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The PDUFA V agreement has provisions to improve FDA review times and increase single-cycle reviews. A new study says FDA is doing fine on those and it’s time to look at other areas for efficiency.

FDA reviews novel drugs and biologics more quickly than the EMA and Health Canada. That is the inescapable conclusion of a Pew-funded analysis comparing the three regulatory agencies on the eve of the reauthorization of the Prescription Drug User Fee Act.

“Regulatory Review of Novel Therapeutics – Comparison of Three Regulatory Agencies,” a report by researchers from Yale and the Mayo Clinic published May 16 in the New England Journal of Medicine, found FDA had a shorter median review time for novel therapeutics approved between 2001 and 2010. Moreover, of drugs approved in both Europe and the U.S. and those approved in both Canada and the US, FDA approved the majority of drugs before the counterparts. That finding is consistent with the Friends of Cancer Research June 2011 report in Health Affairs which said cancer drugs are approved faster in the U.S. vs. Europe.

The study comes as the user fee reauthorization process is (hopefully) nearing the final stages. The industry-negotiated user fee agreement seeks to expedite FDA reviews and avoid multiple review cycles by in effect adding two months to reviews and adding formal agency feedback (like late-cycle meetings). The Pew study suggests that, indeed, there is little room to push FDA to shorten review times, and that instead it may be time to look elsewhere for ways to make FDA more efficient.

“The reason we published it is because we’re interested in how the agency can become more efficient and better to both promote innovation and protect the public health,” said Deputy Director of Medical Programs at the Pew Health Group Allan Coukell. “Part of doing that is really addressing what are the systemic weaknesses and one thing that you often hear is that the U.S. is slower to approve new drugs than other countries. And so we wanted to take a data-driven approach to that and in fact what we find is that the U.S. in general is faster than the EU and Canada.”

The report found that the majority of all the applications involved a single review cycle. For FDA and EMA, the median length of time for the first review was “significantly shorter” for those single-cycle reviews compared to those needing multiple review cycles. Interesting, the FDA total review time was faster despite the fact that the EMA nearly always approved applications after one review cycle.

In the report, the authors note that their findings “contradict recent criticisms of the speed of review by the FDA and lead to questions about whether the speed f the review process is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers.”

“I think what [the report] probably demonstrates is that the user fee programs have been successful in ensuring efficient approvals. It suggests that the challenges are not with review time but perhaps with other aspects of the drug development process,” Coukell said. “We’ll continue to look at other questions. But I think it’s important to recognize that at least by this metric, which is one part of the story, the FDA is faster than regulators in other parts of the world.”

One of the study’s authors, Yale’s Harlan Krumholz, contributed a piece to Forbes entitled, “The FDA Is Faster. Now Let’s Make It Safer.” In it, he says the report’s context may be “useful” in the midst of PDUFA discussions in Congress, noting the agreement is designed to increase the efficiency of the drug approval process. He also said “we need to be able to be equally proud” of post-marketing safety systems as of the efficiency of approvals.

The report suggests further analyses on markers of regulatory safety (label changes, drug withdrawals, black box warnings) among agencies and research on other review responsibilities (applications for reformulated drugs or combination therapies, generic drugs, and medical devices).

It also notes that this study did not examine the time to complete studies required by the FDA or review times for drugs that were not approved.

Pew’s Innovate FDA initiative is focused on ways to optimize FDA performance, recognizing that agency appropriations are unlikely to increase in the near future.

“I think there are questions that have been raised about FDA’s scientific capacity, about their operational efficiency, their ability to hire top scientists, and also around the expectations for clinical trials,” Coukell said. “I think everyone would agree in the abstract that if we could meet the approval standards with trials that were smaller and faster, that would be a good thing. I think everyone would agree on that. The question is do we have an FDA that has the ability to tackle those questions in a really cutting-edge way.”

Tuesday, May 15, 2012

Grow Up America! A Modest Proposal To Improve Obesity Drug Development

Let’s grow our way out of the obesity crisis. Broader use of human growth hormone in children coupled with therapeutic rackings of adults can add precious inches to the nation’s top line. Okay, we’re kidding—but treating regulation of weight loss drugs as a priority response to the obesity epidemic may not actually be in industry’s best interests.

All of a sudden, weight loss drugs seem like a very high priority at FDA.

Two applications—Vivus’ Qnexa and Arena’s Lorqess—that weren’t good enough in 2010 now are urgently needed, at least in the view of the overwhelmingly positive votes for approval by the same advisory committee that turned them down less than two years ago. Both sponsors brought more data in the resubmissions to be sure, but neither brought any data that fundamentally changed the risk/benefit equation that existed in 2010. (In fact, we would argue that both brought data that increased the likelihood that a core safety issue—teratogenicity with Qnexa, valvulopathy with Lorqess—is real and needs management.)

Those votes came despite clear reservations from the same committee about the history of weight loss drugs in the US. Members of the committee made clear their desire to see a different launch model, one taking advantage of FDA’s REMS authorities. There is the move towards a diabetes-style cardiovascular safety bar—radically upping the amount of long term outcomes data needed for weight loss drugs. And there is a less visible but possibly even more important discussion of new outcomes standards, ones that try to better identify the benefits of obesity drugs beyond lower body mass index.

In the current and past issues of The RPM Report, we have published several articles underscoring the frenzied pace of activity.

What unites this mish mash of important but seemingly contradictory actions? The over-riding sense of public health urgency to do something about the obesity epidemic—and the perhaps unintended (or perhaps very much intended) tone of the debate suggesting that FDA better get out of the way or get run over.

All of which leads to our modest proposal, very much in the Jonathan Swift mode of thinking: We need to stop fighting just half the battle.

Sure, shedding 20 pounds is one way to lower your body mass index. But it is not the only one. BMI isn’t just about weight. It is also about height.

America doesn’t just need to lose weight. America needs to get taller.

Yes, we are probably the heaviest people in the world. But Americans used to be the tallest too. As this excellent New Yorker piece pointed out, we lost that lead a generation ago. Indeed, as we confirmed first hand on a recent visit to Copenhagen, there are places in the world where 6 foot 1 is distinctly NOT tall.

So why focus just on weight? After all, BMI goes down as weight goes down, but it also goes down as height goes up. Surely adding a few inches on top is just as good as taking a few off around the middle.

So let’s start pumping our kids full of human growth hormone. Why reserve this therapeutic miracle only for the outliers who are far below average? Let’s give it to kids who are normal height or even taller. HGH in the preschools will mean substantial lower rates of childhood obesity.

Alas, hGH is no good for helping adults grow taller. We need innovation there.

In the meantime, though, the medical device industry can help. The studies are old, but there is strong evidence that the rack can add an inch or two with intense use. And with today’s anesthetics and analgesics, the unpleasant side effects could be readily managed.

Okay, taking the tongue out of the cheek, we don’t seriously believe that anyone would think that routine human growth hormone injections or therapeutic rackings would be a smart way treat obesity. But it is interesting that height is treated as a constant in human physiology, and not something that is generally accepted as a target for pharmacotherapy except in the presence of a clear biological breakdown (growth hormone deficiency and related disorders.) The idea of treating kids who are just short is still controversial—much less the idea of treating kids who are “normal” or even “tall” to make them taller.

Weight, on the other hand, is treated as variable and appropriate for interventions. Yes, it is affected by diet—but so is height, at least during key periods of development. And public health campaigns can have a huge impact on height—just ask the government of Thailand, which embarked on campaign to encourage better childhood nutrition and saw average adult heights increase by 4-5 cm over the second half of the 20^th century.

All of which suggests that the emphasis on longer term outcomes for weight loss drugs may be appropriate. After all, it is not obvious that a drug proven to suppress appetite (which is how Lorqess works) is the same thing as a drug that makes you healthier. It might be at least part of the answer, but there is so much more to the story.

There is tons of data to show that 5% BMI reductions do lead to dramatically improved health outcomes—but those data aren’t based on weight loss driven by pharmaceuticals. Moreover, while Lorqess and Qnexa have shown long-term improvements versus placebo, they haven’t shown that they can reverse the inevitable increase in weight over time. Patients may lose 5% versus baseline, but they gain it back. That is still better than the placebo group—but it isn’t a sign of improving health.

And that is why we suspect the discussions on patient-centered outcomes will be so important in this class. The more that regulators and drug developers can focus on endpoints that matter to patients—reduced sleep apnea, improved walking distance, better quality of life, etc. etc.—the stronger the case will be that weight loss drugs have a role, even if they don’t end the obesity epidemic.

In the meantime, there is a risk to the idea that approving drugs is urgent because of the obesity epidemic. If they don’t end up delivering a lower rate of obesity they may be deemed a failure—even if they are helping plenty of individuals live happier lives.

The obesity epidemic is real and no joke. But asking drugs to solve that problem is, ahem, a very tall order.

Friday, May 11, 2012

FDA De-Risks "Risk Compensation" Argument in Review of Truvada Prophylaxis Claim

FDA can be an effective ally for sponsors when the agency does not agree with highly publicized charges against a pending product. Gilead’s HIV prophylactic indication for uninfected individuals at high risk Truvada is a case in point. The agency set an agenda for the May 10 Antiviral Drugs Advisory Committee that quickly defused the Risk Compensation arguments against an HIV prevention product.

Going into the May 10 meeting of the Food & Drug Administration’s Antiviral Drugs Advisory Committee, one of the high-profile hurdles for the pending application from Gilead for a new prophylactic use of Truvada (emtricitabine/tenofovir disoproxil fumarate) was a lively debate in the HIV/public health community over whether a prevention drug might undercut prevention strategies by encouraging more risky behavior.

This theory of a backfire effect from use of a prevention drug goes by the name of “risk compensation.” But in this case, FDA compensated for the argument by pre-empting it.

FDA was not the sponsor or direct advocate for the application, of course, but the agency clearly viewed pre-exposure prophylaxis (or PrEP) use of Truvada (already addressed as an interim guidance issued by the Centers for Disease Control & Prevention in January 2011) in the context of a continuing HIV new infection epidemic. The agency included an unusually long and detailed analysis (five pages out of a total of 40) to the continuing new-infection trends in its pre-meeting briefing documents.

The head of the FDA Antiviral Drugs Division, Debra Birnkrant, ended her opening remarks to the panel with a quote from Secretary of State Hilary Rodham Clinton in a November 2011 speech to the National Institutes of Health: “Our efforts have helped set the stage for a historic opportunity…to change the course of this pandemic and usher in an AIDS-free generation.”

Comparison to Risk Compensation for Statins

The heavy-lifting to counter the “risk compensation” arguments went to a guest speaker invited by FDA to open the meeting presentations, Susan Buchbinder, director of HIV research in the San Francisco Department of Public Health.

Buchbinder was charged with reviewing the epidemiology background, but she also took on the risk disinhibition charges by reflecting on the extraordinary attention given to the impact of drug use in HIV compared to other classes – specifically the statin class.

“We don’t really know what is going to be happening with risk compensation in a real world setting,” Buchbinder acknowledged. “What we know from male circumcision trials is that it appears that there is not a generalized increase in HIV infection rates within populations, although there may be some subgroups of men who are increasing their risks. That is something that we might expect.”

Buchbinder dispelled the concern over risk compensation for HIV prevention by comparing drug therapy for that purpose with cholesterol lowering drug use. “Compare primary risk of HIV infection in iPrEX where you have a life-threatening infection which is in part behaviorally driven with a 4% incidence per year in placebo arm and a statistically significant but not completely efficacious intervention and you compare that to the use of statins to treat cholesterol again with a life-threatening illness for something that is driven in part by life-style with a lower attack rate in the placebo arm and a lower relative risk reduction.”

She noted that “there has really not been a lot of concern about risk compensation. We are not really asking whether people on statins are going to be eating more ice cream. …One article in the American Journal of Cardiology that suggests that one statin pill offsets a quarter-pounder with cheese and a small milkshake and was recommending actually that maybe what we really need to do is to dispense statins along with the condiments at fast food restaurants.”

Former FDA official and frequent advisory committee member, Susan Ellenberg (University of Pennsylvania), made sure to reinforce the impact of Buchbinder’s comments by asking about the “interesting comparison to statins.” Ellenberg pressed Buchbinder to make the point more direct: “Does that mean little need to worry about risk compensation?”

Buchbinder backed off a bit, noting that risk compensation has to be considered, but then elaborated on the meaning of her comparison: “My point about the cardiovascular community was that the idea there was that they were saying...we know that behavior is not enough …so we know that we need to layer on top of that –without abandoning our attempts to have people have healthier diets and exercise – we need to layer on top of that a biomedical prevention/intervention.”

The early exchange was effective and risk compensation was neutralized as a major issue. There were frequent references to the potential negative impact of a “medical condom” during an extended open public hearing later on, but the issue was already put in context before the presentations of the sponsor and the regulator.

