FDA to Require Advanced Notice of Potential Manufacturing Stoppages Certain drug and biologic manufacturers must notify the FDA at least six months before they believe a product may be perma- nently discontinued or experience an interruption in manufacturing, according to a new proposed rule published Oct. 31. The agency says if six months’ notice is not possible, drugmakers should notify the agency about a potential stoppage “as soon as prac- ticable thereafter, but in no case later than ﬁve business days after the permanent discontinuance or interruption in manufacturing occurs.” “In our experience, even if it’s not possible for an applicant to notify the agency before a permanent discontinuance or an interrup- tion in manufacturing occurs, it should generally be possible for the applicant to provide notice within a day or two,” the FDA says in a summary of the rule. FDA Touts Personalized Medicine Model for Drug Development A new FDA report outlining the agency’s efforts to regulate drug development in the context of personalized medicine promotes the approach as a boon for both innovation and patient safety. The report, released Oct. 29, notes that since 2011, about a third of newly approved drugs used some type of genetic or other bio- marker data in the drug submission to characterize efﬁcacy, safety or pharmacokinetics — tools intrinsic to advancing the promise of personalized medicine. While generally optimistic, the report also lists some of the key concerns the agency has for the future of the drug development approach, including the perceived notion by drugmakers that such an approach may have a lower return on investment due to targeting of smaller populations. Vol. 45, No. 43 Nov. 4, 2013 GPhA calls fourth ANDA stability testing time point an overreach ............. Page 2 FDA Calendar .......... Page 2 Genentech’s leukemia drug is ﬁrst FDA breakthrough therapy approved ...... Page 3 FDA investigators clarify issues with draft inspection guidance................... Page 3 Expedited drug reviews raise safety concerns, indus- try experts warn ....... Page 5 FDA mulls standardized international laboratory data for drug applications .. Page 5 FDA DTC study could impact advertising targeting adolescents ............... Page 7 Combination product mak- ers prod FDA for more guidance................... Page 8 Underperforming diabetes drugs impede Merck re- structuring plans ...... Page 9 FDA asks Ariad to halt U.S. sales of Iclusig ........ Page 10 Briefs ..................... Page 11 Comings & Goings... Page 11 INSIDE THIS ISSUE (See Personalized Medicine, Page 6) (See Shortages, Page 4)
FDA to Require Advanced Notice of Potential Manufacturing Stoppages
Certain drug and biologic manufacturers must notify the FDA at least six months before they believe a product may be perma-nently discontinued or experience an interruption in manufacturing, according to a new proposed rule published Oct. 31.
The agency says if six months’ notice is not possible, drugmakers should notify the agency about a potential stoppage “as soon as prac-ticable thereafter, but in no case later than five business days after the permanent discontinuance or interruption in manufacturing occurs.”
“In our experience, even if it’s not possible for an applicant to notify the agency before a permanent discontinuance or an interrup-tion in manufacturing occurs, it should generally be possible for the applicant to provide notice within a day or two,” the FDA says in a summary of the rule.
FDA Touts Personalized Medicine Model for Drug Development
A new FDA report outlining the agency’s efforts to regulate drug development in the context of personalized medicine promotes the approach as a boon for both innovation and patient safety.
The report, released Oct. 29, notes that since 2011, about a third of newly approved drugs used some type of genetic or other bio-marker data in the drug submission to characterize efficacy, safety or pharmacokinetics — tools intrinsic to advancing the promise of personalized medicine.
While generally optimistic, the report also lists some of the key concerns the agency has for the future of the drug development approach, including the perceived notion by drugmakers that such an approach may have a lower return on investment due to targeting of smaller populations.
Vol. 45, No. 43Nov. 4, 2013
GPhA calls fourth ANDA stability testing time point an overreach .............Page 2
FDA Calendar ..........Page 2
Genentech’s leukemia drug is first FDA breakthrough therapy approved ......Page 3
FDA investigators clarify issues with draft inspection guidance ...................Page 3
FDA asks Ariad to halt U.S. sales of Iclusig ........Page 10
Briefs .....................Page 11
Comings & Goings... Page 11
INsIde thIs Issue
(See Personalized Medicine, Page 6)
(See Shortages, Page 4)
Washington Drug Letter Nov. 4, 2013Page 2
GPhA Calls Fourth ANDA Stability Testing Time Point an Overreach
GPhA wants the FDA to eliminate a proposed requirement that ANDA sponsors submit an additional, fourth stability time point for acceler-ated testing conditions, which the group says is not consistent with international regulations.
Responding to a draft question-and-answer guidance on the testing issue, issued by the agency in August, the group said no other highly regu-lated region in the world requires a fourth stability time point, and that the requirement never came up during stakeholder meetings with the agency.
