Noting a flurry of recent commentaries in peer-review journals, our February Science Matters column in START-UP (link here, free access) discussed how the personal genomics company 23andMe has accelerated the consumer genomics debate through its dust-up with FDA over the lack of evidence and documentation supporting its Personal Genome Service, which FDA warned falls under its definition of a medical device.

The commentaries, in Nature, NEJM, and JAMA are a reminder that genomics is rapidly becoming incorporated not only into the clinic, but into everyday life. It is forcing FDA and other agencies to take a stand on critical technical, legal, and ethical issues, which will influence the strategies of medical diagnostics and pharmaceutical companies as well as labs performing tests directly for the consumer. As we wrote, those regulatory decisions should be made with the awareness that at some point, barriers to consumer access to these data will come down.

In researching the column, we were directed towards a draft report by the Presidential Commission for the Study of Bioethical Issues, “Consuming Genomics: Regulating Direct-to-Consumer Genetic and Genomic Information.” Its authors call the 86-page document “one of the first to analyze the effect of the 23andMe Warning Letter on the industry, to focus on the bifurcation of genetic interpretation and information as an independent medical device, and to analyze future regulatory approaches available to FDA.” Forthcoming in the Nebraska Law Review, a draft is available here.

The report provides a clear, detailed, up-to-the-moment summary of the the regulatory, ethical, and legal issues around DTC genetic testing. It also lays out what FDA considers a laboratory-developed test, what it considers a clinical device for commercialization, what it considers a research exemption, and why. It's a great read for those of us trying to keep straight FDA's thinking on LDTs, its jurisdiction, and the possible dividing lines between regulated and unregulated products, as well as the history of the consumer genomics field. -- Mark Ratner

Note: This post originally stated that the report is from the Presidential Commission for the Study of Bioethical Issues. The authors, Kayte Spector-Bagdady and Elizabeth Pike, work for the Commission. However, the report was written in their personal capacities.

With what seemed to be stellar results from the ARISTOTLE trial, showing the first superiority over warfarin on bleeding and mortality for a novel oral anticoagulant, Bristol-Myers Squibb/Pfizer’s Eliquis (apixaban) was expected to have a clean trip through FDA.

So why was agency approval of the third novel oral anticoagulant to come down the regulatory pathway in recent years delayed by nine months?

The answer, which was largely hidden from investors and competitors, boils down to study conduct and oversight – things that should have been a piece of cake for experienced sponsors.

It turns out that the much-ballyhooed, 18,000-patient ARISTOTLE trial had a few problems, according to FDA review documents that are dissected in the June issue of Elsevier Business Intelligence’s Pharmaceutical Approvals Monthly, part of a regular series of drug review profiles (see the lead story, free for the next 30 days, here).

What were the problems? Well, for one thing there was documented evidence of fraud by employees of BMS and its contract research organization, PPD, at a Chinese study site. It seems these individuals altered source records ahead of an FDA inspection to cover up good clinical practice violations.

FDA’s need to further investigate this issue, as well as the data integrity for other Chinese sites and the impact on the overall ARISTOTLE results, led to a three-month extension in the original PDUFA date.

Publicly, BMS/Pfizer said only that the review extension resulted from its submission of a “major amendment to the application.” An accurate statement? Absolutely. But the fact that this “major amendment” comprised a more detailed accounting of the fraud was a juicy, and likely market-moving, tidbit not shared with the public at-large.

To its credit, BMS discovered the fraud and reported it to the FDA, and the alleged perpetrators were terminated. In contrast, the agency had to root out on its own answers to the second major problem that delayed apixaban’s approval – dispensing errors in ARISTOTLE.

Buried on page 88 of the clinical study report was a statement that 7.3% of subjects in the apixaban group and 1.2% of subjects in the warfarin arm received “a container of the wrong type” of medicine at some point during the double-blind, double-dummy study. This overall high rate of dispensing errors, and the disparity between treatment arms, troubled FDA, in part because these figures were based only on the sponsor’s analysis of one incomplete source of data.

FDA believed further investigation into the true rate of dispensing errors was warranted. Furthermore, agency reviewers seemed incredulous that the unusual number of medication errors failed to prompt a “serious inquiry” by the sponsor prior to NDA submission and that such errors occurred throughout the course of the trial without meaningful corrective measures, suggesting shortfalls in trial oversight.

So annoyed were agency reviewers by the whole situation, including BMS/Pfizer’s partial and evolving responses to FDA’s questions, that the team leader on the application said the NDA would have received a “refuse-to-file” letter had agency staff known about the dispensing errors issue at the time of submission.

Ultimately, FDA issued a “complete response” letter specifically directing the sponsor to get to the bottom of the problem – not that you would have known this from the sponsor’s public statements.

In a press release, BMS/Pfizer said only that the letter requested “additional information on data management and verification from the ARISTOTLE trial.” Again, not a falsehood, but also not exactly the type of information that would have been helpful to assessing what was really going on with apixaban’s prospects for a near-term approval.

Ultimately, the companies submitted data that convinced FDA reviewers that even under a worst-case scenario, the dispensing errors would not have disturbed the key efficacy and safety findings in ARISTOTLE.

So, all's well that ends well for BMS and Pfizer, right?

Well, not exactly. Eliquis failed to gain a coveted mortality benefit claim in the Indications statement, which would have set it apart from its two competitors who beat it to market, Boehringer Ingelheim GMBH’s Pradaxa (dabigatran) and Bayer AG/Johnson & Johnson’s Xarelto (rivaroxaban) (see PAM's analysis of how FDA reviewers picked apart the statistical significance here [$]).