The meeting was not a completely smooth ride for Gilead or FDA. Gilead came away with strong recommendations for prophylactic use in two at-risk populations: (1) uninfected men who have sex with men; and (2) uninfected partners in serodiscordant couples. The sponsor also got a closer, split vote 12-8-2 (abstain) on a third patient group of “other individuals at risk for infection through sexual activity.”

The full meeting took more than 12 hours, tied up on the difficult issues of applying a Risk Evaluation & Mitigation Strategy for a new indication to a product that is already available for other uses. FDA recognizes that is a challenge and got a lot of contradictory advice from the committee and the public hearing on the subject .

The REMS/post-marketing issues will clearly take more time for the sponsor and FDA before final approval of the priority application (with a user fee action deadline in mid-June). But those are control issues that sponsor and regulator look primed to resolve. The risk compensation issue was a more fundamental public health challenge to the application; FDA designed a meeting that took the potential sting out of that challenge early.

Friday, May 11, 2012

A Tale of Two "Me Toos"

FDA’s most recent new molecule approvals illustrate that “me too” drug development is alive and well. It just doesn’t look anything like the stereotype that defined the term in the 1990s.

FDA’s recent new drug approval track record has featured a number of extraordinary breakthroughs for cancer, cystic fibrosis and cardiovascular disease.

But the most recent novel molecules cleared by FDA show that “me too” drug development is alive and well in the drug industry – albeit in a radically different way than the stereotype of industry living off of tweaks of blockbuster molecules to treat “lifestyle” conditions.

On April 29, FDA cleared what sounds like the quintessential “me too” product: a new molecule for erectile dysfunction, avanafil. It will be the fourth PDE IV inhibitor in the class created by Viagra. That sure fits the stereotype. But what isn’t typical is the sponsor: Vivus Pharmaceuticals, a small company best known as the potential marketer of the weight loss combo therapy Qnexa. In fact, Vivus once had a small presence in the ED market with Muse (alprostadil), but divested the brand in 2010 and the firm has no intention of marketing avanafil. So, until Vivus can find a sucker—we mean a sponsor—to take the product off its hands, avanafil will stay off the pharmacy shelves. In other words, this me be a “me too” Viagra, but Vivus isn’t like Pfizer in the 1990s.

Of course, neither is Pfizer.

The world’s largest drug company received the other recent “me too” approval, for the Gaucher’s disease therapy Elelyso (taliglucerase) That drug is a plant-derived version of the enzyme replacement therapy long marketed by Genzyme as Cerezyme, and more recently by Shire as Vpriv.

From a mechanistic perspective, that makes it a classic “me too” – everyone knows that enzyme replacement therapy works for Gaucher’s, so the only challenge is reliably producing the enzyme by synthetic means. No small challenge, but not exactly a breakthrough.

Of course, Gaucher’s is anything but the typical “me too” market: it is an orphan indication, with an estimated 5,000 patients in the U.S. The notion of Pfizer going after a market that size—much less as a third-to-market entrant—would have been unthinkable in the 1990s.

That is two radically different models for “me toos,” neither of which fits the traditional stereotype.

There is one other noteworthy point about the two approvals. Avanafil cruised through the agency, an on-time, first-cycle standard approval. FDA’s own data show how rare that is: only about 40% of standard NME applications are approved on the first-cycle, and many of those have the benefit of an additional three-month extension. Eleyso, on the other hand, took the more typical “standard” review path, receiving a complete response (very much to the surprise of Pfizer and the innovator Protalix) in February 2011.

It is far too small a sample to draw any conclusions, but it is interesting that a small sponsor with a “me too” product for a big market had an easier time with the regulators than the big sponsor trying to break into a very small market.

Wednesday, May 9, 2012

The New PDUFA Deadline: Before the Supreme Court Rules?

Legislators are pushing to get the FDA user fee legislation enacted into law before the Supreme Court rules on health care reform. The goal is to avoid having the bill hijacked by the partisan reaction bound to follow no matter how the high court decides the case. But what about biosimilars?

There's a new urgency on Capitol Hill behind finalizing the Prescription Drug User Fee Act reauthorization (and all the other user fee programs rolled into the pending legislation).

As Politico reports, legislators are eager to wrap up the bill before the Supreme Court rules on the constitutionality of the health care reform law. The logic is sound: no matter how the court rules, you can expect a strong, partisan reaction--and that is not a climate conducive to what appears to be a broad, bipartisan reauthorization for PDUFA.

As Politco put it:

"Industry sources worry the fallout from the ruling, no matter how it goes, could politicize the otherwise relatively bipartisan legislation and slow down, if not derail, its passage."

To be sure, legislators were always talking about wrapping up a bill in June, but in Capitol Hill speak that really meant "let's get it done by August at the latest." Now, though, with everyone expecting a ruling from the court at the end of June, I guess you can start calling June 30 the PDUFA deadline--not the action date for FDA on a specific application, but rather the deadline for Congress to finish the reauthorization or risk some significatn complications.

For the biopharmaceutical industry, moving the bill quickly is smart--except for one thing: the possibility (which, granted, seems remote) that the Supreme Court will strike down every chapter and verse of the law, throwing the whole thing in the trash. Including the legislation creating a biosimilar approval process and granting generous intellectual property protection to innovator biologics.

If that happens, one new section of the PDUFA bill--the new biosimilars user fee program--will be rendered moot. More importantly, industry will miss out on a chance to re-enact the legislation quickly and cleanly, since no one would seriously argue that the biosimilars process itself is an important element of the debate over health care reform. But of course, plenty of people (including the President) would argue with the generous exclusivity provisions, and--as we have laid out here--it is very hard to imagine industry getting the same deal on a stand-alone biosimilar bill.

One thing is certain: the end of June will be an interesting time.

Friday, May 4, 2012

“Lemons for Obesity” Or Sour Grapes? A Key Dissent on Qnexa, With a Twist of Avandia

NIH Cardiologist Michael Lauer takes a page out of the Cleveland Clinic playbook and rips an advisory committee for recommending approval of Vivus’ Qnexa for weight loss without demanding a pre-market outcomes study. But this is no Avandia: Cleveland Clinic cardiologist Michael Lincoff is on the other side of this debate.

When Vivus returned to the Endocrinologic & Metabolic Drugs Advisory Committee on February 22 to try to win a vote in favor of approval of the weight loss therapy Qnexa (phentermine/topiramate), the company had a very strong advocate on its side: Michael Lincoff, the current chair of the Cardiovascular & Renal Drugs Advisory Committee.

Lincoff gave a “cardiologist’s perspective” on the Qnexa application near the end of Vivus’ presentation. He tackled head-on one of the two key questions under consideration: should Vivus be required to do a pre-market cardiovascular outcomes study for Qnexa, or would a proposed post-market study suffice?

Lincoff offered his views for why the totality of the data for Qnexa suggest a very good cardiovascular profile, and specifically why—in his view—a modest increase in heart rate should not be interpreted as an indication of potential risk. Instead, he argued, the more relevant factor is the blood pressure/heart rate product, which suggests an overall beneficial effect of the drug.

Lincoff spoke up throughout the meeting on the feasibility of doing a post-approval outcomes study—and noted he had agreed to serve as the primary investigator. The vast majority of the committee was reassured; the vote in favor of approving Qnexa was an overwhelming 20-2. (Read more on the meeting here.)

Clearly, having the current chair of the Cardio-Renal Advisory Committee on your side surely helps any sponsor addressing a CV safety question.

But it isn’t just Lincoff’s chairmanship that made him a great choice for the sponsor. Lincoff’s day job is vice chair of the Department of Cardiovascular Medicine at the Cleveland Clinic. It is in that capacity that he will be conducting the outcomes trial on behalf of Vivus—and the value of an implied endorsement of the Cleveland Clinic for the sponsor’s plans cannot be overstated.

After all, the focus on CV outcomes for Qnexa (and for the weight loss category overall) is a direct result of the firestorm touched off by the Cleveland Clinic Cardiology Department Chair Steve Nissen in critiques of diabetes safety standards, first in a paper challenging the CV safety profile of Bristol-Myers Squibb’s Pargluva (which cleared the E&M committee but was rejected by FDA) and then in a meta-analysis of the CV outcomes data for Avandia.

It is no exaggeration to say that the entire review of Qnexa has happened in the shadow of Avandia: the first E&M committee review of the weight loss application took place the day after a two-day marathon debate over the marketing status of the diabetes drug. And the re-review occurred just ahead of a two-day discussion in March of expanding the CV standards imposed on the diabetes class because of Avandia into the weight loss category.

So the involvement of Cleveland Clinic in the Qnexa application tells FDA and especially the Endocrine & Metabolism Drugs Division that it will not face second-guessing from that center if it gives Qnexa a pass from the safety standard and approves it with a post-marketing requirement.

Unfortunately for FDA, that does not mean the agency can expect to be immune from criticism from a prominent cardiovascular clinical trial organization if it does indeed approve the drug. The Cleveland Clinic cardiology department may be aligned with the sponsors in this case, but not the head of the National Heart, Lung & Blood Institute Division of Cardiovascular Science, Michael Lauer.

An Important “No” Vote

Lauer was one of the two “no” votes on the panel, and—as one of the few cardiologists participating, it was a “no” that carried added weight.

Lauer raised two critical objections to allowing Qnexa on the market without outcomes data.

First, he refused to accept the reassurance offered by Lincoff about the heart rate increase, insisting that “heart rate is one of the best biomarkers we have.” While Lauer agreed that other surrogate markets (like blood pressure and lipids) look “reassuring,” that just means “we find ourselves in a very confusing place.”

Secondly, Lauer objected to the premise that a post-marketing study could be completed as quickly and easily as Lincoff suggested. Pointedly noting his status as head of a National Institutes of Health clinical trials unit, Lauer said that “we run a lot of clinical trials” and they “always run into problems enrolling subjects.” Those problems will only be enhanced by approving the agent, he said, since “people will interpret it to mean the drug is safe and effective” and will have no incentive to join a trial where they may be randomized to placebo.

Adding another layer of subtext to the differences between Lauer and Lincoff: the two used to be colleagues, with Lauer having been director of clinical research in the cardiology department at the Cleveland Clinic before joining NHLBI.

“The public health issue here is enormous,” Lauer emphasized. Qnexa will “likely be prescribed to millions or tens of millions” so the “consequences of making a mistake here are huge.” And, he added, alluding to the troubled history of weight loss drugs, “unfortunately, we have made a mistake before.”

Lauer’s arguments clearly did not carry the day. The majority view was reflected by Cedars-Sinai cardiologist Sanjay Kaul, who stressed that the significant efficacy of the drug and the lack of available therapies for the morbidly obese population outweigh the important need to rule out CV risks. Kaul supported a post-market study, but stressed that it would be reasonable for FDA to conclude that a pre-market study is in fact required.

Importantly, Kaul did not disagree with Lauer on the importance of heart rate as a signal; Kaul just sees the public health benefit from an effective weight loss agent as offsetting the public health risk if that signal translates into excess CV events.

That dialogue leaves open the possibility that FDA would overrule the panel as it did when the same committee explicitly voted that Orexigen’s Contrave (bupropion/naltrexone) does not need a pre-market CV outcomes study despite a small increase in blood pressure associated with the therapy. Nissen, in fact, is the primary investigator on the Contrave outcomes study.

However, there hasn’t been any indication of that so far. FDA did extend the Qnexa review by three months, setting a July 27 deadline for action. However, according to Vivus, that extension related to ongoing work to define a Risk Evaluation & Mitigation Strategy for the product. In addition, Lauer was not invited to the March 28-29 panel that discussed CV outcomes for weight loss—a notable absence given his point of view on the Qnexa panel. (Read more on that subject here.)

Taking a Page From the Nissen Playbook

Lauer, however, isn’t letting his vote speak for itself. Instead, he took a page from the Cleveland Clinic playbook and published an article in the Annals of Internal Medicine entitled “Lemons for Obesity.” The article appeared online on April 9.

In the article, Lauer recounts his participation in the February 22 Qnexa review and argues that the weight loss category has a history of “lemons”—and that the only wise course is to demand that new drugs prove they are “peaches” before they can be approved.

In the case of Qnexa, Lauer notes the incredibly small number of cardiovascular events seen in clinical trials, and repeating his assertion that “it is impossible to draw any conclusions” about the drug’s CV profile based on that “tiny sample.”

“We cannot assume that an absence of excess cardiovascular events in small trials—trials that yielded only 12 outcome events—means that we can confidently conclude that Qnexa is safe,” Lauer wrote. Nor, he argues, can we ignore the prior history of weight loss drugs with adverse cardiovascular effects.

That means, Lauer wrote, “insisting on a large-scale, preapproval cardiovascular outcomes trial of Qnexa.”

“It would be too risky to rely on post-approval surveillance or to hope that a rigorous trial could be conducted in a timely manner,” he concluded. “If Qnexa prevents cardiovascular events, or at least doesn't increase the risk for them, in a preapproval trial, then we will all know that we have the peach we've been waiting for.”