The guidance recommends that four time points be used in the stability study design for all ANDAs, with the time points reflecting the ini-tial release of the batch, three months, six months and one additional time point of the sponsor’s choosing (WDL, Sept. 2).
“FDA has stated in its draft guidance and final guidance that the purpose for the changes to ANDA stability testing is to be consistent with [the Interna-tional Conference on Harmonisation (ICH)],” GPhA said. “ICH does not include a fourth stability time point for accelerated testing conditions.”
The FDA first floated the six-month stability requirement in draft guidance last year. The pre-vious requirement was for three months of stabil-ity data (WDL, Oct. 1, 2012).
GPhA also requested the agency revise its recommendation that all batches be produced at the same commercial site. Small-scale batches are sometimes manufactured in a separate R&D pilot area and then transferred for manufacturing to a larger facility.
OTC drug manufacturer Perrigo also com-mented on the draft Q&A guidance, citing a rec-ommendation that drugmakers provide statistical analysis of stability data as appropriate. Perrigo said it would be helpful if the agency provided some “specific examples of cases where it would be appropriate to provide statistical analysis and the type of analysis that would be expected.”
The FDA received 29 comments on the draft guidance by Oct. 28, when the comment period closed. To read GPhA’s comments, visit www.fdanews.com/ext/files/10-29-13-GPhAComments.pdf. — Robert King
Upcoming meetings through Nov. 14:
● Nov. 4: The Pediatric Oncology Subcom-mittee of the Oncologic Drugs Advisory Committee will meet to review the FDA’s use of patient reported outcomes in pedi-atric cancer patients. Silver Spring, Md.
● Nov. 5: The Pediatric Oncology Subcom-mittee of the Oncologic Drugs Advisory Committee will meet to discuss the po-tential applicability of pharmacological and cellular manipulation of the immune system as a potential therapeutic interven-tion in various pediatric cancers. Dur-ing the afternoon session, the committee will discuss pediatric development plans for Novartis’ LEE011, a product in early-stage development for adult and pediatric oncology indications. Silver Spring, Md.
● Nov. 12-14: The FDA will hold a training course for clinical investigators. College Park, Md.
Comment deadlines through Nov. 18:
● Nov. 12: Comments due on the draft guid-ance Bioequivalence Recommendations for Fluticasone Propionate; Salmeterol Xin-afoate, docket no. FDA-2007-D-0369-0261.
● Nov. 18: Comments due on the draft guid-ance Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products — Content and For-mat, docket no. FDA-2013-D-1067-0001.
Editor’s NoteThere was no FDA FOIA log available nor any
pharmaceutical company warning letters posted this week. Those features, as well as The Buzz, will return in future issues of the Washington Drug Letter.
FDA Approves First Drug Under Breakthrough Therapy Pathway
The FDA Nov. 1 approved the first drug under its breakthrough therapy pathway, one year after it began accepting applications in the category.
Genentech’s leukemia drug Gazyva (obinutu-zumab) was the first to win approval and was one of 30 applications the FDA has awarded the designa-tion to out of 100 applications it received. The time from its initial IND application in 2009 to approval was 4.9 years, with five months for a review. The FDA has asked Genentech for two minor post-mar-keting commitments related to manufacturing.
While the approval did not represent a sub-stantial change from its PDUFA deadline of December 20, approval times may improve for applications that begin their process as a break-through therapy, and Genentech praised the pro-cess overall.
The breakthrough therapy designation is awarded to drugs that demonstrate potential for significant advances over existing therapies and receive greater FDA staff support, including more frequent meetings with the agency and an FDA contact responsible for shepherding the applica-tion through agency reviews and breaking any log-jams that emerge. The company “had a very col-laborative experience working with the FDA,” said Krysta Pellegrino, a spokesperson for Genentech.
Gazyva is designed to boost the immune sys-tem’s ability to attack cancer cells. It will be used in combination with chlorambucil, another drug used to treat patients with chronic lymphocytic leukemia.
Approval was based on clinical studies of 356 people. Those receiving both Gazyva and chlo-rambucil had an average of 23 months of pro-gression-free survival compared to 11.1 months among participants who received chlorambucil alone, the FDA said.
The drug comes with a boxed warning about risks of hepatitis B virus reactivation and a rare brain disorder known as progressive multifocal leukoencephalopathy.
The FDA’s announcement follows another vic-tory last month for Genentech when its breast cancer drug Perjeta (pertuzumab) was the first drug to gain approval via the FDA’s new accelerated approval pathway carved out for pre-surgery therapies for early-stage breast cancer surgery (WDL, Oct. 7).
