Lawmaker Investigates FDA’s Role In Public-Private Partnership

Sen. Joe Manchin (D-W.Va.) is investigating whether a public-private industry partnership has corrupted FDA decisionmaking and improperly influenced agency attitudes on regulating painkillers.

Citing reports that some drugmakers paid as much as $25,000 for entrée into the so-called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), Manchin said the partnership appears to present a conflict of interest that allows companies to have “undue influence” over the FDA.

“I am gravely concerned by the allegations of ‘pay to play’ between the FDA and pain medicine companies and am calling for a full investigation to see how deep this goes,” Manchin said in a let-ter to FDA Commissioner Margaret Hamburg Oct. 9.

PhRMA: Drugmakers’ Reputation at Stake in Fight to Rout Rx Import Law

A new law passed by the state of Maine allowing for the impor-tation of prescription drugs via internet pharmacies has the drug industry fretting that its image is about to take another hit. Mainers say it’s all about cost, but PhRMA says patient safety has no price.

The law, which went into effect Oct. 9, reflects a first-of-its-kind breakaway from federal restrictions on drug imports — strictures partially predicated on concerns about counterfeits and substandard drugs entering the U.S. supply chain.

The law allows for the direct purchase of drugs from online pharmacies located in Canada, New Zealand, Australia and the UK. The pharmacies would then distribute drugs, often available at a cheaper cost, to consumers. However, critics of the law say the drugs haven’t been screened by the FDA and verified to be safe and effective.

Vol. 45, No. 40Oct. 14, 2013

FDA warns CPM Contract Pharma for flouting GDU-FA facility fee ..........Page 2

FDA Calendar ..........Page 2

Judge gives watchdog group short leash on pharma CIA data hunt ..................Page 3

SCOTUS nixes Novartis appeal on preemption of punitive damages .....Page 3

Feeling patent pain, Eli Lilly places hopes on pipeline prosperity ...Page 5

Complex products, reviews top out FDA GDUFA research plans...........Page 5

FDA issues safety alert on Ariad’s cancer drug, citing adverse events ..........Page 6

Tufts tells sponsors to give CROs freedom .............Page 7

FOIA Log .................Page 8

Briefs .......................Page 9

Legislative Actions ...Page 9

Bayer wins FDA nod for Adempas ................Page 10

The Buzz ................Page 11

INsIde thIs Issue

(See Imports, Page 4)

(See IMMPACT, Page 12)

Washington Drug Letter Oct. 14, 2013Page 2

FDA Warns CPM Contract Pharma For Flouting GDUFA Facility Fee

The FDA has issued its first warning letter to a manufacturer that failed to self-identify and pay its facility fees as mandated by GDUFA.

The warning to Germany’s CPM Contract Pharma reiterates the agency’s intent to enforce compliance with the user fee law’s requirements and comes just weeks after the FDA began post-ing a list of sites that have failed to submit their annual facility fees on time (WDL, Sept. 9).

According to the recently posted warning let-ter, CPM’s failure to self-identify its finished dos-age form (FDF) manufacturing plant and pay GDUFA-required facility fees has rendered its FDF drugs and active pharmaceutical ingredients manufactured at its plant misbranded.

Failure to comply could result in additional regulatory action, the agency warns, including a seizure of its products or a court-ordered ban on doing business. Further, the facility could be placed on import alert, causing drugs manufac-tured there to be turned away at the U.S. border.

The deadline for self-identifying for 2013 was December of last year and the fees for 2013 should have been paid by March 4, 2013. The deadline for self-identifying for 2014 was June 1 and facility fees were due Oct. 1.

Because the fiscal 2014 self-identification period has begun, CPM is not able to self-iden-tify for fiscal 2013 any longer, but still must pay the 2013 fee, according to the letter.

The FDA will not take enforcement action against the company or its products for the fail-ure to self-identify for fiscal 2013 if it completes its 2014 self-identification filing in a timely man-ner, the letter adds. Requests to CPM for com-ment were not returned.

The warning letter to CPM can be read at www.fdanews.com/ext/files/10-03-13-CPM-Let ter.pdf. — Melissa Winn

Comings & GoingsBridget Walsh has been named the vice pres-

ident of federal government relations by Pfizer. Walsh will lead the company’s legislative and regulatory affairs teams.

Pfizer has also elected Shantanu Narayen to its board of directors and appointed him to the board’s corporate governance and science and technology committees. Narayen is the president and chief executive officer of Adobe Systems and serves on Adobe’s Board of Directors.

Perrigo has named former FDA official Keith Webber as head of its regulatory review team, a newly created position. Prior to join-ing Perrigo, Webber served as acting director of CDER’s Office of Pharmaceutical Science.

Christa Wirthumer-Hoche has been named the new head of the Austrian Medicines Agency.