Friday, May 4, 2012

Feasibility Counts At FDA

Venture capitalists and other investors in drug development often howl about FDA policy changes that they view as crippling innovation in certain classes. They may not think FDA listens, but it does. The agency just doesn’t always agree.

When FDA asked its Endocrinologic & Metabolic Drugs Advisory Committee to consider applying the cardiovascular safety standards used for diabetes drugs to the weight loss class, it was (among other things) a firm rejection of the argument that the diabetes guidelines have destroyed innovation in that class. (You can read lots more on that issue here.)

But lest you think this proves FDA has no regard for the real world implications of its policies, think again. In fact, the agency made the case during the March 28-29 advisory committee discussion of weight loss outcomes standards that the diabetes guidelines—while clearly increasing the size of study populations—have actually produced better trials, with data that reflects the real-world patient population who use diabetes drugs. Data that should, at least in theory, make it easier to support adoption of the therapies themselves.

You may not agree with the agency’s perceptions, but it would be wrong to say FDA is ignoring the impact of its policy on drug development.

And, at the same time FDA is quietly but staunchly reaffirming the value of the diabetes standards, the agency is giving ground in another area where new policies prompted a similar outcry: anti-infectives.

The issues are different: with antibiotics, the goal is not long term safety/outcomes, but rather to better define efficacy standards, with a particular concern about the limitations of non-inferiority study designs in settings were the comparator agents are likely to lose efficacy over time as resistance emerges.

FDA’s initial attempts to establish what it views as better study designs and endpoints, however, were greeted by many in the field as simply unworkable. The response, in fact, recalled the many declarations that diabetes is now a “no-fly-zone.” For example, Acorda CEO Ron Cohen highlighted the antibiotics standards as an example of the devastating impact of FDA regulation on biotech during The RPM Report’s FDA/CMS Summit for Biopharma Executives in December. He asserted that the FDA guidances led directly to three firms going bankrupt.

Well, FDA is listening.

“We understand, more than in other areas, this change in the non-inferiority standards, this conversation that we had in the last several year, really did set things back,” Center for Drug Evaluation & Research Deputy Director for Regulatory Programs Douglas Throckmorton said during the Food & Drug Law Institute annual meeting April 24.

“That is something we have heard loud and clear,” he said. In his presentation, Throckmorton discussed FDA’s plans to issue a total of nine guidances on antibiotic development standards, and promised that the standards would “couple feasibility with scientific soundness.”

“We do need to make certain that any conversation in the drug development space around antibiotics needs to include not just, ‘Here is the right science to do,’ but the achievability,” Throckmorton said. “What is the right way to get it done in a way that is efficient and timely?”

So the guidances “are going to talk about what the most appropriate scientific path as we understand it is to assessing whether an antibiotic is useful in a given disease process,” but “they are also going to focus on the feasible.”

“Part of that is going to be drawing on other regulatory science tools. It is going to be making use of adaptive designs. It is going to be making use of different statistical analyses that we haven’t maybe used in the past.”

The guidance will be “not just about how should you do it in the best of all possible worlds, but what is the way to do it in a way that is feasible and accomplishable, to make certain that the products are incentivized and are developed.”

FDA’s receptiveness to concerns about antibiotic drug development are hardly surprising: the dearth of new anti-infectives has been a major public health priority and is something Commissioner Hamburg has emphasized since joining the agency. Perhaps of more immediate importance is the legislative work to encourage antibiotic development as part of the Prescription Drug User Fee Act reauthorization.

But the fact remains: FDA is demonstrating that it can and does listen to concerns from drug developers about the impact of guidance on regulation. It just doesn’t always agree.

Thursday, April 26, 2012

Big Pharma's Health Reform Transition

And then there were none: AstraZeneca CEO David Brennan’s departure means all six big pharma CEOs who shaped the health care reform deal in the US have moved on.

With the departure of David Brennan as CEO of AstraZeneca now set for June, the brand name pharmaceutical industry has completed a rapid and important transition: every one of the key figures in negotiating the health care reform deal with the Obama Administration is now no longer a leader in the sector.

The exodus began with Pharmaceutical Research & Manufacturers of America CEO Billy Tauzin, who announced his own departure from PhRMA before the reform law was actually enacted. In his valedictory address to the trade association in 2010, Tauzin cited the leadership of half a dozen CEOs in making the deal happen.

They were:

Jeff Kindler of Pfizer, who resigned abruptly at the end of 2010.
Richard Clark of Merck, who handed over the reins to Ken Frazier in 2011.
Bill Weldon of J&J, who retired this month.
Kevin Sharer of Amgen, who retires in May.
Brennan, who is stepping down in June after a disappointing start for AZ in 2012.
And Miles White of Abbott, the only one of the six who remains as CEO—but of a company that is spinning out its brand name Rx business under a different CEO.

As we've noted before, the transition in leadership has important implications, as it helps the industry chart a new course no longer tied to the legacy of the deal on reform. In particular, if the Supreme Court strikes down the law, it will be much easier for the industry to work with the next Administration and Congress on picking up the pieces, since the fresh faces can more easily embrace new positions.

It also means the legacy of the reform deal will be left to others to manage. One of the remarkable things about pharma’s support for the reform law was the industry’s willingness to absorb significant costs up front—costs that hit each of those half dozen companies hard at a time of incredible business pressures.

But the up-front costs carry significant long-term returns, in the form of a more dynamic market for the industry on the other side of the patent cliff. Assuming the Supreme Court lets reform go forward, the next generation of pharma CEOs will benefit from that part of the legacy.

This was an unusual group of dissimilar personalities operating large companies in a time of shared challenges: industry-wide patent expirations and a dearth of new products to replace them. They took a bet on improving the long-term structure for the industry—even as their own terms as CEOs may have ended up being shorter than they would have liked.

You can debate whether the deal was a good idea or not, but you have to credit the dealmakers for daring to look past the patent cliff to try to shape a better future for their industry.

Thursday, April 26, 2012

The Downside of Looking on the Bright Side: Viropharma's Optimism Hurts Vancocin Case

Viropharma’s challenge to FDA’s approval of generic versions of Vancocin hasn’t gotten very far in court. One reason: the company’s own statements to investors undercut one of the key components of a preliminary injunction suit.

When Viropharma held an investor call April 10 to announce its response to the approval of generic versions of its vancomycin brand Vancocin, the company was careful not to promise too much.

“The hurdle is high” in challenging FDA approval decisions, said VP-Strategic Initiatives Thomas Doyle. “But I also think we have strong arguments.” Still, “we are in uncharted waters here and we will have to see how things go.”

Viropharma was wise not to raise expectations among investors for a rapid reversal: the company’s preliminary injunction motion was denied by the DC federal court on April 23.

However, Viropharma may not have been as wise in scheduling the call in the first place: comments made by the management team about the outlook despite the Vancocin setback ended up working against the legal challenge.

The ruling in the preliminary injunction action was not a surprise, at least not after federal court Judge Ellen Huvelle’s skeptical questioning during oral arguments April 19. Huvelle’s ruling was an across the board defeat for Viropharma: the court doesn't think it has much chance of winning a case that FDA doesn't know how to apply its own bioequivalence standards, nor did the court see much reason to second-guess FDA's interpretation of the admittedly murky exclusivity statute.

But even if the judge was leaning in the other direction, she indicated that Viropharma would still not be able to block the generic launch. Because one of the standards for an injunction ruling is that the plaintiff demonstrate that it will suffer “irreparable harm” if the action is not blocked right away; otherwise, the court is supposed to allow discovery and a resolution of the case on the merits.

Huvelle concluded that “ViroPharma has not made the requisite showing here.”The judge noted that its representations about the expected loss of revenue from Vancocin were too vague, especially since courts have held that “the mere existence of competition is not irreparable harm, in the absence of substantiation of severe economic impact.”

And, while there is little question that the advent of generic competition will have a significant impact on the Vancocin brand, that is very different than proving irreparable harm to Viropharma as a business.

That’s where the company’s comments on the conference call came back to hurt.

“As to both its alleged economic and reputational harms, ViroPharma’s claims are belied by its own statements,” Huvelle wrote. Picking up a theme helpfully provided by the attorneys representing the newly approved generic entrants, she cited the April 10 call.

“The day after the vancomycin ANDAs were approved, ViroPharma announced to investors that three other drugs, not Vancocin, were the company’s ‘growth drivers.’

“ViroPharma’s CEO stated… the company’s officials had ‘spent [their] entire lives assuming Vancocin was going to go away’ and had ‘been building the company expecting it someday to go away.’

“Perhaps most damning to ViroPharma’s position,” Judge Huvelle continued, “is its CEO’s rosy description, at the end:

‘[W]e have a very strong balance sheet. We have cash flow from the Cinryze business. We have a credit facility that allows us a low cost of capital . . . to pursue the acquisition of things that we believe fit the strategic intent of the company. And we still have Vancocin cash flow[;] it doesn’t go to zero.’”

Leading to this terse conclusion: “ViroPharma has failed to demonstrate irreparable injury.

Wednesday, April 25, 2012

A Question of Priorities

When it comes to explaining the agency’s regulatory priorities, you might think that the annual Food & Drug Law Institute meeting would be a better venue than a venture capital association event. But not during a PDUFA year….

The Food & Drug Law Institute annual meeting is the biggest gathering of lawyers specializing in FDA issues any time, anywhere.

This year's conference coincided with the first mark-up of the next iteration of the FDA user fee bills--a collection of programs that has now expanded to touch essentially every FDA activity.

So where were the directors of FDA's two most important medical products regulatory centers during the annual center directors' breakout portion of the meeting? Why in Santa Clara, of course, addressing the annual meeting of the National Venture Capital Association.

If it seems odd that Center for Drug Evaluation & Research Director Janet Woodcock and Center for Devices & Radiological Health Director Jeff Shuren were on the other side of the country when the critical legislation for drug and device regulation is entering the critical phase of the legislative process and every legal expert in the country was in Washington, well then you don't understand how the legislative process really works.

There were at least two good reasons for Shuren and Woodcock to delegate the annual FDLI update sessions to deputies. The first is a principle analogous to what securities lawyers would call the "quiet period" around a stock offering. The only thing decision-makers at FDA can do by discussing thorny regulatory issues right now is get into trouble. Even a simple recapitulation of prior public comments can be played up on Capitol Hill as evidence that "FDA" is doing or saying something outrageous that proves that a given legislative fix just has to be tacked on to the user fee bills.

But it is also a question of priorities.

The food and drug lawyers are not the critical constituency in shaping the legislative process; they will be the ones left to sort out whatever is enacted.

But the venture capitalists? That is a different story. In the current climate, FDA is keenly aware that it needs to avoid any perception that it is an innovation-killer and job-destroyer. The agency so far has kept Congress from going too far in tacking on unwanted legislative riders in the user fee process, but if anyone is going to upset the apple cart right now, it is far more likely to be someone attending the Santa Clara meeting rather than someone at FDLI.

Monday, April 23, 2012

The Unanswered Labor Question at PhRMA

If the Supreme Court overturns the health care reform act, PhRMA may have to try to reconstruct the innovator-friendly biosimilar pathway that became law with ACA in 2010. The base for that law was built on a strong set of alliances with labor unions. Is PhRMA keeping those ties strong or losing sight of them in the effort to refocus on the more traditional alliances with patient and disease advocacy groups?

The silence in response to a question from the audience at the PhRMA annual meeting in Boston was awkward and almost painful.

The first question to a panel on the “Innovation Ecosystem” came from Fred Mason (president of the Maryland and DC AFL-CIO).

Noting that Maryland Governor Martin O’Malley (D) had been a speaker at the PhRMA annual meeting in 2011 in part because of his state’s creation of a $100 million venture capital fund called InvestMaryland, Mason pointed out that “organized labor supported that addition because we thought it was a good investment and because it creates the jobs in the sector.”

Mason followed up with a question: “How are we going to make sure that those small startup companies that were invested in by the state of Maryland, when they are sold to larger concerns, that there is some return for the state?”

There was an extended period of silence from the four-person panel and the moderator. No answer; and then a call for “next question.”

To be fair to the panelists, none of them spoke directly for the association or had the portfolio to take a position for the industry – especially in the case of one business development exec (Pfizer’s managing director of the Centers for Therapeutic Innovation, Torben Nissen) who would have had to state a position in front of an assembly of very senior industry execs.

But the silence was awkward and the implied message that Mason’s question was off-target for an annual meeting or at least a panel on the new developments in academic and small company partnerships was a long way from the treatment that union leaders received from PhRMA as recently as three years ago.

At an annual meeting in 2009, the association had a large separate session on the shared issues with labor unions in advance of the health care reform debate. In addition to the association’s out-front engagement with the Obama White House on the overall package, PhRMA ran a potent campaign on Capitol Hill with many visits to Democratic offices in conjunction with labor groups. (PhRMA Has Labor Support for Extended Biologics Exclusivity.)