“Gazyva is an important new medicine for people with newly diagnosed chronic lymphocytic leukemia as it more than doubled the time people lived without their disease worsening compared to chlorambucil alone,” said Hal Barron, chief medi-cal officer and head of global product development at Genentech. “We have spent 20 years research-ing blood cancer medicines, and we will continue to study Gazyva to assess its efficacy in other types of blood cancers.” — Nick Otto
FDA Investigators Clarify Issues With Draft Inspection Guidance
FDA draft guidance on what constitutes delaying or denying an inspection continues to leave drugmakers concerned about how to inter-act with agency investigators on issues such as photos and records retrieval.
A group of investigators from the FDA’s Bal-timore district offered their insights and best practices on how to address those issues during a roundtable at FDAnews’ Inspections Summit, which ran Oct. 23-25 in Bethesda, Md.
One key topic discussed at the summit was whether it would be considered limiting an inspec-tion if an investigator is not given access to nec-essary documents for an “unreasonable period of time” (WDL, July 15). Drugmakers commented that the draft guidance provides no explanation on what is “unreasonable” in that regard (WDL, Oct. 7).
It turns out that the answer is 24 to 36 hours, at least for investigators at the FDA’s Baltimore district.
“If you have a problem getting a record, explain it to your investigator,” said investigator Lori Lawless.
Consequences for companies that don’t notify the agency don’t appear to be severe. The agency would issue a non-compliance letter to the com-pany and post it on the FDA’s website — an extension of the agency’s new name-and-shame enforcement push (WDL, Sept. 9).
The agency said it plans to provide some flex-ibility on the reporting requirements. For exam-ple, “if notification under the proposed rule is triggered only by the inability of an applicant to ship at least 90 percent of its full quantity of a particular drug product as reasonably ordered by its customers for more than four weeks (10 per-cent reduction in supply), if an applicant were able to ship 92 percent of its supply (i.e., it expe-riences an eight percent reduction in supply), the interruption would not be reportable to the FDA.”
The proposed rule, which implements a key provision of the FDA Safety and Innovation Act, is expected to have an outsized impact on mak-ers of generic injectable drugs, a sector that has been beset by manufacturing quality problems in recent years.
The agency the same day also rolled out a strategic plan to tackle drug shortages in a two-pronged effort to bring formal oversight to volun-tary early-notification activity that the FDA has encouraged. FDA officials touted some success on early notification, noting that the total number of new shortages decreased from 251 in 2011 to 117 last year.
Who Does It Affect?
Once finalized, the rule would affect appli-cants that hold an NDA or ANDA for life-sup-porting drugs, life-sustaining drugs or products needed to treat or prevent a debilitating disease or condition associated with mortality or morbid-ity. The rule defines “life-supporting and sustain-ing drugs” as “products that restore or continue a necessary bodily function,” fulfilling an indus-try request for greater clarity on the terms (WDL, June 11, 2012).
The early-notification rule also applies to all biologic products such as vaccines, blood or blood components for transfusions, plasma-derived products and recombinants.
The agency asks affected manufacturers to notify the FDA electronically so the notices can be archived. The notification must include the name of the applicant and drug or biologic. The notification should also list a reason for the short-age and give a “best estimate” of how long a manufacturing stoppage will last. If that estimate were to change after the notification is filed, the applicant should notify the FDA.
Manufacturers are affected by the rule, even if it is a contract manufacturer that makes the product. Companies are encouraged to make sure their contract manufacturer has a process that ensures timely reporting to the FDA of any inter-ruptions or discontinuance, the rule states.
Crafting a Shortage Strategy
The strategic plan proposes to offer finan-cial incentives for companies that sustain man-ufacturing and product quality improvements. The plan does not specify what incentives will be offered, noting the FDA’s “ability to offer finan-cial or other economic incentives for innovation and new investments in high-quality manufactur-ing is limited.”
The agency also plans to improve its short-ages database and improve public communication about shortages. Officials on the call touted the development of a smartphone app that could pro-vide instant information on shortages.
Industry reaction was measured, with PhRMA saying it was “reviewing” the plan and rule, and touted industry progress on shortages.
The rule, docket no. FDA-2011-N-0898, is available for public comment until Jan. 3. To read it, visit www.fdanews.com/ext/files/10-31-13-ProposedRule.pdf. The strategic plan can be read at www.fdanews.com/ext/files/10-31-13-StrategicPlan.pdf. — Robert King
Expedited Drug Reviews Raise Safety Concerns, Industry Experts Warn
Because fewer patients are studied as part of the expedited drug approval process, many such drugs hit the market with significant safety ques-tions unanswered, a study released Oct. 28 says.
Drugs approved in 2008 under the FDA’s expedited drug approval program took on aver-age five years of clinical development time to gain approval, compared with seven and a half years for drugs under standard review, according to the study, published in JAMA Internal Medi-cine. And expedited drugs were tested for effi-cacy in an average of 104 patients compared to 580 patients for standard review, it adds.
