‘Complete Response’ Letters

FDA stopped issuing “approvable” and “not approvable” letters in favor of “complete response” letters on Aug. 11, 2008. The following chart lists “complete response” actions recently announced, as well as still-pending “approvable” and “not approvable” actions.

Product/Sponsor		Indication	Effective Date
Recently Announced “Complete Responses”
AVP-825 Sumatriptan, intranasal powder Avanir, OptiNose		Low-dose powder formulation of the 5-HT1 agonist using OptiNose’s closed-palate Breath Powered intranasal delivery technology for acute treatment of migraine	Announced 11/26/2014 (FDA asked Avanir to assess root causes of device use errors and to conduct a new human factors validation study of the device following improvements)
Daclatasvir^b Bristol-Myers Squibb		NS5A replication complex inhibitor for use in combination treatment of genotype 1b hepatitis C virus infection and in combination with other agents for multiple HCV genotypes	Announced 11/26/2014 (FDA wants to see additional data combining daclatasvir with other HCV drugs following Bristol’s withdrawal of its asunaprevir NDA, announced 10/2014; the daclatasvir NDA was filed for combination use with asunaprevir)
Pending “Complete Responses”
Acetadote Acetylcysteine^a Cumberland Pharmaceuticals		New indication for the acetaminophen overdose treatment for use in patients with non-acetaminophen-induced acute liver failure	Announced 12/22/2010 (FDA noted that while transplant-free survival was numerically higher in some coma patients, evidence was insufficient for increasing survival in all patients with acute liver failure)
Ampligen Rintatolimod^b (formerly known as PolyI:polyC12U) Hemispherx Biopharma		Toll-like receptor 3 agonist for treatment of chronic fatigue syndrome	Announced 2/4/2013 (FDA found efficacy and safety evidence insufficient, citing limited size of safety database and discrepancies within submitted data; agency requests at least one additional clinical trial, completion of nonclinical studies and a number of data analyses; first CRL dated 11/25/2009; Hemispherx says it will request end-of-review meeting as precursor to formal appeal)
Arcalyst Rilonacept^a Regeneron		New indication for the interleukin-1 inhibitor for prevention of gout flares in patients initiating uric acid-lowering therapy	Announced 7/30/2012 (FDA requested additional clinical data and additional chemistry, manufacturing and controls information regarding a proposed new dosage form)
Aricept Donepezil, transdermal^a Eisai/Teikoku Pharma/Pfizer		New weekly transdermal patch formulation of the cholinesterase inhibitor for treatment of mild, moderate and severe Alzheimer’s disease	Announced 4/25/2011
Avastin Bevacizumab^a Genentech (Roche)		Anti-vascular endothelial growth factor monoclonal antibody for use in combination with docetaxel (Taxotere) for first-line treatment of women with metastatic HER2-negative breast cancer; sBLA based on the AVADO trial.	Announced 12/16/2010 (Genentech announced concurrently that FDA had started the process of withdrawing Avastin’s Subpart H approval of its approved first line breast cancer use, with paclitaxel)
Avastin Bevacizumab^a Genentech (Roche)		Anti-vascular endothelial growth factor monoclonal antibody for use in combination with either a taxane, anthracycline-based or capecitabine (Xeloda) chemotherapy for first-line treatment of women with advanced (metastatic) HER2-negative breast cancer; based on the RIBBON1 trial	Announced 12/16/2010 (Genentech announced concurrently that FDA had started the process of withdrawing Avastin’s Subpart H approval of its approved first line breast cancer use, with paclitaxel)
Avastin Bevacizumab^a Genentech (Roche)		Anti-vascular endothelial growth factor monoclonal antibody in combination with chemotherapy for second-line use in treatment of women with advanced (metastatic) HER2-negative breast cancer; based on the RIBBON2 trial	Announced 12/16/2010 (Genentech announced concurrently that FDA had started the process of withdrawing Avastin’s Subpart H approval of its approved first line breast cancer use, with paclitaxel)
Axanum Aspirin/esomeprazole^a AstraZeneca		Fixed-dose combination of low-dose acetylsalicylic acid and a proton pump inhibitor for prevention of cardio- and cerebrovascular events in patients requiring continuous low-dose ASA treatment and who are at risk for developing ASA-associated gastric and/or duodenal ulcers	Announced 6/1/2010 (Application withdrawn)
Azilect Rasagiline^a Teva Pharmaceutical Industries		New claim for the monoamine oxidase inhibitor for slowing the progression of Parkinson’s disease	1/2012
Bromday Bromfenac, ophthalmic solution^a Ista Pharmaceuticals		Larger 2.4 mL fill size of the once-daily non-steroidal anti-inflammatory ophthalmic solution (approved in a 1.7 mL fill size) for treatment of inflammation, pain and photophobia following cataract surgery	2/2011 (FDA said the data did not justify the need for increasing the fill volume, that the approved fill volume was sufficient for a full course of treatment of one eye, and a single bottle should not be used to treat more than one eye due to increased risk of microbial contamination) FDA published a notice in the Federal Register 8/3/2011 explaining its refusal to approve the larger size
Bronchitol Mannitol Pharmaxis		Dry powder inhalation formulation of the osmotic six-carbon sugar alcohol for management of cystic fibrosis in patients ages six years and older to improve pulmonary function	Announced 3/19/2013 (FDA questioned adequacy of efficacy evidence, citing treatment-related frequent early dropouts in trial 301 that were not accounted for in the primary statistical analyses and the lack of statistical significance for the primary endpoint in trial 302; FDA also expressed concern about increased occurrence of hemoptysis or bloody sputum, especially in pediatric patients on drug) Pharmaxis agreed with FDA to conduct another Phase III trial and announced 5/28/2013 that it is seeking a partner to for further development and commercialization of Bronchitol in the U.S.
Canagliflozin^a/metformin Johnson & Johnson (Janssen)		Fixed-dose combination of the selective sodium glucose co-transporter 2 inhibitor (Invokana) and the immediate-release biguanide for treatment of type 2 diabetes	Announced 12/12/2013 (FDA requested additional information to support the comparability of the twice-daily dosing of canagliflozin as part of the fixed-dose combination and the once-daily dosing of single-agent canagliflozin)
Cangrelor^b The Medicines Company		Quickly reversible I.V. antiplatelet agent to reduce thrombotic cardiovascular events, including stent thrombosis, in coronary artery disease patients undergoing percutaneous coronary intervention and for patients with acute coronary syndromes or stents who require bridging from oral antiplatelet therapy to surgery	Announced 4/30/2014 (For the PCI indication, FDA suggested clinical data analyses of the CHAMPION PHOENIX and review of data management processes, and requested bioequivalence information on clopidogrel clinical supplies for the CHAMPION trials; for the bridging indication, FDA called for a new trial study in which outcomes such as bleeding are studied)
Carbella Carbamazepine Lundbeck LLC		Intravenous formulation of the anti-epileptic drug for use as replacement therapy in adults who are on a stable maintenance oral dose of carbamazepine to control seizures when oral carabamazepine administration is temporarily not feasible	Announced 10/24/2014 (FDA requested additional chemistry, manufacturing and controls data)
Cariprazine^b Forest Laboratories/Gedeon Richter		Dopamine D3-preferring D3/D2 receptor partial agonist for treatment of schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder	Announced 11/21/2013 (FDA requested more information, including additional clinical trial data; Forest says FDA acknowledged the drug’s efficacy but may want more data to define optimal dosing given cariprazine’s complex pharmacokinetics and metabolism)
Celebrex Celecoxib Pfizer		New claim for the Cox-2 inhibitor for treatment of chronic pain	6/2010 (Pfizer said 2/2014 that the sNDA remains pending while the long-term cardiovascular safety trial PRECISION is ongoing; the trial, expected to complete in 2015, will inform the next steps)
Cinryze C1 esterase inhibitor (human)^a ViroPharma/Lev		New claim for the plasma-derived C1 esterase inhibitor for treatment of acute attacks of hereditary angioedema	Announced 6/4/2009 (Firm reports FDA has requested an additional clinical trial but says agency had no safety concerns) Approval and marketing of Cinryze for acute facial and abdominal HAE attacks is precluded by orphan exclusivity for CSL Behring’s C1-INH Berinert, approved in late 2009