The attention and courtship of labor unions was more open and intense in 2009. That was a different political situation and a different PhRMA leadership: the president before the health care reform law was Billy Tauzin; the president now is John Castellani. PhRMA is also strategically re-emphasizing its connection to patient and disease advocacy groups. That's a move that positions the association well for the patient-centered changes underway at the Food & Drug Administration in terms of the definition of outcome goals in drug development and on reimbursemetn and coverage decisions with government and private payors.

The association is clearly still encouraging unions to stay engaged with pharma. Mason obviously is still invited to the annual meeting and at least two other labor officials were on the attendee list with the Maryland/DC official. But getting a silent, no-response to a question on the return to the state and labor unions for supporting life sciences investment is a long way from the courtship of 2009.

The unions were particularly helpful to PhRMA in the formation of a coalition to get favorable treatment for biosimilars in health care reform. The union support that PhRMA lined up negated one of the important power bases for (then) House Energy & Commerce Chairman Henry Waxman (D-CA.) to rally opposition to the 12 years of protection from biosimilars and the IP-friendly protections for innovators surrounding the FDA pathway.

That coalition led to sizeable majorities for the biosimilar provisions in both the House committee (47-11) and the Senate Health, Environment Labor and Pensions Committee (16-7).

PhRMA President Castellani cites those overwhelming votes in favor of biosimilars when asked if the industry is concerned that they may have to recreate the biosimilars bill as standalone legislation depending on the Supreme Court’s treatment of the Affordable Care Act.

To maintain the support, it may take more than just inviting union leaders at the annual meeting.

And, to the question about jobs and labor’s return-on-support, it is noteworthy that GlaxoSmithKline made its opening bid to close-out Maryland-based Human Genome Sciences a week after the PhRMA annual meeting. The $2.6 billion bid includes projected savings to the purchaser of $200 million in synergies by 2015. That sounds like some substantial job losses (even if not necessarily union losses) in Maryland and another hurdle in holding together the winning 2010 alliance.

It’s time to keep answering union questions; clearly not time for the silent treatment.

Monday, April 23, 2012

The Limitations of Antibiotic Incentives

Congress is on the verge of enacting important new incentives for antibiotic development. At the same time, a federal court hearing on the Vancocin generic approvals underscores the importance of doing things the right way.

On Capitol Hill, there is broad consensus that enhanced incentives for drug development are a key piece of the puzzle in addressing the threat of resistant infections. As an April 18 House hearing on the user fee reauthorization process made very clear, the GAIN Act will be part of the 2012 package, with the only question being exactly how broad the incentive should be, and whether it should include special regulatory provisions in addition to longer exclusivity periods. (For more on the progress with GAIN and other incentives, see our coverage in the latest issue of The RPM Report.)

The next day in a federal courtroom a few blocks away, antibiotic incentives received a very different hearing.

In that case, Viropharma is challenging FDA’s April 9 approval of generic versions of Vancocin (vancomycin). The approval came after a protracted debate over bioequivalence standards for the product, which is approved to treat enterocolitis in the gastrointestinal tract caused by Staphylococcus aureus (including methicilin-resistant strains) and diarrhea associated with Clostridium difficile (CDAD).

Viropharma still believes FDA improperly relied on in vitro studies rather than requiring in vivo trials, but Judge Ellen Huvelle made clear during the hearing that she is not inclined to second-guess FDA’s reading of its own regulations.

Instead, the hearing focused more on Viropharma’s second argument: that Vancocin is entitled to three-years of exclusivity under an incentive provision enacted into law in 2008.

As Viropharma’s lead attorney, Christian Vergonis of Jones Day, noted, Congress decided to grant antibiotics the benefits of Hatch/Waxman exclusivity in 1997 as part of the first Prescription Drug User Fee Act reauthorization process.

However, that protection applied only to antibiotics approved after that date, and (in Vergonis’ telling, at least) Congress was unsatisfied with that limitation and corrected it in 2008, enacting a provision as part of a non-FDA bill stipulating that antibiotics approved before 1997 are eligible for the three-year supplemental exclusivity protection of Hatch/Waxman.

In Viropharma’s view, FDA is unfairly depriving the company of that exclusivity for a supplement approved by the agency in December.

FDA’s denial of exclusivity is based on the agency’s view that the new “conditions of use” added to Viropharma’s label are not significant enough to trigger the exclusivity. All indications from the April 19 court hearing are that Judge Huvelle is likely to agree that FDA’s interpretation was reasonable, and deny the injunction request accordingly.

So the first lesson is clear: whatever legislators say about the importance of an incentive, the real impact will be determined by how FDA interprets and applies the statute.

And so is a second lesson: FDA’s (and even a court’s) application of the statute to specific circumstances is likely to be shaped by the agency’s perception of the merits of the sponsor.

In the case of Viropharma, Department of Justice attorney Andrew Clark made clear the government’s view of the efforts the sponsor went to defend its exclusivity. FDA’s 85-page letter denying Viropharma’s petition to block generics “demonstrates the lengths the company has gone to prevent generic competition,” Clark said.

He noted the company’s assertion that the loss of exclusivity would hamper its ability to invest in R&D. “I’m wondering how much of the R&D budget was spent on this legal onslaught.”

Judge Huvelle also noted the cost of the antibiotic (which she suggested was about $1,000 week) and indicated sympathy with the argument that availability of cheaper generics is clearly in the public interest, especially at a time of shortages.

Viropharma’s efforts to protect its brand have prompted an inquiry from the Federal Trade Commission, and an FTC attorney observed the April 19 hearing.

A final lesson is more speculative but also critical: the importance of an incentive is likely to be shaped by the circumstances of its enactment.

Vergonis’ narrative about the incentive at issue in the Viropharma case is noteworthy for what it skips over: the provision enacted in 2008 was considered for inclusion in the user fee reauthorization for 2007, but dropped at the last minute.

In the context of the broader user fee legislation, the provision fell victim to concerns that it did not properly balance the interests of brands and generics.

But the advocates did not drop the issue there. Instead, lobbying continued and the provision was slipped into an unrelated bill on the Social Security Act—enshrined in law, but stripped of context.

Indeed, critics of Viropharma cite the push for enactment as an example of what they see as the excessive zeal shown by the company in protecting its brand. Those same critics will be cheering if Huvelle indeed declines to block the generic approval.

There is a logical problem there: if the provision was enacted at the behest of Viropharma, then surely it must be intended to protect Viropharma’s brand from competition.

But logical fallacies are commonplace once a sponsor’s motives are in doubt.

The current debate over GAIN has led to a much broader consensus—the bill has bipartisan support and the endorsement of FDA, at least in broad outlines. That may mean more generous interpretation of the provisions down the road by FDA. But sponsors should remember the lessons of Viropharma: the enthusiasm for incentives tends to be less strong in practice than in legislative formulation.

Friday, April 20, 2012

Eliquis Advisory Committee Meeting Is Off

Bristol-Myers Squibb anti-clotting agent was slated to go to panel on May 22 but the meeting is no longer happening.

When thinking about Bristol-Myers Squibb/Pfizer’s bloodthinning agent Eliquis (apixaban) going to an FDA panel, an old saying comes to mind: if a tree falls in the forest, does it make a sound?

For Eliquis, a more apropos saying would be: if an undisclosed advisory committee meeting is cancelled, was one ever scheduled to take place?

The answer is: yes.

Eliquis was slated to go on the first day of a two-day Cardio-Renal Drugs Advisory Committee meeting on May 22. The second day, May 23, was scheduled for a review of Johnson & Johnson’s agent

Xarelto (rivaroxaban) for a new indication in acute coronary syndrome (ACS).

The second day is still happening. The first is not.

On April 11, it was confirmed that Xarelto would be the topic for discussion on May 23. As for the planned May 22 date, it is no longer happening.

That likely means that the drug is on track for approval.

We previously cited three reasons why the agency might want to take the anti-clotting agent to an advisory committee (See “What’s Going on with Eliquis and Xarelto at FDA?”):

Impaneling the Jury: threatening the sponsor with the prospect of a committee meeting in order to precipitate an agreement over unresolved regulatory issues.
Publicly Vet an Internal Disagreement: go to panel in order to have a public discussion over internal disagreements regarding safety and/or efficacy of the drug. Think Eli Lilly’s Effient (prasugrel).
Concerns Over Pradaxa: There have been reports of severe bleeding with Boehringer-Ingelheim’s blood thinner Pradaxa (dabigatran) due to reports of serious bleeding events. The agency may have wanted to pursue with outside experts whether there is a larger class effect.

We still don’t know which if any of those reasons prompted FDA to ready for an advisory committee review of apixaban. What is clear is that FDA’s outstanding concerns appear to have been answered.

Xarelto’s user fee deadline is June 27 and, because of a three-month extension triggered by a submission of additional information, the user fee deadline for Eliquis is June 28.

Thursday, April 19, 2012

Musical Tables in Generic Drug Litigation

Generic drug litigation remains a prominent part of food and drug law practices. But with the growing complexity of the case law—and the blurring lines within industry—it is very hard to predict which client and which attorney will be on what side. Back-to-back hearings on Provigil and Vancocin make that clear.

“Here we are again.” That is how DC federal court Judge Ellen Huvelle greeted Edward Anthony Figg of Rothwell, Figg, Ernst & Manbeck during an April 19 hearing on Viropharma’s attempt to restore the exclusivity for its Vancocin brand vancomycin.

Figg was in court on behalf of Watson, one of three generic manufacturers granted ANDA approvals for Vancocin on April 10. Figg had appeared before Huvelle the day before, representing Mylan in a different case related to a first generic drug launch, involving Cephalon’s Provigil (modafanil).

Huvelle expressed ironic pleasure that at least one other person was dealing with complex generic drug litigation “back to back.”

Come to think of it, the phrase “complex generic drug litigation” is probably redundant: almost 30 years after the Hatch/Waxman Act the layers of unintended consequences and interlocking precedents has rendered essentially every case complicated. (The Provigil case in particular is a doozy: start here for background. For more on Vancocin, start here.)

Still, the back-to-back hearings underscore the reality of “brand vs. generic” cases in 2012: if it was ever true that the “brands” argued one side and the “generics” another on any given policy issue, it is no longer true today. In part, that reflects the layers of complexity that have evolved in generic drug law where cases are every bit as likely to pit generic vs. generic as they are generic vs. brand. But it also reflects the increasingly fuzzy line between a “brand” and a “generic” in a world of authorized generics—and broad product lines.

Figg offers a case in point.

It wasn’t just the identity of his client that changed between the two hearings. Figg also literally changed sides. On April 18, he sat on the judge’s right, as the plaintiff seeking an injunction to block the agency’s grant of “first generic” exclusivity to Teva for modafanil. On April 19, he sat at the other table in the hearing room, alongside the Department of Justice and FDA attorneys who were the defendants in both cases.

As Judge Huvelle noted when questioning Figg in the Provigil suit, on Wednesday he was asking the court to reverse the agency’s interpretation of its own statute and regulations; on Thursday, he was arguing that the agency’s interpretations should be subject to considerable deference in the court.

Before the hearing, Figg exchanged pleasantries with DoJ attorney Anthony Clark. The two have appeared in court together before, but both found it amusing to be seated together for once.

DoJ and FDA sent a different team for the Provigil case, but in that instance they were little more than bystanders. The arguments on behalf of the defense were made primarily by Michael Shumsky of Kirkland & Ellis, representing Teva, which intervened in the case as the recipient of FDA’s unexpected grant of exclusivity. Shumsky, actually, represented two clients: the Teva USA generic business and Cephalon Inc. as the owner of the Provigil brand. Both, as Shumsky noted, are wholly owned subsidiaries of Teva Ltd. – but, he insisted, each has separate interests at stake—Teva in defending its “first generic” rights and Cephalon as the brand holder. Oh, and of course, a shared interest in an “authorized” generic manufactured by Cephalon but sold by Teva under an “arm’s length contract” that “is carefully monitored” to assure market-based pricing.

The distinction between Teva USA and Cephalon is an important part of the arguments in the case, since Mylan was arguing that the Teva/Cephalon merger should have voided any rights to exclusivity held by Teva. Judge Huvelle didn’t have much patience for Shumsky’s attempts to assert the separateness of his two clients—but it did make for some entertaining confusion about whether “Teva” or “Cephalon” argued a given point.

This may be a good opportunity to mention that Figg wasn’t the only lawyer to attend both hearings and hope for FDA to lose on April 18 but win on April 19.

Federal Trade Commission attorney Marcus Meier participated in the Provigil hearing, with FTC submitting an amicus brief in support of Mylan’s lawsuit. FTC is not formally a party to the Viropharma case, but Meier sat in the courtroom audience for the hearing, a visible reminder that the antitrust agency has opened an investigation of Viropharma and clearly wants the Vancocin monopoly to end for good.

