AstraZeneca Faces DOJ Probe Into Brilinta Phase III Clinical Trial The Department of Justice is investigating a Phase III study of AstraZeneca’s (AZ) heart drug Brilinta, which analysts and experts say could revolve around allegations of data falsification. The investigation into the PLATO trial of Brilinta (ticagrelor) was revealed by AZ in its third quarter earnings report. The PLATO trial supported the drug’s initial approval in 2011. AZ said it received an investigative demand from the DOJ’s civil division seeking documents and information regarding PLATO, which happened to be the subject of a critique published in last month’s International Journal of Cardiology . The trial review found, among other concerns, “an estimated 23 definite or possible cardiovascular events or deaths on tricagrelor were either not submitted for adjudica- tion, inactivated, deleted or were downgraded to ‘softer’ endpoints.” FDA Drug Approvals Fall in 2013, But a Brighter 2014 is Projected The FDA is expected to approve 34 new drugs this year, down from a record 43 approved in 2012. That drop is expected to be tem- porary, though, as more drugmakers adjust their pipelines to take advantage of the agency’s breakthrough therapy pathway. The FDA so far this year has approved 28 new drugs and biologics, and six more are expected to get approval before the end of the year. However, a new report released Nov. 13 by research firm Eval- uatePharma projects more approvals at the agency next year as the FDA speeds reviews of some 30 breakthrough designation applica- tions it has awarded, out of 100 submitted. The FDA Safety and Innovation Act created the pathway to speed approval for drugs that treat serious or life-threatening ill- nesses, giving them priority over me-too drugs that offer little improvement in treatments. Vol. 45, No. 45 Nov. 18, 2013 The FDA’s fiscal 2013 user fees remain impounded, yet no plans have emerged in Congress to free up the funds ........................ Page 2 The FDA says it may ex- tend some comment dead- lines after Regulations.gov was down for a few days earlier this month ..... Page 3 Drugmaker account in- formation may have been compromised after a hack broke into CBER’s online submission system ... Page 3 J&J faces more Risperdal le- gal woes after its $2.2 billion settlement with the Depart- ment of Justice........... Page 5 Briefs ....................... Page 6 FDA Advisors recommend approval of Hetlioz, Vanda’s sleep drug................. Page 7 Comings & Goings ... Page 8 The Buzz ................ Page 11 The FDA has delayed its review of Sarepta Thera- peutics’ muscular dystrophy drug, citing a competitor’s trial outcome .......... Page 12 INSIDE THIS ISSUE (See Approvals, Page 8) (See Brilinta, Page 4)
Transcript
AstraZeneca Faces DOJ Probe Into Brilinta Phase III Clinical Trial
The Department of Justice is investigating a Phase III study of AstraZeneca’s (AZ) heart drug Brilinta, which analysts and experts say could revolve around allegations of data falsification.
The investigation into the PLATO trial of Brilinta (ticagrelor) was revealed by AZ in its third quarter earnings report. The PLATO trial supported the drug’s initial approval in 2011.
AZ said it received an investigative demand from the DOJ’s civil division seeking documents and information regarding PLATO, which happened to be the subject of a critique published in last month’s International Journal of Cardiology. The trial review found, among other concerns, “an estimated 23 definite or possible cardiovascular events or deaths on tricagrelor were either not submitted for adjudica-tion, inactivated, deleted or were downgraded to ‘softer’ endpoints.”
FDA Drug Approvals Fall in 2013, But a Brighter 2014 is Projected
The FDA is expected to approve 34 new drugs this year, down from a record 43 approved in 2012. That drop is expected to be tem-porary, though, as more drugmakers adjust their pipelines to take advantage of the agency’s breakthrough therapy pathway.
The FDA so far this year has approved 28 new drugs and biologics, and six more are expected to get approval before the end of the year.
However, a new report released Nov. 13 by research firm Eval-uatePharma projects more approvals at the agency next year as the FDA speeds reviews of some 30 breakthrough designation applica-tions it has awarded, out of 100 submitted.
The FDA Safety and Innovation Act created the pathway to speed approval for drugs that treat serious or life-threatening ill-nesses, giving them priority over me-too drugs that offer little improvement in treatments.