Clolar Clofarabine^a Genzyme		New indication for the oncologic for first-line therapy of previously untreated adults 60 years and older with acute myeloid leukemia who have at least one unfavorable prognostic factor	Announced 10/6/2009 (FDA recommends a randomized, controlled clinical study be conducted; firm will meet with FDA to determine if ongoing study will meet that requirement)
Corifollitropin alfa^b (also known as MK-8962; Elonva in Europe) Merck		Long-acting follicular stimulant formulated with Washington University’s carboxyl terminal peptide technology for subcutaneous injection for use in controlled ovarian stimulation in women using assisted reproductive technology	Announced 7/29/2014
CorVue Binodenoson^b King Pharmaceuticals (Pfizer)		Selective adenosine A2A receptor agonist for use as a cardiac pharmacologic stress SPECT imaging agent as an adjunct to non-invasive myocardial perfusion imaging tests to detect perfusion abnormalities in patients with or at risk for coronary artery disease who are unable to perform a cardiac exercise stress test	Announced 10/21/2009 (Likely discontinued: Pfizer acquired King in early 2011 and does not list CorVue as an active project)
Dacogen Decitabine^a Eisai Inc.		New indication for the DNA hypomethylating agent for newly diagnosed acute myelogenous leukemia in patients over age 65 who are not candidates for induction chemotherapy	3/6/2012 (FDA asked for a new clinical trial, saying that the pivotal study did not show statistically significant superiority over the control arm)
Doribax Doripenem, inj.^a Johnson & Johnson		New indication for the carbapenem antibiotic for treatment of nosocomial pneumonia	10/2010 (Previous “complete review” letter received 8/19/2008)
Doxil Doxorubicin liposomal inj.^a Johnson & Johnson (Centocor Ortho Biotech)		New indication for the liposome-encapsulated chemotherapeutic for use in combination with Taxotere (docetaxel) for treatment of advanced breast cancer patients who have relapsed following prior anthracycline therapy	Announced 9/10/2009
Duavee Bazedoxifene^b/conjugated estrogens Pfizer Inc./Ligand Pharmaceuticals		Combination of the selective estrogen receptor modulator and conjugated estrogens for the treatment of non-hysterectomized women with moderate-to-severe vasomotor symptoms and vulvar and vaginal atrophy associated with menopause and for the prevention of post-menopausal osteoporosis (dosing for PMO and vasomotor symptoms is 0.45 mg CE/20 mg bazedoxifene; dose for VVA is 0.625 mg/20 mg)	Announced 10/3/2013 (“Complete response” letter issued for VVA claim, which uses a higher dose of conjugated estrogens than the vasomotor symptoms and PMO prevention claims, which were approved 10/3/2013)
Dulera Mometasone furoate/formoterol fumarate dihydrate^a Merck		New indication for the inhaled corticosteroid and long-acting beta-2 adrenergic agonist combination for treatment of chronic obstructive pulmonary disease	Q4 2011
Erbitux Cetuximab^a Lilly/Bristol-Myers Squibb		New indication for the epidermal growth factor receptor inhibitor in combination with vinorelbine and cisplatin for the first-line treatment of non-small cell lung cancer	4/2012 (Sponsors do not plan to resubmit the filing, based on the FLEX study)
Exelbine Vinorelbine emulsion Adventrx		Injectable emulsion formulation that suspends the chemotherapeutic in nanoparticles designed to protect the venous endothelium during administration and reduce the injection site reactions common with the marketed formulation (Pierre Fabre’s Navelbine), for first-line treatment of advanced non-small cell lung cancer	Announced 8/9/2011 (FDA requested the sponsor repeat the pivotal bioequivalence trial because it could not verify the authenticity of the drug products used in the submitted study, and requested more information regarding product quality and CMC)
Fentora Fentanyl, buccal tab.^a Cephalon (now a subsidiary of Teva)		New indication for the buccal tablet formulation of the opioid for management of breakthrough pain in opioid tolerant patients with chronic pain conditions	9/13/2008
Feraheme Ferumoxytol^a AMAG Pharmaceuticals		Broader indication for the iron oxide injection, expanding from the original indication, treatment of iron deficiency anemia in adults with chronic kidney disease, to treatment of all adult patients with IDA who have failed or could not tolerate oral iron treatment	Announced 1/22/2014 (FDA requested additional clinical trial data with a primary composite safety endpoint of serious hypersensitivity/anaphylaxis, cardiovascular events and death; FDA also proposed evaluating alternative dosing and administration schedules to the rapid I.V. injection studied)
Flibanserin^b Sprout Pharmaceuticals		Serotonin agonist/antagonist and partial dopamine 4 agonist for treatment of hypoactive sexual desire disorder in premenopausal women	Announced 12/11/2013 (FDA accepted Sprout’s appeal of the letter through FDA’s formal dispute resolution process 12/3/2013, and Sprout announced 2/11/2014 FDA wants to see two additional Phase I drug interaction studies and a Phase I driving stimulator study; NDA’s original sponsor, Boehringer Ingelheim, received prior “complete response” letter in 2010)
Flutiform Fluticasone propionate/formoterol fumarate Skyepharma		Fixed-dose combination of the inhaled corticosteroid fluticasone and the long-acting beta agonist formoterol with hydrofluoroalkane propellant for metered dose inhaler use for maintenance treatment of asthma in patients 12 years of age and older	1/2010 (Letter and subsequent meeting with FDA 6/2010 indicate "significant additional clinical work" is needed, including additional dose-ranging data; Skyepharma carried out CMC work but says NDA still needs considerable work and would have “substantial” post-approval safety study similar to current LABA products) Skyepharma will not pursue approval in U.S. unless a third party covers costs. Abbott returned U.S. marketing rights 8/2010.
Genasense Oblimersen Genta		Bcl-2 inhibitor in combination with chemotherapy for treatment of patients with relapsed or refractory chronic lymphocytic leukemia	Announced 12/2/2008 (In response to Genta’s 12/2008 appeal under FDA’s dispute resolution process, FDA determined available data to be inadequate to support approval and requested an additional trial, Genta announced 3/6/2009)
Gencaro Bucindolol HCl^b ARCA biopharma		Beta blocker and mild vasodilator for treatment of chronic heart failure in patients with a specific, common genetic variation	Announced 6/1/2009 (FDA requested additional clinical efficacy trial, as well as additional clinical pharmacology studies and non-clinical studies to further characterize metabolites; sponsor notes amendments submitted 5/2009 were not reviewed prior to CRL; amendments dealt with comparative effectiveness, clinical pharmacology, pharmacogenetics and toxicology/metabolism and may be referenced in the response. ARCA subsequently has received an SPA for a new Phase III trial in a genotype-defined heart failure population)
Geodon Ziprasidone^a Pfizer		New indication for the atypical antipsychotic for treatment of acute bipolar manic or mixed episodes in children and adolescents aged 10 to 17 years	4/2011 (FDA said the reliability of the data supporting the sNDA had not been demonstrated; previous CRL received 10/2009)
Giazo Balsalazide^,1.1 g tab.^a Salix		New higher-strength tablet formulation of the 5-ASA prodrug balsalazide (marketed by Salix as Colazol 750 mg capsules), dosed as three tablets twice daily as opposed to Colazol's three capsules thrice-daily, for treatment of mild-to-moderate active ulcerative colitis in patients 18 years and older	4/27/2010 (FDA raised concerns about deficiencies at a contract manufacturing facility. Previously "approvable" 5/16/2008; FDA requested a new trial. Salix believed its NDA was sufficient and responded 6/2008 without a new trial; FDA issued a "complete response" 12/22/2008. Based on discussion with FDA, Salix reworked existing trial data and filed a response 10/2009.) Approved for men only 2/3/2012
