J&J to Pay $2.2 Billion to Resolve Risperdal Off-Label Marketing

In the third-largest healthcare fraud settlement ever, Johnson & Johnson (J&J) and its subsidiaries will pay more than $2.2 billion in criminal and civil fines for off-label promotion of three drugs.

In the criminal case, the company will plead guilty to off-label promotion of schizophrenia drug Risperdal (risperidone). Though approved for schizophrenia and acute mania associated with bipo-lar 1 disorder, the company acknowledged criminal liability for also promoting the drug for dementia in elderly patients and downplay-ing the risks of stroke associated with the drug.

The civil settlements extend to two drugs in addition to Risp-erdal. Invega (paliperidone), also approved for schizophrenia, was also marketed for dementia. Natrecor (nesiritide), approved for treat-ment of patients following severe heart failure, was marketed for

Vol. 45, No. 44Nov. 11, 2013

GAIN Act incentives spur Roche to expand antibiotic portfolio ...................Page 2

FTC final rule puts pharma patent agreements under the microscope ...............Page 3

QbD quality systems should document design space tests ..........................Page 3

FDA Calendar ..........Page 4

FDA eyes more pre-ANDA meetings to speed submis-sion reviews .............Page 5

FDA’s GDUFA implementa-tion leads to ANDA rejec-tion avalanche ..........Page 5

FDA plans to emphasize metrics, not documentation, in inspections ...........Page 6

Hospira rebounding as Rocky Mount remediation wraps up ...................Page 7

FDA GCP inspections in-crease; violations drop, says 15-year study ............Page 8

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

FDA guidance offers endpoints for tuberculosis clinical trials ..........Page 11

INsIde thIs Issue

(See Labeling, Page 4)

(See J&J, Page 8)

FDA Moves to Give Generic Drugmakers New Safety Labeling Update Powers

The FDA is proposing to give generic drugmakers the power to revise product labeling in response to safety issues prior to agency approval — a power that brand drugmakers already have.

Under a new proposed rule, generic manufacturers would make the labeling change by filing a “changes being effected” supplement (CBE-0) for their drugs. The CBE-0 should contain:

● The application number of the drug product(s) involved; ● A description of the labeling change proposed in the supplement; ● The basis for the change, such as data from adverse event

reports or published literature; ● A copy of the product labeling proposed in the CBE-0 sup-

plement; and ● Confirmation that the brand drugmaker was notified of the

CBE-0 supplement.

Washington Drug Letter Nov. 11, 2013Page 2

GAIN Act Incentives Spur Roche To Expand Antibacterials Portfolio

New incentives designed to encourage devel-opment of antibiotics that target drug-resistant infections are having their intended effect and reviving interest in the antibiotics business.

Swiss drugmaker Roche says it plans to part-ner with Swiss-owned Polyphor to develop a drug that targets a leading cause of hospital-borne infections, and the initiative is made viable by the provisions of the 2012 Generating Antibi-otic Incentives Now (GAIN) Act.

Polyphor is developing the antibiotic treat-ment known as POL7080, which targets Pseudo-monas aeruginosa, a bacterium that causes one in 10 hospital-acquired infections in the U.S., according to the U.S. Centers for Disease Con-trol and Prevention. POL7080 has demonstrated safety and tolerability in a Phase I clinical trial, according to Roche.

Under its deal with Polyphor, Roche will pro-vide a $38 million upfront payment for the rights to the experimental treatment, and an additional $510 million plus royalties when key regulatory and commercial milestones are met.

As a qualified infectious disease product (QIDP) under the GAIN Act (WDL, June 17), POL7080 would be eligible for an additional five years exclusivity granted at the time of product approval; priority review for marketing

applications for designated products; and fast-track approval.

The Polyphor licensing deal complements Roche’s portfolio by adding antibiotics to the cur-rent focus areas in virology, Roche spokesman Luke Willats told WDL Nov. 5. — Nick Otto

Comings & GoingsThe U.S. Pharmacopeial Convention (USP) has

appointed FDA official Jon Clark vice president of chemical medicines – external development. He joined USP on Oct.14. For the past ten years, Clark had served as associate director for policy develop-ment in CDER’s Office of Pharmaceutical Science.