Eliquis generated just $22 mil. in its first full quarter on the market, according to Bristol's first-quarter earnings report.

-- Sue Sutter (s.sutter@elsevier.com)

FDA is holding more advisory committees than ever and it’s hard for some not to get lost in the mix.

Take the May 19 Endocrinologic & Metabolic Drugs Advisory Committee meeting, for example. The committee was convened to review data from an outcomes trial that was more than a year old, with no overall safety signal, for a class of drugs that have been on the market for years.

Nevertheless, the panel meeting proved to be an important one, not only for the sponsor involved, Abbott Laboratories, but for drug developers in general.

To recall, the advisory committee was convened to review the results of the ACCORD-Lipid trial and how they relate to the approved indication for Abbott Laboratories’ Trilipix (fenofibric acid) for coadministration with a statin.

The results from the National Heart, Lung and Blood Institute-conducted ACCORD study were released in March 2010. The trial was the first major cardiovascular outcome trial to evaluate the combination of fenofibrate (Abbott’s Tricor) with a statin in a diabetic population and compare it to statin monotherapy.

After an average follow-up of 4.7 years, there were 291 (10.5%) major fatal or nonfatal cardiovascular events in the fenofibrate-simvastatin therapy study arm and 310 (11.3%) events in the simvastatin monotherapy study arm; the results were not statistically significant.

Not a great result for Abbott, to be sure, considering the company’s Trilipix/Tricor franchise generates over $1 bil. in US revenue. Panelist William Hiatt (University of Colorado Denver), a former chairman of the Cardio-Renal Advisory Committee, was blunt: “It’s a clearly negative trial.”

Abbott was clear upfront that the company had nothing to do with ACCORD. James Stolzenbach, Dyslipidemia Divisional VP, who handled the MC duties for the company during the sponsor presentation, made clear that Abbott was not seeking a new indication for Trilipix nor did the company conduct or have a role in conducting the ACCORD study; Stolzenbach “apologized in advance” to the committee if Abbott could not answer all the questions asked of them because the firm was not privy to the full dataset.

Stolzenbach’s comments underscored the fact that Abbott was a bystander for a critical regulatory re-review of one of its most important product franchises. In essence, the company was watching while one agency, FDA, was figuring out what to do with the results of a government-run study conducted by another agency, NIH.

The way the advisory committee review was set up and played out, it appeared clear that FDA has wanted Abbott to conduct another trial of a fibrate/statin combo for some time and the way to do it was take the question to panel in the absence of an overt safety signal that would trigger the agency’s authorities under the FDA Amendments Act.

In a memorandum dated April 25 from Division of Metabolism & Endocrinology Products Deputy Director Eric Colman to the committee, a key question—question 6—was originally proposed with five options for the committee to vote on and the committee could recommend more than one action:

a) allow continued marketing of Trilipix’s indication for coadministration with a statin without revision of the labeling;

b) withdraw approval of Trilipix’s indication for coadministration with a statin;

c) allow continued marketing of Trilipix’s indication for coadministration with a statin with revision of the labeling to incorporate the principal findings from ACCORD-Lipid;

d) Require the conduct of a clinical trial designed to test the hypothesis that, in high-risk men and women at LDL-C goal on a statin with residually high TG and low HDL-C, add-on therapy with Trilipix versus placebo significantly lowers the risk for MACE; and/or

e) other.

But in the draft questions to the advisory committee, question 6 was broken up into two parts, A and B. Question 6A asked the committee to vote first (“yes” or “no”) on whether FDA should require a new study as described above in d). Question 6B asked the committee to vote for only one option of the following: no change to the Trilipix indication, withdraw the indication for coadministration with a statin, or allow continued marketing of Trilipix with a revision of the labeling to include the principle findings from ACCORD.

The panel voted unanimously (13-0) that Abbott should conduct another clinical study. Specifically, the trial should study the hypothesis that in high-risk men and women at LDL-C goal on a statin with residually high triglyceride levels and low HDL-C, add-on therapy with Trilipix versus placebo significantly lowers the risk of major adverse cardiovascular events (MACE).

Now, it appears as though Abbott will have to conduct a large clinical study that, if positive, would show an outcome benefit for a more defined patient population than the broader FDA-approved indication the company already has.

We asked Cleveland Clinic cardiologist Steve Nissen, an occasional Cardio-Renal panelist, for his take on the ACCORD study. “These drugs have done amazingly well in the absence of any evidence of a health outcome benefit,” he said. “Trilipix was approved to ‘reduce triglycerides’ based upon the premise that high trigs are associated with pancreatitis. Only one problem – no one has ever demonstrated that lowering trigs with fenofibrate or fenofibric acid actually reduces the incidence of pancreatitis.”

Nevertheless, the Trilipix advisory committee review highlighted the lack of control Abbott had over the review of its product. That outcome could befall other sponsors as they are further removed from postmarket evaluations of their products.

Call it Bystander Syndrome.

Industry is looking for a PDUFA, but could end up with a FDAAA as it searches for an acronym for the biosimilar user fee to join the lexicon of bureaucratic alphabet soup.

It is an important question, mainly because the series of letters likely will become the most-recognized method of referencing the program. (Of course, how the program might actually run is another important question, one explored in this week's edition of "The Pink Sheet.")