Heplisav Vaccine, hepatitis B virus (rHBsAg-1018 ISS)^b Dynavax		Vaccine that combines hepatitis B surface antigen with a novel Toll-like receptor 9 agonist adjuvant (1018 ISS) to enhance immune response, for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 to 70 years of age	Announced 2/25/2013 (FDA needs further evaluation of safety in the broad age group sought, but indicated willingness to discuss more restricted use; FDA also cited concern that novel adjuvants may cause rare autoimmune adverse events and requested additional data from the process validation program and clarifying information on manufacturing controls and facilities related to quality assurance for the commercial product) Dynavax announced 6/10/2013 that FDA decided more subjects would be needed for safety analysis, because a restricted indication would not address the shortfall in the safety database and would unnecessarily limit the population that could benefit
Humira Adalimumab^a AbbVie		New indication for the tumor necrosis factor blocker to reduce signs and symptoms in adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation by elevated C-reactive protein or magnetic resonance imaging who are inadequate responders or intolerant to a non-steroidal anti-inflammatory drug	Q3 2013
Hydrocodone controlled-release/acetaminophen^a Abbott		Controlled-release formulation of hydrocodone with activity over 12 hours compared with four-to-six hour dosing for immediate-release hydrocodone (Vicodin)/APAP products, for treatment of pain	Announced 10/20/2008
Iclaprim^b Acino Holding AG (acquired from original sponsor Arpida, 2010)		Synthetic diamino-pyrimidine antibiotic for I.V. treatment of complicated skin and skin structure infections, including methicillin-resistance S. aureus	Announced 1/19/2009 (FDA requested an additional clinical study or studies showing non-inferiority to an approved comparator; Acino met with FDA 11/2010 to discuss future avenues of development in light of 8/2010 acute bacterial SSI guidance, and as of 1/2012 is exploring alternative development options for the drug)
Ilaris ^a Canakinumab Novartis		New indication for the interleukin-1 beta blocker for treatment of gouty arthritis	Announced 8/29/2011 (FDA requested clinical data on the benefit-risk profile in refractory patients)
Imagify Perflubutane polymer microspheres, inj. suspension^b Acusphere		Ultrasound imaging agent to assess myocardial perfusion for the detection of coronary artery disease (amended to limit use to subsets of patients undergoing pharmacologic stress techniques)	Announced 3/11/2009 (FDA said additional clinical work would be required for the broad CAD indication; will discuss alternatives with sponsor, which had submitted a limited indication 2/2009) FDA granted Acusphere a special protocol assessment 6/2011 for a new two-year trial
IXinity Factor IX, recombinant^b (also known as trenonacog alfa, IB1001, IN1001) Emergent BioSolutions (Cangene)		Intravenous recombinant Factor IX protein for treatment and prevention of bleeding episodes in patients with hemophilia B	7/29/2014 (FDA requested additional data analyses and noted CMC deficiencies; after previous 2/2013 CRL, FDA defined a path to approval requiring additional manufacturing and development information but no additional clinical data; on 7/29/2013, FDA lifted clinical hold placed on two ongoing Phase III studies in 7/2012 due to higher than expected incidence of anti-CHO antibodies, and Cangene re-initiated ongoing studies and begin new adult and pediatric studies using a modified manufacturing process)
Levodopa/carbidopa intestinal gel (also known as LCIG; marketed as Duopa overseas) AbbVie		Gel formulation of levodopa and carbidopa administered directly to the small intestine via a procedurally implanted tube connected to a portable pump for up to 16 hours of continuous drug delivery for treatment of advanced Parkinson’s disease	3/28/2014 (FDA’s concerns centered on the delivery system) Resubmitted 7/11/2014; approved 1/9/2015
Linjeta Modified recombinant human insulin (formerly VIAject) Biodel		Proprietary injectable formulation of recombinant human insulin that allows insulin to disassociate from a hexameric form to a monomeric form, thus promoting a more rapid delivery of insulin to the blood than currently marketed rapid-acting insulin analogs for treatment of diabetes	Announced 11/1/2010 (FDA pointed to numerous deficient areas in the NDA, including clinical trial, statistical analysis and manufacturing issues; FDA requested two new Phase III trials, one each in type 1 and type 2 diabetes)
Lixivaptan^b Cornerstone Therapeutics (Chiesi Farmaceutici division; acquired CardioKine)		Selective vasopressin V2 receptor antagonist for treatment of symptomatic hypervolemic and euvolemic hyponatremia associated with heart failure and syndrome of inappropriate antidiuretic hormone	Announced 11/1/2012 (FDA requested additional clinical and non-clinical information)
Lucassin Terlipressin^b Ikaria, Inc./Orphan Therapeutics		Synthetic vasopressin analogue for treatment of hepatorenal syndrome type 1	11/2009 (FDA requested an additional clinical trial) Ikaria acquired ownership of Lucassin 3/2010 and started the Phase III REVERSE trial 11/2010.
Luveniq Voclosporin^b Lux Biosciences/ Isotechnika		Oral formulation of the next-generation calcineurin inhibitor for treatment of noninfectious uveitis involving the intermediate or posterior segments of the eye	Announced 8/4/2010 (FDA recommended an additional trial be conducted) Lux announced 12/27/2012 that it would not move forward with the NDA after a Phase III trial did not meet its primary endpoint.
Macrilen Macimorelin^b Aeterna Zentaris		Ghrelin agonist for oral administration to induce growth hormone release to evaluate adult growth hormone deficiency	Announced 11/6/2014 (FDA requested a new confirmatory clinical trial due to the pivotal study’s failure to meet the primary efficacy endpoint and data deficiences related to lack of complete and verifiable source data for determining whether patients were accurately diagnosed with AGHD)
Melblez Kit Melphalan chemosaturation system Delcath Systems		Drug/device combination comprising high-dose melphalan chemotherapy with the Delcath Hepatic Delivery System for liver-targeted treatment of unresectable ocular melanoma that is metastatic to the liver (revised to exclude cutaneous melanoma, at FDA’s recommendation, from original inidication for unresectable metastatic melanoma in the liver)	9/13/2013 (FDA’s requests include a new randomized controlled trial using an overall survival endpoint to assess safety and efficacy and to demonstrate that clinical benefit outweighs risks)
Milprosa Progesterone vaginal ring Teva Pharmaceutical		Silicone-based flexible transvaginal ring for weekly dosing of progesterone for luteul phase support in women undergoing in vitro fertilization	2011 (FDA requested a safety and efficacy study in women over 34 years of age prior to approval or as a post-marketing commitment) Teva said 2/2014 that it aims to resubmit in 2014
MoxDuo Morphine/oxycodone QRxPharma/Actavis (Watson)		Fixed-dose combination of the opioids in an immediate-release oral capsule for treatment of moderate to severe acute pain when use of an opioid analgesic is appropriate	Announced 5/27/2014 (FDA requested clinical information demonstrating a clear benefit in either efficacy or safety for the fixed-dose combination over oxycodone and morphine alone in an appropriate population; previous “complete response” letters issued 8/2013 and 6/25/2012)
Naproxcinod^b NicOx		Nitric-oxide donating form of naproxen as the first of a new class of anti-inflammatory agents, cyclooxygenase-inhibiting nitric oxide donators, for treatment of symptoms of osteoarthritis	Announced 7/22/2010 (FDA recommended one or more long-term controlled studies to assess cardiovascular and gastrointestinal safety, as well as additional studies to demonstrate a clinically meaningful therapeutic benefit attributable to the nitric oxide donation) NicOx appealed under FDA’s Formal Dispute Resolution process 7/2011. At an unrelated 4/3/2012 meeting, NicOx proposed a new NDA with data for the lower of the two doses in the original NDA in OA of the knee only.
Neupro Rotigotine, transdermal patch^a UCB		New indications for the transdermal patch for treatment of advanced Parkinson’s disease and moderate to severe primary restless legs syndrome	Announced 4/23/2010 (While FDA agreed that UCB's 6/2009 sNDA proposal for new refrigerated storage conditions could alleviate the crystal formation problem that prompted the 3/2008 Neupro withdrawal, the agency recommended a definitive resolution of the crystallization problem by reformulating the product. A previous action letter of 12/15/2008 also addressed drug crystal formation. UCB says it is working on a room-temperature stable, improved formulation.)