Pharmaceutical executive Stephen Zaruby has been named the president and chief executive officer of Aurinia Pharmaceuticals. Previously, he was president of ZymoGenetics, which was acquired by Bristol-Myers Squibb. He has also held several executive positions at Bayer Health-care Pharmaceuticals and Bayer AG.

EMD Serono has appointed Paris Panayioto-poulos its president and managing director. Panayi-otopoulos joins EMD Serono from the company’s Japan affiliate, Merck Serono, where he has served as president and managing director since 2012.

KV Pharmaceutical has named former John-son & Johnson executive Janet Vergis to its board of directors.

Former Pfizer executive Bruce Freundlich has been named senior vice president of medical affairs for Antares Pharma.

Date Requester Requested Information9/23/2013 Eli Lilly Form 483 issued to Dyax’s Cambridge, Mass., facility.

9/24/2013 X-Gen Pharmaceuticals Drug product dosage forms, inspectional status for last three years for Indoco Remedies’ Goa, India, facility.

9/25/2013 Catapult Adverse event reports for Jetrea

9/26/2013 Porzio Life Sciences Establishment inspection reports and 483s from 6/28/11 for Caraco Pharmaceutical’s Cranbury, N.J. facilty.

9/26/2013 Procter & Gamble Inspection records from 1990 to 2013 for GlaxoSmithKline’s Memphis, Tenn., facility.

FDA FOIA LOG

The FDA received 235 FOIA requests the week of Sept. 23 including the following.

View the complete FOIA log for the week of Sept. 23 at www.fdanews.com/ext/files/11-06-13-FOIALog.pdf.

Washington Drug LetterNov. 11, 2013 Page 3

QbD Quality Systems Should Document Design Space Tests

Drugmakers using quality-by-design (QbD) concepts should have a written plan for when and how they will evaluate the need for design space verification under their quality systems.

Such a plan should be available at the manu-facturing site and be part of change control, vali-dation and/or knowledge management strategy, the FDA and the European Medicines Agency (EMA) say in joint question-and-answer guid-ance posted by the EMA Nov. 4.

Applicants are also advised to include a “high-level overview” of how the plan will func-tion over the proposed product’s lifecycle to ease the review and approval process, the Q&A reads. Regulators expect a design space verification pro-tocol to be part of a marketing application.

A design space verification protocol should include:

● A list of scale-dependent parameters that could impact critical quality attributes that haven’t been verified at a commer-cial scale;

● Definition of the potential risks for up-grading to a commercial scale; and

● A discussion of whether a control strategy can address those risks.

Design space is a range of parameters in the manufacturing process. It can be applicable to different types or scales of manufacturing operations, and include quality attributes such as bioequivalence; stability and manufacturing robustness (WDL, Nov. 7, 2011). Design space verification demonstrates that those parame-ters and attributes are capable of maintaining product quality on a larger scale, the new guid-ance says.

Read the Q&A at www.fdanews.com/ext/files/11-05-13-QA-DesignSpaceVerification.pdf. — Robert King

FTC Final Rule Puts Pharma Patent Agreements Under the Microscope

Drugmakers will soon have to seek Federal Trade Commission antitrust review for all proposed licensing agreements for “exclusive” patent rights.

The rule expands the meaning of “exclusive patent rights” to adapt to increasingly compli-cated licensing deals in which drug companies transfer most, but not all, of the patent rights to “make, use, and sell” under an exclusive license.

Under current rules, companies could retain limited rights to a product and avoid FTC scru-tiny, but still effectively transfer the exclusive rights to a product.

Under the new rules, in determining report-ability, the parties should analyze what the licen-sor is transferring to the licensee and determine “whether the license conveys the exclusive right to commercially use the patent or part of a pat-ent,” according to the rule.

After the companies report a proposed deal, the FTC and Department of Justice will conduct

a preliminary review to determine whether the agreement raises any antitrust concerns that war-rant closer examination. During the preliminary review, the parties must wait 30 days before clos-ing their deals, Peter Kaplan, an FTC spokes-person, told WDL Nov. 7. The waiting period is halved to 15 days in the case of a cash tender or bankruptcy transaction.

Based on what the agency finds, it will either:

● Terminate the waiting period and allow the parties to consummate their transaction (of-ten referred to as an “early termination”);

● Let the waiting period expire, which allows the parties to consummate the transaction; or

● If the initial review has raised competition issues, the review may be extended and the parties may be asked to turn over more in-formation (referred to as a “second request”).