The Prescription Drug User Fee Act is the oldest user fee and PDUFA has long been accepted as a classic acronym.

The 2007 FDA Amendments Act elicited the opposite response. It was criticized shortly after passage for its awkward, A-filled acronym. One person at the time said FDAAA was among the worst acronyms in recorded history.

Many seemed to prefer an alternate title for the bill: the FDA Revitalization Act. It would have shortened to FDARA, a much more pronounceable acronym.

So where would the biosimilar user fee fit in the acronym vernacular? BUFA or BSUFA would continue the “UFA” naming concept.

Shorter acronyms are preferred and the user fee likely will not elicit its own legislation, so maybe the “A” should be dropped. That would leave BUF or BSUF, but both seem awkward-sounding.

Indeed, negotiators for the generic user fees that are expected to be created sometimes refer to that program as GDUF, but it's unclear if they are being serious.

Maybe the biosimilar user fee will require a break from tradition, just like the negotiating process FDA is employing to create the program, and employ no acronym. After all, biosimilars are similar, but not the same, as their reference products.

Patricia Knight, president of Knight Capital Consultants, and a former chief of staff for Sen. Orrin Hatch, R-Utah, one of the principal authors of the legislation, said crafting a title for it “was just horrible.”

“We could get through some of the hardest stuff, but we were stumped on the title,” Knight said May 4 during a conference on the future of biosimilars in the U.S.

“We were throwing out ideas and we decided to pay a tribute to the Drug Price Competition and Patent Term Restoration Act, so it would be parallel to the Biologics Price Competition and Innovation Act. Truth be known, that title was picked in a contest.”

Are you more creative than Congress? Take our poll below to vote for your favorite biosimilar user fee acronym or offer your own.

– Derrick Gingery










Photo by Flickr user woody1778a used under Creative Commons license.

On the eve of FDA’s Antiviral Drugs Advisory Committee reviews of the first protease inhibitors for hepatitis C, the drugs’ sponsors – Merck (boceprevir) and Vertex Pharmaceuticals (telaprevir) – are no doubt scrambling to make sure everything is in order.

Presumably, the companies have already locked down their slide decks, put the finishing touches on their presentations, researched the backgrounds of the committee’s standing members and shipped their AdComm teams off to hotels near FDA’s White Oak headquarters, where the meetings will take place.

Boceprevir and telaprevir are viewed as therapeutic breakthroughs in the treatment of HCV, both having shown improved cure rates when added to the current standard of care. However, the drugs have complicated and differing dosing regimens, which are likely to be an area of AdComm discussion.

Merck, which will present its case on April 27, is an old hand at the AdComm process, having most recently gone before a panel in December when it unsuccessfully sought to add prostate cancer risk reduction language to the label of its BPH drug Proscar. Vertex, on the other hand, is making its maiden voyage on the USS AdComm. The company will present its case on April 28 and should benefit from hearing panelists’ questions and concerns in their review of boceprevir the day before.

No matter how well prepared the sponsors think they might be, the AdComm road is littered with landmines. That, in a nutshell, was the message conveyed by AdComm meeting veterans at the Center for Business Intelligence’s Second Annual Forum on Effective Preparation for FDA Advisory Committees in Washington, D.C. last month.

At the two-day conference, battle-hardened veterans of the AdComm process – including pharma employees and consultants who make their living preparing drug companies for meetings – shared experiences from the trenches and offered some best practices to consider when tackling what has become a significant hurdle in drug development.

Some suggestions fall in the common sense category. It's imperative not only to have good communications with FDA leading up to an AdComm, but also to begin the meeting planning process early. Practicing presentations and Q&A is not surprisingly also considered good AdComm hygiene. But the CBI speakers voiced some additional pearls of wisdom that sponsors appearing before FDA committees might want to keep in mind, starting with…

Know Your AdComm
Pete Taft, founder and CEO of PharmApprove, a company that provides AdComm meeting preparation services, said sponsors should be ready to deal with four general types of personalities on FDA panels:

the expert – someone who knows a lot about your field and possibly your product, and is going to be well prepared for the meeting;

the judge – an individual who is swift to make judgments about your product or argument;

the thoughtful one – a quiet panel member; and,

the naysayer – the “Simon Cowell of AdComs” who you can either fight or forget about securing their vote.

PharmApprove has interviewed former AdComm members to find out how they prepare and what they expect from sponsors. At the top of their list is this nugget of wisdom...

Keep It Simple, And Don’t Be Irritating
The importance of clarity and simplicity in a sponsor’s presentation was echoed by FDA Director of Advisory Committee Oversight Michael Ortwerth, the lone agency presenter at the CBI conference. “That’s a really important thing, that the message is clear … and slides are very well put together,” Ortwerth said. “When you have slides that are so busy and so ladened and heavy, then you can’t focus on what the actual issue is.”

If AdComm members don’t like busy slides, they’re also not thrilled with sponsors or presenters who come off as cocky or overconfident. “I’ve always had this intuitive sense that if we press the committee or cause them to feel irritated, that some of that emotion will be transferred to their rational thinking,” said Taft, whose suspicion has now been confirmed. He noted the comments of a former AdComm chairman, who said: “You don’t want to make me angry about you, because then I transfer that from you onto the data and onto the drug.”