Vol. 45, No. 45Nov. 18, 2013
The FDA’s fiscal 2013 user fees remain impounded, yet no plans have emerged in Congress to free up the funds ........................Page 2
The FDA says it may ex-tend some comment dead-lines after Regulations.gov was down for a few days earlier this month .....Page 3
Drugmaker account in-formation may have been compromised after a hack broke into CBER’s online submission system ...Page 3
J&J faces more Risperdal le-gal woes after its $2.2 billion settlement with the Depart-ment of Justice ........... Page 5
Briefs .......................Page 6
FDA Advisors recommend approval of Hetlioz, Vanda’s sleep drug.................Page 7
Comings & Goings ... Page 8
The Buzz ................Page 11
The FDA has delayed its review of Sarepta Thera-peutics’ muscular dystrophy drug, citing a competitor’s trial outcome ..........Page 12
INsIde thIs Issue
(See Approvals, Page 8)
(See Brilinta, Page 4)
Washington Drug Letter Nov. 18, 2013Page 2
Congress Idle as FDA User Fees Remain Impounded
Despite a recent ruling by the White House Office of Management and Budget (OMB) that $85 million in already collected fiscal 2013 FDA user fees remain impounded and unavailable for the agency to use, no plans have yet emerged in Congress to free up the funds.
In a bid to restart the debate about the seques-tration of the fiscal 2013 user fees, Rep. Anna Eshoo (D-Calif.) and a dozen other lawmakers had pressed OMB earlier this year to affirm the FDA’s opinion that the user fees were unavailable (WDL, Aug. 12).
The bipartisan group of lawmakers also asked for details about where the fees are being held, whether they would be used to further FDA activities for use by other federal agencies and whether the fees would earn interest.
“The sequestered fees remain as an unavail-able balance in FDA’s salaries and expenses account and are not diverted to other uses,” OMB clarified in its response to Eshoo. The fees also do not accrue interest, OMB added.
The House and Senate have both introduced bipartisan legislation that would protect user fees from sequestration starting in fiscal 2014. How-ever, neither bill applies retroactively to the fiscal 2013 fees (WDL, Aug. 12).
Both bills are stalled while the House and Sen-ate continue to negotiate the fiscal 2014 budget.
A House and Senate congressional budget conference committee met earlier this month to begin negotiating a new budget deal, but there was no specific discussion about a plan that would eliminate the sequestration threat over a 10-year period, Steven Grossman, deputy exec-utive director of the Alliance for a Stronger FDA, says.
The congressional budget conference com-mittee is expected to have an agreed-upon budget plan by Dec. 13. — Melissa Winn
Upcoming meetings through Dec. 10:
● Nov. 19: The Endocrinologic and Metabol-ic Drugs Advisory Committee will meet to discuss BioMarin’s BLA for Vimizim (elo-sulfase alfa) for the treatment 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.
● Dec. 9: The Gastrointestinal Drugs Advi-sory Committee and the Drug Safety and Risk Management Advisory Committee will hold a joint meeting to discuss two BLAs for Entyvio (vedolizumab injec-tion) submitted by Millennium Pharma-ceuticals. The first BLA seeks approval of the drug for the treatment of adults with ulcerative colitis. The second proposes an indication for the treatment of certain adults with moderately to severely active Crohn’s disease. Silver Spring, Md.
● Dec. 10: The FDA will hold a public meeting to discuss patient-focused drug development for fibromyalgia. Silver Spring, Md.
Comment deadlines through Nov. 25:
● 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.
● Nov. 20: Comments due on the FDA’s re-port Communication Report with Special Attention to Underrepresented Subpopu-lations, docket no. FDA-2013-N-0745.
● Nov. 25: Comments due on the FDA’s public workshop for patient-focused drug development for narcolepsy, docket no. FDA-2013-N-0815-0001.
FDA May extend Comment Deadlines After Temporary Regulations.gov Outage
Drugmakers looking to access FDA-related guidance and regulations via the federal website Regulations.gov were hampered by technical glitches that took the site down for several days earlier this month. The technical difficulties have prompted the FDA to consider extending comment deadlines for certain drug-related regulations and guidance.
The agency has yet to determine exactly which dockets were affected by the downtime. But the FDA’s centers are reviewing pending dockets to decide which deadlines to extend, CDER spokes-man Kristofer Baumgartner told WDL Nov. 14.
“The website’s reliability issues have caused delays in getting website content posted and gen-eral website updates. We have corrected those issues and will resume posting accurate and timely information,” he added.
Dockets that were affected by the outages and that may see comment period extensions include the agency’s new proposed rule on preventing and mitigating drug shortages, issued a few days ahead of the downtime (WDL, Nov. 4). Other dockets affected by the online interruptions include:
● Draft guidance, Patient Counseling In-formation Section of Labeling for Human Prescription Drug and Biological Prod-ucts — Content and Format, docket no. FDA-2013-D-1067. Comments were due on Nov. 18;
● Draft guidance, Endocrine Disruption Potential of Drugs: Nonclinical Evalua-tion, docket no. FDA-2013-D-1039. Com-ments were due on Nov. 19;
● The report, Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Prod-ucts, docket no. FDA-2013-N-0745. Com-ments were due on Nov. 20;
● Draft guidance, Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products, docket no. FDA-2013-D-0576. Comments were due on Nov. 22;
● Therapeutic Area Standards Initiative Project Plan, docket no. FDA-2013-N-1277. Comments are due Dec. 23; and
● Research, Experimental Study of Direct-to-Consumer Promotion Directed at Adolescents, docket no. FDA-2013-N-1151. Comments are due Dec. 30. — Johnathan Rickman
CBeR Hacked; Drugmaker Account Information May Be Compromised
The FDA says someone hacked into CBER’s online submission system last month and may have put users in danger of having their online personal identity stolen.