Daiichi Sankyo has named Glenn Gormley as chairman and president and Glen Barrett its acting head of the commercial division.

Upcoming meetings through Oct. 17:

● Oct. 16: The Endocrinologic and Metabolic Drugs Advisory Committee will meet to discuss Amarin’s sNDA for Vascepa (icos-apent ethyl) capsules. Silver Spring, Md.

● Oct. 17: The Anti-Infective Drugs Ad-visory Committee will meet to discuss susceptibility interpretive criteria for systemic antibacterial drugs and for dos-ing recommendations in product labeling. Silver Spring, Md.

Comment deadlines through Oct. 25:

● Oct. 25: Comments due on the draft guid-ance Bioequivalence Recommendations for Risperidone Injection, docket no. FDA-2007-D-0369-0244.

FDA CALeNDAR

Washington Drug LetterOct. 14, 2013 Page 3

Judge Gives Watchdog Group Short Leash on Pharma CIA Data Hunt

Government watchdog group Public Citizen, seeking reams of sensitive documents related to drugmakers’ corporate integrity agreements (CIA), was brought to heel by a federal judge Oct. 4, who granted access to some materials but kept “confidential” information out of reach.

The case, brought by Public Citizen as part of an attempt to shine a spotlight on the effectiveness of CIAs, pitted the watchdog against HHS and two drugmakers — Purdue Pharma and Pfizer. In her ruling, Judge Beryl Howell of the U.S. District Court for the District of Columbia ordered HHS to hand over information about any agencies inves-tigating the drugmakers and the status of any of those investigations. The titles and responsibili-ties of Purdue and Pfizer employees released from their duties due to criminal activity should also be made public, Howell ruled.

On the other hand, the court agreed with HHS and co-defendants Pfizer and Purdue that some compliance information deemed “commer-cial and confidential” could remain under wraps. Howell rejected Public Citizen’s argument that records documenting illegal acts should never be withheld as confidential commercial information.

The term “commercial” is not limited only to lawful activities, the judge wrote.

“We are disappointed in that portion of the ruling,” Julie Murray, a spokesperson for Public Citizen told WDL Oct. 7.

The judge found that for the majority of docu-ments sought in the case, however, HHS and the drugmakers had failed to argue effectively for their confidentiality, but said she would give the parties a second chance to make their case. That decision was also disappointing, Murray said.

The parties have until Nov. 8 to provide the court with an updated list of the records remain-ing in dispute and a proposed briefing schedule for any further proceedings.

Purdue is reviewing the court’s decision to determine what implications, if any, the deci-sion could have on the status of annual reports the drugmaker submitted to the HHS Office of Inspector General (OIG) regarding its CIA pro-gram, spokesman James Heins told WDL.

Purdue fully complied with the reporting requirements of its CIA with HHS OIG, which concluded in July 2012, he said. The exemption of certain documents from FOIA requests “encour-ages greater transparency by companies as they fulfill such reporting requirements,” he added.

SCOTUS Nixes Novartis Appeal On Preemption of Punitive Damages

The Supreme Court Oct. 7 refused to hear an appeal of a case brought by Novartis, in which the drugmaker argued that punitive damages backed by juries are preempted by the 1938 FD&C Act. The rejection sets a troubling precedent for an industry beset by injury lawsuits, experts say.

The case stems from a personal injury law-suit in which Novartis claims a jury unlawfully ordered it to pay hundreds of thousands of dollars in punitive damages to a North Carolina fam-ily. The damages relate to alleged misconduct in the marketing and labeling of Novartis’ Zometa (zoledronic acid) and Aredia (pamidronate diso-dium), two bone-targeted therapies.

Citing several previous Supreme Court rul-ings, the drugmaker claimed in its June peti-tion that federal law prohibits states from grant-ing individuals the power to enforce federal drug marketing standards or “to punish perceived vio-lations of those standards” (WDL, July 15).

But the court denied its petition without comment — a “significant” development that could impact several other cases pending against Novartis in states like California, New York and

(See CIA, Page 4)

(See Novartis, Page 8)

Washington Drug Letter Oct. 14, 2013Page 4

PhRMA, the Maine Pharmacy Association, various Maine pharmacy and retail groups and independent pharmacies filed suit in September seeking to nullify the law after their entreaties to the FDA and the Drug Enforcement Administra-tion failed to elicit a reaction.

The lawsuit, filed in the U.S. District Court for the District of Maine, contends the state law violates a provision in the 1938 FD&C Act strictly prohibiting importation of foreign drugs unapproved by the FDA.

“The FDA has repeatedly stated that federal law preempts any and all state laws that would facilitate the private importation of foreign phar-maceutical products,” the lawsuit reads.