AdComm prep needs to be heavy on practice, planning and contingency planning, the speakers said. In the course of advance planning, it’s important that sponsors …

Don’t Let Belly Dancers Get In The Way
Don Cilla, vice president and product development team lead at AstraZeneca’s MedImmune division, led the company’s AdComm team for the June 2010 review of motavizumab for prophylaxis of respiratory syncytial virus. He recommends conducting AdComm team practice sessions and holding pre-meeting preparations in the same hotel ballroom that FDA will use for the meeting (when they’re not being held at White Oak). At the time of the motavizumab meeting “there was a convention of belly dancers that had that room booked for the three days leading up to it, so we couldn’t get in there to practice.”

If the company's AdComm team is all staying, and eating, together as a group for two or three days before a meeting, they should …

Avoid Eating The Mayonnaise
One of the speakers at the CBI conference recounted how a consultant, upon seeing open mayonnaise sitting at a buffet, banned all condiments at future meals so as to avoid the risk that team members would come down with a debilitating case of food poisoning on the day of the big meeting. “We had backups for everybody,” Cilla said of his team for the motavizumab meeting. “We didn’t know if they were going to get the bad mayonnaise or the Mexican food the night before or if they just couldn’t get there.”

While sponsors should plan for anything and everything to go wrong logistically, there are some factors they may have no control over. This includes the possibility that committee members will be suffering from …

An Avandia Hangover
Back-to-back scrutiny of different drugs on consecutive days can have a detrimental effect on those coming at the end of a multi-day meeting, suggested Alexander Fleming, president and CEO of the consulting firm Kinexum.

Case in point is Vivus’ obesity drug Qnexa. At a July 15 meeting, FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10-6 against approval due to safety concerns. The negative vote took some FDA officials by surprise, but Fleming believes timing was a crucial factor. The Qnexa review marked the third consecutive day of work for the committee, its two previous days having been spent on an extensive and intensive review of the cardiovascular safety of GlaxoSmithKline’s diabetes drug Avandia.

“If nothing else, the advisors had to be exhausted” by the time they got to Qnexa, Fleming said. Calling the AdComm timing “pure bad luck” for Vivus, Fleming said the company knew “this was going to be a real disadvantage to them ... and only in retrospect do you see how it really had a major effect.”

Sponsors also may have no control over an AdComm’s walk down the path of …

Comparative Effectiveness And Cost
Disease background presentations by the sponsor are a hallmark of any product-specific AdComm. A good presentation will include a comparison of products that are on the market, including mechanism of action and limitations, said Mary Rofael, COO of scientific and regulatory communications at ProEd Communications, a firm that provides AdCom prep services.

“Many of you will say we’re here at an advisory committee, the committee should focus on evaluating the benefit/risk of a particular product,” Rofael said. “In this day and age you can’t stop people from thinking about comparing it to what they’re using currently or what’s on the market. It’s just a discussion that’s going to take place. Whether or not you engage in it, that’s a different story, but it’s important to anticipate it because these kinds of questions are being asked more and more today.

“It’s almost like the question of cost,” Rofael continued, venturing down a road that almost no sponsor wants to travel during an AdComm. “The advisory committee room is the only room where cost is not discussed … but eventually I think it’s going to make its way in. People are starting to ask about the cost of products and what the burden of cost is on the health care system.”

Aside from the detour down the cost path, what’s a sponsor to do when an AdComm’s discussion of the data starts …

Spiraling Out Of Control?
If the panel’s conversation has gone awry at some point after the sponsor’s presentation, the best a company can hope for is that the meeting agenda includes an upcoming break, said PharmApprove principal Martha Arnold. “If there’s a situation where things just are spiraling out of control, and … you think perhaps the committee is dealing with information that is just plain wrong, that there’s been a misinterpretation either of your data or FDA’s data, if there’s a break you have an opportunity to at least approach the chair” and express concern, she said.

If there are no further scheduled breaks, the sponsor could pass a note to the panel’s industry representative “or tap them on the shoulder and say, ‘Hey, can you help us out here,’” said Bruce Burlington of DB Burlington Consulting, who often serves as the industry rep on AdComms. “Alternatively, if it’s really outrageous, just stand up and say, ‘Mr. Chairman, I request your permission to insert a correction in the discussion at this point.’”
It may be more problematic, however, for sponsors to insert themselves into the process of …

Question-Morphing
Anyone who has sat through at least a handful of AdComms can confirm that panelist confusion over the wording of FDA’s questions is a fact of life, often leading to discussions as to whether and how the questions should be re-written on the fly. While these question-writing “audibles” can be disconcerting for sponsors, so can the initial questions themselves.

CBI conference attendees cited tremendous variability among review divisions in the types of questions posed at AdComs, ranging from straightforward questions on risk/benefit to queries that run multiple pages and “in essence make the FDA case in the form of a question,” one conference attendee said.

FDA’s Ortwerth acknowledged room for improvement in how review divisions ask questions. “It is important that there be consistency in the way we try to communicate. … There needs to be the right way to communicate something and a clear way to communicate something and not to drive the direction of the answer.”

Even if sponsors are able to navigate all the trouble spots outlined above, they need to keep in mind that they can …

Spend Big Money, But Still Lose Big
Preparing for an AdComm involves shelling out big bucks, all of which can be for naught if a drug is decimated when it comes to the panel’s vote. MedImmune’s Cilla said his company spent approximately $900,000 on AdCom preparations for motavazimub, which included the cost of consultants, meeting space and four mock panel meetings at approximately $60,000 each. The investment resulted in a 14-3 AdComm vote against approval, which was followed by an FDA “complete response” letter and the company’s decision to withdraw the BLA.