The agency says it detected an unauthorized network access on Oct. 15 during the government shutdown, and discovered hackers were able to obtain user account information.
On Oct. 18, the agency emailed account hold-ers about the hack and asked users to reset their passwords. In addition, it says users may need to take additional precautions. If CBER users employ their FDA password on other websites, the agency advises them to change those passwords and moni-tor those sites for unauthorized activities. If this includes financial accounts, users should consider placing a fraud alert on related accounts.
On Nov. 8, the agency quietly made the issue public by posting a message about the hack on the CBER submission site that states information for certain users including their first and last names, phone numbers, email addresses, usernames and passwords had been compromised, and they should take measures to protect their online identity.
The CBER site is used to submit information on biological product deviations, blood establish-ment registrations and tissue establishment regis-trations. So far, the agency says no system data has been altered, but it is also still analyzing whether there were any unauthorized logins to the system.
CBER declined further comment on the hack-ing incident, citing an ongoing investigation. — Ferdous Al-Faruque
GSK’s Heart Drug Flops In Phase III Clinical Trial
GlaxoSmithKline’s experimental coronary heart disease drug darapladib failed to reduce heart attacks, strokes and major cardiovascu-lar events in a closely watched Phase III clini-cal trial, deflating some expectations for GSK’s Phase III pipeline.
The STABILITY trial of darapladib, a selec-tive and orally active inhibitor intended to reduce cardiovascular events in heart disease patients, enrolled more than 15,000 partici-pants across 39 countries. The massive trial is one of two evaluating the candidate. The other, SOLID-TIMI 52, has enrolled more than 13,000 participants in 36 countries.
With STABILITY, GSK reached some sec-ondary endpoints, which await further analysis, and revealed no major serious adverse event risks, GSK said. The UK drugmaker will wait until the results of SOLID-TIMI 52, expected sometime next year, before deciding what to do next.
Some Wall Street analysts greeted the news with a shrug, citing prior doubts that the poten-tial blockbuster treatment would succeed. One analyst noted that the setback is the second recent Phase III setback for GSK; the drugmaker’s can-cer vaccine MAGE-A3 failed a Phase III trial earlier this year.
“It has been a red flag that with both candi-dates, no other pharmaceutical companies were chasing the same dream,” Bernstein analyst Tim-othy Anderson said Nov. 12. “If MAGE-A3 was a hot target then other cancer-focused pharma com-panies would have been pursuing the opportu-nity with their own products, but this was not the case,” he added.
The poor results for darapladib come as GSK’s Phase III drug candidates have begun to thin, Anderson noted. The company has numer-ous drugs in Phase III trials supporting supple-mental indications, including the leukemia drug Arzerra (ofatumumab) and its lupus treatment
Benlysta (belimumab). But most eyes are on GSK’s rheumatoid arthritis drug sirukumab, asthma drug mepolizumab and dabrafenib/tra-metinib for melanoma.
GSK acquired the rights to darapladib when it bought Human Genome Lifesciences last year for $3 billion. — Robert King
The authors of the review say it highlights serious deficiencies that need to be clarified to healthcare providers, and they urged regulators to reevaluate the data in full.
“If it was proven that there was data falsifi-cation, Brilinta could conceivably find regulators pulling their support from the drug and mandat-ing its removal from the market,” Bernstein ana-lyst Tim Anderson says.
While conceding that a DOJ prosecution has a low probability, Anderson adds it is impor-tant for investors to consider the possible damage the probe may create. He said it could halt AZ’s efforts to increase global sales of the drug, which totaled $89 million last year.
So far, the Justice Department has declined to comment on its investigation and AZ is saying little more on the matter other than it is cooperat-ing with the authorities.
AZ spokeswoman Michele Meixell tells WDL the company remains confident in the results of the PLATO trial. She notes the trial was guided by a 10-member academic group who oversaw the medical, scientific and opera-tional conduct of the study and had independent access to the data.
“The PLATO trial was fully reviewed and rig-orously analyzed by the FDA,” she added, result-ing in the drug’s approval (WDL, July 25, 2011).
The European Medicines Agency has also asked AZ for clarity on the DOJ probe. — Nick Otto, Ferdous Al-Faruque
J&J Faces More Risperdal legal Woes After $2.2 Billion Settlement
Johnson and Johnson’s guilty plea and $2.2 billion settlement with the U.S. government to resolve off-label marketing claims for its anti-psychotic Risperdal leaves the company with more legal fights ahead of it.