Most deals reviewed by the FTC and DOJ are allowed to proceed after the first preliminary review, according to the FTC.

(See FTC, Page 9)

Washington Drug Letter Nov. 11, 2013Page 4

Labeling, from Page 1

Under current law, a branded drugmaker usually implements labeling changes around the time it submits the CBE-0 supplement. The FDA will review the supplement and then either approve it or send a letter to the drugmaker with proposed changes. Currently, generic mak-ers must wait for agency approval before imple-menting the change.

The agency plans to post CBE-0s for NDA, ANDA and BLA products on a new web page. Because of this new feature, the agency wants all CBE-0s to be submitted in a structured prod-uct labeling format that can be posted online, the FDA said.

The proposed rule touches on issues raised in a 2011 Supreme Court decision in the case of Pliva v. Mensing. In that case, the court rejected the notion that generic companies have an obli-gation to request label changes after new adverse events were found (WDL, July 11, 2011).

“The federal statutes and regulations that apply to brand-name drug manufacturers dif-fer, by Congress’ design, from those applicable to generic-drug manufacturers,” Justice Clarence Thomas wrote for the majority. The FDA and Congress may change the law and regulations if they desire, he adds.

GPhA Nov. 8 questioned if the agency has the authority to issue the rule in the wake of the court’s decision.

The group also said it is concerned that mul-tiple generic drugmakers could file conflicting safety information for the same generic product, leading to “unnecessary confusion and uncer-tainty for prescribers and patients.”

The proposed rule is scheduled to be pub-lished in the Federal Register Nov. 13. The public has until Jan. 12 to comment. The proposed rule is available at www.fdanews.com/ext/files/11-08-13-ProposedRule.pdf. — Robert King

Upcoming meetings through Nov. 25:

● Nov. 12-14: The FDA will hold a training course for clinical investigators. College Park, Md.

● Nov. 13: The Peripheral and Central Nervous Systems Drug Advisory Com-mittee will meet to discuss Genzyme’s sBLA for Lemtrada (alemtuzumab injection) as a treatment for patients with relapsing forms of multiple. Silver Spring, Md.

● Nov. 14: The Peripheral and Central Ner-vous Systems Drug Advisory Committee will meet to discuss Vanda Pharmaceu-ticals’ NDA for Hetlioz (tasimelteon) for the treatment of non-24 hour sleep-wake disorder in blind individuals without light perception. Silver Spring, Md.

● Nov. 19: The Endocrinologic and Meta-bolic Drugs Advisory Committee will meet to discuss BioMarin’s BLA for Vimizim (elosulfase alfa) for the treat-ment of Morquio A syndrome. Silver Spring, Md.

● Nov. 25: The FDA will hold a public meeting on meta-analyses of randomized controlled clinical trials for the evaluation of risk to support regulatory decisions. Silver Spring, Md.

Comment deadlines through Nov. 18:

● Nov. 12: Comments due on the draft guidance Bioequivalence Recommen-dations for Fluticasone Propionate; Salmeterol Xinafoate, docket no. FDA-2007-D-0369-0261.

● Nov. 18: Comments due on the draft guid-ance Patient Counseling Information Section of Labeling for Human Prescrip-tion Drug and Biological Products — Content and Format, docket no. FDA-2013-D-1067-0001.

FDA CALENDAR

Washington Drug LetterNov. 11, 2013 Page 5

FDA Eyes More Pre-ANDA Meetings to Speed Approval Process

The FDA intends to grant more drugmaker requests for pre-ANDA meetings as a way to work with industry to ensure quality ANDA sub-missions, FDA officials say.

The agency hopes the meetings will reduce the number of review cycles a submission needs to complete before finally winning the FDA’s approval, the agency’s acting director of the Office of Generic Drugs Kathleen Uhl told WDL Oct. 30.

That’s a win-win for the agency and the industry, she said, noting that ANDA submis-sions returned to a drugmaker for a second review cycle could also forfeit a generic’s “first-to-file” status.

Still, not all meeting requests can or will be granted, Robert Lionberger, OGD’s acting deputy director of science, said at the FDA/GPhA Tech-nical Conference Oct. 29.

Of the 21 pre-ANDA meeting requests made to the FDA in fiscal 2013, the agency has held or scheduled five, denied six and 10 remain pending.