Sanofi-Aventis Associate Vice President of Global Regulatory Affairs Kevin Malobisky said his company spent about $1.3 million preparing for one meeting that resulted in a 14-0 vote against approval – an apparent reference to the unsuccessful June 2007 AdComm for the obesity drug Zimulti (rimonabant).

Were IN VIVO Blog writing an AdComms for Dummies manual, we might put it this way: it's expensive and a lot of work to prep for an AdComm, but you have to do it. Even so, there's no money-back guarantee.

Maybe we should start consulting--at least we've got a sense of humor.

-- By Sue Sutter (s.sutter@elsevier.com)

Josh Sharfstein's departure back to the friendly Democratic climes of Maryland left HHS management and FDA Commissioner Margaret Hamburg with a decidedly tough bill to fill.

Where do you find someone who (1) has expereince testifying on Capitol Hill, (2) does not incite more animosity from the GOP House investigators, (3) who understands the arcane inner workings of FDA recalls and enforcement authority (a current Congressional interest), (4) is viewed favorably by regulated industry, and (5) still embodies the qualities of diversity and activism espoused by the Democratic administration?

Luckily right in the commissioner's current staff. Hamburg has already recruited that individual previously and he currently holds a top position at FDA: John Taylor, Counselor to the Commissioner for the past 14 months.

Taylor was named acting principal deputy commissioner on the day of the official announcemnet of Sharfstein's departure to head the Maryland Department of Health. Taylor's first term is for 60 days.

Taylor has 20 years of working experience with FDA issues (four outside the agency working for Abbott, 2005-2007, and two with BIO, 2007-2009) and virtually a lifetime of understanding of the agency, having grown up in a family with long service to FDA.

Taylor has worked within FDA's chief counsel's office during the Bush I and Clinton Administrations (1991-1996), was a senior policy advisor to FDA Commissioner Jane Kenney. He stayed on into the Bush II administration and served in enforcement and regulatory affairs positions under Mark McClellan.

The expereince with McClellan and with former GOP Congressman Jim Greenwood (the head of BIO) gives him the type of GOP sponsors who may get him a more civil hearing on Capitol Hill than would have been been given to Sharfstein, a protege of California Democrat Henry Waxman.

Taylor is a great immediate choice. It may be hard to find someone better after 60 days.

There was more bad news on Dec. 27 for those developing anti-nerve growth factor (NGF) drugs: U.S regulators put Regeneron's candidate REGN475, in development with Sanofi-Aventis, on hold late last week, Regeneron said in a regulatory filing Monday.

The latest setback for an NGF inhibitor was triggered by a patient in another company's trial developing a serious bone disorder, known as avascular necrosis. It's caused when a lack of blood supply causes bone tissue to die.

Following similar concerns around other NGF-targeting drugs in 2010, it's no surprise that by now FDA believes the whole class of drugs could be unsafe. Regeneron says as much in its filing: "The FDA believes this additional case provides evidence to suggest a class-effect." No word yet if or when REGN475, also known as SAR164877, will get a green light, but Regeneron noted that there are no current trials of the drug either enrolling or recruiting patients.

Trials in osteoarthritis pain of Pfizer's anti-NGF candidate tanezumab, believed to have been the most advanced in development, were put in hold in June 2010 following FDA concerns that a number of patients' osteoarthritis symptoms were worsening, rather than improving. In some cases this led to joint replacements. Because of the hold, Pfizer terminated most of its tanezumab trials earlier this year, but it is pressing on with two trials to study the drug, one in combination with opioid medication, the other as a standalone treatment in patients with chronic pancreatitis, according to clinicaltrials.gov.

None of this will provide much Yuletide cheer to the likes of Abbott, which paid a whopping $170 million up-front for PanGenetics' Phase I anti-NGF antibody last year, or AstraZeneca, whose MedImmune subsidiary has a Phase I stage anti-NGF antibody for osteoarthritic pain in the knee. J&J picked up a similar candidate from Amgen in 2008. [UPDATE: AZ and J&J have in fact suspended their programs, reports Bloomberg.]

Also in the pain domain but more positive was the news that King Pharmaceuticals and Pain Therapeutics' re-submission of abuse-resistant oxycodone (Remoxy) was accepted by FDA. This time, Pfizer will be pleased: it has agreed to buy King for a cool $3.6 billion.

Image by flikrer johnnyalive used under a creative commons license.

The three obesity drugs—Vivus’ Qnexa, Arena’s Lorqess, and Orexigen’s Contrave—pending at FDA haven’t suffered from a lack of buzz in the investment community.

The trio of therapeutic candidates have the high-risk/high-reward profile that Wall Street typically flocks to.

In fact, the drugs are being so closely monitored by investors that two peripheral y relevant events—one that has happened and one that will happen—are garnering almost equal attention because of their impact on the three obesity drugs: the FDA advisory committee safety reviews of GlaxoSmithKline’s diabetes drug Avandia and Abbott Laboratories’ diet pill Meridia.

Qnexa was recently voted down by FDA’s Endocrinologic & Metabolic Drugs Advisory Committee due to concerns over the drug being used by large populations and a lack of long-term cardiovascular safety data (See “Weighing the Regulatory Climate,” The RPM Report, September 2010). In that instance, there was clearly an echo-effect from the prior two days of deliberations over the cardiovascular risks associated with Avandia.