Nexium Esomeprazole^a AstraZeneca		New claim for the proton pump inhibitor for reduction in risk of low-dose aspirin-associated peptic ulcers and peptic ulcer bleeding	6/2011 (Second CRL; first action letter announced 6/1/2010) Response for peptic ulcer bleeding submitted 12/2012
Nomegestrel acetate/17-beta estradiol (also known as NOMAC/E2; marketed as Zoely in Europe) Merck		Monophasic combination oral contraceptive comprised of a highly selective progesterone-derived progestin and an estrogen for prevention of pregnancy	11/4/2011 Merck said 2/2014 that it is discontinuing the Phase III NOMAC/E2 trial being conducted in the U.S.; the decision was not based on new safety or efficacy findings
Norethindrone, transdermal Actavis		Progestin-only transdermal patch that provides continuous delivery of norethindrone with once-weekly dosing for prevention of pregnancy	Announced 12/24/2013 (FDA raised questions about the difference between the patch used in clinical trials and the to-be-marketed patch, which represents a different size/formulation)
Octagam 10% Immune globulin intravenous [human] 10%^a Octapharma AG		New 10% formulation of the I.V. immune globulin, approved in a 5% formulation as Octagam, for treatment of idiopathic thrombocytopenic purpura	12/2/2013 (FDA cited CMC concerns similar to those identified in previous CRLs received 6/2012 and 6/9/2010) Resubmitted 1/10/2014; approved 7/11/2014
Onrigin (formerly Cloretazine) Laromustine^b Vion		Alkylating agent for use as a single agent for remission induction treatment for patients 60 years of age or older with de novo poor-risk acute myeloid leukemia	Announced 12/14/2009 (FDA has requested a randomized clinical trial to support the indication, but Vion says it does not have the funds for another clinical trial, although it did receive an SPA for a Phase III trial in response to the CRL) Vion went out of business 4/8/2010
Oritavancin^b The Medicines Company (formerly Targanta)		Lipoglycopeptide antibiotic for treatment of complicated skin and skin structure infections, including cSSSI caused by methicillin-resistant Staphylococcus aureus	12/8/2008 (FDA requested an additional clinical trial enrolling sufficient number of patients with MRSA; TMC is conducting Phase SOLO-1 and SOLO-2 trials in acute bacterial SSSI, including MRSA, with 2013 NDA submission target)
PA32540 Aspirin 325 mg/omeprazole 40 mg Pozen		Coordinated-delivery oral tablet with an immediate-release proton pump inhibitor layered around a pH-sensitive coating of a high-dose aspirin core for once-daily use for secondary prevention of cardiovascular disease in patients at risk for aspirin-induced ulcers	4/25/2014 (FDA cited deficiencies found in inspection of an active ingredient supplier’s manufacturing facility) Class 2 resubmission announced 7/1/2014
PA8140 Aspirin 81 mg/omeprazole 40 mg Pozen		Coordinated-delivery oral tablet with an immediate-release proton pump inhibitor layered around a pH-sensitive coating of a low-dose aspirin core for once-daily use for secondary prevention of cardiovascular disease in patients at risk for aspirin-induced ulcers	4/25/2014 (FDA cited deficiencies found in inspection of an active ingredient supplier’s manufacturing facility) Class 2 resubmission announced 7/1/2014
Plan B One-Step ^a Levonorgestrel 1.5 mg Teva Pharmaceutical Industries		Switch to full over-the-counter availability of the single-dose emergency contraceptive, currently available without a prescription only for pharmacist distribution to consumers 17 years and older	12/7/2011 (HHS Secretary Sebelius directed FDA to issue a “complete response” letter when she invoked her authority to override FDA’s conclusion that the sNDA should be approved)
Plumiaz Diazepam nasal spray Acorda (Neuronex)		Nasal spray formulation of the benzodiazepine anticonvulsant for treatment of refractory epilepsy patients with acute repetitive seizures (cluster seizures)	Announced 5/2/2014
Posidur SABER-Bupivacaine Durect Corporation		Long-acting depot formulation of the local anesthetic using Durect’s SABER technology to treat post-surgical pain for up to three days after surgery	Announced 2/12/2014 (FDA requested additional clinical safety studies, saying the NDA did not demonstrate that Posidur was safe when used in the manner described in proposed labeling)
Pristiq Desvenlafaxine^a Pfizer		New indication for the serotonin-norepinephrine reuptake inhibitor for treatment of moderate-to-severe vasomotor symptoms associated with menopause	Announced 9/8/2011 (Second “complete response” letter for the sNDA) Pfizer withdrew the sNDA 2/2012
Probuphine Buprenorphine implant Titan Pharmaceuticals/Braeburn Pharmaceuticals		Long-acting subdermal implant formulation of buprenorphine (available in sublingual tablets) using Titan’s ProNeura continuous drug delivery system for six months of maintenance treatment of opioid dependence in adults	Announced 4/30/2013 (FDA requested additional data supporting efficacy, including data demonstrating opioid blockade at relevant doses of agonists, the effect of higher Probuphine doses that more closely approximate blood levels associated with 12-16 mg daily sublingual doses, and human factors testing of training in insertion and removal of implant)
Prochieve Progesterone vaginal gel, 8% Watson Pharmaceuticals/ Columbia Laboratories		Topical progesterone for reduction of risk of preterm birth in women with a singleton gestation and short uterine cervical length in the mid-trimester of pregnancy	2/24/2012 (FDA said the treatment effect did not meet the necessary level of statistical significance, and raised the issue of the U.S. sub-cohort’s robustness of efficacy compared with the overall trial efficacy; FDA requested additional clinical data. FDA denied request for Formal Dispute Resolution, Watson announced 10/26/2012.)
Prolia Denosumab^b Amgen		RANK ligand inhibitor for treatment and prevention of postmenopausal osteoporosis in women, and treatment and prevention of bone loss in patients undergoing hormone ablation for either prostate or breast cancer	Announced 10/19/2009 (Letter requests additional information on post-marketing surveillance program, updates safety information and a new clinical program for the prevention of PMO claim) Class 2 response submitted in late 1/2010 for PMO treatment claim only; approved 6/1/2010
Qutenza Capsaicin patch, 8% NeurogesX		New indication for the prescription-strength capsaicin dermal patch for management of pain due to HIV-associated peripheral neuropathy, also known as HIV-associated neuropathy and HIV-distal sensory polyneuropathy	3/7/2012 (FDA said additional data would be needed from at least one adequate and well-controlled trial) Sponsor does not anticipate investing in further clinical studies for Qutenza
Rabeprazole, extended-release^a Eisai		New extended-release 50 mg capsule formulation of the proton pump inhibitor (marketed in a delayed-release 20 mg tablet as Aciphex) for the healing and maintenance of healing of erosive gastroesophageal reflux disease and for the treatment of symptomatic GERD	2/1/2011 (FDA requested an additional study to support approval) Eisai announced 9/2/2011 that it would discontinue global development.
Reasanz Serelaxin^b (also known as RLX030) Novartis		Recombinant form of the human hormone relaxin-2/relaxin receptor agonist for treatment of patients with symptomatic acute heart failure through reduction of the rate of worsening of heart failure	Announced 5/16/2014 (FDA wants further evidence of efficacy; Novartis says it will expedite clinical program, including ongoing 6,300-patient Phase III RELAX-AHF-2 trial, to supplement pivotal RELAX-AHF study submitted in BLA)
Relistor Methylnaltrexone^a Progenics Pharmaceuticals Inc./Salix Pharmaceuticals		New indication for the peripherally acting mu opioid receptor antagonist for subcutaneous injection treatment of opioid-induced constipation in patients with chronic non-cancer pain	7/27/2012 (FDA requested additional clinical data, including a large well-controlled chronic administration trial to address safety concerns about chronic use of mu-opioid antagonists in patients taking opioids for chronic pain) On 7/14/2014, sponsors announced resolution of Formal Dispute Resolution proceedings: FDA said data previously submitted could support approval with submission of labeling, safety update, and proposal for post-marketing observational cardiovascular outcomes trial. sNDA resubmitted 7/29/2014; approved 9/29/2014
Remoxy Oxycodone, controlled-release^a King Pharmaceuticals (Pfizer)/ Pain Therapeutics		Abuse-resistant long-acting oral formulation of the opioid for twice-daily treatment of moderate to severe pain requiring continuous opioid use for an extended period of time, using Durect Corporation’s Oradur technology to produce a tamper-resistant, high-viscosity liquid formulation in a hard gelatin capsule	Announced 6/24/2011 (A manufacturing issue is central to the CRL; previously received CRL 12/2008; Pfizer said 2/2013 that it has analyzed two recent bioavailability studies and other experiments to optimize formulation composition and analytical methods, and initiated a confirmatory bioavailability study Q4 2012 to assess PK profile of modified formulations to clarify if FDA’s concerns can be addressed adequately; a 3/2013 meeting with FDA identified a regulatory pathway making resubmission before mid-2015 unlikely; Pfizer confirmed 2/2014 that new clinical studies will include a pivotal bioequivalence study bridging the modified Remoxy formulation with the original formulation and an abuse potential study with the modified version)
Restanza Cethromycin^b Advanced Life Sciences		Second-generation ketolide antibiotic for once-daily, oral treatment of mild-to-moderate community acquired pneumonia	7/31/2009 (FDA requested additional clinical data; company believes another trial in more severe CAP patients will likely be required) Advanced Life Sciences suspended operations 5/2011 due to lack of liquidity.