FTC’s intervention in the Provigil case puts the agency in the unusual position of essentially urging the court to over-rule FDA’s interpretation of its own statute (even though FTC’s brief explicitly says that it is not doing that.) In Viropharma, FTC wants FDA’s interpretation upheld.

In fact, Judge Huvelle’s questioning on both days suggested she shares FTC’s concerns about competition. In the Provigil case, she repeatedly declared her frustration over the fact that (as it appears to her) “reverse payment” settlements delayed generic competition for seven years—and now there is potentially another six months before a true generic. However, as The Pink Sheet DAILY notes, Huvelle also seemed frustrated at the lack of any basis for the court to intervene—and used Meier’s appearance to note FTC’s own failure to anticipate the exclusivity determination in its review of the Teva/Cephalon merger.

Huvelle seemed more comfortable with the idea that her ruling in Viropharma might better match her sense of how the case “ought” to come out—and that probably means Viropharma won’t be able to undo the generic launches already in the market.

If our read on the hearings is right, Huvelle’s rulings may end up seeming horribly inconsistent: extending a brand-only marketplace for Provigil on the one hand while upholding the generic launches for Vancocin on the other. In fact, the judge would be siding with FDA in both cases.

Huvelle herself lamented how rarely the Waxman/Hatch model seems to work the way it should. But “the statute is the statute and we aren’t going to write a better statute sitting here.”

Wednesday, April 11, 2012

R&D vs. The Inverted U

Lucky for Big Pharma's R&D heads that the Pharmaceutical Research & Manufacturers of America annual meeting comes at the beginning of a budget cycle.

On April 12, author Malcolm Gladwell regaled a rapt lunch audience with a convincing analysis of the non-productive over-resourcing efforts, where more spending after a critical amount becomes counter-productive, a phenomenon he dubbed "the inverse U curve."

For example, Gladwell pointed out, parents focus on class size as a key metric, despite evidence that shows class sizes below about 20 students are less successful. Yet many school systems devote resources to lowering class size, rather to other more productive uses. He also cited the early work on childlood leukemia at the National Institutes of Health, where dramatically under-resourced research produced dramatic advances in therapy.

If only those 2012 R&D budgets were not already locked in....

Wednesday, April 11, 2012

Life After 2012: The FDA/CMS Summit for Biopharma Executives -- Save the Date!

The pending Supreme Court ruling on health care reform. The fast-paced effort to enact a new user fee program--complete with major changes to the new drug approval process and first-ever generic and biosimilar user fees. And a presidential election. We'll have more than ever to talk about at The RPM Report's FDA/CMS Summit for Biopharma Executives on December 10-11 in Washington DC. Register now for this can't-miss event!

There has never been a year quite like 2012.

The Supreme Court will rule on health care reform this summer, and industry will either have to ramp up preparations for a massive expansion in the insurance market in 2014—or pick up the pieces if some or all of the law is voided.

The new rules for drug reviews will be enacted by Congress soon thereafter, with the reauthorization of the Prescription Drug User Fee Act and the creation of new generic drug and biosimilar user fee programs. Those programs will bring sweeping changes in the rules for success in drug development and life-cycle management—and the final law will likely include many add-ins that may be even more important to industry.

Last but not least, the voters will decide in November whether Barack Obama returns for a second term, or Mitt Romney takes over as President—and which party will be ascendant on Capitol Hill for the next two years. With deficit reduction sure to take center stage, biopharma companies will need to know who will be deciding what to cut—and how to make sure that the climate for innovation is protected.

That is an incredible series of unpredictable events. But one thing is certain: industry will need to adapt quickly to the new rules and new rule-makers.

Don’t be caught unprepared. Join us at the eighth annual FDA/CMS Summit for Biopharma Executives to hear from leaders in government and industry about what the key events of 2012 mean for the biopharma industry in the years to come.

So, save the date: December 10-11 and plan to join us in Washington, DC for the can't miss biopharma regulatory and reimbursement policy event of the year. Visit our website for more information.

Wednesday, April 4, 2012

The Popularity of "Special Pop": Antibiotics Incentives and PDUFA V

The Infectious Diseases Society of America’s “Special Population” approval mechanism has proponents within FDA and industry. That makes it look like a good proposal to complement the market incentives for anti-infectives being pushed under the GAIN Act add-on to PDUFA V. There is one big hurdle, however: GAIN’s major legislative proponent, Rep. Phil Gingrey (R-GA) does not like the limitations on use post-approval.

The Generating Antibiotic Incentives Now Act may have a companion piece of anti-infective legislation joining it in the PDUFA V user fee omnibus. A strong effort is evolving – with encouragement from some top officials at the Food & Drug Administration – to add language which would set up a limited-population approach to accelerating some anti-infective drug regulatory reviews. That would be a complement to the five-year market exclusivity extension for qualified products proposed in GAIN.

The Infectious Diseases Society of America is building support for a proposal to alter FDA’s approval process for some anti-infectives and allow the agency to have more control over the use of the product once approved.

IDSA is trying to define a process in which an anti-infective could be studied in a substantially smaller (faster, cheaper) clinical trial. A Special Population Limited Medical Use drug would have a narrow indication, and its labeling would include a description of that population, the rationale for limiting use, and a special SPLMU logo. The labeling would be designed to limit marketing and use to a tightly restricted population as a way to help with antibiotic stewardship and to learn more about the rapidly approved products.

The IDSA proposal is important to the broader drug industry as a change to FDA’s approval process that FDA leaders actually seem to like, which makes it a potential model for other drug classes in the future. FDA has been effectively deflecting many suggestions to change the nature of its approval process in PDUFA V. The agency says that its current authorities allow it sufficient flexibility to make rapid approval decisions.

The IDSA proposal was released March 8, coinciding with a House Energy & Commerce Health subcommittee hearing on user fee add-ons. Although it was only mentioned in written testimony by the Infectious Diseases Society of America, Center for Drug Evaluation and Research Director Janet Woodcock gave it some prominence by directly addressing the concept in her testimony that day.

Woodcock said on March 8 that that “we actually feel that a much abbreviated development program, a very small development program, which would be an incentive, would be highly feasible if linked to the concept of good antibiotic stewardship post-market.”

Woodcock further indicated the agency’s interest in the IDSA proposal by appearing with the society at a Capitol Hill briefing on March 30. Woodcock was accompanied by Ed Cox, head of CDER’s Office of Antimicrobial Products. In the current climate with FDA trying to hold back add-ons to PDUFA, having Woodcock at that type of briefing is close to a ringing endorsement by the agency.

The “special pop “approach has not made it into legislative language yet. It is not in a recently circulated House user fee discussion draft. That’s not much of a surprise, given that the House draft carries a date, March 8, that’s the same as the unveiling of the IDSA proposal. Perhaps more significantly, it’s also not in the Senate antibiotic discussion draft released March 29.

The Senate bill moves the antibiotic incentives activity forward by addressing one of the issues from the March 8 House Energy & Commerce Committee hearing; it modifies the way the GAIN Act defines what drugs qualify for its incentives, granting additional flexibility to FDA. (See "GAIN is Great: Now Who Gets the Benefits?" The RPM Report, March 2012.)

So there’s certainly no guarantee that SPLMU make it into the PDUFA reauthorization; the strongest sign of potential movement is FDA’s support.

GAIN sponsor Phil Gingrey (R-GA) could be a formidable hurdle for IDSA. Gingrey, a doctor, is wary of including stewardship in his bill and he is against further federal controls on prescribing practices. (See "Antibiotics Stewardship Remains an Open Question on Capitol Hill," The Pink Sheet, March 19, 2012.)

Still, staffers (including those of GAIN sponsors) got additional information at the March 30 briefing and IDSA has letters of support from several sponsors, such as Anacor Pharmaceuticals Inc., Rempex Pharmaceuticals Inc., Trius Therapeutics Inc., Nanotherapeutics, Rib-X Pharmaceuticals Inc., Basilea Pharmaceutica Ltd., to complement FDA’s interest.

A “Strong Signal” to Docs

If a small trial in a limited population sounds like something FDA can already do, that’s because it is. The legislation would address the authority for special labeling.

“FDA has a long-standing pronouncement that we’ve made, which is true and would remain true under this, that we won’t interfere with the practice of medicine,” Woodcock told the March 30 briefing. FDA is still recovering from the late but strong negative response from the medical community to some of its early REMS restrictive efforts.

FDA views SPLMU as a “strong signal” to physicians, payers, and formulary committees that a compound has become the standard of care for a special designation and population. Woodcock said the agency can’t send that signal effectively now. FDA could undertake to set up a limited use approach through regulation but that type of process could take eight years and create additional problems.

Both Woodcock and IDSA emphasized practitioner discretion. Brad Spellberg, from UCLA’s David Geffen School of Medicine, noted that most inappropriate antibiotic use is actually on label and driven by marketing; the power of the IDSA proposal is the specificity of the indication. Practically, off-label use of products approved with limited use labeling would be held back by the higher prices that would be associated with the products. (IDSA says the pathway should allow a pricing premium.) And off-label use can still be warranted: Spellberg cited an example where a drug might be approved under SPLMU for lung infections caused by a lethal bacteria – a physician might use it off-label to treat a brain infection of the same bacteria.

Unlike a REMS, the SPLMU labeling could shift the burden of appropriate use enforcement to the health care community, and away from drug sponsors. FDA can use Sentinel to see how well it’s working for stewardship, but neither FDA nor pharma will be punishing docs for usage.

Beyond Antibiotics – to Obesity?

Trust for America’s Health Executive Director Jeff Levi said he believed the SPLMU authority could be used in other chronic conditions, like obesity, which he said has a “different kind of stewardship.” FDA doesn’t currently have the authority to “say very overtly this is an intervention that should only be used for the morbidly obese.” Both antibiotics and obesity drugs are not self-limiting like life-threatening conditions are. This mechanism also allows consumers a way to know the risk for their subpopulation, allows FDA to recognize the non-identical needs of different consumers, and makes it easier for physicians to say no.

It also provides sponsors an opportunity to “learn while they earn” and in some instances learning about the safety profile could help with an expanded indication down the road. SPLMU is intended to be potentially temporary in certain instances, if sponsors decide to do the full studies.

Whether to keep a “special pop” legislative provision just to antibiotics or to broaden it will depend on the level of trust Congress has in the FDA, Levi said “I think it’s safe to say that having this kind of targeted authority will not be overused because it’s not in the interest of drug companies to seek a narrower indication.”

FDA’s Non-position Position

Woodcock was asked at the briefing whether FDA technically supports SPLMU. “Well, the Administration hasn’t taken a position on this,” she said. “It came up very quickly. I’m saying, as Janet Woodcock, head of the center for drugs, and he’s saying as Ed Cox head of the antibiotic group at FDA, we think this tool would address a number of the problems, and we could provide drug development programs that would be incentivizing for companies to get back into this space if we had such a tool. That’s what we’re saying.”

IDSA’s VP-Public Policy & Government Relations Bob Guidos noted that the Administration already has a position around PDUFA, so it’s hard for them to take a position beyond that. Woodcock added that she and FDA Commissioner Margaret Hamburg have talked about these ideas. “The Commissioner feels this is a very positive step that could be taken by Congress but it’s not an Administration initiative that we’re putting forward.

“From FDA’s standpoint, it’s a novel proposal and we are interested in hearing questions that people have. But we have to do something” in the anti-infective area, Woodcock said. FDA has participated very openly in efforts to restart drug development in the antimicrobial field. By supporting the IDSA proposal in this limited area, the agency is also sending a message that it is pro-reform where necessary which could give it more credibility on Capitol Hill fighting other efforts to encourage broader reforms such as the simmering interest in adaptive licensing schemes.

Regulatory Certainty Is Effective Incentive

The solution to re-energizing antimicrobial development, Woodcock noted, will take multiple actions. Among these, “probably the most important factor” is a clear, predictable development pathway, she said. Venture capitalists want to know what the pathway is – even if it’s hard.

“How much could this ameliorate the crisis? I don’t know,” Woodcock said. “We at FDA have only been talking about this a little with different groups and public discussions. We’ve heard from two companies that said they’d like to pursue this. One question is: how many companies can we lure back?”

A clear pathway would be the “greatest incentive” to get sponsors back into antibiotics. FDA will continue to work on that clarity from the science side, because the agency remains in charge of describing the standards and endpoints for the approval of drugs.

Spellberg noted how the Special Pop approach might work. Sponsors might have a drug in development for a broader indication like CABP or UTI but encounter road blocks (i.e. too much dosing to tolerate for those indications). With this mechanism, they could retool for something like acinetobacter; before they would have just killed the drug. Woodcock agreed. It’s also possible that a sponsor might study a drug broadly but only seek approval for a small group through SPLMU, she said. Then there could be concerns because information would exist about the drug’s ability to work in non-resistant infections. FDA would need a series of workshops to talk about various scenarios but “that can be done once we get through this part.”