Requests for comment to the U.S. Attor-ney’s Office in Maine and Maine’s Attorney General were not returned as of press time. The FDA declined to comment, citing a lack of resources to do so due to the ongoing federal government shutdown.

Liability Question

The pharmaceutical industry, continually contending with injury liability cases, could face more lawsuits as the law takes hold, Mit Spears, PhRMA’s executive vice president and general counsel, suggested in comments to WDL.

“It’s our reputation that’s going to be at stake, not CanaRx,” he said, referencing the Canadian internet pharmacy that some municipalities in Maine have already contracted with to provide drugs for their public workers.

The internet pharmacy in 2003 was warned by the FDA about its distribution of drug sup-plies from “unregulated sources” and potential to expose U.S. consumers to “risky” products. The agency also expressed concern about the pharma-cy’s shipping practices.

Maine’s new law would also “blow a hole” in the industry’s efforts to support a nationwide

pharmaceutical track-and-trace system, Spears said. “As an industry, we have spent a ton of time, money and energy making sure that prod-ucts are distributed securely and handled prop-erly,” he added.

Spears called the law “irresponsible” because other states could adopt similar measures. “We need a court to rule this out,” he said.

To read the lawsuit, visit www.fdanews.com/ext/files/10-10-13-MaineImportLawsuit.pdf. The law can be read at www.fdanews.com/ext/files/10-10-13-MaineLaw.pdf. — Robert King

In May 2007 the company pleaded guilty to misleading the public about OxyContin’s (oxyco-done) risk of addiction, and agreed to pay $600 million in what was at the time one of the larg-est pharmaceutical settlements in U.S. history. Purdue’s president, top lawyer and former chief medical officer pleaded guilty as individuals to misbranding charges, a criminal violation, and agreed to pay a total of $34.5 million in fines. The company also entered into a CIA.

Pfizer in 2009 trumped that record arrange-ment with its own $2.3 billion settlement to resolve criminal and civil cases arising from the illegal promotion of several of its drugs. As a result of that investigation, the drugmaker entered into a five-year CIA with HHS OIG that requires annual reviews of the company’s compli-ance program (WDL, Sept. 7, 2009).

Public Citizen sought the records from HHS under the Freedom of Information Act after reports of continued violations by the companies called into question the effectiveness of CIAs.

HHS OIG has shown a willingness to permit companies, including Pfizer, to enter into agree-ment after agreement to resolve repeated allegations of misconduct, Public Citizen says. “The public has a right to judge for itself whether OIG is engaging in meaningful oversight through corporate integrity agreements,” Murray argued. — Melissa Winn

CIA, from Page 3

Imports, from Page 1

Washington Drug LetterOct. 14, 2013 Page 5

Feeling Patent Pain, eli Lilly Places Hopes on Pipeline Prosperity in 2014

Eli Lilly is hoping to win several drug approvals next year to weather expiring pat-ents, but for now plans to cut back on operating expenses to stay competitive. Sluggish growth in certain emerging markets has put a damper on sales, the pharma giant noted Oct. 3.

The new cost-cutting plan comes despite the drugmaker having the strongest pipeline in the company’s 137-year history, with 13 candidates in Phase III or in regulatory review. But patents for two Lilly blockbusters are expected to expire before the pipeline produces drugs ready to mar-ket: the anxiety drug Cymbalta (duloxetine HCl) and osteoporosis drug Evista (raloxifene).

Cymbalta generated nearly $5 billion and Evista about $1 billion in global sales last year.

Lilly told investors it plans to reduce operat-ing expenses and incrementally repurchase $5 billion in company stock.

Meanwhile, the company is crossing its fin-gers that its long-term innovation strategy will begin bearing fruit by at least mid-2014 — hopes shared by some Wall Street analysts, who appear particularly bullish about Lilly’s ramucirumab as a therapy for gastric cancer.

The company pointed to U.S. and European regulatory submissions for two Type 2 diabetes drugs empagliflozin, which it is developing with Boehringer Ingelheim, and dulaglutide. It also touted positive results for necitumumab for patients with metastatic squamous non-small cell lung can-cer, and expects a regulatory submission next year.

Despite facing heavy odds in the treat-ment sector, Lilly is committed to advancing its Alzheimer’s drug, solanezumab, which is being closely watched by competitors and ana-lysts alike. The candidate has faced a number of bumps, but fresh Phase III trials are just now get-ting underway. Ramucirumab disappointed in a late-stage trial examining its effects on meta-static breast cancer, with missed endpoints.

Lilly isn’t the only drug giant forced to refo-cus its business strategy with expiring patents on the horizon. Merck announced Oct. 1 job cuts and a refocus on new research areas after slump-ing sales for the asthma and allergy drug Singu-lair (montelukast sodium) and other generic com-petition (WDL, Oct. 7). — Robert King

Complex Products, Reviews Top Out FDA GDUFA Research Plans

The FDA has put equivalency of complex products and postmarket reviews at the top of its fiscal 2014 GDUFA research agenda.