Rituxan Rituximab^a Genentech/Biogen Idec		New indication for the anti-CD20 antibody for treatment of earlier stage rheumatoid arthritis patients who have failed to respond to disease-modifying anti-rheumatic drugs, including methotrexate	Announced 10/19/2009 (Letter cites risk of progressive multifocal leukoencephalopathy with the biologic)
Rizatriptan, oral film (also known as RHB-103) IntelGenx/Red Hill Biopharma		Orally disintegrating polymeric film formulation of the 5-HT1 receptor antagonist using IntelGenx’ VersaFilm technology that is bioequivalent to Merck’s Maxalt MLT (rizatriptan orally disintegrating tablets) for treatment of migraine	Announced 2/4/2014 (FDA’s questions primarily relate to third-party chemistry, manufacturing and controls issues and to product packaging and labeling) Resubmission announced 3/3/2014, but sponsors said 4/24/2014 that FDA requested further CMC clarifications and that the current raw material supplier was holding compliance discussions with FDA not specific to RHB-103
Ryzodeg Insulin degludec^b/insulin aspart Novo Nordisk		Soluble insulin combination of the ultra-long-acting basal insulin analog with a bolus boost of rapid-acting insulin (NovoRapid) in a fixed ratio of 70% degludec and 30% aspart for treatment of type 1 and type 2 diabetes	2/8/2013 (FDA requires a dedicated cardiovascular outcomes trial prior to approval; letter also notes that no approvals will be granted until questions in a 12/12/2012 warning letter regarding environmental monitoring samples from Novo’s Bagsvaerd, Denmark aseptic filling facility are resolved; Novo says it responded to manufacturing letter late 12/2012)
SecreFlo ^b Secretin, synthetic Repligen		Synthetic version of the human hormone secretin for use in combination with magnetic resonance imaging to improve detection of pancreatic duct abnormalities in patients with pancreatitis	Announced 6/22/2012 (FDA requested additional clinical efficacy and safety trial data; Repligen noted that no specific safety concerns were cited) Repligen is no longer actively developing SecreFlo, as of 3/2014
Sefelsa Gabapentin extended-release (formerly known as Serada) Depomed		Extended-release formulation of the antipsychotic, using Depomed’s Acuform oral delivery technology to target ER delivery to the upper GI tract when dosed with food, for non-hormonal treatment of moderate to severe vasomotor symptoms due to menopause	Announced 5/31/2013 (Depomed said it will not invest further in Sefelsa development)
Semprana Dihydroergotamine (formerly Levadex) Allergan (MAP Pharmaceuticals)		Ergot alkaloid formulated for oral inhalation using MAP’s TEMPO inhaler for acute treatment of migraine in adults	Announced 6/30/2014 (FDA’s concerns centered on specifications around content uniformity in the improved canister-filling process submitted in response to second CRL and on standard for device actuation; previous CRLs issued 4/2013 and 3/26/2012)
Serdolect Sertindole^b Lundbeck		Atypical antipsychotic for treatment of schizophrenia	Announced 6/25/2009 (FDA requested additional data to buttress its understanding of the appropriate patient population) U.S. development ceased 8/2010
Seroquel XR Quetiapine, extended-release^a AstraZeneca		New indication for the extended-release formulation of the atypical antipsychotic for treatment of generalized anxiety disorder in adults	Announced 2/27/2009 (AstraZeneca said 7/30/2009 that it was prioritizing its major depression sNDA over the GAD sNDA)
Simponi Golimumab^a Centocor Ortho Biotech (Johnson & Johnson)		Expanded indication for the tumor necrosis factor inhibitor for moderately to severely active rheumatoid arthritis to add claims for inhibiting progression of structural damage in RA, inducing major clinical response, and maintenance of reducing signs and symptoms in methotrexate-naïve patients, inadequate MTX responders and TNF inhibitor-experienced patients	Announced 7/22/2011 (On the basis of the letter and discussions with FDA, J&J will not pursue a structural damage claim in the U.S., as of 1/22/2013)
Simponi Golimumab^a Centocor Ortho Biotech (Johnson & Johnson)		Expanded indication for the tumor necrosis factor inhibitor to add claims for inhibition of the progression of structural damage and maintenance of improvement in signs and symptoms and physical function in the treatment of patients with active psoriatic arthritis	Announced 9/9/2011 (On the basis of the letter and discussions with FDA, J&J will not pursue a structural damage claim in the U.S., as of 1/22/2013)
Sodium oxybate^a, oral solution (formerly Rekinla and JZP-6) Jazz		Sodium salt form of gamma-hydroxybutyrate that interacts with GABA(B) and GHB receptors in a 375 mg dose strength (as opposed to the 500 mg strength Jazz markets for cataplexy and narcolepsy as Xyrem) for treatment of fibromyalgia	Announced 10/11/2010 (Additional clinical studies are needed; FDA asked sponsor to address appropriate patient population, methods for ensuring safe use and the proposed REMS, as well as the concentration and trade name)
Sollpura Liprotamase^b (formerly Altus' Trizytek, TheraCLEC) Lilly (formerly Alnara)		Non-porcine, recombinant enzyme replacement therapy comprising amylase, lipase and protease to improve maldigestion in people with exocrine pancreatic insufficiency	Announced 4/15/2011 (FDA said another clinical trial would be necessary)
Sugammadex^b Merck (Organon USA) (Previously known as Bridion)		Selective relaxant binding agent to reverse neuromuscular blockade induced by rocuronium and vecuronium as part of general anesthesia during surgical procedures	Announced 9/23/2013 (FDA raised concerns about “operational aspects” of a hypersensitivity study required by previous “not approvable” letter in summer 2008; FDA cancelled 7/2013 advisory committee meeting to review results of agency inspection of a clinical trial site in the hypersensitivity study)
Sustol Granisetron, extended-release Heron Therapeutics (formerly A.P. Pharma) (also known as APF530)		Long-acting subcutaneous injection formulation providing five days of therapy with the 5-HT3 antagonist utilizing the company’s proprietary Biochronomer delivery system for the prevention of acute- and delayed-onset chemotherapy-induced nausea and vomiting	Announced 3/28/2013 (FDA requests re-analysis of Phase III data reclassifying patients as receiving highly or moderately emetogenic chemotherapy, a human factors study assessing usability of syringe system, and refinement of a product quality analytical test method and action to address deficiencies noted in facility inspections; previous CRL announced 3/19/2010)
Symbicort Budesonide/formoterol fumarate^a AstraZeneca		New pediatric indication for the inhaled corticosteroid/long-acting beta-2 agonist combination for long-term maintenance treatment of patients ages six to 11 with severe, persistent asthma	Announced 4/6/2009 (FDA said data was inadequate to establish dose and to establish how individual components contribute to the combination product in pediatrics) Phase IV trial of Symbicort vs. ICS alone started 9/2011.
Taltorvic Ridaforolimus^b Merck/Ariad Pharmaceuticals		Oral mTOR inhibitor for maintenance treatment of metastatic soft-tissue or bone sarcomas in patients who had a favorable response to chemotherapy (disease did not progress after at least four cycles)	Announced 6/5/2012 (FDA said an additional clinical trial or trials will be needed to assess safety and efficacy)
Tivopath Tivozanib^b AVEO Oncology/Astellas Pharma		Oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1, 2 and 3 for treatment of advanced renal cell carcinoma patients who have had no prior systemic therapy	Announced 6/10/2013 (FDA said inconsistent progression-free survival and overall survival results and imbalanced post-study treatment made pivotal TIVO-1 trial uninterpretable, necessitating another study, and said proposed dissolution acceptance criterion was not supported by data provided; Aveo had already restructured after negative advisory committee vote and will not pursue an RCC claim)
Tolvaptan^a Otsuka		New use of the selective V2 vasopressin receptor antagonist (approved as Samsca for hyponatremia) to slow kidney disease in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease	Announced 8/30/2013 (FDA requested additional safety and efficacy data)
Toremifene GTx		Selective estrogen receptor modulator, used at a higher dose than is approved for breast cancer (80 mg vs. 60 mg), for prevention of bone fractures in advanced prostate cancer patients taking androgen deprivation therapy	Announced 11/2/2009 (FDA requested a second Phase III trial and a clinical trial showing treatment does not have a detrimental effect on either time-to-disease progression or overall survival) Discontinued
Treanda Bendamustine^a Teva Pharmaceuticals		New indication for the alkylating drug for use in combination with rituximab for first-line treatment of non-Hodgkin lymphoma	10/2012 (Teva reports that while the BRIGHT trial met its non-inferiority endpoint, FDA requested progression-free survival data that was not available from the trial; Teva does not plan to conduct further U.S. registration trials)
Tresiba Insulin degludec^b Novo Nordisk		Ultra-long-acting basal insulin analog that forms multi-hexamers upon subcutaneous injection, resulting in a soluble depot, for treatment of type 1 and type 2 diabetes	2/8/2013 (FDA requires a dedicated cardiovascular outcomes trial prior to approval; letter also notes that no approvals will be granted until questions in a 12/12/2012 warning letter regarding environmental monitoring samples from Novo’s Bagsvaerd, Denmark aseptic filling facility are resolved; Novo says it responded to manufacturing letter late 12/2012)
Twirla Ethinyl estradiol/levonorgestrel, transdermal Agile Therapeutics/Corium (formerly AG200-15)		Once-weekly low-dose combination hormonal contraceptive patch for three weeks of use followed by one week off, formulated with Agile’s Skinfusion active and peripheral adhesive system, for prevention of pregnancy	2/2013 (Agile will start a new Phase III trial in H1 2014 with a simplified, single-arm design with improved site monitoring and data collection procedures, as recommended by FDA; the agency also questioned the Pearl Index values in the submitted Phase III trials, which were higher in both the active and control arms than had been seen in registration trials for other hormonal contraceptives, and requested more information on the process of laser-etching label information on each patch)
Vascana (MQX-503) Nitroglycerin, topical MediQuest		Topical formulation of nitroglycerin, using MediQuest’s Topical Amphi-Matrix delivery technology, for treatment of Raynaud’s disease	10/2008 (FDA cited concerns regarding intrasubject variation in the pivotal trial, and proposed a new “cold room” study to ensure a consistent, controlled environment)
Vectibix Panitumumab^a Amgen		Expanded indication for the epidermal growth factor receptor antagonist, approved for metastatic colorectal cancer patients who have failed three specific drugs, for first-line treatment of mCRC	7/29/2011 (FDA requested updated safety analysis and additional analyses of overall survival data from the 181 and 203 studies, using more mature data sets; FDA also said clearance would be contingent upon approval of a KRAS companion diagnostic being developed with Qiagen N.V.) Resubmitted late 2013 for use in combination with FOLFOX chemotherapy for first-line treatment of patients with wild-type exon 2 KRAS metastatic colorectal cancer
Vectibix Panitumumab^a Amgen		Expanded indication for the epidermal growth factor receptor antagonist, approved for metastatic colorectal cancer patients who have failed three specific drugs, for second-line treatment of mCRC	7/29/2011 (FDA requested updated safety analysis and additional analyses of overall survival data from the 181 and 203 studies using more mature data sets; FDA also said clearance would be contingent upon approval of a KRAS companion diagnostic being developed with Qiagen N.V.)