“We’re getting at least ten calls a day from elderly patients and their families” ready to file fresh injury suits, Stephen Sheller, founding partner, Sheller, P.C., and counsel to numerous injured plaintiffs, told WDL Nov. 14.
These new lawsuits will add to pre-existing Risperdal (risperidone) claims. As of Sept. 29, J&J had approximately 490 claims in Risperdal injury lawsuits pending in the U.S., accord-ing to the company’s latest earnings report filed with the SEC Nov. 4. Many of those were filed on behalf of teenage boys alleging the drug, which increases prolactin levels, caused them to grow breasts.
But none of those suits are directly affected by the drugmaker’s criminal plea because they don’t involve elderly dementia patients, Sheller says.
The drugmaker “carefully orchestrated” its guilty plea with the DOJ to include only the elderly, so that it wouldn’t impact any of these ongoing personal injury lawsuits, Sheller said.
The settlement agreement with DOJ resolves all of the federal government’s claims under the False Claims Act and settles Risperdal Medicaid-related claims for 45 states that joined the DOJ’s suit, according to the J&J filing.
The settlement does not, however, resolve outstanding Risperdal Medicaid-related claims brought by five states that did not join the gov-ernment’s suit, J&J spokesperson Pamela Van Houten told WDL.
There are state cases pending in Kentucky and Mississippi and appeals in progress in Arkansas, South Carolina, and Louisiana, she said.
J&J’s settlement with DOJ, which extended to two drugs in addition to Risperdal, the schizo-phrenia drug Invega (paliperidone) and the heart drug Natrecor (nesiritide), is the third-largest healthcare fraud settlement ever (WDL, Nov. 5). — Melissa Winn
CDeR Director Seeks Pathway for limited-Use Antibiotics
The FDA wants Congress to create a swift-approval pathway for antibiotics that target spe-cific patient populations, CDER Director Janet Woodcock said Nov. 15.
Under this pathway, drugmakers wouldn’t have to conduct “huge, noninferiority trials to support antibiotics for a large population,” she told report-ers following her appearance at a hearing of the House Energy & Commerce Committee’s Sub-committee on Health. “It would provide a clear and predictable path to approval … without a huge development program,” Woodcock added.
The “quid pro quo” would be an understanding that these drugs are not used to treat broader diseases such as pneumonia. “Broad and irresponsible use of antibiotics is one of the causes of the epidemic of resistance, although it is not the only cause,” she said.
How to send that message is of some debate. Woodcock said the agency wouldn’t want to put restrictions on antibiotic use, and that maybe drug packaging information could help.
If approved, the pathway would build on the success of the GAIN Act, a provision of the FDA Safety and Innovation Act that provides exclusivity perks and other incentives to promote development of antibiotics that target drug-resistant infections.
Some lawmakers have promised to intro-duce new legislation to address the deficit. Reps. Phil Gingrey (R-Ga.) and Gene Green (D-Texas) intend to introduce legislation to create the Lim-ited Population Antibacterial Drug approval path-way, which would allow a lower standard for approval for drugs that treat serious infections, sources tell WDL. — Robert King
FDA Approves Generic AciphexThe FDA has approved the first generic versions
of Aciphex (rabeprazole sodium) delayed-release tablets, used to treat gastroesophageal reflux disease (GERD) in adults and adolescents, ages 12 and up.
Dr. Reddy’s Laboratories, Kremers Urban Pharmaceuticals, Lupin Pharmaceuticals, Mylan Pharmaceuticals, Teva Pharmaceuticals and Tor-rent Pharmaceuticals Ltd. have all received FDA approval to market generic rabeprazole.
Rabeprazole is in a class of medications called proton-pump inhibitors. The medication works by decreasing the amount of acid made in the stom-ach, treating the symptoms of GERD such as heartburn, regurgitation of acid, and nausea.
FDA Plans Sentinel UpdateThe FDA and the Engelberg Center for Health
Care Reform at the Brookings Institution plan to bring industry stakeholders together to discuss the status of the agency’s Sentinel Initiative and future plans for medical product surveillance.
The public workshop, dubbed the “Sixth Annual Sentinel Initiative” will also cover high-lights of key Mini-Sentinel and related activities and provide an update on active surveillance col-laborations and program extensions.
As part of the workshop, which is an FDA commitment within the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), will engage stakeholders to discuss current and emerging Sentinel projects and facilitate stake-holder feedback and input on Sentinel projects that would be appropriate to determine the fea-sibility of using Sentinel to evaluate drug safety issues that may require regulatory action or post-marketing commitments.
The public workshop will be held on Jan. 14, 2014 in Washington, D.C.
To attend the public workshop, stakeholders must be must registered before Jan. 14, 2014, and can do so by visiting www.cvent.com/d/jcqhyy.