That year, the agency approved 20 drugs — eight under expedited pathways and 12 under standard review.
“We’re living in a world in which patients are exposed to the drugs first, and we’re learn-ing about the risks postmarket,” Thomas Moore, one of the study’s authors, told WDL. And, while approval times continue to increase, postmarket safety actions have slowed, he added.
According to Moore, senior scientist, drug safety and policy at the Institute for Safe Medica-tion Practices, by 2013, many of the postmarket-ing studies conducted to gather additional evi-dence on the safety of the eight expeditiously approved drugs had not been completed.
Overall, the FDA required 85 postmarketing stud-ies for 19 of the 20 drugs approved, the study showed. By January 2013, only 26 of the study commitments had been fulfilled and another eight had been sub-mitted for FDA review. Further, substantial addi-tional risks were discovered in the four-year period after approval, the study notes. Five of the drugs later received new or expanded boxed warnings.
“When you take shortcuts, you take risks,” Moore said. “If you’re only conducting studies in 104 patients, you’re not getting any information on vulnerable subgroups,” he added. And shortened clinical trial times also mean studies are failing to glean critical information on long-term effects.
The FDA in late June issued guidance detail-ing how to make use of, and differentiate between, its four expedited programs (WDL, July 1).
In the draft guidance, the agency notes the “possibility that clinical benefit may not be veri-fied in post-approval confirmatory trials.” Thus, it adds, “the FDA recognizes, as a general matter, that it is preferable to have more than one treat-ment approved under the accelerated approval pro-visions” for the same indication. — Melissa Winn
FDA Mulls Standardized International laboratory Data for Drug Applications
After years of consideration, the FDA says it may soon require drugmakers to submit lab data using Système International (SI) units instead of U.S. conventional units when filing drug appli-cations, making the UK the lone holdout using ounce and fluid ounce measurements.
FDA spokesperson Stephen King told WDL Oct. 30 the agency currently does not have a standard method of measurement for data sub-missions, and that sponsors “can and do” submit data in either measuring standard, which creates inconsistency for reviewers.
By allowing sponsors to file a single set of data in drug applications across multiple regulatory authorities, the move would present a “significant cost benefit,” King said. It will also allow clinical researchers in different parts of the world to share data and collaborate on research topics without requiring up-front data conversions, he added.
The agency is considering a gradual and piecemeal transition to the SI system by continu-ing to allow certain lab results to be presented to the agency using conventional units.
“CDER and CBER are currently evaluating com-mon and therapeutic area-specific lab tests to deter-mine which pose significant interpretation risks dur-ing the review of new drug applications,” the FDA said. “While this evaluation is underway, sponsors are strongly encouraged to solicit input from review divisions as early in the development cycle as pos-sible to minimize the potential for conversion needs during NDA/BLA review.” — Ferdous Al-Faruque
“With the successes of the past couple of years, the use of targeted approaches with com-panion diagnostics or based on some other fac-tors has really shown that this is a viable model for drug development,” Mike Pacanowski, an associ-ate director of CDER, told reporters during a meet-ing followed by a tour of the FDA’s campus in Sil-ver Spring, Md. “Whether it’s going to be as much value to the industry as blockbuster approaches I think that remains to be seen,” he added.
The FDA notes some of the industry concerns may be offset by increased safety and effective-ness of the drugs that can be based on smaller trial designs and “leads to rapid uptake, premium pricing and increased patient compliance.”
Rick Pazdur, director of the agency’s Office of Oncology and Hematology Products, told reporters that in terms of cancer drug develop-ment, personalized medicine isn’t deterring spon-sors. On the contrary, niche drug markets are actually seeing more competition, he said.
Pazdur also raised the question of whether all cancer drug trials needed to be randomized, especially in situations where the treatment has shown to be extremely effective in subpopula-tions based on previous evidence. He said it is a conversation that the agency and stakeholders need to have to improve drug development in the personalized medicine context.
The FDA report also notes that co-develop-ment of multiple medical products is essential to the success of personalized medicine, including companion diagnostics, but acknowledged there are key challenges regulators and sponsors need to tackle. The first such issue noted by the agency is timing and alignment of the development strat-egies of the products.
“This can be challenging, since sometimes the need for the companion diagnostic may not be evident until late in the development of the drug, or the need to change the test might arise during the course of the trial,” the report states. The agency also notes it may be challenging to
find a balance between a narrow patient popula-tion and a trial design with sufficient power. The FDA, in both these cases, refers sponsors to its guidance on enrichment strategies released late last year (WDL, Dec. 24, 2012).
Other challenges noted by the agency in the report include limited understanding of the intrin-sic biology of diseases being studied; complexity in understanding conditions that involve multiple biomarkers; and the lack of infrastructure to col-lect, analyze, integrate, share and mine data.