The agency’s Office of Generic Drugs is spending more time on review and policy devel-opment for complex products as branded drug-device combos, implants and transdermal sys-tems take on new technology. More scientific investigations are needed to support guidance that can clarify the ANDA pathway for complex products, the FDA said in a recent web post.

Other research topics named as priorities for fis-cal 2014 include postmarket evaluation of generic drugs, equivalence of locally acting products, ther-apeutic equivalence evaluation and standards, and computational and analytical tools. The annual list, a requirement of GDUFA, is prepared based on input from industry and other stakeholders (WDL, May 22).

The agency’s postmarket research plans would include surveillance and monitoring meth-ods for generic drugs and efforts to better under-stand how patients view the quality and effective-ness of generic drugs.

The FDA will also further investigate whether generic drugs have the same therapeutic effectiveness as their brand counterparts, particu-larly for drugs highlighted by industry and stake-holder comments as products of concern. Those singled out for assessment in fiscal 2014 include anti-epileptic drugs, immunosuppressant drugs, buproprion, drugs to treat attention-deficit hyper-activity disorder and cardiovascular drugs.

(See GDUFA, Page 8)

Washington Drug Letter Oct. 14, 2013Page 6

FDA Issues Safety Alert on Ariad’s Cancer Drug, Citing Adverse events

The FDA issued a drug safety alert Oct. 11 for Ariad’s cancer drug Iclusig after one-fifth of patients in a postmarket clinical trial were found to have developed blood clots and narrowing of blood vessels that puts them at higher risk for heart attacks and strokes.

The agency is advising all patients on Iclu-sig (ponatinib) to seek medical help if they expe-rience any symptoms of a heart attack or stroke and is advising physicians to consider whether the benefits of continuing patients on the drug outweigh the risks.

The announcement comes only days after Ariad revealed the FDA had put a hold on all Iclusig trials due to concerns with a growing number of patients that have developed serious arterial thrombosis or blood clots.

While the risk for blood clots and narrowing of veins was known during the drug’s approval last year and stated in the labeling, it wasn’t until a follow-up review of Ariad’s PACE trial that researchers realized the risk was greater than they knew.

“None of the adverse events cited in our dis-cussions with the FDA are any different than adverse events that are both listed in the black box warning and in the full prescribing information,” Jeffrey Krasner, an Ariad spokesman, told WDL. “We were aware of these safety problems, but what happened is the longer the trial was done the longer the accumulative number of patients that were affected.” Krasner, however, says the rate of adverse events has remained relatively the same.

When Iclusig was approved, it was con-sidered a promising new treatment for chronic myeloid leukemia (CML) and Philadelphia chro-mosome positive acute lymphoblastic leukemia in patients who had exhausted other alternatives. However, the 11-month data from Ariad’s PACE trial used to support the drug through the FDA’s accelerated approval process program at the time showed about 8 percent of patients were at risk of serious arterial thrombosis. Now a 24-month

follow up has found at least 20 percent of trial participants developed blood clots and narrow-ing of blood vessels, and of those over half were deemed serious.

Despite the FDA’s warnings, Ariad is still optimistic about its only commercially viable product. Per the agency’s request, the company has stopped recruiting patients to all its Iclusig trials and has lowered doses for patients still in Iclusig studies. Ariad told WDL lower doses of the drug were still efficacious.

“We already have trial data which show that efficacy is maintained at the lower doses we are now moving towards,” said Krasner. He also added Ariad is working with the FDA to get the hold lifted, based on the lower dosage.

Soon after Ariad announced the clinical hold Oct. 10, its stock plummeted almost 70 percent.

The agency says it is still investigating the drug and will update the public when more infor-mation is available. — Ferdous Al-Faruque

GMP Training for Contractors and Visitors

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GMP Training for Contractors and Visitors, an 18-minute DVD from FDAnews, will give an instant overview of the special considerations of working in a pharma manufacturing facility. Addressing contamination control, per-sonal hygiene, dress code, behavior, and more, you’ll be sure that all contractors and visitors get the message about GMP compliance.

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Washington Drug LetterOct. 14, 2013 Page 7

Andrulis Slaps Celgene With Method-Of-Use Patent Suit

Andrulis Pharmaceuticals has slapped Celgene with a lawsuit claiming its competitor illegally encourages physicians to prescribe a combination of cancer drugs covered by its method patent.

Celgene promotes the use of its cancer drugs Thalomid (thalidomide) and Revlimid (lenalido-mide) in combination with GlaxoSmithKline’s Alkeran (melphalan), directly infringing one or more claims of Andrulis ’346 patent, the suit claims. The patent covers the treatment of cancer with thalidomide alone or in combination with other agents similar to melphalan.

