacta (eltrombopag), and Lilly has hinted that its antiplatelet agent Effient (prasugrel), partnered with Daiichi Sankyo, could have some form of a REMS – although Lilly is suggesting it would be on the less intensive end of the spectrum. Both NDAs received three-month review extensions, an emerging pattern for reviewing REMS proposals.

The premature press release snafu for Amgen’s Nplate also revealed that a REMS program called NEXUS is slated to accompany the approval of romiplostim, a fusion protein that, like Promacta, treats idiopathic thrombocytopenic purpura.

FDA’s new authority opens a new parlor game of guessing which applications could be REMS-worthy. According to Pharmaceutical Approvals Monthly, there are at least 30 NMEs pending with user fee deadlines coming up during the second half of the year. Which ones could have a REMS?

Pfizer/Ligand’s Fablyn (lasofoxifene) for treatment of post-menopausal osteoporosis: The post-Evista SERM class has had trouble clearing the final approval hurdle at FDA, in part because of safety issues. Prior to the Fablyn submission Jan. 15, lasofoxifene (then Oporia) was found not approvable for prevention of PMO in 2005, and then not approvable again, for treatment of vaginal atrophy, in 2006. Wyeth’s SERM Viviant (bazedoxifene) has been approvable twice for osteoporosis prevention and once for treatment. Further data was requested on stroke and venous thrombotic events.

Johnson & Johnson’s paliperidone palmitate: Can the once-monthly version of J&J’s antipsychotic Invega do better than the “not approvable” letter issued to Lilly’s fellow atypical antipsychotic Zyprexa for its once-monthly depot, Zyprexa LAI? The long-acting injection formulations may have a new risk of excessive sedation. Given J&J’s flagging public enthusiasm for the project, and its renewed interest in Alkermes’ claim that its technology can now support a once-monthly version of Risperdal Consta, does J&J really care?

Schering-Plough’s Bridion (sugammadex): The prospect of the first selective relaxant binding agent, which was just approved in the EU, has stirred up the anesthesia market. But signals from FDA could indicate caution. The agency extended the user fee goal by three months to review a hypersensitivity study. And in an unusual set of events, a March advisory committee supported approval, but could not make a formal recommendation because data had been submitted shortly before the panel met.

Moving beyond the bounds of pending NMEs opens a plethora of potential REMS. One likely candidate is Cephalon’s fentanyl product Fentora. The advisory committee review of a breakthrough cancer pain indication for the approved drug focused on the inadequacies of the existing RiskMAP. Other extended-release pain products, like Labopharm’s tramadol formulation, are also potential REMS contenders.

Review the list yourself and play along at home. What else looks REMS worthy to you?

--Bridget Silverman

New Drug Approvals at the Half: 2008 Looks A Lot Like 2007, And That Isn’t Good

So do you want the good news or the bad news?

Let's start with the bad. So far, the number of new molecular entities and novel biologics approved by the Food & Drug Administration in the first half of 2008 is actually lower than it was at this time last year. FDA approved six NMEs by the end of June 2008, one less than the seven NMEs approved by the mid-point of 2007.

And history suggests the second half will look kind of like the first. In recent years, roughly half of the yearly total of NME approvals fall between January and June. In 2007, seven of 16 NMEs were approved by June 30; in 2006, nine of 18 fell in the first six months; and in 2005, seven of 18 NMEs were approved halfway through the year. (For more analysis of FDA’s approval performance at the half, see the July issue of Pharmaceutical Approvals Monthly.)

Given that 2007 ended up being quite possibly the worst year ever for innovative pharmaceutical launches, those are not trends anyone should be excited about. Only 16 NMEs made it through the agency last year, the lowest single-year total in a quarter century--which is before the modern generic drug industry took shape and made new molecules so vital to the health of brand name companies.

So what's the good news? Well, despite the slow start andFDA's recent history of slow finishes, we would be willing to be that the agency will in fact beat last year's NME total.

Why? First off, the agency has at least 30 pending applications for NMEs with user fee deadlines that fall during the second half of the year. (Want the list? Click here to see it, courtesy of Pharmaceutical Approvals Monthly.)

Of course, FDA has officially decided that it no longer has to meet the official user fee deadlines – given the overload of work stemming from the new drug safety legislation on an already strained staff. That certainly complicates any predictions for the rest of the year--but it also means FDA has a handful of applications that are overdue for action. And, it looks to us like the trend is for missed deadlines to end in approvals, rather than requests for more data and new review cycles.

User fee goals have been missed for three NMEs under review by the Division of Cardiovascular and Renal Products alone this year: Cardiome/Astellas’ Kynapid (vernakalant) and Solvay’s Pulzium (tedisamil), both anti-arrhythmics with user fee goal dates in mid-January, and The Medicines Company’s Cleviprex (clevidipine) for acute hypertension in May.