Vyndaqel Tafamidis meglumine^b Pfizer		Oral agent that stabilizes the protein transthyretin for treatment of the progressive autosomal neurodegenerative disease transthyretin amyloid polyneuropathy, also known as familial amyloid polyneuropathy	Announced 6/18/2012 (FDA requested a second efficacy study to establish substantial evidence of effectiveness as well as additional information on data submitted in the NDA)
Xarelto Rivaroxaban^a Johnson & Johnson/Bayer HealthCare		New prevention indication for the oral anticoagulant to reduce the risk of secondary thrombotic cardiovascular events in patients with acute coronary syndrome in the first 90 days after an ACS event (original sNDA requested continuous use)	Announced 2/14/2014 (Sponsors did not disclose content of the letter, but on 1/16/2014 an FDA advisory committee recommended against approval, saying sponsors’ exploratory analyses of treatment effect and bleeding risk at particular time points in the ATLAS ACS 2 TIMI 51 trial were not sufficient to overcome a lack of statistical robustness and data quality concerns in the overall study; previous “complete response” letters issued 3/4/2013 and 6/21/2012; FDA denied J&J’s 5/13/2013 request for formal dispute resolution in 6/2013 but suggested limiting duration of use to 30 days)
Xarelto Rivaroxaban^a Johnson & Johnson/Bayer		New indication for the oral Factor Xa inhibitor anticoagulant in combination with standard antiplatelet therapy to reduce the risk of stent thrombosis in acute coronary syndrome patients	Announced 2/14/2014 (Sponsors did not disclose details of the letter, but the ATLAS ACS2 TIMI 51 trial, which is pivotal for both the stent thrombosis sNDA and an sNDA for cardiovascular risk reduction in ACS, raised advisory committee and FDA concern about data quality and statistical robustness; previous “complete response” letter announced 6/28/2013)
Xgeva Denosumab^a Amgen		New indication for the RANK ligand inhibitor for prophylactic use in men with castrate-resistant prostate cancer to reduce the risk of developing bone metastases	Announced 4/26/2012 (FDA found the effect on bone metastases-free survival to be insufficient to outweigh risks, and requests another trial showing favorable risk/benefit that is generalizable to the U.S. population)
Xifaxan Rifaximin 550 mg tabs.^a Salix Pharmaceuticals		New indication for the high-dose 550 mg tablet formulation of the gut-selective antibiotic for treatment of non-constipation or diarrhea-predominant irritable bowel syndrome and IBS-related bloating	3/7/2011 (FDA’s concerns relate primarily to what Salix calls a “newly expressed need” for retreatment information. An advisory committee 11/16/2011 considered the IBS data, with a focus on the clinical study design for retreatment of patients; retreatment study initiated Q1 2012, ongoing as of 5/2014) Resubmission of sNDA announced 8/29/2014
Zalviso Sufentanil sublingual microtablet system AcelRx Pharmaceuticals		Patient-activated, non-invasive handheld analgesia system that delivers 15 mcg of sufentanil as needed with a 20 minute lockout period between doses, for management of moderate to severe pain in adults in a hospital setting	Announced 7/25/2014 (FDA’s concerns mainly related to the device component, including reducing the incidence of optical system errors requiring premature drug cartridge change, changing to the device’s instructions for use to address misplaced tablets and conducting human factors testing of new instructions, and shelf-life stability)
Zavesca Miglustat^a Actelion		New indication for the substrate reduction therapy for treatment of progressive neurological manifestations in adult and pediatric patients with Niemann-Pick type C disease	Announced 3/9/2010 (FDA requested additional preclinical and clinical information)
Zmax Azithromycin^a Pfizer		New indication for the macrolide antibiotic for treatment of pediatric acute otititis media and pediatric acute bacterial sinusitis	5/2011 (AOM claim sNDA based on pharmacokinetic data was previously “approvable” 9/2007; sNDA filed 1/2010 contained both AOM and ABS pediatric claims)
Pending “Approvables”
Accretropin Recombinant human growth hormone^a Cangene	Recombinant human growth hormone for treatment of growth failure in children with growth hormone deficiency and short stature associated with Turner syndrome		3/11/2007 (Withdrawn as of 8/2009)
Alvesco Ciclesonide Sanofi-Aventis/Altana	Inhaled corticosteroid for treatment of persistent asthma in patients four years of age and older		10/21/2004 (Approved for patients 12 years and older 1/10/2008; labeling approved 12/17/2012 specifies lack of efficacy in patients 6 months to 4 years old)
Ariflo Cilomilast^b GlaxoSmithKline	Phosphodiesterase-4 inhibitor for treatment of chronic obstructive pulmonary disease in patients poorly responsive to albuterol		10/23/2003 (Development discontinued 2007)
Arixtra Fondaparinux^a GlaxoSmithKline	Synthetic factor Xa inhibitor for use in patients with acute coronary syndromes		2/1/2007
Arxxant Ruboxistaurin^b Lilly	Oral protein kinase C-beta inhibitor for treatment of diabetic retinopathy		8/17/2006 (Lilly dropped Arxxant from active development 4Q 2011)
Azimilide^b Forest Laboratories/Blue Ash Therapeutics (formerly Procter & Gamble’s Stedicor; Warner Chilcott acquired P&G’s Rx business in 2009, licensed azimilide to Blue Ash 1/2010)	Class III antiarrhythmic agent originally submitted by P&G 12/10/1998 for maintenance of sinus rhythm in patients with atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycaridias; Blue Ash reactivated the IND in 2010 for use in patients with a history of life-threatening ventricular arrhythmias who have an implantable cardioverter defibrillator		2006 (FDA, having reviewed the SHIELD I Phase III study, requested an additional clinical trial) Blue Ash received agreement from FDA in 2010 that one additional clinical trial could support NDA submission; Forest licensed worldwide rights 4/2011 and initiated the SHIELD 2 trial 11/2011 under a Special Protocol Assessment with FDA
Bonefos Clodronate^b Berlex (Bayer Schering)	Oral bisphosphonate for use as adjuvant treatment for reducing occurrence of bone metastases in stage II/III breast cancer		1/6/2005 (FDA wants to see results of the NSABP-sponsored B-34 trial, which started in 2001 and is expected to complete 3/2013)
Efaproxyn Efaproxiral^b (RSR-13) Allos	Radiation sensitizer for use as an adjunct to whole brain radiation therapy for the treatment of brain metastases from breast cancer		5/27/2004 (FDA requested results from ongoing ENRICH study; trial completed enrollment 8/2006) Discontinued 6/2007
Extravan Travoprost 0.004% & timolol 0.5%^a Alcon	Fixed combination of firm’s prostaglandin analog travoprost (Travatan) and the beta blocker timolol for the treatment of glaucoma		Announced 9/17/2004 (Alcon has initiated multiple trials, including Phase IV in patients uncontrolled on timolol initiated 4/2011; Phase IV in patients uncontrolled on bimatoprost (3/2011); and a completed Phase IV replacement trial (2/2009) and Phase IIIb, initiated 3/2007)
Fuzeon Enfuvirtide^a Roche/Trimeris	New claim for use with Biojector 2000 needle-free injector		Announced 11/23/2005 (Letter requests additional information from supporting trial) sNDA withdrawn 10/2007
Galvus Vildagliptin^b Novartis	DPP-4 inhibitor for treatment of type 2 diabetes		2/23/2007 Development discontinued in U.S. as of 1/2010
Hemopure Hemoglobin glutamer, bovine (HBOC-201) OPK Biotech LLC (acquired from Biopure in bankruptcy)	Oxygen therapeutic delivered intravenously for treatment of signs and symptoms of acute anemia in adults undergoing orthopedic surgery, and to eliminate, delay or reduce the need for red blood cells in these patients		7/30/2003 (Biopure submitted proposed protocols for three requested preclinical studies. OPK Biotech says it is collaborating with the U.S. Navy on a preclinical study out-of-hospital treatment of hemorrhagic shock from traumatic injury, as of 2011)
Indiplon, immediate-release capsule^b Neurocrine	Non-benzodiazepine GABA-A receptor agonist for treatment of insomnia in adult and elderly patients		12/12/2007 (Second approvable letter requested three additional studies: clinical safety and efficacy studies in the elderly and a preclinical pregnancy study. Complete response announced 6/14/2007 to the first approvable letter of 5/15/2006)
Indiplon, modified-release tab.^a Neurocrine	Non-benzodiazepine GABA-A receptor agonist for treatment of insomnia in adult and elderly patients		5/15/2006 (No longer in active development)
Intal HFA Cromolyn^a, nebulizer solution (20-957) King (acquired from Aventis)	Non-CFC formulation of the asthma therapy		Announced 10/30/2003; earlier letter issued 5/1999 (Discontinued 2007)
Kynapid Vernakalant^b Cardiome (formerly in partnership with Merck)	Intravenous anti-arrhythmic for conversion of acute atrial fibrillation to sinus rhythm		8/8/2008 (FDA seeks additional safety data and an additional Phase III in a narrower patient population of patients with recent onset AF who do not have a history of heart failure; the Phase III ACT5 trial launched in 2009 but was halted in 2010 after a patient died from cardiogenic shock) While Merck discontinued oral vernakalant 3/2012, Cardiome said Merck had met with FDA regarding the I.V. form and had agreed to analyze ACT5 data. But Merck terminated the Cardiome collaboration 9/26/2012; Cardiome indicated it hoped to continue with vernakalant.