What’s in a Meeting Request?

Drugmakers hoping to snag a pre-ANDA meeting with the FDA to discuss a submission should have clear and specific questions they want answered and must present the agency with an agenda for the meeting as they make their request, Lionberger said.

The more focused the request, the more likely it will be to be granted, he added.

The agency will also more likely grant a request supported by data new to OGD or a meeting in which the drugmaker seeks to discuss pilot studies with alternative approaches, he said.

Pre-ANDA meeting requests for drugs that have no alternative generics available or for a product with unique regulatory science issues are also more likely to be granted.

The agency most often rejects requests that lack focus, detail problems without proposing

solutions, contain questions that could be answered in simple correspondence, contain no data, lack an agenda or merely seek to “get acquainted” with reviewers.

Although pre-ANDA meetings are not a requirement of the Generic Drug User Fee Act of 2012 (GDUFA), the agency hopes to use some of the staff resources hired under the act to grant more meeting requests.

The benefit of successful meetings will directly link to the GDUFA goals, Lionberger said.

OGD last month issued draft guidance on “refuse-to-receive” standards, which follows an initiative unveiled in July intended to lessen the number of ANDAs that are initially rejected due to unavailable drug master files (WDL, Oct. 7).

The deadline to comment on the FDA’s draft guidance ANDA Submissions — Refuse-to-Receive Standards, docket no. FDA-2013-D-1120, was Oct. 31. It can be read at www.fdanews.com/ext/files/09-30-13-ANDA.pdf. — Melissa Winn

FDA’s GDUFA Implementation Leads To ANDA Rejection Letter Avalanche

In the FDA’s first year of implementing the Generic Drug User Fee Act, the agency issued some 1,250 complete response (CR) letters for ANDAs, a whopping increase from the fewer than 50 issued in fiscal 2012.

The stark increase in the period from Oct. 1, 2012 to Sept. 30, 2013 is a result of the FDA’s commitment under GDUFA to chip away at a backlog of 2,866 pending ANDAs and 1,882 pend-ing prior approval supplements (PAS). The agency agreed to clear 90 percent of the backlog by the end of the first five-year iteration of GDUFA in September 2017 (WDL, Dec. 12, 2011).

Under GDUFA, the agency also commit-ted to forego “piecemeal” ANDA deficiency notices, and issue CR letters for all generic drug

(See GDUFA, Page 12)

Washington Drug Letter Nov. 11, 2013Page 6

FDA Plans to Emphasize Metrics, Not Documentation, in Inspections

The FDA plans to shift its focus during facility inspections away from examining docu-mentation, such as standard operating proce-dures, and place more emphasis on a facility’s operational metrics.

“We really want to know more about the results,” not the design, of a facility’s quality system, CDER Director Janet Woodcock said Nov. 4.

The agency plans to require drug manu-facturers to submit data about specific quality metrics within a year or two; it is still deciding what metrics to require, although officials have floated metrics such as batch failure rates or complaint data.

Woodcock, speaking at the 2013 annual meeting of the International Society for Phar-maceutical Engineering (ISPE) in Washing-ton, D.C., said the FDA wants to find metrics that would be appropriate and simple. ISPE is currently conducting a project to solicit feed-back from industry on objective and useful met-rics. The goal is to develop a white paper that is acceptable to industry and regulators that defines the best metrics for use in a risk-based inspec-tion program (WDL, Sept. 16).

Woodcock said that many companies already belong to quality organizations such as Six Sigma, and use measures that assess how well they are doing. However, some companies have complained that such measures and metrics are “internal tools” that would be too burdensome for them to report and cause confusion in the marketplace.

The push for quality metrics is tied to legisla-tive mandates in the FDA Safety and Innovation Act to conduct more risk-based inspections. The FDA doesn’t plan to publish quality scores for individual companies, said Woodcock. The goal is to publish “the state of quality of manufactur-ing in the pharmaceutical industry,” she said.

By publishing an overview of how the indus-try is doing as a whole, “individual companies can benchmark themselves against that,” Wood-cock said.

She added that the agency is willing to con-sider a reward for companies with a good quality record. One such incentive could be more regula-tory freedom to operate, Woodcock said, but she declined to elaborate on that concept.