The FDA and several federal and state attor-neys have been investigating Celgene since 2011 for illegal promotions of Thalomid and Revlimid for unapproved uses, according to the suit. The uses of Thalomid or Revlimid without dexa-methasone or in combination with melphalan to treat multiple myeloma are all unapproved uses, according to Andrulis.

Celgene and its sales representatives have encouraged the prescribing of Revlimid and Tha-lomid in combination with melphalan by providing doctors with press releases and reprints of articles touting favorable results of the drug combination in clinical trials, the suit states. Additionally, Celgene has distributed to doctors National Comprehensive Cancer Network information or materials relating to the use of melphalan-prednisone-thalidomide therapy and/or melphalan-prednisone-lenalidomide therapy to treat patients with multiple myeloma.

Several doctors reporting favorable results from clinical trials involving Celgene’s cancer drugs have been secretly compensated by the drugmaker through consultancy agreements or honorariums, Andrulis asserts. Celgene’s “will-ful” acts of infringement have not been corrected by obtaining a license or any other form of roy-alty agreement, Maryland-based Andrulis adds.

Andrulis has demanded a jury trial in the case and has asked for unspecified damages. Requests to Celgene for comment were not returned.

Revlimid was approved by the FDA in 2005 for use in combination with dexamethasone in patients with multiple myeloma who used at least one prior therapy. The drug raked in more than $3.7 billion in sales last year. Celgene continues to explore new indications for Revlimid. Thalomid was originally approved by the FDA in 1998. The drug is also indicated for use with dexamethasone for the treat-ment of multiple myeloma. — Melissa Winn

Tufts Report to Sponsors: Give CROs More Freedom

Drug sponsors need to move away from “old-world” thinking based on risk-averse attitudes towards contract research organizations (CROs) and allow them more autonomy so they can prove their worth, according to an industry expert.

Kenneth Getz, a director at the Tufts Cen-ter for the Study of Drug Development, which published a recent report on the relationships between sponsors and CROs, says the biggest barrier to successful partnerships is the cultural legacy many sponsors have where they feel the need to “police and micro-manage” their CROs.

The Tufts R&D Management Report, released Oct. 8, looks at how sponsor and CRO relationships have developed over the past decade and identifies key areas that could be improved to help all parties meet their goals.

Getz says he was surprised with how candidly sponsors and CROs are now talking about their partnerships especially considering the “rosy” spin they had on the topic only a few years ago.

A survey conducted by the Avoca Group, a New Jersey-based clinical outsourcing consult-ing firm, is cited in the Tufts report. According to the survey, less than half of sponsors are satisfied with the quality of service from clinical service providers but almost 9-in-10 CROs are satisfied with the service they provide. Based on the feed-back from 400 sponsors and CROs, there seems to be a disconnect between the research partners on how they perceive each other’s work.

(See Report, Page 10)

Washington Drug Letter Oct. 14, 2013Page 8

Florida, the family’s legal counsel, John Vecchi-one told WDL Oct. 8.

“The proposition that mere federal regula-tion immunizes a company from punitive dam-ages apparently did not even attract four votes for review of the issue,” he said.

Further, the federal district courts now “have a blue print for approaching these cases … with firm confidence that they will be upheld upon review even to the highest court in the land,” Vecchione added.

While the precedent directly affects Novar-tis, “We are starting to see significant plaintiff friendly appellate decisions emerge from this liti-gation that will be useful for plaintiffs in other pharmaceutical cases down the road,” he said.

A Novartis spokeswoman told WDL the drugmaker filed its petition with the Supreme Court because the case poses an important issue not previously addressed by the Court: whether a jury can award plaintiffs punitive damages “despite the fact that the company was consis-tently in compliance with the FDA-approved pre-scription drug labeling.”

The ability for juries to do so threatens the availability of necessary and often life-saving medications for patients, she said. The drugmaker anticipates the court will address the arguments raised in the petition in the future, she added.

The North Carolina jury in the case of Novar-tis v. Fussman awarded the plaintiff, Herbert Fussman, $12.6 million in punitive damages for

injuries his late wife had sustained as a result of taking the two Novartis drugs. The amount of damages awarded was later reduced to $867,000 because of state law caps.

An appeals court judge upheld punitive dam-ages, saying the evidence showed the drugmaker intentionally covered up information about side-effects of the drugs. — Melissa Winn

Date Requester Requested Information

9/3/2013 Cempra Pharmaceuticals Wockhardt’s response to a Form 483 issued to an Indian facility.

9/3/2013 Dr. Reddy’s Laboratories Summary basis for approval for Dr. Reddy’s ANDA for atorvas-tatin calcium.