Special Population Approach Might Work in Conjunction with Orphan Incentives

Several comments at the March 30 briefing, prompted by a Congressional staffer question, suggested that the SPLMU approach could lead to orphan incentives.

“This designation might actually enable you to get an orphan designation too because you’re actually saying we’re not sweeping in the whole population,” Woodcock said. The SPLMU designation is directed at the same problem with orphan drugs – companies coming in with “factitious” populations and end up with the drug being used in everyone. “This designation, if it works, will restrict the use to the orphan population. I can’t guarantee that in writing, but I think it would work to enable more antimicrobials to get that orphan designation.”

Spellberg noted that IDSA has talked about orphan drugs for antibiotic resistance for ten years; indeed the topic came up at a 2010 House Energy & Commerce Committee hearing on antibiotics where Spellberg proposed that it should be used. “Our understanding has been that FDA is not comfortable/willing to consider a resistant form of an infection as a distinct group from the overall broader population.”

That’s because of the current statute, Guidos said. “But if this were created, that would change the game.” FDA’s Office of Antimicrobial Products Director Ed Cox agreed it might work.

Woodcock said if FDA could “get” SPLMU, patients could be treated with the new drug in the ER, but then taken off based on culture information. “We’d have to talk about that, but it’s very intriguing and a good point. If we got this, I suspect it could solve the problem and provide orphan exclusivity for many of these.”

That would be icing on a cake that many parties seem interested in discussing. Woodcock emphasized that the normal pathway for broader antibiotic indications with non-inferiority trials will, of course, remain. “Most people have made the calculation that that pathway isn’t worth it,” she said. “But we think this more targeted pathway will be attractive to a lot of small companies, who we’ve already heard from.”

Thursday, March 29, 2012

FDA Advisory Committee Members and COI: A Proposal for Conflicted Experts

Would a small change in the advisory committee procedure serve as a middle ground in the disagreements over conflicts of interest at panel meetings?

In a recent story by The RPM Report, we outlined the conflicts over conflicts of interest in the FDA advisory committee regulations.

To summarize, on the one hand drug industry sponsors and some high-ranking FDA officials in the drug center have openly discussed loosening some of the conflict of interest rules for serving on advisory panels in order to make sure the foremost experts on a given topic are included to give their expert advice on a specific product application or important drug development problem. A change to the rules could come in the form of legislation in the prescription drug user fee act reauthorization (PDUFA V) this year.

On the one hand, consumer advocates worry that proposed legislation would undermine the advisory committee process. They say FDA hasn’t reached its caps on waivers for conflicted members, there have been overall declines in advisory committee vacancies over the past few years, and the agency hasn’t reached caps on waivers for conflicted members.

FDA Commissioner Margaret Hamburg is caught in the middle, calling the issue “thorny” when asked if new legislation is needed.

Here’s a proposal: tweak the open public hearing session at advisory committees.

FDA could maintain the COI standards detailed in the FDA Amendments Act as they are but add a new feature: FDA-designated public discussant during the open public hearing. Let’s call it the FPD.

This would be an individual or individuals who may have conflicts but they are specifically chosen by FDA to make public comments on the subject being reviewed during the open public hearing—at the beginning of the session. The FPD would have to list their conflicts at the beginning of their remarks (just like everyone else). But their opinion is elevated by a degree because they are an FDA-designated speaker.

We want to hear your thoughts on an FDA-designated public discussant. To send us your comments, click here.

Monday, March 26, 2012

Marqibo Gets a Shot at FDA Approval With Panel Endorsement--Finally

Journey of vincristine drug formulation gets through ODAC with tepid endorsement after once being the posterchild for “how low can you go” drug development.

After a long wait, Marqibo finally got past an FDA advisory committee.

On March 21, FDA’s Oncologic Drugs Advisory Committee voted 7-4 (with two abstentions) that Talon Therapeutics’ Marqibo (vincristine sulfate liposomal injection) demonstrated a favorable risk-benefit profile in a narrow indication for adult patients with Philadelphia Chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more treatment lines of anti-leukemia therapy.

The new formulation was developed by Talon to increase the tolerable dose of vincristine while reducing its dose-limiting neurotoxicity.

FDA’s review found the complete remission + achieved complete remission with incomplete blood count recovery [CR + CRi] rate to be 15.4% with a median duration of 28 days. The committee felt that result was good enough to meet the efficacy bar in an un-met medical need population. Talon conducted a single-arm, Phase II study of 65 patients to support the accelerated approval.

One couldn't watch the ODAC review of Talon’s Marqibo application without uncomfortable memories from almost eight years ago, when it was Enzon/Inex’ application for Marqibo that was before the ODAC. Enzon/Inex were seeking an indication for relapsed aggressive non-Hodgkin's lymphoma.

It was at that very meeting in December 2004 that Marqibo was made the posterchild of “how low can you go” drug development.

Inex had submitted a 119-patient Phase II study for accelerated approval of Marqibo; Enzon had acquired Inex very late in the development process. In the study, patients on Marqibo demonstrated an approximately 21% unconfirmed response rate that included a large number of partial responses.

FDA’s top cancer drugs review manager Richard Pazdur drove the point home that it was time to take drug development in oncology to a higher level and not simply do what he characterized as the bare minimum to try and get a drug to market.

"When we have a meeting like this, we have a litany of sponsors come in and pose this question to us: What is the lowest response that you will take? What is the fewest number of patients you will take?" Pazdur said. "It's called how low can you go?"

A lot has changed for Marqibo, including the sponsor and a narrowed indication. In addition, Talon has a Phase III confirmatory study tentatively ready to go should FDA approve the drug on its user fee decision date of May 13.

A key turning point in the March 21 ODAC meeting was an argument made by panelist Mikkael Sekeres (Cleveland Clinic). He noted five patients made it to hematopoietic stem cell transplantation. Sekeres said getting to transplantation is a critical endpoint because it can get a patient to cure: “We can debate the median durations, but we haven’t focused on the fact that they now have a chance to be cured and they didn’t before.”

That argument combined with assurances over the confirmatory study gave Marqibo a shot. But it still remains to be seen whether approval is next.

The recommendation by ODAC was positive but tepid and it left some room for interpretation by FDA. For example, ODAC Chairman Wyndham Wilson (NIH) said he wasn’t sure how he was going to vote right up until the actual vote (he voted “yes”). That isn’t the conviction of a convinced expert advisor.

In addition, there were two abstentions. Although the abstentions were more positive, they were abstentions nonetheless. In other words, FDA could easily view the vote as a split panel as a signal to FDA to do what it thinks is best.

On May 13, it will be clear what FDA thinks is best. For Marqibo it will either be the finish line or finished in a long regulatory journey.

Thursday, March 22, 2012

NME Filings Up: A Bit of Context

New molecular entity filings jumped in 2011, thanks to a number of late year filings. But let's not celebrate too soon.

FDA’s latest glossy report on innovation includes one nugget of real news: the Center for Drug Evaluation & Research received 39 new drug applications for never before marketed molecules during calendar 2011.

That is a huge increase from the 23 received in 2010, and suggests that the low filing level of 2010 was a one year aberration and not a sign of a looming catastrophe.

It didn’t look that way in December, when Office of New Drugs Director John Jenkins presented his update on the review statistics for the year at The RPM Report’s FDA CMS Summit for Biopharma Executives. At that time, there were just 29 filings—a rebound to be sure, but still a distressingly low number for an industry heading over a patent cliff, and definitely not an encouraging sign that the agency could build on its 30 NME approvals in 2011. As Jenkins put it during the December conference, FDA can’t approve drugs if it doesn’t have applications.

So it turns out 2011 was much better year for R&D output than it looked at the end of December. In fact, the 39 submissions would be the highest total in the past dozen years. That is good news indeed.

But let’s not get too carried away.

Thirty-nine NME filings is better than the average of 30 over the past decade, but it still isn’t a leap forward from historical norms. Indeed, it is barely three-quarters of the peak year for filings which came in 1995, with 50. In fact, CDER received more than 40 submissions for four years in a row during those halcyon days—and back then it didn’t even count biologics in the tally. (CDER took responsibility for most therapeutic biologic reviews in 2003; before then they were submitted to the Center for Biologics Evaluation & Research.)

In fact, if you look at the past two years, the average is just 31 NMEs, suggesting no sign that the output from development is anything but stagnant.

And then there are those 10 filings that came after Jenkins prepared his data for the December presentation. That suggests that more than 25% of the NMEs submitted in 2011 came in during the final month of the year. (In fact, FDA’s report notes that 12 of the 39 NMEs counted by the agency are “projected,” since an actual determination of NME status comes upon approval).

Once upon a time, December was the month for NME approvals, with as many as half of the annual tally of new molecules approved by the agency getting the nod in the final month—or, really, the final days—of the year. That all changed with user fees and the era of review deadlines.

But increasingly, December is the month of NME filings, as sponsors strive to achieve a key development milestone before the end of a calendar year. Nothing like making those investor updates (or annual performance targets) look good.

Of course, rushing to complete an NDA filing isn’t necessarily the best way to get to an approval. So let’s wait and see how many of those December submissions actually make it through.

Still, 39 filings is far better than 23. Here’s hoping even more innovative therapies make it through development in 2012.

Tuesday, March 13, 2012

Mandatory Mail, Thanks To FDA?

Vivus’ weight loss drug Qnexa cleared committee thanks in large part to a REMS proposal that FDA hopes is less burdensome than a traditional pregnancy prevention program. But will the agency really end up mandating a mail-order-only drug distribution network for a mass-market product?

In December, New York governor Andrew Cuomo signed into law a provision prohibiting insurers and employers from implementing mandatory mail order provisions in the state—the most important victory to date in the seemingly never-ending battle between community pharmacy and large pharmacy benefit management/mail-service companies.

At the same time, Vivus Inc. was working on a novel risk management program for its weight loss drug Qnexa (phentermine/topiramate) which just might turn into an unprecedented FDA-mandated mail-order program for a mass-market indication.

Welcome to the next phase in the evolution of the uneasy relationship between the Risk Evaluation & Mitigation Strategies and the pharmaceutical supply chain.

The REMS for Qnexa was the central issue up for discussion by FDA’s Endocrinologic & Metabolic Drugs Advisory Committee when it re-reviewed the weight loss application February 22. The challenge was crafting a proposal to minimize pregnancy exposures to Qnexa wthout cutting off access to topiramate for other indications where the medical need in pregnant women may outweigh the risk of birth defects associated with the drug.

To get out of the dilemma, FDA proposed a new model for a REMS: a program that relies on a certified network of dispensing pharmcies, but not on physician certification or patient registration. It is a model that FDA’s own safety team described as imperfect—but it succeeded in getting the committee to “yes,” with a 20-2 vote in favor of approval of the drug. ("Setting the Stage: Qnexa and the Power of REMS" — The RPM Report, March 2012)

From FDA’s standpoint, the “skeleton” proposal outlined by the agency is, in the words of Office of New Drugs Director John Jenkins, “what we thought was a reasonable approach to mitigating risk in this situation, where you have the two components in this combination that are already approved and generically available for other indications, without a REMS program.”

But the “fleshing out” of that skeleton by Vivus included a remarkable feature, not previously included in a REMS: a proposal to limit distribution to a network of national mail-service pharmacies. Vivus Senior Director-Global Medical Affairs Barbara Troupin presented the idea to the panel, and reported that the company has already had discussions with PBMs who would cover 70% of the US population.

Troupin highlighted the level of control such a network would give the sponsor: even without prescriber and patient registration, Vivus would have a greatly enhanced ability to target its education and training efforts by tapping into the databases of the mail service operations.

A mail-order only REMS would be a remarkable proposition, and just the latest example of the way that the REMS authorities can transform controversial practices (like speakers bureaus or scripted medical science liaison presentations) from questionable practices into required activities a sponsor is obliged to perform to comply with its REMS commitments. ("Regulatory Alchemy: The Transformative Power of the Opioid REMS" — The RPM Report, June 2011)

And it would be a remarkable development in the reconsideration of REMS based on the initial feedback—okay, complaints—from across the health care system about the burdens REMS impose on providers. Physicians have objected. So have hospitals. Kaiser submitted a very important citizen’s petition that helped prompt an agency-wide reconsideration of how best to use the new drug safety tools. ("REMS 2.0: FDA Refining New Drug Safety Tools" — The RPM Report, December 2010)

But it was really the pharmacists who complained first. After all, it is often at the pharmacy counter that the exact burdens and obligations of a REMS become most apparent.

Can it really be that the answer is to bypass the pharmacy counter altogether?

Mixed Reaction

It is by no means certain that the final Qnexa REMS will include the mail-order-only component.

While the vote for approval was overwhelming, the response to the specific idea of limiting access to mail was much more mixed.

Committee member Lamont Weide (University of Missouri) was the most outspoken dissenter. “I was never so happy as when I had to give up my mail order pharmacy,: he said. “I can’t imagine a mail order pharmacy being able to provide medicines every 30 days on time and having patients not be missing them. I just can’t see it working….It is not going to work. It is that simple. It will not work.”