The upside for drugmakers under the risk-based inspection regime is that better-performing companies would face fewer inspections (WDL, Sept. 30).

The idea of financial incentives for compa-nies that make manufacturing and product qual-ity improvements was floated in a strategic plan to combat drug shortages unveiled last spring. The plan didn’t elaborate on what the incentives could be, and noted that the agency has a lim-ited ability to offer such rewards (WDL, Nov. 4). — Robert King

Preparing for the EUGMP Inspection

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FDAnews reached out to four au-thorities on European drug manu-facturing quality for their expertise. The result is a handbook you’ll refer to whenever the EU inspec-tors come to call. In plain English, this guide touches all the bases: what types of inspections EU drug regulators conduct, the qualifications of inspectors, sample inspection documentation, contents of an inspection report, and much more. So don’t wait. Order your copies of Preparing for the EU GMP Inspection today.

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Washington Drug LetterNov. 11, 2013 Page 7

Hospira Rebounding as Rocky Mount Remediation Wraps Up

More than three years after Hospira’s Rocky Mount, N.C., plant was warned for lax quality control, prompting a painful manufacturing slow-down and a costly remediation, the drugmaker expects to near the “top end” of production capa-bility in 2014, Hospira’s chief said Nov. 6.

Company-wide remediation efforts have cost the generic injectable drugmaker $458 million since it was first warned by the FDA in 2010 for particulate contamination problems. Since then, it has struggled with shortages as it labored to maintain scaled-back production under the scru-tiny of third-party auditors.

In 2013, the company is posting quarterly revenue increases again, and a recent inspection of Hospira’s Lake Forest, Ill., facility resulted in no Form 483, Hospira CEO Michael Ball said on a conference call.

Production at Rocky Mount has been steadily ramping up and revisions to its qual-ity system to improve its investigations capacity are now at a point where sustainable compliance can be assured in the eyes of third-party audi-tors, he added.

Some less significant manufacturing defi-ciencies continue to trouble the drugmaker, however. In August, it received a three-observa-tion Form 483 at its Kansas plant. FDA inves-tigators criticized the McPherson, Kan., facil-ity for an inadequate response to finding glass particles in sterile lyophilized drugs. During the inspection of the facility, the agency found that inspections into the particles were conducted long after discovery.

For example, Hospira received a customer complaint in April and received a sample on May 20 but didn’t complete the investigation until June 24. Investigators also found that Hospira failed to classify glass particulates as a “critical defect” even though there is a potential for caus-ing adverse health consequences, the form reads.

Ball said on the conference call that the com-pany responded with a corrective action plan and does not expect a warning letter.

To view the McPherson Form 483, go to www.fdanews.com/ext/files/10-23-13-Hospira483.pdf. — Robert King

CDER, CDRH Work Together To Reduce Duplicate Data

Developers of drugs with companion diag-nostics should see fewer requests for duplicate data from CDRH and CDER, as the FDA begins to see payoffs from its effort to increase commu-nication between its centers.

Chris Leptak, medical officer in CDER’s Office of New Drugs, said that over the last four years the agency has worked to break down the silos within the FDA as more new products cross drug-device barriers. Teams from CDER and CDRH now communicate and share information regularly, he said, in contrast to past years.

A greater number of early submissions from manufacturers has also helped the process, noted Pamela Bradley, staff fellow, CDRH. Both spoke at the DIA Meeting on Personalized Medicine and Companion Diagnostics in Alexandria, Va. Nov. 6.

Some manufacturers try to avoid FDA review by refusing to file a premarket approval for a companion diagnostic on the theory that the drug is so important it might be approved on its own. That approach backfires more often than not.

Leptak encouraged companion diagnos-tic manufacturers to meet with the FDA and ask CDER staff about concerns with their CDRH application or vice versa. Both centers are gener-ally aware of potential trouble spots due to early-stage communications. However, he made a spe-cial note about Special Protocol Applications. On these, CDER’s responses for device or diagnostic concerns are nonbinding.

Bradley noted, however, that, when an NDA and an investigational device exemption are both filed on the same product, some duplication of information is inevitable. — Elizabeth Orr

Washington Drug Letter Nov. 11, 2013Page 8

FDA GCP Inspections Increase; Violations Drop, Says 15-Year Study

While the number of FDA inspections of clin-ical investigators has grown in the last 30 years, the proportion of objectionable findings has dra-matically decreased, says a new report.