The report also aims to underscore the poten-tial patient benefits of treatments developed under personalized medicine. Such therapies carry accu-rate product labels that specify the narrow popu-lation they were developed for. The agency also notes the increased importance of conducting postmarketing studies of such products because of the smaller patient populations studied.
Read the report at www.fdanews.com/ext/files/10-28-13-Personalized-Medicine.pdf. — Ferdous Al-Faruque
FDA Recordkeeping, Dangerous Documents and Writing for Compliance™
Every day, we write casual emails, meeting minutes and sticky notes, never anticipating that an FDA inspector or other third party will read them. But these are exactly the types of correspondences that are often used to determine an orga-nization’s overall compliance profile. And thanks to product liability lawyers, these notes also need to be defensible…from criminal actions and lawsuits.
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FDA DTC Study Could Impact Advertising Targeting Adolescents
The FDA plans to study how adolescents interpret direct-to-consumer (DTC) advertise-ments, research that could impact how drugmak-ers develop postmarket advertisements and how the agency regulates them.
The FDA hopes to see how adolescents pro-cess the benefit-risk profile of a prescription drug, which could impact how that profile is communi-cated in marketing.
Another concern is subtle messages in ads that are expected to influence adolescent deci-sionmaking, such as peer and family perceptions of stigma. Those messages could prompt an ado-lescent to pay less attention to an ad’s risk infor-mation, the FDA said.
The study would be a randomized, controlled study of three different age groups: 13-15, 16-19 and 25-30. The participants would view a 30-min-ute web-based promotional campaign for a fake attention deficit hyperactivity disorder drug or a fake acne drug, two types of pharmaceuticals commonly prescribed to adolescents.
Parents for the first two age groups, who are responsible for buying pharmaceuticals, will also be included, to explore similarities and differ-ences in perceptions of the advertisements, the agency said. The FDA hopes to receive a total of 6,350 respondents.
“Adolescents may be particularly likely to give more credence to benefits that occur imme-diately and may be likely to discount risks that do not occur immediately,” the agency said. “Other research suggests that adolescents are more likely to engage in risk behavior.”
How the drug industry tailors DTC ads has been the subject of congressional and agency scrutiny for years. PhRMA developed a series of “guiding principles” that drugmakers can vol-untarily follow for DTC ads, including alert-ing patients and healthcare professionals about an upcoming DTC marketing campaign (WDL, Dec. 15, 2008).
The notice, docket no. FDA-2013-N-1151, is available for comment until Dec. 30. To read it, visit www.fdanews.com/ext/files/10-30-13-DTC StudyNotice.pdf. — Robert King
FDA Pulls Amarin’s SPA for Vascepa Trial, Casting Further Doubt on sNDA
In a surprise move, the FDA has rescinded the special protocol assessment (SPA) for Amarin’s ANCHOR study of its heart drug Vascepa, the com-pany’s third setback in two weeks after a disappoint-ing advisory vote led Amarin to slash staff in order to stay afloat as it tries to win an expanded indication.
The agency’s decision to rescind the ANCHOR SPA follows an Oct. 16 meeting of the Endocrino-logic and Metabolic Drugs Advisory Committee, in which the panel members voted 9-2 against approval of Amarin’s sNDA for Vascepa. Admitting the pro-cess for approval will be “an uphill battle” after the advisory vote, Amarin slashed its workforce in half last week in a bid to remain solvent (WDL, Oct. 28).
An SPA reflects the agency’s view that an uncompleted Phase III trial’s design, clinical
endpoints and statistical analyses are acceptable to support regulatory approval upon its comple-tion. However, it can be retracted for myriad reasons, including substantial scientific issues unveiled during the course of the trial. That’s what happened to Amarin in this case.
The FDA said results from three separate out-come trials of other heart drug candidates “fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascu-lar events” in the intended patient, the drugmaker said Tuesday in a regulatory filing. The agency “no longer considers a change in serum triglycer-ide levels as sufficient to establish the effective-ness” of Vascepa (icosapent ethyl) to reduce car-diovascular risk in patients with serum triglyceride levels below 500 mg/dL, the company noted.
Combination Product Makers Prod FDA for More Guidance
The FDA’s failure to provide combination product manufacturers with timely guidance and responses to queries is impeding innovation, a group representing more than two dozen drug-makers says in a citizen petition.
The Combination Products Coalition (CPC) also says there are too few combination product-related records posted on the agency’s website, and guidance specific to that sector that does get issued is too broad and does not reflect the com-plexity of combination products. But those are just symptoms of the larger problem of micromanaged guidance development at the FDA, the group says.