9/3/2013 AbbVie Imports and PREDICT scores from Jan. 1 to July 15, 2013, for AbbVie.

Novartis, from Page 3

With regard to therapeutic equivalence, the agency will research methods and standards that contribute to a generic drug’s ability to offer the same therapeutic benefit as its brand equivalent. Research in this area will include identifying a pathway for generic versions of abuse-deterrent formulations, methods for bioequivalence study analysis, product quality standards such as qual-ity by design, patient use factors and risk-based equivalence standards for narrow therapeutic index drugs (NTIs).

An FDA advisory committee in 2011 rec-ommended tighter bioequivalence standards for generic versions of NTIs, saying small differ-ences in dosing can lead to dangerous side effects (WDL, Aug. 1, 2011).

In addition, the agency will investigate the use of modeling and simulation tools.

The FDA’s full list of fiscal 2014 GDUFA reg-ulatory research priorities can be found at www.fdanews.com/ext/files/10-07-13-GDUFA-Priorit ies.pdf. — Melissa Winn

GDUFA, from Page 5

FDA FOIA LOG

The FDA received 232 FOIA requests the week of Sept. 2 including the following.

View the complete FOIA log for the week of Sept. 2 at www.fdanews.com/ext/files/10-10-13-FOIALog.pdf.

Washington Drug LetterOct. 14, 2013 Page 9

FDA Postpones Advisory MeetingCiting the ongoing government shutdown,

the FDA has postponed two upcoming meetings of the Allergenic Products Advisory Commit-tee. The panel falls under CBER, which is not privy to the user fees helping to fund some of the agency’s ongoing activities during the shutdown. (WDL, Aug. 5)

The committee was scheduled to meet Nov. 5 to discuss Stallergenes’ Oralair, an allergen extract tablet for the treatment of certain grass allergies.

On Nov. 6, the committee was to discuss the merits of ALK-Abello’s BLA for its investiga-tional allergy vaccine tablets developed through a partnership with Merck. The BLA was accepted by the FDA for review in March.

Advisory committee meetings that can be “conducted with carryover user fee balances will be handled on a case-by-case basis,” the FDA said in a recent web post.

FDA Approves Pfizer’s DuaveeThe FDA Oct. 3 approved Pfizer’s novel estro-

gen drug Duavee to treat moderate-to-severe hot flashes and to prevent osteoporosis after menopause.

It is the first drug approved by the agency to combine conjugated estrogen with an estro-gen agonist/antagonist (bazedoxifene). Hor-mone replacement therapies carry a high risk of uterine cancer that bazedoxifene is intended to lessen.

Specifically, the bazedoxifene compo-nent of Duavee reduces the risk of endometrial

hyperplasia or excessive growth of the lining of the uterus, which could be a precursor to cancer of the uterine lining, Pfizer said Oct. 3.

PhRMA Lauds Rare Disease Drug FocusMore than 450 new medicines are being

developed by American biopharmaceutical com-panies for rare and sometimes overlooked dis-eases, according to PhRMA.

Due to advances in science and technology, biopharmaceutical scientists are “better equipped than ever before to bring new treatments and hope to patients battling one of the nearly 7,000 rare diseases,” PhRMA president and CEO John Castellani said.

The 452 medicines and vaccines in development for rare diseases — all in human clinical trials or under review by the FDA — include 105 for cancer, 85 for genetic disorders, 65 for blood cancers and 32 for neurological disorders, the report states.

FDA Approves OTC NasacortThe FDA Oct. 11 gave the go ahead for Sanofi

to begin OTC sales of its Nasacort nasal spray. An FDA advisory panel July 31 voted 10-6, with two abstentions, that Sanofi’s prescription hay fever remedy Nasacort AQ (triamcinolone acetonide aqueous) is a safe candidate for an OTC switch.

It’s the first and only medicine in its class to be available without a prescription and will be marketed by Sanofi’s consumer healthcare divi-sion, Chattem, Sanofi says.

Chattem anticipates Nasacort will be avail-able in Spring 2014.

Bill Name and Number

Bill Sponsor(s) Comittee Date

IntroducedMost Recent

Action Text of Bill

FDA Appropria-tions Resolu-tion, 2014 (H.J.Res. 77)

Rep. Robert Aderholt (R.-Ala.)

House Ap-propriations Oct. 3, 2013

Passed the House, referred to the Senate.

Make continuing appropriations for the Food and Drug Adminis-tration for fiscal year 2014, and for other purposes.

BRIeFS

LeGISLATIVe ACTIONSU.S. CONGReSS

The following bills involving HHS and FDA regulation moved forward recently:

Washington Drug Letter Oct. 14, 2013Page 10

Bayer Wins FDA Nod for its Lung Disease Drug Adempas

The FDA Oct. 8 approved Bayer’s pulmonary hypertension drug, giving the green light for two different treatments at flexible dosage levels rec-ommended by agency advisors.