Lercanidipine^b (21-377) Forest	Calcium channel blocker (immediate-release formulation) for treatment of hypertension		8/1/2002 (FDA asked for further clinical studies) Modified-release formulations were subsequently tested but development not active as of 2004
Luvox CR Fluvoxamine, controlled-release^a Jazz Pharmaceuticals/Solvay	Extended-release formulation of the selective serotonin reuptake inhibitor for treatment of obsessive compulsive disorder and social anxiety disorder		Announced 12/21/2007 (Second approvable letter; requests clarification regarding chemistry, manufacturing and controls) Full response submitted 12/28/2007; approved 2/28/2008 for OCD indication only
Mucinex with codeine Guaifenesin/dextromethorphan/codeine, tab.^a Adams Respiratory Therapeutics	Additional use for extended-release combination formulation for prescription treatment of cough associated with the common cold, inhaled irritants and stable chronic bronchitis		Announced 10/29/2007 (FDA requested data on use with food) Likely discontinued
Namenda Memantine^a Forest	New claim for use of the NMDA receptor antagonist for treatment of mild to moderate Alzheimer’s disease		Announced 7/25/2005 (FDA confirmed non-approvable status for mild AD patients 5/2006)
Omnaris Ciclesonide^a Altana	Claim for use of the corticosteroid in treating nasal symptoms associated with seasonal and perennial allergic rhinitis in children ages 2-11 years		10/23/2006 (sNDA submitted 11/21/2007 for seasonal allergic rhinitis in children ages 6-12 years was approved 11/21/2007)
Oxyprim Oxypurinol Cardiome	Active metabolite of the xanthine oxidase inhibitor allopurinol for the treatment of allopurinol-intolerant hyperuricemia (gout)		6/23/2004 (Development suspended 9/2004)
Photrex Rostaporfin Miravant	SnET2-photodynamic therapy for treatment of wet age-related macular degeneration with any classic component (includes predominantly and minimally classic as well as lesions with or without occult components)		9/30/2004 (Letter requests additional confirmatory clinical trial) Discontinued 2005
Preos Parathyroid hormone^a NPS	Recombinant full-length human parathyroid hormone to stimulate bone growth for treatment of osteoporosis in postmenopausal women with or without a previous fracture, subcutaneous injection formulation		3/9/2006 (NPS said it would only pursue development in osteoporosis with a partner, 2/2012)
Prestara (formerly Aslera) Prasterone^b Genelabs (licensed to Watson through action letter; Watson sold off its Genelabs shares by 2005)	Treatment of women with systemic lupus erythematosus to limit bone loss while on low-dose glucocorticoids		8/12/2002 (FDA requested confirmatory study, initiated by firm 1/2003, but it failed to meet primary endpoint. In 1/2006, FDA indicated an additional trial would be needed for a signs and symptoms of SLE claim; Genelabs said it could not conduct such a trial alone) Genelabs said it would not pursue BMD loss in lupus patients 1/2006
Prolacria Diquafosol tetrasodium (INS365), 2% ophthalmic solution^b Allergan/Inspire	Ocular P2Y2 receptor stimulator that enhances secretion of water, salt, mucin and lipids for treatment of dry eye		Announced 12/2/2005 & 12/19/2003 (Inspire received a special protocol assessment for another Phase III trial in 2009)
Pulminiq Cyclosporine, nebulizer solution APT Pharmaceuticals/Chiron	Aerosolized cyclosporine to increase survival and prevention of chronic rejection in patients receiving allogeneic lung transplants, for use in combination with standard immunosuppressive therapy		7/14/2005 (Letter requests confirmatory clinical study) APT Pharmaceuticals acquired lung transplant rights from Chiron parent Novartis 6/2007; Phase III CYCLIST trial to improve bronchiolitis obliterans syndrome (BOS)-free survival completed enrollment 2/2010.
Requip CR Ropinirole^a GlaxoSmithKline	14-hour controlled-release version of the non-ergot dopamine agonist for the treatment of restless legs syndrome		Announced 8/10/2007 (Discontinued; additional Phase III trial completed 11/2008)
Risperdal Risperidone^a Johnson & Johnson	Atypical antipsychotic for treatment of schizophrenia in children ages 13-17		Announced 6/21/07
Rufinamide^b Eisai	Triazole derivative for use as adjunctive therapy in Lennox-Gastaut syndrome in children 4 years and older; and as adjunctive therapy for partial-onset seizures with and without secondary generalization in adults and adolescents ages 12 and olderr		9/15/2006 (Approved for the Lennox-Gastaut syndrome indication 11/14/2008)
Saforis Glutamine MGI (now Eisai)	Powder for oral suspension form of glutamine for prevention and treatment of oral mucositis in patients receiving mucotoxic therapy; uses firm’s proprietary UpTec delivery system		10/12/2006 (Letter requests additional trial to establish efficacy) Eisai acquired MGI 1/2008; Phase III ongoing as of 2/2012
SPD465 Shire	Extended-release formulation of the triple-beaded mixed amphetamine salts for symptom control of attention deficit/hyperactivity disorder for adults; contains same active ingredient as firm’s Adderall		Announced 5/18/2007 (FDA is seeking clarification of additional data)
Tacrolimus (FK506), modified-release^a(formerly Prograf MR) Astellas	Once-daily formulation of the immunosuppressant for prophylaxis of organ rejection in kidney transplant patients		3/13/2008 (Previous “approvable” letter received 1/19/2007)
Tacrolimus (FK506), modified-release^a(formerly Prograf MR) Astellas	Once-daily, modified-release formulation of firm’s immunosuppressant for prevention of organ transplant rejection in liver transplant patients		4/30/2008 (Previously approvable 1/19/2007)
Tygacil Tigecycline^a Wyeth	New indication for the glycylcycline antibiotic for treatment of community-acquired pneumonia		Announced 5/29/2008 (Likely discontinued)
Valstar Valrubicin Indevus (acquired by Endo 2009)	Sterile solution of valrubicin for intravesical instillation therapy of bacillus Calmette-Guerin-refractory carcinoma in situ of the urinary bladder		Announced 8/17/2007 (FDA cites need for CMC clarification)
Vfend Voriconazole^a Pfizer	New pediatric indication for the azole agent for treatment of fungal infections		12/2005 (In 4/2010, based on a new pharmacokinetic study, FDA and Pfizer agreed on a dosing regimen for pediatric patients in three ongoing trials)
Viviant Bazedoxifene^b Pfizer (formerly Wyeth)	Selective estrogen receptor modulator for treatment of postmenopausal osteoporosis		5/21/2008 (FDA seeks additional data; some data submitted 2009) Pfizer said 2/2014 that it is reassessing the next steps for the Vivant NDAs in light of the 2013 approval of DuaVee (bazedoxifene/conjugated estrogens)
Viviant Bazedoxifene^b Pfizer (formerly Wyeth)	Second-generation selective estrogen receptor modulator for prevention of postmenopausal osteoporosis		Announced 12/24/2007 (Second approvable letter; requested further data on stroke and venous thromboembolism, also raises data collection and reporting issues. First approvable letter issued 4/23/2007; some data submitted 2009) Pfizer said 2/2014 that it is reassessing the next steps for the Vivant NDAs in light of the 2013 approval of DuaVee (bazedoxifene/conjugated estrogens)
Zortress Everolimus (formerly Certican) Novartis	Rapamycin derivative macrolide immunosuppressant/mTOR inhibitor (approved with different dosing for renal cancer as Afinitor) for use with cyclosporine to prevent acute rejection episodes following heart and kidney transplantation		8/27/2004 & 10/20/2003 (Novartis has continued to study kidney transplant use but has not responded on the heart indication. The 2004 letter referenced Novartis' 2/27/2004 NDA amendment containing two open-label kidney transplant studies; FDA cited limited regulatory value of studies lacking a control group. Novartis submitted a full response on 6/30/2009 with a new Phase III kidney transplant study) Approved for kidney transplant patients 4/20/2010
Pending “Complete Reviews”