The citizen petition offers five general prin-ciples for reforming guidance development at the agency, which the group says should appeal broadly to the drug and device industry at large:
● Limit input from agency managers. “As compared to regulations, guidance is more informal and therefore should not require anything approaching the review and si-gnoff required for rulemaking.” A reduction in reviews could be balanced with “more robust post-release quality review … and appeal procedures,” the group recommends;
● Proposed guidance should be finalized within a year of appearing on the FDA’s agenda, but without compromising the quality of its recommendations;
● “Push the authority to answer questions in writing down to levels well below that of
writing guidance,” as this just takes existing guidance and explains it, the CPC said; and
● Establish a process through which the agency can monitor and audit interpreta-tions of the guidance to ensure it remains consistent with the document. This pro-cess should include a mechanism “to cor-rect any interpretation errors on a go-for-ward basis,” the group said.
A fifth principle calls on the agency to be “con-tinuously improving” guidance. In that regard, the CPC proposes the creation of a “feedback loop” at the FDA, separate from the usual appeals process.
The group also encourages the agency to consider best practices and guidance (not standards) offered by manufacturers and other industry stakeholders. And the issuance of “micro guidance,” or guidance on a narrow topic, as a supplement to existing guidance processes would be helpful, the CPC said.
On a macro level, there are numerous areas where the CPC would like to see additional guid-ance, spokesman Brad Thompson told WDL. The group would like to see additional guidance in the human factors area, more recommendations regarding clinical trial conduct and companion guidance to the final rule on good manufacturing practices for combo products, issued in January, he said (WDL, Jan. 28).
Read the CPC’s citizen petition at www.fdanews.com/ext/files/10-30-2013-CPC_CP.pdf. The group’s general principles can be found at www.fdanews.com/ext/files/10-30-2013-CPC_GGP.pdf. — Johnathan Rickman
Party Name Court Case
Most Recent Action Date
Most Recent Action Case Topic
PhRMA v. HHS, HRSA et. al.
U.S. District Court for the District of Columbia
13-01501 9/27/13 10/25/13 Briefing schedule set
340B orphan drug exclusion rule
Eisai v. DEAU.S. Court of Appeals for the District of Colum-bia Circuit
13-1243 8/19/13 10/22/13
Eisai petition for a writ of mandamus to redress unrea-sonable delay by the DEA is denied
Scheduling of controlled substances
Recent federal court actions involving the FDA and drug industry:
Sunovion Brochures for COPD Drug Flagged By FDA for Overblown Claims
The FDA has handed Japanese drugmaker Sunovion an untitled letter for overstating effi-cacy claims about its bronchodilator Brovana in four patient brochures.
The letter, posted Oct. 29, singles out state-ments emblazoned across the brochures trumpet-ing that patients that take Brovana (arformoterol) “may get back to daily living.”
The ads go on to ask if the patient has to use a nebulizer four or more times a day, and if the patient isn’t able to breathe in all of the medicine when using a competitor’s dry-powder inhaler.
The agency took umbrage with that market-ing language, noting that it suggests Brovana is the “right” chronic obstructive pulmonary disease COPD therapy and superior to other therapies.
“Specifically, these claims and presentations suggest that Brovana will be effective for patients who have not had success with other COPD ther-apies based on Brovana’s ability to overcome the potential challenges associated with these therapies,
such as their respective dosing regimens,” the FDA said. The agency added it isn’t aware of any head-to-head studies supporting Sunovion’s assertion that Brovana is clinically superior to other therapies.
Another claim in the ads flagged by the FDA concerned statements that Brovana would be eas-ier to use for patients whose hands don’t move as well to handle an inhaler. The claim is mislead-ing, the agency said, noting that the directions for using Brovana involve opening and removing a ready-to-use vial and setting up a nebulizer.
The FDA also rapped Sunovion for putting risk information in small font, single spaced and surrounded by little white space. This effectively “undermines the communication of important risk information,” the agency said.
Sunovion has initiated a review of the issues raised in the untitled letter and is taking the mat-ter “very seriously,” spokeswoman Tricia Mori-arty told WDL Oct. 30.
To read the untitled letter, visit www.fdanews.com/ext/files/10-30-13-UntitledLetter.pdf. — Robert King
Despite attempts to pad its patent cliff fall with a massive R&D restructuring plan, Merck is still hurting in large part due to poor sales of its blockbuster diabetes franchise for Januvia and Janumet in the U.S.
While international sales of the franchise had grown 15 percent, U.S. sales had declined 8 per-cent during the third quarter, underscoring “a very competitive market,” Adam Schechter, Mer-ck’s president of global human health, said on an Oct. 28 conference call.
Facing delayed regulatory approvals and a sea of generic challengers, the company last month announced severe restructuring plans includ-ing letting go of an additional 8,500 employ-ees (WDL, Oct. 7). Merck also said it was no longer going to sell the diabetes drug Juvisync
(sitagliptin with simvastatin) in the U.S. and Puerto Rico potentially due to competition from Janumet (sitagliptin with metformin).