Bayer’s Adempas (riociguat) tablets won approval for the treatment of adults with persis-tent, chronic thromboembolic pulmonary hyper-tension (CTEPH) after surgical treatment or inop-erable CTEPH, and for the treatment of adults with pulmonary arterial hypertension (PAH).

The approval nod makes Adempas the first soluble guanylate cyclase stimulator to treat pul-monary hypertension. The class of drugs helps arteries relax to increase blood flow and lower blood pressure. Adempas is also the first of its class shown to work in patients with CTEPH, FDA officials say. Canadian regulators last month approved the drug for the CTEPH indication.

Bayer was awarded priority review for Adempas based on two Phase III trials: CHEST-1 to evaluate Adempas on CTEPH, and PATENT-1 to evaluate the drug on PAH. In both trials, researchers used the six-minute walk-ing distance test and found statistically signifi-cant evidence that patients on the drug in the CHEST-1 trial were, on average, able to walk farther than those on placebo. And patients on the drug in the PATENT-1 trial were similarly able to tread farther.

An advisory panel this summer unanimously recommended approval of the drug, and rejected FDA suggestions to cap doses at 1.5mg, three times a day. The agency approved prescribing instructions calling for dosing to start at 1 mg three times a day and allowing for 0.5 mg-dose increases up to 2.5 mg three times a day after two weeks of treatment.

The FDA also followed through on a recom-mendation made by its Cardiovascular and Renal Drugs Advisory Committee to add prescribing language noting Adempas’ “hypotensive effect.” The drug also carries a boxed warning that it

may cause fetal harm and directs female patients to use Bayer’s risk evaluation and mitigation strategy as part of treatment.

Adempas is expected to hit U.S. shelves shortly, with Bayer spokeswoman Marcy Funk telling WDL distribution could begin “as early as today.” — Nick Otto

So where do sponsors and CRO’s begin to improve their understanding? The report’s authors suggest removing unrealistic and unclear expec-tations on both sides is a good start. This can be accomplished through the use of quality agreements.

Avoca suggests quality agreements between sponsors and CROs can help them define the expec-tations they have of each other to improve their part-nership. However, only half of sponsors surveyed said they always or often use such agreements.

Sponsors and CROs should also acknowledge the differences in their priorities and business models and try to work toward their goals. The Tufts report recommends sponsors share “a high degree of transparency” with CROs regarding their pipelines to allow CROs to implement better resource management. Another key recommen-dation is for sponsors and CROs to clearly define each other’s processes, policies and procedures “as if they are part of the same organization.”

The FDA has recently issued a slew of guid-ances to encourage more centralized oversight of clinical sites and use of risk-based monitoring by sponsors and CROs. Last month, the agency issued a final guidance outlining the agency’s expecta-tions of sponsors, CROs, and investigators on how to electronically capture source data. The agency in August also issued a final guidance on how risk-based monitoring should be conducted to allow sponsors and CROs to follow trial developments in real time. The guidance reiterated that stakehold-ers should embrace risk-based monitoring to reduce time and cost in terms of resources to conduct trials (WDL, Aug. 12). — Ferdous Al-Faruque

Report, from Page 7

Washington Drug LetterOct. 14, 2013 Page 11

Sidney Wolfe was the direc-tor of Public Citizen’s Health Research Group from its cre-ation in 1971 until June 2013, when he stepped into the role of senior adviser. He co-founded the Health Research Group with Ralph Nader in 1971. Since 1995 he has been an adjunct professor

of internal medicine at the Case Western Reserve University School of Medicine.

WDL: Public Citizen sued HHS after they denied your FOIA request for certain documents related to two drugmakers’ corporate integrity agreements (CIA). What is Public Citizen’s inter-est in these documents?

I became interested in CIAs after Pfizer [in 2011] entered into a settlement with the Department of Justice for illegal marketing of one of its drugs. Not only was Pfizer already under a CIA at the time, but this was for the identical violation. I won-dered: Is there something wrong with the way these CIAs are being enforced? So, under the Freedom of Information Act, we requested documents pertain-ing to Pfizer’s CIA and CIA documents for a sec-ond drugmaker, Purdue (see story, page 3).

We wanted to review the documents to see what could be going wrong with the enforce-ment of these agreements. There are several pos-sibilities we wanted to look at, namely whether companies are withholding information from the independent monitors assigned to their case, whether independent monitors are withholding information from the HHS Inspector General, or whether the Inspector General may not be enforc-ing the agreements as vigilantly as it could be. Depending on which one of those, if any, is hap-pening, we can look at solutions such as new leg-islation or increased focus on enforcing CIAs.