The number of clinical investigator inspec-tions averaged 329 a year between 1997 and 2012 compared to an average of 235 a year between 1977 and 1996. That is due to an increase in the number of for-cause inspections in the U.S. and an increase in data-audit inspections in emerging market countries.

Despite the increase of those inspections, the number of data audit site inspections where the FDA did not require or ask investigators to take actions based on their observations increased to 55.8 percent between 2007 and 2011 compared to 16.9 percent between 1987 and 1991. For-cause inspections where no action was necessary jumped in the same time frame, from 3.8 percent to 38 percent.

For-cause inspections also tend to have more frequent deficiency reporting than data audit inspections. Inspections that result in “no action indicated” outcomes tend to hap-pen in for-cause inspections at half the rate of data audit inspections. Conversely, instances where inspectors require corrective actions from investigators tend to happen eight times as often in for-cause inspections compared to data audit inspections.

The study, Guide to Global Clinical Trial Inspection Trends, was authored by Johan Karl-berg, former director of the Clinical Trials Centre at the University of Hong Kong.

Karlberg also found in the past 15 years the number of citations against investigators for failing to follow protocol or keep adequate records remained steady at 32 percent and 23 percent, respectively.

By contrast, citations such as using inad-equate consent forms, maintaining drug

accountability and failing to report adverse drug reactions have individually dropped from 13 per-cent to about 4 percent over the same period.

The study also found more than a quarter of investigators are inspected more than once by the FDA and results generally improve during the second, third and fourth inspections.

For more information on the report, visit www.fdanews.com/store/product/detail?productId=44742. — Johnathan Rickman

patients with less severe heart conditions. J&J acknowledged that its marketing, as well as kick-backs paid to physicians and nursing homes, prompted healthcare providers to make false claims to Medicare and Medicaid for its drugs.

The settlement includes $485 million in criminal fines and forfeitures and $1.72 billion in civil penalties to be shared between the states and U.S. government. J&J will also operate under a five-year corporate integrity agreement with the HHS Office of Inspector General sub-jecting it to stringent reporting and other trans-parency requirements.

The J&J healthcare fraud settlement is sur-passed only by a $2.3 billion settlement agreed to by Pfizer in 2009 (WDL, Sept. 7, 2009) and a $3 billion settlement signed by GlaxoSmithKline in 2012 (WDL, July 23, 2012).

J&J previously agreed in 2012 to pay $181 million and enter into a consent decree with 36 states and the District of Columbia to settle alle-gations that its subsidiary Janssen marketed Ris-perdal in violation of consumer protection laws (WDL, Sept. 3, 2012).

The Nov. 4 announcement brings all fed-eral investigations into Risperdal to a close, J&J said. The $2.2 billion in charges is not expected to result in an additional charge to the company’s earnings, J&J added. — Johnathan Rickman

J&J, from Page 1

Washington Drug LetterNov. 11, 2013 Page 9

EC Wants New Data RegulationsFor personalized medicine to grow, regula-

tors need to find new ways to protect data quality and manage large amounts of regionally and eth-nically diverse patient information, the European Commission says.

While an increasing number of companies are moving toward personalized medicine as genome sequencing and other technologies become avail-able, regulatory bodies can’t keep pace.

To keep up, regulators are urged to:

● Develop common reporting standards to efficiently translate millions of analyses into clinically meaningful information;

● Create Europe-wide biobanking to sup-port research;

● Draft new guidelines on the use of clinical data generated retrospectively from datasets;

● Develop new statistical analysis methods capable of using data derived from the multiple sources that support personalized medicine development; and

● Standardize insurance requirements for trials.

FDA Updates Enoxaparin WarningThe FDA Nov. 6 in a drug safety alert rec-

ommended new drug dosing recommendations for anticoagulant drugs such as Sanofi’s Lovenox (enoxaparin) when used with patients also receiv-ing a spinal catheter.

The new recommendations, which include timing suggestions for administering and remov-ing the catheter as well, aim to decrease the risk of spinal bleeding and paralysis in these patients.

Epidural or spinal hematomas are a known risk of enoxaparin in the setting of spinal pro-cedures and are already described in the boxed warning and the warnings and precautions sec-tions of the labels for Lovenox and generic enoxaparin products.