Now investors are wondering if the case will be the same for Arena: Lorqess will be vetted by the Endocrinologic & Metabolic Drugs panel on September 16, the day after a joint committee review with the drug safety panel of Meridia to determine whether that drug should be taken off the market due to an increased risk of nonfatal myocardial infarction and stroke.

Orexigen’s Contrave is tentatively scheduled to go before an FDA panel on December 7.

Orexigen CEO Michael Narachi believes going third is an advantage, he explained during an interview with “The Pink Sheet” after announcing a partnership deal with Takeda.

“Being last up for review will provide tremendous learnings for our own regulatory review process. This will enable us to better understand the FDA's approach to evaluating the risk/benefit of obesity therapies, their perspective on potential post-marketing requirements and which of those may be broadly applicable versus drug specific.” (read coverage of Orexigen’s partnership deal with Takeda in “The Pink Sheet” by clicking here).

In other words, Orexigen is sitting back and watching—up close.

One detail that demonstrates just how important the regulatory lessons from Avandia, Qnexa et al. are to Orexigen was the company’s physical presence for the three-day advisory committee reviews of Avandia and Qnexa in July.

The July advisory committee meetings were held at the Hilton Hotel in Gaithersburg, Maryland, where FDA hosts more high-profile panel meetings due to more space.

We’re not sure Orexigen officials were there in person at the Hilton but the company showed up in force at the Holiday Inn just down the street.

We doubt Orexigen got lost. The firm had a pseudo-command center set up apparently to monitor the developments of the Avandia and Qnexa reviews as preparation for what may lie ahead in December.

That’s a smart strategy considering many of the themes from prior reviews, such as the need for long-term cardiovascular outcomes data beyond one year and an appropriate risk evaluation and mitigation strategies (REMS) program, will repeat themselves at the Contrave meeting.

Maybe Vivus should have stayed at a Holiday Inn too.

There's lots of buzz right now about the potential for FDA to seek jail time for executives involved in quality control problems. This piece on CNN.com, for example.

Readers of the IN VIVO Blog, however, have nothing to worry about. For the past two years we've been noting the calls for executive accountability, and comments by FDA officials and others about their sweeping ability to hold top executives responsible for failures they may not even have been aware of under the so-called Park doctrine. (Start here or here).

So all of you can relax, because you made sure that your compliance with FDA standards is beyond question.

Didn't you?

There was some disharmony at Jazz Pharmaceuticals’ FDA panel review of its drug Rekinla for fibromyalgia.

FDA’s Arthritis Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee voted 20-2 against recommending Rekinla (sodium oxybate) for a supplemental indication for treatment of fibromyalgia on August 20; sodium oxybate is currently approved for the reduction of daytime sleepiness and cataplexy in patients with narcolepsy under the trade name Xyrem. (See our coverage in "The Pink Sheet" DAILY, here.)

Anyone that has been to an FDA panel meeting knows there are ebbs and flows that contribute to the final outcome.

One of those critical points came in the late morning during the FDA question and answer session, following the agency’s formal presentations.

Enter Drugs Safety & Risk Management committee member and outspoken drug industry critic Sidney Wolfe (director of Public Citizen’s Health Research Group). Wolfe explained that he had obtained publicly available documents that cast negative light on the trustworthiness of the sponsor to responsibly market Rekinla if the panel delivered a positive recommendation and FDA approved the drug.

To resolve parallel criminal and civil allegations of off-label marketing for Xyrem by their Orphan Medical division, Jazz entered a guilty plea and paid $20 million in monetary penalties as part of a settlement with the US Attorney’s Office for the Eastern District of New York. (To view the press release, click here).

Committee Chair Kathleen O’Neill (University of Oklahoma College of Medicine) tried to cut Wolfe off, saying the session was only for questions to FDA and could only address the material in front of the panel on that day.

Wolfe continued to read a summary of the off-label marketing settlement and said he eventually would have a question.

With Wolfe unwilling to stop reading, FDA took the seemingly unprecedented action of cutting off Wolfe’s microphone. That step has become routine during the open public hearing where there is a time limit but this was one of their own advisory committee members.

Wolfe turned the microphone back on and finally got to his question: Why, he asked, did FDA not mention the Xyrem off-label settlement in its presentations to the committee? After all, he argued, it was relevant to the decision at hand: could the sponsor be trusted to market Xyrem—also known as gamma-hydroxybutyrate (GHB)—to a much broader indication than it was already approved for?

FDA Division of Anesthesia & Analgesia Products Bob Rappaport stepped in and first instructed Wolfe to stop talking when the panel chair requests that he stop talking, explaining that it was her prerogative.

Rappaport continued that Wolfe’s reading of the documents were the first time he had ever heard of the off-label case and that it was not relevant to the Rekinla review despite the fact that both Xyrem and Rekinla are the same drug (sodium oxybate). Rappaport then admonished Wolfe for not providing the documents to FDA earlier, noting that he had called FDA's advisory committee management staff earlier in the week to raise an issue, but not provided the information he was reading at the meeting.

[UPDATE: Wolfe tells us "I had never previously told FDA officials that I had obtained these documents since I assumed, as it turned out incorrectly, that they were aware of them because FDA's Office of Criminal Investigation had been involved in the criminal prosecution. Why they were unaware, as Rappaport said, is another issue."]