WDL: Several drugmakers under CIAs con-tinue to be rapped for similar accusations of

illegal marketing and sales practices under the False Claims Act. Do you think CIAs are effective?

It’s important to note, these are not allega-tions against these companies. These are ille-gal activities which even the drugmaker itself admits to having done. So the question that looms large is, how do you prevent this behav-ior? Corporate integrity agreements are a good idea in theory. The question is, how are they being enforced? The fact that these compa-nies keep doing this despite being under a CIA, means these illegal sales and marketing prac-tices have become a part of their business model. They make more money conducting these illegal practices and paying the fine, than they would otherwise. The system is broken.

WDL: How does the system get fixed?

That’s why we want to look at these docu-ments, to see where the problem exists. One thing for sure, there need to be larger fines for these violations and people need to go to jail. No exec-utives have ever gone to jail over these illegal activities. The fines for conducting these activi-ties are big, but they are not big enough. Even a $3 billion fine is a piece of change when com-pared to some of these drugmakers’ earnings.

Public Citizen released a report last year detailing the industry’s criminal and civil pen-alties. What we found on a federal level is that financial penalties continue to pale in compari-son to company profits, and a parent company is only rarely excluded from participation in Medicare and Medicaid for the illegal activi-ties. We also found most states, including some with the highest prescription drug expenditures, don’t pursue investigations on their own. Stron-ger legislation and more robust enforcement are needed on a federal and state level to deter this unlawful behavior.

To view the Public Citizen report, visit www.fdanews.com/ext/files/10-11-13-Public_Citizen.pdf.

THe BUzz

Washington Drug Letter Oct. 14, 2013Page 12

“If these allegations are true, they explain why it has taken the FDA almost a year to reach a deci-sion to reschedule hydrocodone even after their own expert advisory panel recommended it.”

Since the agency’s Drug Safety and Risk Man-agement Advisory Committee in January voted to recommend implementing tighter restrictions on hydrocodone combination products, Manchin has prodded Hamburg to immediately upschedule the opioid drugs to deter abuse (WDL, May 20).

Reports of the agency’s involvement in IMMPACT “raise serious doubts about the FDA’s ability to make objective and scientifically based decisions” regarding the treatment of painkill-ers, Manchin said. “Even worse,” he added, “when challenged by … the National Institutes of Health of the stigma of this ‘pay to play’ process, the FDA balked and continued with the arrangement.”

Those comments refer to emails dredged up by attorney Craig Mayton, a partner at the Ohio-based law firm Isaac Wiles, related to the conver-sations of IMMPACT partnership organizers.

Under the Freedom of Information Act, May-ton requested the e-mails from the University of Washington, where IMMPACT organizer Den-nis Turk teaches as a professor of anesthesiology. Mayton then distributed more than 400 pages of them to various news outlets. Echoing Man-chin’s motives, Mayton told WDL he requested the e-mails to shed light on the pressing issue of opioid abuse, which he said is wreaking havoc in his home state.

Manchin asked Hamburg to hand over reams of information about the FDA’s involvement in IMMPACT, including a list of the companies that paid to attend the meetings, as well as the amount of money that went to the agency or any individu-als at the FDA. He also asked for a list of the rec-ommendations that arose from the discussions.

From ACTTION to IMMPACT

According to the FDA, IMMPACT is a “pri-vate organization” that, in July 2011, became a part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportu-nities, and Networks (ACTTION) initiative, which the agency formed with the University of Roches-ter to help advance development of pain drugs.

The FDA at the time touted ACTTION as part of the agency’s larger regulatory science push, and encouraged industry, patient groups, foundations and other stakeholders to take part.

FDA spokesman Steven Immergut told WDL the agency continues to support public-private partnerships such as ACTTION, noting it’s one of many that the FDA is involved with. “Col-laborations such as these play important roles in identifying and addressing knowledge gaps, pub-lic health questions, and unmet medical needs that plague many therapeutic areas,” Immergut said. He added that the agency is aware of the concerns raised by Manchin and others, but said the FDA is “unaware of any improprieties asso-ciated with ACTTION or IMMPACT, or with the agency’s involvement in the public-private part-nership.” — Johnathan Rickman

IMMPACT, from Page 1

Reporters: Nick Otto, Elizabeth Orr, Ferdous Al-Faruque, Lena Freund, Robert King

President: Cynthia Carter; Content Director: Dan Landrigan; executive editor: Johnathan Rickman

Copyright © 2013 by Washington Business Information Inc. All rights reserved. Washington Drug Letter (ISSN 0194-1291), an executive briefing on the regulation of pharmaceuticals, is published weekly, 50 issues, for $1,347. Photocopying or reproducing in any form, includ-ing electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictly prohibited with-out the publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may reproduce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400.

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