Perrigo Recalls Generic TylenolPerrigo is recalling 18 batches of its infant
suspension liquid because some of the packages may contain a syringe without dose markings, making inaccurate dosing and overdose possible, the FDA said in a Nov. 1 safety alert.
Perrigo is recalling infant acetaminophen liq-uid in 160 mg/5 mL size packages, sold in 2 and 4 ounce bottles with syringes. The syringes are supposed to have a white or yellow plunger with dose markings for 1.25, 2.5, 3.75 and 5 mL.
“There are no issues or concerns with respect to the safety or efficacy of the product, only the potential that the oral dosing device in a relatively small number of packages could be unmarked,” said Perrigo CEO Joseph Papa said. There have been no reports of complaints and no products have yet been found with the unmarked dosing syringes.
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GSK’s Academic Collaborations Net Several Prospective Pipeline Drugs
GlaxoSmithKline is close to designating sev-eral new chemicals ready for clinical research as a result of successful collaborations with aca-demia, the drugmaker said Nov. 6.
GSK’s novel drug discovery program, Discov-ery Partnerships with Academia (DPAc), has led to nine collaborations in nine disease areas, the pharma giant said. The novel approach to finding new drug candidates includes academic partners as “core members of drug-hunting teams,” where GSK’s partners share the risk and reward of innovation.
Industry leaders have stressed the need to find these innovative research and development models as financial constraints tighten research budgets.
A lack of funding opportunities is driving new partners into each other’s arms, former PhRMA board chair Chris Viehbacher has said. “If we come up with these new models, we can really capitalize on these new opportunities,” he added.
As part of GSK’s DPAc program, which launched in 2010, the drugmaker says it funds activities in the partner laboratories and provides in-kind resources to “progress a program from an idea to a candidate medicine.”
The academic partner and GSK “speak regu-larly to share data, critique that data and decide on the next steps,” according to Stephen Tapscott of the Fred Hutchinson Cancer Research Center.
Under the DPAc program, Tapscott’s team is collaborating with GSK to identify drugs that could be effective in interfering with DUX4, the gene found responsible for causing facioscapulo-humeral muscular dystrophy.
GSK is also collaborating with Vanderbilt University research teams to find treatments for childhood obesity. As part of the partner-ship, Vanderbilt is conducting the pharmacol-ogy and pre-clinical testing, while GSK attempts to develop chemically similar compounds to ones previously realized by Vanderbilt, but with improved activity and efficacy.
As part of that agreement, GSK provides research support to Vanderbilt and additional payments for meeting project milestones and a share of royalties. The goal is to begin Phase I human trials by 2016.
Collaborations formed under GSK’s DPAc program also include developing new treatments for genetic diseases, preventing multiple organ failure, working with small molecule stabilizers and preventing muscle atrophy, the drugmaker added. — Melissa Winn
FDA Advisers Recommend Approval Of Vanda’s Sleep Drug for the Blind
FDA advisers overwhelmingly voted Nov. 14 to recommend approval of Vanda’s sleep drug tasimelteon for the visually impaired despite some concern over a clinical trial’s primary endpoint.
The Peripheral and Central Nervous Sys-tem Drugs Advisory Committee voted 11-0 that the drug, dubbed Hetlioz, was adequately safe and 10-0, with one abstention, that it has demon-strated efficacy. The one abstention was Justin Zivin, University of California San Diego, who disagreed with the endpoints used by Vanda.
While the sponsor preferred to use a biomarker, the agency asked for endpoints that could show clinical benefit. Vanda eventually used entrainment in addition to several secondary endpoints to show nighttime and daytime sleep and napping outcomes to bolster data from two Phase III trials.
While FDA reviewer Devanand Jillapalli said the agency was initially concerned with a Type 1 error arising from trials due to the fact the end-points were chosen after the studies had begun, he noted the agency was satisfied the drug’s clini-cal benefit had been independently verified with substantial evidence.
Tasimelteon is intended to help treat blind people who suffer from Non-24, a sleep-wake disorder caused when patients’ circadian rhythms are disrupted due to lack of light.
The FDA has set Jan. 31, 2014 PDUFA date for the drug. — Ferdous Al-Faruque
Washington Drug Letter Nov. 18, 2013Page 8
Soliris Recall Could Cost Alexion $25 Million to Fix
Alexion’s recall and replacement of vials of its rare disease drug Soliris could cost the company between $10 and $25 million in the fourth quarter, the drugmaker said in a Nov. 12 SEC filing.
The recall and replacement was prompted by the presence of visible particles observed as part of Alexion’s periodic testing of retained samples. “Post-release testing from the two affected lots met quality specifications prior to the recent obser-vations,” the filing states. “There have been no identifiable safety concerns attributed to the prod-uct consumed from these lots to date,” it adds.