After voting “yes” on approval, Weide reiterated his reservations. “I am anti mail order pharmacy. It is just not going to work. Please work on something else.”

Several other committee members appeared equally skeptical, although less caustic.

By relying solely on mail order, “the interaction between the pharmacist and the patient would be minimized,” Almut Winterstein (University of Florida College of Pharmacy) said. “To me it seems a bit smoke and mirrors to say this would mitigate risk.”

Vivus’ Troupin responded by emphasizing the benefits. “By doing the pharmacy system and the network, we actually have the ability to know who the patients and the providers are, which means we can target the providers for education, we can target patients for education, we can do assessments of the tools, understand the medication guide, do assesement of whether they understand it for comprehension, do assessments of whether they are complying with contraceptive guidance and using pregnancy tests. That allows us a channel. It gives us strength that we can’t do if we don’t have that channel.”

Winterstein was unconvinced. “If you certified pharmacies you could always get that data,” she said. The mail-only approach “makes it a lot easier for you,” but only at the cost of losing the face-to-face interaction with a pharmacist.

While it is theoretically true that the company could track as carefully through a retail network, “the challenge is the sheer number of them to try to aggregate comparable data,” Troupin replied. But “we do lose that face-to-face piece of it.”

Eric Felner (Emory University) also argued against relying on mail, citing his experience with pediatric human growth hormone. “Growth hormone is a disaster getting that through mail order,” he said. Felner argued that it would be better to adopt a more restrictive prescriber certification model. “I think the mail order would be very difficult.”

Not everyone on the panel was as skeptical. Michael Rogawski (UC-Davis), for one, believed the sponsor’s idea was very persuasive. “I want to raise my voice in support of the REMS program,” he said. “The one area initially I was concerned about was the distribution through mail-order pharmacies…If that mechanism could be used to collect Phase IV data both on teratogenicity and the cardiovascular risk, that could be very powerful.”

Robert Clancy (University of Pennsylvania) even suggested that the mail order distribution could be enhanced by including a pregnancy test kit in each monthly shipment, as a tangible reminder to women of the need to avoid pregnancy exposure.

FDA will have to weigh that feedback as it completes the Qnexa review. But, while it wasn’t universally popular, it is also clear that the mail-order-only REMS idea didn’t bother anyone on the committee enough to vote against approval because of it.

And that may mean it is only a matter of when, not if, FDA gets into the mandatory mail business.

Friday, March 9, 2012

Reagan-Udall May Get Funding; DeLauro Probes Hamburg On the Details

FDA is no longer prohibited from providing funding to the Reagan-Udall Foundation, but Rep. Rosa DeLauro still questions its “uniqueness.”

The Reagan-Udall Foundation may finally get some money.

The controversial public-private partnership came up at the very end of the House Agriculture Appropriations Subcommittee hearing on the FDA’s FY 2013 budget request in questions to FDA Commissioner Margaret Hamburg.

Rep. Rosa DeLauro (D-Connecticut) noted that the subcommittee did not include a ban on FDA funds supporting Reagan-Udall in 2012. “I understand that in the absence of such a funding prohibition, the agency is required to direct funds to the foundation, but no funding was included specifically for the foundation,” she said. “Can you tell me where these funds were diverted from at the agency and how much money are we talking about?”

DeLauro, of course, is the former chair of the subcommittee who inserted a line in the FDA appropriations bill for 2008 prohibiting the agency from transferring any funds to the Reagan-Udall Foundation – which Congress had directed FDA to create just three months earlier. (See “Undermining the Foundation: High Stakes in Fight Over Reagan-Udall,” The RPM Report, April 2008.) DeLauro, a critic of undue industry influence, had concerns about the foundation. She likewise opposed the creation of the generic drug user fee (now almost a reality), and at this hearing called user fees an “abdication of Congressional responsibility.” (Not surprisingly, she wasn’t a big fan of the FY 2013 FDA appropriations bill – of the 17% increase from FY 2012, a full 98% would come from user fees.)

So what is the status of Reagan-Udall funding? No funds have yet been transferred and no decision has been made about how much. After some pressing from DeLauro, Hamburg said she’s “thinking about taking it from monies in the Office of the Commissioner.” As for the amount, Hamburg guessed at a $500,000 to $1.25M range – this is in fact the range authorized in FDAAA.

But Hamburg thinks the funding is important. “We have an opportunity, with the appropriate safeguards in terms of criteria for who the Reagan-Udall Foundation gets money from and how it’s used, but to make a real difference and to serve as an adjunct to the FDA mission in terms of important research consortia and activities.”

A Unique Role?

DeLauro probed why Reagan-Udall should get guaranteed funds, when other foundations and nonprofits have to compete. In particular, she asked if the foundation staff have “particular FDA expertise” that set them apart.

Hamburg called Reagan-Udall “obviously a unique entity” due to its goals of supporting the FDA mission and cited the Foundation for the National Institute of Health and the CDC Foundation as models. In fact, she suggested Reagan-Udall has more safeguards, firewalls, and transparency about where the money comes from/is used for due to FDA’s role as a regulatory agency. She maintained that it has potential to benefit FDA in ways another foundation couldn’t. DeLauro was not convinced:

DeLauro: We can’t get this talent or this information from anything that currently exists?

Hamburg: I think it would play a unique role, I really do.

DeLauro: Well, it would be interesting to find out what that unique role is. I’ll be honest with you: I’ve never been able to figure out the uniqueness of the Reagan-Udall Foundation and how it is creating another effort here when there is an NIH foundation and other sources.

Hamburg: My hope is, and we’re starting to see this in some of the projects that they’re bringing up, that they will really be able to do collaborative research and other activities that reflect critical needs and gaps in FDA knowledge or programs. [The research] is not related to any given product that would come before us, but is related to the knowledge that we need to have.

DeLauro: I understand that and I’m all for knowledge, but I’m wondering if the knowledge isn’t in already existing foundations or nonprofits to get that information.

Hamburg: They are addressing gaps. But I’d be happy to discuss more with you and especially as we’re starting to stand up projects, maybe be able to show you how there is really a unique and vital contribution.

Indeed, the foundation has made some progress. A status update of Reagan-Udall at a September 2010 Prescription Drug User Fee Act stakeholder meeting mentioned “ a program to accelerate the development of tuberculosis treatments, a project to promote the harmonization of science-based food standards, and an effort to mine aggregated patient data to inform evidentiary standards for subgroup labeling and special population analyses in breast cancer trial.”

The same set of minutes said the Foundation noted that its appropriated funding has been “negatively impacted” by concerns over industry influence, and Reagan-Udall aims to build the trust through “strong policies regarding conflicts-of-interest and transparency.”

Thursday, March 8, 2012

A Picture is Worth a Thousand Words: The Difference Between "Yes" and "No" During an FDA Advisory Committee (or, Slide 42)

One FDA advisory committee urges a sponsor to get graphic in its REMS for a weight loss drug. Another committee rejects an expanded label after FDA shows a picture of the risk in its presentation.

How graphic should FDA get?

That is a key question in litigation over FDA’s proposed tobacco warning labels, with a federal court judge ruling at the end of February that FDA is going too far with its proposed images to highlight the dangers of smoking. You know, dead bodies, smoking via a tracheotomy, diseased lung tissue, etc. etc.

You get the theory: a picture is worth a thousand words, and the warnings will resonate with that kind of illustration. And the lawsuit suggests that cigarette makers agree that the warnings will be all too effective in discouraging smokers (or, at the very least, undermining their own branding).

We’ll leave it to the courts to sort that one out.

But when it comes to advisory committees, graphics are—apparently—just as powerful.

During the February 22 review of Vivus’ weight loss drug Qnexa, the primary topic of conversation was whether a proposed Risk Evaluation & Mitigation Strategy would be sufficient to allow marketing of the drug despite the risk of teratogenicity associated with one of the active ingredients (topiramate). The answer, clearly, was yes: the committee voted 20-2 in favor of approval. (Read the coverage in The Pink Sheet, here.)

But the panel also had a lot of things to say about the specifics of the REMS—including several members who urged the sponsor to include a picture of child with a cleft palate in the educational materials for patients. You really need an image to drive home the risk, they suggested, to make sure that women of child bearing potential get the message.

Interestingly, though, there was no picture shown of an infant with a cleft palate during the meeting itself, nor during the prior review of Qnexa (which was rejected by the same committee in 2010). So the discussion of the birth defect risk was very abstract, focusing on the strengths and weaknesses of various database analyses and discussions about whether the risk of oral cleft is increased by a factor of two or a factor of five in topiramate-exposed pregnancies. But no emotionally charged pictures of newborns with birth defects.

Amgen might wish it had that luck when it went before a panel earlier in February, seeking a broader claim for its bone strengthening therapy Xgeva (denosumab) in the prostate cancer setting. Xgeva is approved for use to prevent skeletal related events in patients with bone metastases, and the company hoped for a new claim to delay progression to bone mets in the first place.

FDA clearly was skeptical. Its presentation highlighted the fact that Amgen’s clinical data showed a statistically significant but modest delay in time to progression (about four weeks) without any unequivocal indication of clinical benefit (like a reduction in SREs, much less survival).

And, as FDA’s review team argued, the issue wasn’t just borderline efficacy: exposure to Xgeva carries a risk of side effects, and particularly of osteonecrosis of the jaw, which occurred in as many as 5% of patients studied.

Amgen noted that the understanding of ONJ has increased dramatically, and the company believes prevention, detection and treatment strategies have greatly helped reduce the impact of the side effect.

But FDA’s presenters showed a picture of ONJ. (Slide 42, here.) Nothing like a close-up of a diseased mouth to make you squirm.

In that case, the committee sided with the FDA reviewers, rejecting the indication 12-1. (Read more here.)

So a picture may or may not be worth a thousand words. But it just might be the difference between “yes” and “no.”

Friday, March 2, 2012

The Challenge of Having Less Evidence and Progressive Approval

Not too long ago, The RPM Report wondered aloud whether Pharmasset’s hep C drug would be a good candidate for progressive approval. A disclosure by the company about problems with a subset of patients shows why accelerated pathways can sound great in theory, but run up against issues in practice.

In the second half of 2011, the idea of a new progressive approval pathway gained some momentum in Congress, precipitated by support from biotech industry advocates and venture capitalists.

The idea of progressive approval essentially boiled down to this: it would be an appropriate pathway if the evidence submitted by a sponsor is likely to predict a clinic benefit for a designated population and use. FDA could use regulatory tools such as risk evaluation and mitigation strategies (REMS) to control and monitor progressive approvals in the postmarket, for example.

Nevertheless, the progressive approval pathway would still be one that theoretically requires less evidence than existing regulatory pathways.

In November, as discussions over progressive approval were reaching a crescendo, The RPM Report wondered out loud what kind of therapy in the real world would serve as a progressive approval candidate. We mentioned Pharmasset’s hepatitis C compound 7977 as one possibility; 7977 would be part of the first all-oral, interferon-free drug regimen for hep C if approved.

At the time, Pharmasset—which hadn’t yet been acquired by Gilead—publicly announced that all 40 patients who received 7977 had sustained viral response (SVR) close to cure after 12 weeks.

But on February 17, Gilead announced some negative news as it relates to 7977: null responders (those who failed interferon therapy) from one study had relapsed after treatment with 7977.

Gilead announced the majority of hepatitis C genotype 1 patients (most common form) with a prior “null” response to an interferon-containing regimen enrolled in the ongoing ELECTRON study experienced viral relapse within four weeks of completing 12 weeks of treatment with 7977 plus ribavirin.

News of the relapsing nulls caused a walk-back from some of the excitement that has enveloped the hep C class since the approvals of Merck’s Victrelis (boceprevir) and Vertex’ Incivek (telaprevir) and since Gilead’s $11 billion dollar acquisition of Pharmasset.

But it also demonstrates some of the practical challenges associated with accelerated pathways to FDA approval based on less evidence, whether it be smaller studies, patient population subgroups, or less follow-up.

The RPM Report looked at Pharmasset and Hep C in part because at the April FDA advisory committee reviews of Victrelis and Incivek, a senior FDA review manager noted that arguments were made to FDA that the agency should have accelerated the review and approval of the breakthrough therapies on Phase II results only. Instead, FDA waited for Phase III data before approving both treatments.

“These data answer an important question about the use of GS-7977 and ribavirin for the treatment of genotype 1 null responder patients, suggesting that additional direct acting antivirals may be necessary to effectively treat this patient population,” Gilead’s Norbert Bischofberger, EVP of Research and Development and Chief Scientific Officer said in a statement. “We will continue to explore a number of therapeutic approaches to address this significant unmet medical need, including combinations with other oral antivirals.”

In the meantime, calls for legislating progressive approval have been dropped in exchange for some tweaks to the accelerated approval pathway.