FDA Holds Curis Drug Trial The FDA has stopped enrollment in a Phase I

trial of Curis’ experimental cancer drug, calling for more information about the treatment after a reported death.

The agency placed a partial hold on the trial for CUDC-427 after a patient died of liver fail-ure one month after discontinuing treatment, the drugmaker said Nov. 6.

The small molecule drug is intended to pro-mote cancer cell death by antagonizing inhibitors of apoptosis proteins. CUDC-427 could be used as a monotherapy or in combination with other anticancer agents, Curis said.

The open-label, single-agent dose escalation study started in the first quarter of this year.

There are currently no patients being treated with CUDC-427, as the trial participants discon-tinued treatment due to disease progression or patient or physician discretion, Curis said.

BrIefs

PhRMA opposes the rule, arguing that the new requirements unfairly single out drugmak-ers and will heap significant financial and report-ing burdens on the group’s 50-plus members. The FTC disagrees, saying the “uniqueness” of pharma licenses results in exclusive licensing deals not seen in any other industry.

The newly amended rule will not apply to deals between brand and generic drugmakers for the market of authorized generics, as those are typically “non-exclusive,” Kaplan told WDL.

The final rule is expected to be published in the Federal Register soon, according to the FTC website, and the amendments will be effective 30 days after its publication.

The amended rule Premerger Notification; Reporting and Waiting Period Requirements can be read at www.fdanews.com/ext/files/11-07-13-FTC.pdf. — Melissa Winn

FTC, from Page 3

Washington Drug Letter Nov. 11, 2013Page 10

REGISTER ONLINE & SAVEwww.fdli.org/enforcement2013

Who Should Attend?This conference is designed for

attorneys of all experience levels, regulators, compliance experts, consultants and academics in primarily the drug, medical device, biologic, food and dietary supplement industries. The conference will also touch on tobacco, animal drug, and cosmetic industry issues.

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About the ConferenceAcross all agency-regulated products, the Food and Drug Administration (FDA) is expected to continue its heightened enforcement efforts. The Department of Justice and States’ Attorney General offices are becoming increasingly active in issuing Consent Decrees and Corporate Integrity Agreements. Public advocacy groups are voicing their concerns that compliance is a top priority.

This two-day conference will thoroughly examine the changes in law, regulation and practice in the last year and predict changes in the year ahead. Attendees will hear from top regulatory agency officials, including Office of Compliance directors invited from all six product Centers at FDA, the Department of Justice, HHS Office of the Inspector General (OIG), industry and the private bar.

The conference will feature the inaugural Eric M. Blumberg Memorial Lecture (in honor of the long-time FDA attorney who passed away earlier this year) and case studies of litigation strategies presented by attorneys who handled the actual cases.

Whether you are a regulator, litigator, compliance specialist or consultant, it is critical to keep up with the changing trends in enforcement, litigation and compliance.

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Washington Drug LetterNov. 11, 2013 Page 11

Updated EMA Antibiotic Development Guidelines Push Streamlined Filings

Drugmakers seeking approval in the EU for antibiotics that target multidrug-resistant infections will be allowed to use limited data to move prod-ucts more quickly to market under new European Medicines Agency (EMA) guidelines posted Nov. 7.

As soon as sufficient pharmacokinetic and phar-macodynamic data are available indicating a “strong possibility” that the candidate addresses an unmet need, applicants are urged to discuss the results with EU regulators to determine whether a limited pre-licensure clinical development program is possible.

After the candidate is initially approved, companies will be required to create and monitor a post-approval program that further substanti-ates safety and efficacy, the EMA says.

Guido Rasi, the agency’s executive direc-tor, touted the guideline revision as an evolution in advancing new antibacterial drugs targeting pathogens resilient to current therapies, which he said cause more than 25,000 unnecessary deaths each year in the EU.

The addendum also includes more detailed guidance on patient-selection criteria and pri-mary endpoints.

The EU update follows draft guidance issued by the FDA in July allowing for more flexibil-ity in developing antibacterial drugs for patients with unmet needs.

The guidance — released in a Q&A format around the one-year anniversary of the Generat-ing Antibiotic Incentives Now, or GAIN, Act — proposed four drug development approaches that the FDA hopes will help streamline and incentiv-ize development of drugs for patients with anti-bacterial drug-resistant infections.