Wall Street analysts reacted negatively to the pharma giant’s latest setback, citing “continued weakness” in Merck’s Januvia (sitagliptin) and Janumet franchise sales.
That franchise may be headed for “even more intense competition” from potentially upcoming SGLT-2 inhibitor drugs its competitors are devel-oping: Bristol-Myers Squibb and AstraZeneca’s Forxiga (dapagliflozin) and Eli Lilly and Boehringer Ingelheim’s empagliflozin, Leerink Swann analyst Seamus Fernandez said Oct. 29. Empagliflozin ear-lier this year met its primary endpoints in lowering blood sugar levels in four Phase III trials.
Two single-pill DPP-4/SGLT2 inhibitor combo drugs are also under development by the same competitors. — Ferdous Al-Faruque
Two weeks after the FDA issued a safety alert for Ariad Pharmaceuticals’ sole product Iclusig, the agency has asked the drugmaker to temporar-ily halt U.S. sales of the leukemia drug.
In its request, the agency cited the same safety concerns noted in its alert to physicians: the risk of life-threatening adverse events, including blood clots and severe narrowing of blood vessels.
The FDA on Oct. 11 urged physicians to either pull patients off the medication or manage their dosages appropriately (WDL, Oct. 14). The agency also put a hold on postmarket clinical tri-als of the drug last month.
The drugmaker has been in “ongoing dis-cussions” with the FDA since then to negoti-ate updates to the U.S. prescribing and labeling information for Iclusig (ponatinib), Ariad Chair-man and CEO Harvey Berger said on a confer-ence call Oct. 31. Implementing a comprehensive risk evaluation mitigation strategy for the drug is also on the table, he added.
The ultimate labeling for the drug once it returns to market “will be narrower,” Berger said.
But Berger called the FDA’s shutdown of U.S. sales a regulatory overreach, which he attributed to a “disconnect” between physicians’ current understanding about the prescribing patient pop-ulation for Iclusig and the narrower indication it will return to market with, he told investors.
“We do not believe suspension of the market-ing of Iclusig was the only approach to ensure its appropriate utilization,” he said. The drug has not been pulled from store shelves in other markets, Berger noted.
The agency Oct. 31 issued updated, strength-ened recommendations for Iclusig, warning that patients currently taking Iclusig who are not responding to the drug should immediately dis-continue treatment and discuss alternative treat-ment options with their doctors.
The FDA also says those patients currently taking Iclusig and responding to the drug could be treated under a single-patient IND application or expanded access registry program while FDA’s safety investigation continues.
Iclusig was approved for adults with chronic myeloid leukemia (CML) and Philadelphia chro-mosome positive acute lymphoblastic leukemia in December 2012. — Melissa Winn
The FDA’s conclusion is based on the fresh results from Merck’s HPS2-THRIVE trial of MK-0524A (niacin/laropiprant), Abbott’s ACCORD Lipid trial of Trilipix (fenofibric acid) and Abbott’s AIM-HIGH trial of Niaspan (niacin extended-release) in combination with a statin. Those outcome trials showed mixed results in lowering cardiovascular risks in certain patients.
Amarin is seeking a second indication for Vascepa as a treatment for patients with mixed dyslipidemia at high risk for coronary heart dis-ease and currently taking statins. The drug was first approved in 2012 as an adjunct to diet and exercise to lower triglyceride levels in adults with severe hypertriglyceridemia.
Amarin said it is working with the FDA to schedule a meeting to discuss the issue. But the SPA withdrawal, which Amarin said was unfore-seen and potentially unprecedented, significantly dampens the drugmaker’s chances of winning approval for a second indication for Vascepa.
During a meeting for the initial application back in 2008, the FDA noted that before it could approve a new indication for treating patients with elevated TG levels, the agency would need a 12-week study with lipid endpoints and a cardio-vascular outcomes study. That study, REDUCE-IT, is ongoing and investigating whether Vascepa 4g improves residual cardiovascular risk.
Requests to the company for further comment were not returned. — Melissa Winn
GSK’s Potiga Gets Boxed WarningThe labeling for GlaxoSmithKline’s anti-sei-
zure drug Potiga (ezogabine) has been updated to include a new boxed warning, underscoring risks of abnormalities to the retina in the eye, potential vision loss and skin discoloration, the FDA said in a safety communication Oct. 31.
The agency is advising healthcare practitio-ners to limit the use of the drug to those patients who have not responded adequately to several alternative therapies.
Also included in the updated label are warn-ings regarding the risk for discoloration of the skin, nail, mucous membrane and whites of the eyes (WDL, May 6). The FDA is working on modifying the current Risk Evaluation and Miti-gation Strategy for Potiga to address those risks.