More recently, Theravance announced that the July 21 user fee date for its antibiotic televancin was passing without FDA action. Amgen also announced that the user fee deadline for Nplate was among the cohort of drugs where FDA was consciously missing the PDUFA date (after accidentally releasing a press release that the thrombocytopenia product was being approved).

That means FDA has at least five pending applications where an answer is overdue. We're betting that most of those will end up approved at some point this year.

Then there is the impact of one of the biggest changes to FDA’s review authorities under the new law: the creation of mandatory Risk Evaluation & Mitigation Strategies. Thus far, FDA has used the REMS to breathe life into drugs that were stuck at the agency for years.

We'll talk more about those trends in some upcoming posts, but the bottom line is that we still expect the NME tally this year to come in ahead of last year.

Still, let's keep some perspective: if by some miracle FDA approves all 30 pending NMEs this year, it will end up with a total of 36 overall. More than double last year's tally--but just an average year for the 1990s.

Sadly for the innovative industry, its clear that the best to hope for this year is to recovery from abysmal to the merely dreadful.

For Amgen's Nplate, No News is Good News

In case you didn’t have it circled on your calendar, July 23 was the user fee deadline for Amgen’s romiplostim (Nplate). And according to Amgen, FDA didn’t pick up the phone yesterday with a final answer on the platelet drug.

Without delving into specifics, Amgen says it was told by FDA that the agency will miss Nplate’s Prescription Drug User Fee Act deadline. The company says it is “optimistic that a final decision will be made soon,” but wouldn't speculate on exactly when the agency will be making an approval decision.

Maybe Amgen won’t speculate, but we will. We think the delay is actually good news for Nplate, and signals that—barring any last-minute surprises—an approval is just around the corner.

Simply put, if FDA weren’t pretty confident of the approvability of Nplate, it would have issued an “approvable” letter outlining its concerns with the BLA. Amgen would need to address FDA’s questions, submit a response and wait to hear back. (We should note that starting August 11, FDA will start sending "complete response" letters for all rejections.)

In this case, the review group is taking advantage of a new policy giving them the discretion to miss PDUFA deadlines. And it is fairly easy to see why the final review might take a bit longer than expected: Nplate will have a mandatory Risk Evaluation & Mitigation Strategy, or REMS, a new feature of the regulatory process created by legislation enacted last year. FDA is setting precedents with every REMS, and the agency has already extended or missed several deadlines for products covered by that authority.

There is a major caveat: when it comes to drug time lines, industry is treading in somewhat unknown territory these days. So while past history would suggest that a missed deadline would mean that approval is imminent, there is always a chance that the agency will let the application hang for a while.

That is certainly happening with FDA’s Cardio-Renal division, which has missed user fee dates for at least three NMEs this year: two anti-arrhythmics—Cardiome/Astellas’ vernakalant (Kynapid) and Solvay’s tedisamil (Pulzium)—and The Medicines Company’s clevidipine (Cleviprex) for acute hypertension.

But the oncology group has no history of letting applications linger. Quite the opposite: FDA doesn't always approve applications for cancer and related therapies, but it almost always acts quickly.

One thing is clear: as last week's slip-up by Business Wire illustrates, Amgen is ready to issue the approval press release whenever FDA is.

Prasugrel: My August Looks Free…and So Does My September

Eli Lilly’s prasugrel team may have some free time on its hands in August and September if FDA’s advisory committee calendar is any indicator.

After FDA extended the priority review deadline of the novel anti-platelet drug by three months on June 23—the deadline was June 26—to September 26, speculation began in earnest around whether the drug would be required to go before the agency’s Cariovascular and Renal Drugs Advisory Committee.

August 19-20 had been tentatively blocked off for a meeting of the Cardio-Renal panel and Wall Street, FDA watchers and industry stakeholders pointed to the dates as a strong possibility for a prasugrel review.

Well, a quick look at FDA’s advisory committee calendar shows the blocks have suddenly disappeared. Moreover, September is completely free of any advisory committee meetings and no new Cardio-Renal meeting has been added to the end of July. We should note that a tentative Peripheral and Central Nervous System Drugs Advisory Committee meeting blocked off for August 6-7 has been postponed.

Do with that what you want. Of course, FDA can add a meeting at any time.

But, if FDA sticks to the extended review deadline and the calendar remains as is, it appears that prasugrel will not go before an advisory committee before a final decision on the application is made. That’s probably a positive sign for Lilly because the committee would have been used to address uncertainties with the application and the postmarket surveillance REMS program.

If, however, FDA adds a meeting in late August or early September, that almost certainly means the prasugrel review will miss another deadline.

A Lilly official says the company still has not been informed by FDA that prasugrel will require an advisory committee review. FDA says there is no Cardio-Renal panel scheduled as of right now. We still think prasugrel will be approved on its first cycle.

We’re not going to rehash our reasoning but you can read it by clicking here and the follow-up is here.