“A decreased rate of antibacterial drug devel-opment poses a significant public health con-cern,” the FDA said.

With any approach, the drug development program should provide in vitro activity of the investigational drug, the mechanism of action,

whether mechanisms of resistance to other drugs affect its activity, and pharmacokinetic/phar-macodynamic evaluations from animal models. Selection of appropriate endpoints will depend on the specific serious bacterial disease being stud-ied, the FDA’s guidance notes.

View the EMA update at www.fdanews.com/ext/files/11-13-pathogens.pdf. — Nick Otto

FDA Guidance Offers Endpoints For Tuberculosis Clinical Trials

Sponsors designing clinical trials for drugs or multi-drug regimens for treatment of tuberculosis should focus on one of three endpoints:

● No growth of M. tuberculosis on sputum cultures during treatment;

● An endpoint comprised of survival and evaluation of M. tuberculosis on serial spu-tum culture examinations during treatment and 12 months following treatment; and

● Improvement or resolution of symptoms when therapy is completed.

The endpoints are outlined in FDA draft guid-ance published Nov. 5 designed to offer flexibility to drugmakers when approaching tuberculosis trials.

With regard to safety, sponsors should discuss with the agency the size of the needed preapproval safety database during drug development, with 500 patients generally considered appropriate. Since drug-resistant tuberculosis is an unmet clini-cal need, a database of approximately 300 patients may be sufficient, according to the guidance.

Sponsors are encouraged to meet with the agency to discuss development plans for Phase III clinical trials to address the potential for drug resistance and/or comorbid conditions.

The guidance also offers inclusion and exclu-sion criteria for the trial’s patient population, rec-ommending the use of rapid diagnostic tests to find out who is possibly drug resistant.

The draft guidance, docket no. FDA-2013-D-1319, is available for public comment until Feb. 4. It can be read at www.fdanews.com/ext/files/11-05-13- TuberculosisGuidance.pdf. — Robert King

Washington Drug Letter Nov. 11, 2013Page 12

submissions that have completed the review cycle but are not ready for approval, Uhl told attendees at a conference in Washington, D.C., last month.

The change, she told WDL, is part of her office’s larger efforts to reduce the number of ANDA review cycles.

Drugmakers are required to respond to a CR letter within one year of its issuance, or risk hav-ing their drug application withdrawn, Uhl noted.

Adequate responses should address all defi-ciencies noted in the CR, she added. Partial responses will not be accepted, processed as a resubmission or kick-start a new review cycle, she added.

Under GDUFA, OGD has also agreed to schedule 30-minute teleconferences with generic drugmakers upon request to discuss CR letters. Requests must be submitted in writing within 10 days of the FDA’s issuance of the letter.

There are no performance goals for hosting the teleconferences in the first two years of GDUFA, although the FDA says priority will be given to expedited and first major amendment applications.

Just fewer than 560 of the fiscal CR letters issued in fiscal 2013 were issued with inspec-tion, while 690 were issued with the anticipation of a future inspection. Although the latter are not required as part of the FDA’s commitments under GDUFA, the agency has issued them as an effort

to be more transparent and better communicate with industry, Uhl said.

The OGD in fiscal 2013 also approved a lit-tle more than 425 original abbreviated new drug applications and 560 prior approval supplements.

PAS approvals more than doubled from the 260 approved in fiscal 2012, and while ANDA approvals were down slightly from the 500 approved in fiscal 2012, the agency has met every single year one commitment under GDUFA, Uhl told drugmakers at the conference.

The agency also performed completeness and acceptability reviews for over 1,700 drug mas-ter files in GDUFA’s first year of implementation, resulting in nearly 1,400 DMFs being placed on the Available for Reference List.

Under GDUFA in fiscal 2013, the FDA col-lected $296 million of the $299 million autho-rized by Congress, with a large percentage of that coming from facility fees for the nearly 2,200 sites that have self-identified.

The FDA has also posted a list of manufac-turing facilities that have failed to submit their annual facility fee required under GDUFA.

Being named to the list has huge implica-tions not only for the facilities themselves, but also drugmakers contracting work out to them. The FDA said it will not receive new ANDAs or prior approval supplements referencing the facili-ties until the outstanding fee is paid. The agency will also not process applications submitted by the owner or any affiliates of the listed facilities. — Melissa Winn

GDUFA, from Page 5

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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