The drama appeared to have come to a close with Rappaport’s comments; however, the FDA official returned after the lunch break and the open public hearing with a prepared statement:

“The issue that Dr. Wolfe raised this morning is a matter related to compliance and is not related to the topic under discussion today, unless there has been an accusation of data integrity problems with this application – and I’m not aware of any data integrity concerns. The only other way that the case referred to by Dr. Wolfe could be pertinent to this application would be if it was brought up to impugn the sponsor in the hopes that the committee would be punitive towards them in your deliberations and recommendations regarding this application. However it is important for you to recognize that that would not really be punitive to the sponsor but would really be punitive to the patients.”

At that point, Jazz Pharmaceuticals' Chief Compliance Officer Janne Wissel added a few remarks.

"We do have a corporate integrity agreement because we assumed responsibility for the acts of Orphan Medical at the time we purchased the company. The Department of Justice, as well as the OIG concluded at the end of their investigation that the behaviors of Jazz Pharmaceutical were not the same as those of Orphan Medical. However, we assumed responsibility for those actions.

"We have completed three years under our corporate integrity agreement where we have reports that are based on information and an audit conducted by an independent review organization with respect to our compliance for promoting our product within our labeling. All of those reports have concluded that we are promoting our product within labeling and that we are compliant with respect to the aspects of our corporate integrity agreement."

Wolfe was not given an opportunity to respond at the meeting, so we asked him if he would care to after the fact. He emailed us the following statement:

The previous RiskMap program and the Xyrem Success Program, that were agreed upon in 2002 by Orphan as a condition of approval of Xyrem for narcolepsy, included extremely restricted distribution through one pharmacy, education of doctors and patients and a registry of patients getting the drug.

One of the questions our advisory committee was being asked to respond to was the adequacy of the new REMS program for the expanded use of oxybate for treating fibromyalgia .

Xyrem’s manufacturer, Orphan, violated the above mentioned restrictions on distribution by illegal, criminal off-label marketing and was successfully prosecuted for this. When I discovered this, a week before the hearing, I assumed that the reason why it was not included in the Advisory Committee’s briefing materials was that for some reason the FDA did not want us to know about it. This seemed peculiar, since the prosecution of the company seemed quite relevant to our evaluation of whether the new REMS program could be expected to be effective.

As I asked in my question to FDA, following the material I read from the US Attorney’s prosecution of Orphan, Why didn’t the agency provide the material to us?

Dr. Rappaport’s surprising answer was that they were not aware of the criminal prosecution. He later added that this was really a matter involving FDA compliance and that it was not “related” to the issues being discussed by the committee because it did not involve data integrity.

Although it is the compliance part of FDA that was involved in investigating this (the FDA Office of Criminal investigation was also involved), the idea that the details of this criminal prosecution involving violations of the agreed-upon restricted marketing of this dangerous drug were not relevant to our deliberations seems irrational.

Dr. Rappaport went on to say that since it was not relevant to our discussion, the only reason I brought it up was to “impugn the sponsor” and thereby turn the vote against them. This would, he said, “not really be punitive to the sponsor but would
really be punitive to the patients.”

Following Dr. Rappaport’s after-lunch statement, Jazz Pharmaceutical, the owner of Orphan since June, 2005—including, according to the US Attorney, for at least seven months while the illegal activities were occurring--stated to the Advisory committee that the company had been essentially exonerated by the US Attorney’s office and was under a corporate integrity agreement with the HHS Inspector General. This statement, like Dr. Rappaport’s, is also incorrect since, in its non-prosecution agreement with Jazz, the US attorney stated on July 13, 2007:

“Based on the evidence gathered during this investigation, the government maintains that it would be able to prove that JPI [Jazz Pharmaceutical Incorporated], as a consequence of the criminal conduct committed by its subsidiary Orphan ("the Unlawful Conduct"), is likewise guilty of introducing and causing the introduction of a misbranded drug into interstate commerce, in violation of 21 U.S.C. 331(a) and 333(a)(2).”

It’s unclear how much of an impact the Wolfe-Rappaport discussion had on the final 20-2 negative vote for Jazz. But it’s clear the public disagreement was a notable turning point in the panel deliberations.

The agency later said “the issue raised this morning by Dr. Sidney Wolfe related to Jazz Pharmaceuticals marketing practices and compliance activities for sodium oxybate is not related to the topic (that was) under discussion. The FDA weighs all of the comments made by committee members equally but will only be considering the safety and efficacy information discussed today as it evaluates sodium oxybate to treat patients with fibromyalgia.”

--Ramsey Baghdadi

You can be forgiven for skipping yesterday's Cardiovascular and Renal Drugs Advisory Committee. After an incredible series of important committee topics (Avandia! Qnexa! Opioid REMS! Avastin! Brilinta!), a day long session focused on pediatric study endpoints for pulmonary arterial hypertension drugs doesn't exactly cry out for attention.

But it was a doozy. Not so much for what the committee decided...or maybe failed to decide. Heck, this was a mess of a meeting, and our colleagues did an amazing job to make sense of the outcome in "The Pink Sheet" DAILY.

No, this was a doozy of a meeting because it is laying the groundwork for what could be a very interesting regulatory decision by FDA: granting a six-month pediatric exclusivity extension for sildenafil, the active ingredient in Pfizer's PAH drug Revatio and another product you might have heard of called Viagra.

Yes, it is true: Pfizer is (we think) going to get a six month pediatric exclusivity extension for an erectile dysfunction product. In fact, we would go so far as to say after the meeting, by any fair interpretation of how the program works, Pfizer should get an extension.

Viagra? Viagra has no role in the pediatric population--except to increase the numbers of children in the US. (Badda Bing!)