The biotech declined to state the exact num-ber of vials affected by the market correction, but said they represent less than one percent of its total inventory.
The move follows an August recall and replacement of a single lot of Soliris (eculi-zumab) due to the presence of similar visible particles. The lot recalled in August, and the two current affected lots, were filled by the same contract vialer, Alexion says. Upon further investigation, Alexion now believes it has iden-tified the filling process step that resulted in the presence of particles. The company has since implemented the change necessary to correct the issue, the filing states.
Alexion has engaged an additional contract vialer for Soliris, using the corrected process step, which is expected to be approved in 2014.
Alexion declined requests for more details about the process step at issue and the total num-ber of vials recalled. — Johnathan Rickman
The coveted designation provides products a priority review schedule of six months. However, since the drugmaker “works closely with the FDA throughout the clinical and filing processes, many believe that even faster decisions are pos-sible,” the report says. Companies that redirect their research efforts toward these categories could benefit tremendously.
To access FDA Approval Rates: Niche Prod-ucts Driving Record Success, visit www.evaluate group.com/Public/Reports/EPVantage-FDA-Appr ovals.aspx. — Robert King
letter Issue Date Company Name Issuing Office Subject Close Out
Date
11/8/2013 Aegerion Pharmaceuticals Office of Prescription Drug Promotion
Misbranding Juxtapid (lomitapide) Not Issued
Approvals, from Page 1
FDA WARNING leTTeR(S)
FDA Warning Letters Posted on Nov. 11, 2013
Comings & GoingsFormer Novo Nordisk general counsel
James Shehan has joined Hyman, Phelps & McNamara. Shehan’s work at the firm will focus on the handling of federal enforcement actions; corporate compliance and GMPs; Hatch-Wax-man and advertising litigation; private and pub-lic transaction due diligence; drug development; and biosimilars.
Bristol-Myers Squibb has made changes to its senior management team, including appoint-ing Giovanni Caforio to the newly created position of executive vice president and chief commercial officer. Charles Bancroft, execu-tive vice president and chief financial officer, will also take on an expanded role that includes the business development and strategy groups. Murdo Gordon has been appointed president, U.S.; and Beatrice Cazala, executive vice presi-dent of commercial operations, will also transi-tion to a new, unnamed role at the company.
FDA Advisors Wary of Sanofi’s lemtrada as First-line MS Drug
A panel of FDA advisors Nov. 14 overwhelm-ingly voted against approval of Sanofi’s Lemtrada for an expanded indication to treat relapsing mul-tiple sclerosis (MS).
Citing data from two pivotal studies of Lem-trada (alemtuzumab), agency advisors high-lighted potential risks of autoimmune and thy-roid diseases and various adverse events in dismissing the drug as a first-line therapy for MS patients, voting 16-0, with two abstentions, along those lines.
However, the Peripheral and Central Nervous System Drugs Advisory Committee also voted 12-6 that data for Lemtrada did show substantial evidence of effectiveness in relapsing MS, giving the sponsor — and FDA officials — conflicting messages.
To allay safety concerns, Sanofi subsidiary Genzyme is proposing to provide monthly blood tests for patients and to analyze adverse event reports. The drugmaker also proposes to restrict the MS drug’s distribution to certified and trained physicians.
Since the approval of Biogen Idec’s MS drug Tysabri (natalizumab) in 2004, patient blood test-ing has become much more rigorous and much improved, Edward Fox, University of Texas and an advisor to Genzyme, said. “I don’t see it becoming lax. I haven’t had trouble,” he added.
But the advisory panel was generally uncon-vinced, with David Blumenthal, Case West-ern Reserve University, saying there’s “no going back” if an approval nod later turned sour.
The vote was preceded by a generally neg-ative assessment by FDA reviewers, who also raised concerns about trial design and bias in pre-meeting briefing documents.
Agency officials said bias may have occurred in the supporting studies that could have affected relapse rates.
The failure to blind patients and treating phy-sicians in the open-label design of the trials was also disconcerting to agency reviewers.
Lemtrada is currently approved in the U.S. as a treatment for B-cell chronic lymphocytic leu-kemia. It is approved in the EU as a treatment for adults with relapsing-remitting MS. — Nick Otto
Daiichi Sankyo Receives Untitled Letter for False Efficacy Claims
The FDA has handed Daiichi Sankyo an unti-tled letter for making claims in a brochure that two of its hypertension treatments helped lower blood pressure in patients with severe hypertension, despite a lack of substantial supportive evidence.
In a mailing to physicians promoting Benicar (olmesartan medoxomil) tablets and Benicar HCT (olmesartan medoxomil-hydrochlorothiazide) tab-lets, the drugmaker reported results from an open label, uncontrolled trial. However, FDA cited three reasons why the promotion failed to satisfy requirements for efficacy claims:
● The trial lacked placebo control or blinding; ● The trial it cited excluded patients with
severe hypertension; and ● The mailer featured a bar graph that
depicted a greater reduction in blood
pressure than was actually seen in the clinical trial.