Alexion Nabs Breakthrough DesignationAlexion is the latest drugmaker to be awarded
a breakthrough designation from the FDA, receiving the nod for ALXN1101, a potential replacement therapy for the treatment of patients with a rare metabolic disorder known as molyb-denum cofactor deficiency (MoCD) type A.
In granting the designation, the agency rec-ognizes the life-threatening nature of the genetic disorder, which causes catastrophic and irrevers-ible neurologic damage within the first weeks of life, said Martin Mackay, Alexion’s global head of research and development.
The drugmaker has already completed dosing with the synthetic cPMP in a study of healthy vol-unteers and plans to work closely with the FDA on subsequent drug development, which is more com-pressed under the breakthrough scheme.
The breakthrough designation development came on the same day that Alexion reported third quarter earnings highlighting soaring sales — and grand future plans — for the company’s lead product Soliris (eculizumab), approved in 2007 to treat paroxysmal nocturnal hemoglobinuria.
Mass. Senate Passes Compounding BillThe Massachusetts state Senate passed a
bill Oct. 30 requiring compounding pharma-cies that custom mix sterile drugs to obtain a special license from the state pharmacy board. Those pharmacies would then be required to submit to annual inspections and adhere to reporting requirements.
Differing from a House bill passed last month, the Senate bill would exempt certain seg-ments of the industry, including hospital pharma-cies (WDL, Oct. 7).
Comings & GoingsCDER has named John Whyte to serve as its
first Director of Professional Affairs and Stake-holder Engagement. In this newly created posi-tion, Whyte will work with healthcare profes-sionals, patients, patient advocates and others involved in the use of medicines, providing them with a focal point for advocacy, enhanced two-way communication and collaboration.
Teva Pharmaceuticals CEO Jeremy Levin has resigned and will be replaced by the compa-ny’s executive vice president and chief financial officer Eyal Desheh on an interim basis.
Astellas has named Jeffrey Winton its senior vice president, chief communications officer. Winton will report to the company’s chief execu-tive officer. He will be responsible for corporate brand and reputation management in the Amer-icas. Astellas Pharma Global Development, a subsidiary of Astellas, has promoted Mark Weinberg to vice president of global clinical sci-ence and hired Robin McGarry to serve as vice president, global medical safety.
AstraZeneca has appointed Marc Dunoyer to serve as chief financial officer. He will join the company’s board as an executive director effec-tive Nov. 1. He succeeds Simon Lowth who stepped down on Oct. 31.
Lawless said she would understand if records are stored two time zones away and will take 24 to 36 hours to get. “Are we going to be happy about it? No, there is nothing I can do, but at least you can get me the records,” she said.
If after 36 hours there are still no records then that is a problem, Lawless said.
If the records are on-site then they shouldn’t take 24 hours to obtain, said Rachel Harrington, drug specialist for the FDA. She said she would be lenient if the records were off-site, but the company should give her something else to look at which is more accessible, such as standard operating procedures.
Lawless added that the agency doesn’t take a company’s original records. If an investigator is insistent on taking the originals, the company should call the district office, she said.
Another controversial part of the guidance focused on the thorny issue of taking photographs during an inspection. The guidance asserts that refusing to allow photos could lead to a company’s products being deemed adulterated (WDL, July 29).
The issue is actually cut-and-dry for the investigators at the summit. “We don’t take pic-tures for frivolous purposes,” Lawless said. “We take pictures as evidence to document an objec-tionable observation. We don’t just take random pictures of equipment.”
Harrington gave an example of a recent inspection, in which she noticed a large, black
splatter on a HEPA filter. She said that she asked if she could take a photo of the splatter, since it would be easier to have a picture of it than describe it in words.
“We give you the option of taking a picture with us,” Lawless said.
Investigators also offered up some useful best practices and tips for what to do during and after an inspection, including:
● Copy original records onto differently colored sheets of paper to more easily identify which records are the originals and which are for the agency;
● After an inspection closes, a company can expect to receive a Form 483 within 45 days, but sometimes a district can get backlogged. If a company doesn’t have an establishment inspection report within two to three months, call and ask the dis-trict what happened;
● Investigators have no problem with an open corrective and preventative action (CAPA) report. However, the company must demonstrate it is still working on implementing that CAPA; and
● Don’t be afraid of performing an honest internal audit, because investigators can’t look at a company’s internal audit report. “That is because we want you to do those internal audits and be open and honest and not be afraid that if you put some-thing in there it will be held against you,” said Harrington. — Robert King
Inspections, from Page 3
Reporters: Nick Otto, Elizabeth Orr, Ferdous Al-Faruque, Lena Freund, Robert King
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