Okay, okay: the pediatric extension won't be for Viagra; it will be for Revatio--a truly important therapy for the rare but debilitating condition of PAH. And all indications are that the Pfizer product does have an important role in treating the 500-600 children in the US who suffer from the disease. Pfizer has done extensive research on that population, despite significant challenges finding a viable endpoint given that no one wants to run long-term placebo controlled trials in this setting.


The pediatric exclusivity program was created in 2002 to encourage sponsors to conduct studies in children, by granting them an extra half-year of patent life/exclusivity for completing studies pursuant to a written request by FDA. Pediatric research, everyone agrees, is a very challenging and neglected field, and the law has clearly worked to encourage many more studies than would have occured without it. The Revatio program looks exactly what the law was supposed to deliver.

But the law (as implemented by FDA) is clear: the extension applies to the active ingredient, and so--if Pfizer gets a reward--the basic sildenafil patent will be extended from March 27, 2012 until September, 2012.


That is obviously a big deal for Pfizer. Revatio sales in the US were $300 million last year, so an extra six months is nothing to sneeze at. But Viagra is almost $1 billion, so that's where all the action is. (Badda Bing!, again.)

Now, Pfizer claims Viagra will be protected from generic competition until 2019, thanks to a use patent covering the ED claim. However, use patents tend not to hold up against generic challenges, and Pfizer is already facing a challenge from Teva. On the other hand, given the unusual circumstances of Viagra's development, the use patent on ED may be more robust than most.

Nevertheless, the patent extension will still matter. Obviously it delays the earliest possible date for a generic Viagra in the event Pfizer loses the case. In the more likely event that litigation is still pending, it will delay by six months the earliest possible date that Teva could consider an "at risk" generic launch. That in turn would affect the terms of any possible settlement of the litigation (assuming pending "pay for delay" legislation in Congress doesn't put the kibosh on settlements altogether.)

The extension will also put off the date on which Pfizer will have to wrestle with the possiblity that generic versions of Revatio will start eating into the Viagra market. Revatio is marketed as a 20 mg pill, while Viagra is available as 25, 50 and 100 mg pills. As brands, Revatio retails for slightly less per pill than Viagra ($15.60 vs. $17 on drugstore.com), but it certainly doesn't make economic sense to take two Revatios instead of one Viagra. If Revatio generics are widely available, those economics could change.

So, no matter how you look at it, Viagra will benefit from the pediatric exclusivity award.

Here's the thing: the pediatric exclusivity program has strong support, but it isn't without its critics. When the program came up for reauthorization in 2007, some members of Congress wondered why a sponsor might be given an extra six months of sales for a multi-billion brand in exchange for conducting a relatively small, inexpensive study in children.

It is fair to say those arguments will come up again in 2012--especially if FDA grants an extension to Viagra, every politician's favorite target for criticizing Big Pharma.

Look for more coverage of how the advisory committee wrestled with this issue in an upcoming issue of The RPM Report.

FDA just wrapped up a two day public meeting to review the implementation of its Risk Evaluation & Mitigation Strategy authorities.

The hearing involved almost 70 different presentations from a diverse base of stakeholders offering input into how to make sure that REMS best allow drugs to be marketed safely without disrupting the entire health care system.

It also featured an unusually active and engaged panel of FDA officials; these agency meetings are often fairly magisterial in nature, with FDA listening but saying nothing. Not here: questions and comments aplenty.

So there is tons to digest, and we will have plenty of coverage of the meeting in The Pink Sheet, The Pink Sheet DAILY, and The RPM Report.

But we wanted to take note of how the meeting began, since we think that says volumes about where FDA is going with REMS.

The very first presenter was the American Society of Clinical Oncology’s Karen Hagerty. As we have written, ASCO has some concerns with how FDA has been developing REMS, and especially with how the agency and Amgen put together a new program for use of erythropoiesis stimulating agents in oncology. ASCO wants to make sure that they have more input in the development of REMS in the future.

That, to us, is the key theme of the two day hearing—and it surely says something about FDA’s openness to that theme that it kicked off the two days with a panel of providers, including ASCO, the American Medical Association, specialty pharmacy execs, and Kaiser. Industry (the Pharmaceutical Research & Manufacturers of America, the Biotechnology Industry Organization, Eli Lilly) came second.

The input of outside stakeholders is what prompted FDA to reconsider its REMS implementation—and we’re betting those stakeholders will end up gaining more input into the actually crafting of REMS for products going forward.

It won’t be easy: after all, as FDA officials pointed out, they regulate sponsors and many of the discussions about the potential need for and design of a REMS has to remain confidential. But providers and other stakeholders want in, and they are not likely to give up until they get in.

Take Kaiser. The non-profit health plan submitted a petition at the end of last year that really kicked off the REMS reappraisal at FDA. And Kaiser is clearly committed to seeing the process through: the non-profit had three different representatives speak during the meeting, making a total of six presentations on each of the six topics identified by FDA for the agenda.

For sponsors, the concerns raised by providers may sound like a blessing. After all, anything that stops FDA from slapping restrictive distribution programs and other post-marketing controls on new products willy nilly has to be a good thing, right?

Sure. But one other thing is clear from the two day meeting: REMS are here to stay. Providers don’t want them eliminated altogether, they just want a seat at the table in helping to shape programs before they are launched. We’re not sure how or when they will get their way, but we bet they will eventually. And then sponsors may pine for the days when the REMS was theirs to control.