The agency is asking Daiichi Sankyo to stop distributing the mailer. The company said it has complied with the request.
“Daiichi Sankyo is currently reviewing the contents of the letter and will work to quickly identify any other marketing pieces that may include a similar representation of this data,” spokeswoman Alyssa Dargento told WDL. “The piece in reference was a one-time distribution and is no longer given to physicians.”
The untitled letter to Daiichi Sankyo is the 14th untitled letter issued by the FDA this year. At this time last year, the agency had already issued 23 such letters.
The untitled letter can be read at www.fdanews.com/ext/files/11-08-13-UntitledLetter.pdf. — Robert King
As Audit Questions linger, CMS Clarifies on Sunshine Act Reporting
Although drugmakers are still unclear about how and when their compliance with the Physi-cian Payment Sunshine Act will be audited or enforced, the Centers for Medicare & Medic-aid Services (CMS) has shed some light on some parts of the law. In newly published guidance, the agency has told drugmakers:
● Payments made outside the U.S. must be reported;
● Companies must report the 10-digit Na-tional Drug Code that matches a drug or biologic associated with a payment;
● Donations provided to a teaching hos-pital’s foundation at the request of or on behalf of a physician are reportable;
● Companies do not need to report the name of third parties, such as contractors, that indi-rectly provide a research payment to a physi-cian or other entity covered under the law;
● Legal proceedings that require physician involvements are excluded from report-ing, including, legal defense, prosecu-tions, settlement or judgment of a civil or criminal action and arbitration or other legal action;
● Only applicable manufacturers and appli-cable group purchasing organizations that have reportable payments or other trans-fers of value, ownership or investment in-terest, or both are required to register; and
● Retroactive reporting is not required. Enti-ties determined to be applicable manu-facturers because they have at least one
product that became a covered drug, have a grace period of 180 days following a drug, biological or medical supply becoming covered to begin complying with the data collection and reporting requirements.
CMS has also slightly raised 2014’s minimum reporting threshold under the act from gifts or pay-ments valued at $10 to $10.18 for individual pay-ments, and $101.75 for aggregate payments, up from the 2013 limit of $100. The thresholds track the con-sumer price index and will be adjusted annually.
In addition to clarifying details, CMS also plans a series of introductory educational webinars about the Sunshine Act, the first of which is sched-uled for Nov. 19. That webinar, covering registra-tion and data submission components, will be fol-lowed by an open-discussion session Dec. 3.
The Sunshine Act requires disclosure to CMS of manufacturer payments to physicians and teaching hospitals. Drugmakers must first report data by March 31, 2014. CMS will publish the data on a public website in September 2014 (WDL, Feb. 4).
At least one lawmaker, Rep. Robert Andrews (D-N.J.), is also asking CMS to further change its rules by exempting food served at events con-nected to continuing medical education from the requirements.
To register for the webinar, go to https://event.webcasts.com/starthere.jsp?ei=1025494. For more information on the act, visit www.cms.gov/Regul ations-and-Guidance/Legislation/National-Physi cian-Payment-Transparency-Program/index.html. — Robert King, Johnathan Rickman
Date Requester Requested Information
9/30/2013 Dr. Reddy’s Labs Summary basis for approval for Sun Pharma’s ANDA for doxorubicin HCl liposomal injection.
9/30/2013 Deerfield Institute Form 483 issued on March 15, 2013, to Biogen Idec.9/30/2013 Jones Day Approval for Dr. Reddy’s Labs’ ANDA for azacitidine.
9/30/2013 Isabella Biedenharn Adverse Event Reports for Yasmin (drospirenone/ethi-nyl estradiol).
FDA FOIA lOG
The FDA received 100 FOIA requests the week of Sept. 30 including the following.
View the complete FOIA log for the week of Sept. 30 at www.fdanews.com/ext/files/11-13-13-FOIALog.pdf.
Richard Bergström is the director general of the Euro-pean Federation of Pharmaceu-tical Industries and Associations (EFPIA). Bergström, a pharma-cist by training, was previously director general of LIF, Swe-
den’s research-based pharmaceutical industry group. He also held senior positions at Roche and Novartis.
WDL: How can the industry better communi-cate prescription information and better commu-nicate with patients?
Direct-to-consumer advertising is not allowed in the EU. And we do not want it. But we want to be able to provide factual infor-mation. However, most countries do not even allow companies to put the labeling on their websites. A few years ago the European Com-mission suggested that companies should be allowed to provide factual information on web-sites. The European Parliament concurred and pointed to the Swedish model: the website www.fass.se is run by industry and has all the product information. Unfortunately, the propos-als were blocked by the member states. On [get-ting] information to patients, Europe is stuck in the last century.