Sen. Kay Hagan (D-NC) introduced the TREAT Act on February 15, which has a good chance of making into the PDUFA V reauthorization legislation.

The explicit intent of TREAT is to encourage broader use of the AA/Fast Track authorities, with the pathways open for treatments targeting unmet medical need, significantly advancing the standard of care, or highly targeted therapies for distinct sub-populations.

The bill would replace the existing Fast Track provisions of the FD&C Act (enacted in 1997) with new language more explicitly linking Fast Track and AA. From FDA’s point of view, TREAT aligns much better with FDA’s current authorities and procedures.

And there’s plenty of time to consider progressive approval as part of PDUFA VI.

Thursday, March 1, 2012

BMS' Apixaban Tentatively Scheduled For May 22 FDA Advisory Committee Meeting

FDA will review the company’s anti-clotting agent a day before looking at a new indication for J&J’s Xarelto in ACS.

FDA’s Cardio-Renal Drugs Advisory Committee is expected to review Bristol-Myers Squibb/Pfizer’s anti-clotting agent Eliquis (apixaban) on May 22. The sponsor is seeking an indication for prevention of stroke and systemic embolism in patients with atrial fibrillation.

In the absence of a formal public announcement, the plan is still tentative.

The Cardio-Renal panel is also tentatively scheduled to meet on May 23, with the likely topic of that meeting to be Johnson & Johnson’s competing agent Xarelto (rivaroxiban) for a new indication in acute coronary syndrome (ACS).

Bernstein analyst Tim Anderson was the first to speculate that Eliquis was headed for an advisory committee review: first in a Feb. 9 note and then in a Feb. 29 follow-up note.

BMS and Pfizer jointly announced on Feb. 29 that FDA had extended the user fee deadline for Eliquis from March 28 to June 28.

“Subsequent to the filing of the NDA, the companies submitted additional information about the Eliquis clinical program to the FDA, which constitutes a major amendment to the application and will require additional time for review,” the companies said in a statement.

The companies added that “at this stage” there were no plans for an FDA advisory committee meeting to review Eliquis.

The uncommon circumstance recalls a similar situation with Eli Lilly’s anti-clotting agent Effient (prasugrel). FDA’s review of the agent was delayed, followed by a period of uncertainty before FDA convened the Cardio-Renal committee. The application was eventually approved.

Monday, February 27, 2012

"Next Steps" in COPD Regulatory Trials: Active Comparators Urged By Outgoing FDA Committee Chair

Forest's aclidinium breezed through an advisory committee review with a strong vote in favor of approval. The panel, however, also included an interesting call for more head-to-head trials in COPD from the outgoing panel chair. That may impact Forest's Phase IV work--but more importantly it may be a sign of the future expectations for other sponsors in the active COPD development area.

Post-market cardiovascular safety trials are emerging as a standard feature for new anticholinerigcs for chronic obstructive pulmonary disease. The trials are the legacy of FDA’s 2007-2010 post-marketing investigation into the safety profile of Pfizer/Boehringer-Ingelheim's long-acting muscarinic antagonist Spiriva (tiotropium).

That safety focus is not a surprise given the agency's long-term interest in the full class of inhaled bronchodilators. What is new is that the after-approval safety work is evolving into a standard for comparative efficacy as well.

That was one of the important secondary messages from the February 23 review of Forest Labs' aclidinium bromide NDA by the Pulmonary-Allergy Drugs Advisory Committee.

Forest anticipated a call for post-market safety analysis going into the meeting. One of the prime reasons for calling the meeting, in fact, was concern by the FDA internal review staff that Forest might not have enough premarket safety data for approval. The advisory committee voted 10-3-1 that the sponsor had adequate safety data for approval with the understanding that more safety work would be conducted post-approval. the pro-approval safety vote was one of three posiitive votes on the application at the meeting; Forest received a strong 12-2 vote on the key risk-benefit vote.

The company also got a lot of commentary about the nature of the follow-on study.

Perhaps the most interesting comments on the post-approval studies and COPD development criteria came from the departing chair of the committee, Jerry Krishnan (University of Illinois Hospital & Health Sciences System). In what was essentially a valedictory address on the status of COPD drug development criteria delivered as an explanation of his vote in favor of the aclidinium approval, Krishnan urged FDA to push sponsors for more information on relative efficacy and relative safety within the class.

Krishnan, backed by a vocal contingent of other committee members, urged FDA to push for active comparator arms in Forest’s post-approval safety (which will also be designed to support an extended indication for exacerbation of COPD).

This is not what Forest had planned. The company said it was willing to allow a broader range of prior active treatments than in the NDA filing studies, but the trial is planned as a one-to-one randomization on about 4,000 patients of 400 mcg aclidinium and standard of care to placebo and standard of care.

It may also not be what FDA had in mind.

The fact that Krishnan is a departing chair may take away some of the short-term impact of his suggestions, but his comments indicate the level of demand and expectation within the pulmonary specialty practice for comparative data in the COPD class. “I would encourage the FDA to think about the pragmatic trial that we may be suggesting as the post-marketing study, to have an active comparator,” Krishnan said. “I think having a placebo also makes sense.”

Krishnan said “there is no rule that says you can’t have a placebo and an active comparator. I would select either a long-acting beta-2 agonist or another LAMA or however it is decided, but having an alternative that is in current practice would provide a more complete picture of where this new drug fits with what else we have on the shelf.” He said the ultimate goal would be to provide more information to “decision-makers” not represented on FDA advisory committees about a “thoughtful discussion of relative efficacy” or relative “effectiveness" from a pragmatic trial.

Krishnan said that “we have an obsession with placebo-controlled trials. I understand the historical basis of how we got there and the benefit of having placebo controls. This is not a forum to go through that discussion. But rather, I think we are all recognizing that we have plenty of treatment options. What we really need to know is: is this providing the added value in some way?”

He said a comparative trial would also help address relative safety. In essence, FDA brought the issue of direct comparative work to the fore by stressing in its materials for the meeting and during presentations on the internal review that it is “natural” to view the risk-benefit equation for aclidinium in terms of other approved COPD drugs.

Krishnan further pushed for a broader population in the post-market studies. “We all know that drugs, once they get approved, get used in populations well beyond the tightly controlled eligibility criteria,” the chair said. “I think the time has come to think through how that might affect the post-marketing studies.” A number of advisory committee members noted that if Forest designs the study to support a new, extended indication (efficacy against exacerbations in COPD) that could have the benefit of involving a sicker population in the tirals and thus creating a trial close rto real world use of the product.

Krishnan also suggested that future COPD work focus more attention on patient symptom measures. Prompted by repeated comments from the advisory committee patient representative, Judith Currier (Springfield, VA.), Krishnan argued incorporating “measures of functional capacity such as a six-minute walk or other measures” that would be more relevant to patients.

The advisory committee chair’s comments reflect the broad range of treatments approved for COPD and the activity on new agents underway, with over 50 products in development according to a recent tabulation by the Pharmaceutical Research & Manufacturers of America.

One of the products in late stage development is GlaxoSmithKline’s muscarinic antagonist and LABA combo: GSK 573719/vilanterol. GSK appears to be anticipating an evolution to an active comparator standard. The company's Phase III development program for the LAMA/LABA combo includes substantial comparative work. GSK reports, for example, an ongoing study (NCT01316913) that compares two doses of the combo to muscarinic antagonist agent alone and to the active comparator tiotropium. The study was started in March 2011 as part of a 5,000-patient development program which has one large safety study and four pivotal trials. The four-arm study has estimated enrollment of 832 and is scheduled for completion in September 2012.

Forest's plan to combine a post-market indication expansion study with the demands for more CV safety data demonstrates another developing trend in the COPD: the chimera safety/efficacy post-market study.

BI demonstrated that as an effective approaching 2009 by adapting a four-year placebo controlled study on 6,000 patients (UPLIFT) that was underway to support a labeling expansion to COPD exacerbations, long-term effects on lung function and reduction in respiratory failure. BI used safety data from that study to help address a safety review initaited by FDA four years after Spiriva's initial approval in early 2004.

As post-market safety trials, FDA can mandate the trials under the atuhority the agency received from the FDA Amendments Act in 2007. By combining an efficacy objective with the trials, the sponsors are using the mandate to expand the product labeling as well as defend against safety issues.

At the February 23 meeting, one Forest consultant on cardiovascular issues, Peter Kowey (Jefferson Medical College), said that the company has faced a challenge turning its post-marketing new indication study into a safety study as well. "The intention here is not only to look at safety but at the same time to further define the effect of the drug on moderate or severe COPD exacerbations," Kovey acknowledged.

He further acknowledged that the dual objectives create difficulties in the design of the trial. He noted that the upper bounds of the confidence is 1.5 but "we really don't know what that number should be." Kowey pointed out there is "no precedent for doing this: looking for exacerbations and tacking on cardiovascular safety."

Monday, February 27, 2012

FDA Drug Shortage Event is Good News for APP and Hospira, But Made-in-USA Theme is Off the Mark

An FDA press conference on drug shortages highlighted the role two US manufacturers are playing in alleviating critical supply issues. But when it comes to avoiding shortages, the solutions are as global as the product chains themselves.

FDA convened a press conference February 21 to showcase two drug shortage success stories: ramped up production/approvals for methotrexate and temporary importation of an alternative for Doxil. It’s not the first time the agency has used either method, so the intent was clear – harness the timing of the two (plus the release of a shortage notification guidance) to demonstrate that FDA is doing everything in its power to ameliorate the critical supply issues affecting a number of vital therapeutics.

But the press conference also offered an opportunity for some manufacturers to look pretty good.

Hospira, Sandoz and Mylan all ramped up production of methotrexate. On February 15, Bedford said it would release its stocks produced before its November 2011 manufacturing suspension. And FDA granted an expedited approval of APP Pharmaceuticals’ application for preservative-free methotrexate on February 17. APP also ramped up production of the older preservative-containing formulation.

Two of those manufacturers—APP and Hospira—shared the dais with Commissioner Hamburg (and several other representatives of patients and providers) at the White Oak press event.

APP Pharma VP-Quality Assurance Mitchell Ehrlich was quick to point out that APP has a history of stepping in to fill shortages, including help with heparin, propofol, acyclovir, among many others – a sort of poster child of shortage help, often becoming the primary manufacturer of various drugs.

“As a US-headquartered pharmaceutical manufacturer,” Ehrlich added, “APP believes that in-house manufacturing is a more reliable way to supply the market than a virtual supply chain based on overseas, third-party production facilities.”

That made-in-the-USA theme certainly plays well in the context of drug shortages as national news in the context of election year politics, since the issue rose to the level of an Executive Order announced as part of the Obama Administration’s efforts to demonstrate active engagement in solving critical economic problems. (See “The Next ‘Surge’: Drug Shortages,” The RPM Report, November 2011.)

That theme, though, doesn’t stand up to scrutiny when it comes to the drug shortage problem—especially when one of the big developments on display involved FDA’s decision to allow temporary importation of India’s Sun Pharma Global FZE’s Lipodox as an alternative to alleviate the Doxil shortage.

Drug shortages are a complex problem that will definitely to need a multifaceted solution. (See "The Drug Shortage Problem: Good Solutions are as Hard to Find as Some Critical Products," The RPM Report, October 2011.) It looks like at least some components of that will reach beyond the U.S.

As a matter of fact, the idea of an all-American solution to shortages didn’t really survive Ehrlich’s prepared remarks, since he ended by emphasizing the committee to high quality, reliable supply within APP and its parent company. That would be Fresenius Kabi, headquartered in Germany.

Hospira was represented on the panel by CEO Mike Ball, who announced that Hospira shipped a month’s supply of methotrexate the day before the event, with another shipment expected at the end of the month, more in mid-March, and more beyond then. Ball said the ramp up of methotrexate didn’t take away from the other production. “It’s not a situation where we didn’t have the capacity to do it,” Ball said. “We do have the capacity; it’s the ability of sourcing the active ingredient with oncolytics.”

While Ball did say that 90% of Hospira’s production is in the US, the company’s response to the methotrexate shortage involves ramping up production at its Mulgrave, Australia oncologics facility. And, in the longer term, the company is upping its capacity with a 1.1-million square foot in Vizag, India.

As a practical matter, Hospira’s focus in the US is less on expanding production than on preserving the ability to produce at all: the company is deep in remediation activities to address issues cited at its North Carolina facilities. (See “Hospira on the Ball: Paying Attention to FDA Complaints Under New CEO,” The RPM Report, November 2011.)

Indeed, the opportunity for Ball to stand side-by-side with FDA officials to talk about good news on manufacturing must have been especially welcome in that case. Especially since Ball’s message seemed to go over well.

“As you’ve just heard from Mike Ball, drug supplies are global in nature,” said FDA Commissioner Margaret Hamburg. “Many components come from around the world. FDA must have the ability, resources, dollars and people, to go around the world.”

Monday, February 27, 2012

Advisory Committees End the Streak of "No": Negative Overtones Remain