WDL: How can industry better use emerging technology to advance personalized medicine?
The biggest challenge in delivering on the promise of personalized medicine is the lack of regulatory pathways. Even if the FDA showed in its recent (and excellent) report how the agency uses its tools and f lexibilities as best as they can, we are still stuck in a model that expects tens of thousands of patients in ran-domized controlled trials. We need more adap-tive approaches, including relying more on real-world data. In Europe, the EMA is simi-larly in the right place intellectually, but most
guidelines still do not reflect today’s under-standing of disease. We are piloting adaptive pathways, including the use of pragmatic trials in Phase III.
In addition, there is an urgent need for new incentives for new indications. If we are sup-posed to go back and repurpose all the existing (and abandoned) medicines using the new sci-ence, who would invest in off-patent medicines? Incentives for companion diagnostics and valida-tion of biomarkers should also be considered.
WDL: In the U.S., generic injectables seem to top the list of drug shortages. Is that the case in the EU? EFPIA recently released good practice guidelines to tackle the problem. What more can industry do to avoid shortages?
The European situation is more complicated than in the U.S. People mix up the problems. We have 28 countries with national package con-figurations and different government-regulated prices. This results in parallel trade that fluctu-ates and can cause shortages. Also, a company may for commercial reasons (such as repeated price cuts by the government) decide not to con-tinue in one specific country. Both these exam-ples are reported in debate as “shortages.”
Turning to “real” shortages where the com-pany wants to supply a drug but cannot, we have the same problem as in the U.S. with off-patent products. We are currently working with the EMA and the other stakeholders (wholesal-ers, pharmacists, parallel distributors) on better reporting systems. I think industry can do a bet-ter job in expressing to payer groups when mar-ket conditions are not sufficient. Maybe the only benefit of regulated prices is that they can go up if the arguments are right. The French govern-ment allowed price increases for a range of older products that were at threat of being decommis-sioned. But that was a rare event. Many payers are not open for such a discussion.
Sarepta’s Muscle-Wasting Disease Drug Sidelined by Competitor’s Trial Failure
The FDA has delayed Sarepta Therapeutics’ NDA submission for its Duchenne muscular dys-trophy (DMD) drug because of a failure in tri-als of a similar drug. It’s the latest instance of a drugmaker’s development program being side-lined as a result of the FDA citing a competitor’s trial outcome.
Sarepta had hoped to submit its NDA for eteplirsen, the drugmaker’s lead drug candidate, next year based on positive results from a small Phase II study showing the drug increased produc-tion of dystrophin. The muscle-wasting disease DMD, which affects only boys, is associated with specific errors in the gene that codes for dystrophin.
But the recent trial failure of a competing drug made by GlaxoSmithKline and Prosensa, and previous negative reports about a similar drug’s efficacy, raise considerable doubt about the use of dystrophin as a biomarker, the FDA said in comments prior to a meeting with Sarepta.
Citing a lack of confidence in the capacity of the dystrophin biomarker to predict clinical ben-efit, the FDA called an NDA filing for eteplirsen premature. The agency has advised Sarepta to reconsider the endpoints and enrollment criteria for its planned confirmatory study of eteplirsen.
Specifically, the agency questioned the use of a six-minute walk test to demonstrate the drug’s clinical benefit. The test excludes both young boys with DMD who cannot perform such a
demanding test and older boys who can no longer walk, the agency said.
“We are concerned that seemingly unavoid-able limitations on enrollment could undermine study feasibility,” the agency cautioned. “Motor scales that measure broader range of function and demand less sustained effort” could be appropri-ate for a much wider range of boys.”
The FDA’s request to discuss different clinical endpoints and different DMD subpopulations for its confirmatory clinical trial, along with their ques-tions about dystrophin as an acceptable biomarker, will delay the start of the confirmatory trial “until at least the second quarter of 2014,” the drugmaker said Nov. 12. A follow-up meeting with the agency has been scheduled for later this month.
In a similar case, the FDA last month rescinded the special protocol assessment (SPA) for Amarin’s ANCHOR study of its heart drug Vascepa for similar reasons. Results from three separate outcome trials of other heart drug candi-dates failed to support Amarin’s hypothesis, the FDA said at the time (WDL, Nov. 4).
FDA spokeswoman Lisa Kubaska told WDL that CDER strives to provide advice to spon-sors about their proposed development plans that is based on the agency’s current understanding of the available science. “In some cases, emer-gence of new scientific information may result in a change to our previously stated advice, and CDER strives to promptly notify sponsors of such changes so that new development pathways can be explored,” she said. — Melissa Winn
Reporters: Nick Otto, Elizabeth Orr, Ferdous Al-Faruque, Lena Freund, Robert King
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