Aranesp Darbepoetin alfa^a Amgen	New claim for once every-two-week and maintenance once-monthly dosing regimens for chronic kidney disease patients with anemia not on dialysis		Announced 10/13/2006 (Discontinued)
Gardasil Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine^a Merck	Labeling expansion to include efficacy data showing cross-protection against additional cervical cancer-causing HPV types responsible for greater than 10 percent of cervical cancers, data on protection against additional gynecological cancers (vaginal and vulvar) and data on immune memory		Announced 6/25/2008 (FDA said that the data submitted do not support extending Gardasil’s indication to include non-vaccine HPV types) Approved for prevention of vaginal and vulvar cancer caused by HPV types 16 and 18 in girls and women ages 9 to 26 on 9/12/2008
Pending “Not Approvables”
Advair Diskus 500/50 Fluticasone/salmeterol inhalation powder^a GlaxoSmithKline	Higher dosage form of the long-acting beta agonist bronchodilator for the treatment of chronic obstructive pulmonary disease		8/6/2007 (FDA asks for head-to-head data with firm’s 250/50 mcg strength)
Angiomax Bivalirudin^a The Medicines Company	New indication for the thrombin-specific antithrombotic for treatment of acute coronary syndromes initiated in the emergency setting		Announced 5/28/2008 (Discontinued)
Arcoxia Etoricoxib^b Merck	Follow-on to firm’s withdrawn COX-2 inhibitor Vioxx for treatment of osteoarthritis		4/27/2007 (FDA requested additional data in support of the benefit/risk profile for the proposed doses; previously “approvable” 10/2004)
Bifeprunox^b Wyeth/Solvay	Atypical antipsychotic for the treatment of schizophrenia		Announced 8/10/2007 (Firms pursued “maintenance” indication for stable adult patients with schizophrenia, but discontinued the program in 2009) NDA withdrawn
Dapoxetine^b Johnson & Johnson	Selective serotonin reuptake inhibitor for prevention of premature ejaculation		10/26/2005
Gepirone ER,^btab. Fabre-Kramer Pharmaceuticals	Serotonin receptor agonist for treatment of adults with major depressive disorder		Announced 11/2/2007 (Third “not approvable” letter; firm cites efficacy concerns) Discontinued
Injectafer Ferric carboxymaltose, I.V. Luitpold (Daiichi Sankyo)	Intravenous iron replacement product for iron deficiency anemia in postpartum patients and women with heavy uterine bleeding		Announced 3/12/2008 (FDA requested additional clinical trials to collect more information about mortality signal vs. oral iron; first “not approvable” letter in 6/2006 also cited mortality signal) Resubmission for treatment of iron deficiency anemia announced 10/13/2011
Istradefylline^b Kyowa	Adenosine A2A antagonist as an adjunct to carbidopa/levodopa to improve motor functioning in Parkinson’s disease patients with motor response complications		2/25/2008 (FDA questioned if efficacy findings support clinical utility, and requested summary of nonclinical mineralization findings and clinical pharmacology follow-up information)
Lexapro ^a Escitalopram Forest	New indication for use of the SSRI in panic disorder		Announced 3/1/2005 (Also “not approvable” 2/25/2004) Discontinued as of 2010
Lexapro ^a Escitalopram Forest	New indication for use of the SSRI in social anxiety disorder		3/25/2005 (Letter raises questions about single study center) Discontinued as of 2010
Loratadine/montelukast^a Merck/Schering-Plough	Combination of Merck’s leukotriene antagonist Singulair and Schering-Plough’s Claritin for treatment of allergic rhinitis symptoms in patients who want relief from nasal congestion		4/25/2008
Marqibo Vincristine Ilex/Enzon	Liposomal-encapsulated vincristine for single-agent treatment of patients with relapsed aggressive non-Hodgkin’s lymphoma previously treated with at least two combination chemotherapy regimens		1/14/2005 (Letter recommends additional clinical studies with improved designs)
Mifamurtide^b IDM Pharma	Immunomodulator for the treatment of nonmetastatic osteosarcoma		Announced 8/27/2007 (Firm says FDA requested additional data from additional clinical trials)
Fablyn Lasofoxifene^b Pfizer/Ligand (formerly Oporia)	Next-generation selective estrogen receptor modulator for prevention of osteoporosis in postmenopausal women		Announced 9/13/2005 (Pfizer withdrew NDA as of 4/2011 and returned all rights to Ligand 7/2011)
Orapem Faropenem medoxomil^b Replidyne	Orally bioavailable ester prodrug of faropenem for treatment of acute bacterial sinusitis, community-acquired pneumonia, acute exacerbations of chronic bronchitis and uncomplicated skin and skin structure infections		10/20/2006 (Replidyne discontinued Phase III enrollment in 2007-2008 to conserve funds after Forest terminated collaboration in 2007; Replidyne returned rights to Asubio Pharma 8/2008 when it could not find a new partner) Discontinued
orBec Oral beclomethasone dipropionate, tab.^a Soligenix (formerly Dor Biopharma)/Sigma-Tau Pharmaceuticals	New use for tablet formulation of the immunosuppressant to treat acute gastrointestinal Graft-versus-Host disease		Announced 10/19/2007 (FDA requested additional clinical data; confirmatory Phase III SUPPORTS trial commenced 10/2009 but terminated 9/2011 when it was considered unlikely to achieve primary endpoint)
Parecoxib^b Pfizer	Injectable pro-drug of firm’s withdrawn COX-2 inhibitor Bextra (valdecoxib)		Announced 9/20/2005 (Also not approvable in 2001) Discontinued
Prexige Lumiracoxib^b Novartis	COX-2 inhibitor for the treatment of osteoarthritic pain		Announced 9/27/2007 (Second “not approvable” letter; FDA requests additional studies, data on liver profile) Withdrawn from major markets (2008)
Pulzium Tedisamil^b Solvay	Potassium channel blocking Class III anti-arrhythmic drug for treatment of recent onset atrial fibrillation or atrial flutter		1/18/2008 Sponsor will not pursue U.S. development (2/2009)
Risperdal Risperidone^a Johnson & Johnson	New indication for treatment of psychosis in Alzheimer’s dementia		Announced 5/26/2005
Symlin Pramlintide^a Amylin	Additional claim for the glucose metabolism regulator for treatment of type 2 diabetes in combination with basal insulin alone (without mealtime insulin)		Announced 10/1/2007 (FDA cites inadequate efficacy; firm says it plans to pursue the indication)
T-Pred Prednisolone acetate/tobramycin Ista	Topical, fixed-dose combination of the corticosteroid and aminoglycocide antibiotic for treatment of inflammatory ocular conditions for which a corticosteroid is indicated and where bacterial ocular infections or a risk of bacterial infection exists		5/3/2007
Tredaptive (formerly Cordaptive) Laropiprant^b/niacin Merck	Combination of extended-release niacin and firm’s novel DP1 flushing pathway inhibitor, which selectively blocks the binding of the prostaglandin PGD2 to its DP1 receptor, for treatment of elevated LDL cholesterol, low HDL cholesterol and elevated triglyceride levels either alone or with a statin, as an adjunct to diet and exercise		4/28/2008
Vadova Carbidopa/levodopa Impax	Extended-release formulation of the Parkinson’s disease combination treatment		Announced 3/7/2006 (Letter cites chemistry deficiencies); second “not approvable” letter announced 1/30/2008, cites concerns about nomenclature and medication errors) No longer in active development; an NDA for a next-generation formulation of ER carbidopa/levodopa, IPX-066, was submitted 12/2011
Valstar ^a Valrubicin Indevus (acquired by Endo 2009)	Sterile solution of valrubicin for intravesical instillation to treat bacillus Calmette-Guerin-refractory carcinoma in situ of the urinary bladder		Announced 12/19/2007 (Manufacturing facilities deficiencies cited for previously approvable sNDA to return Valstar to market. Drug was withdrawn in 2002 due to impurities in original formulation.)
Vitaros (formerly Alprox TD) Alprostadil, cream NexMed/Warner Chilcott	Topical treatment of erectile dysfunction		Announced 7/22/2008 (Transgenic mouse carcinogenicity study is the major issue) As of 2010, Warner Chilcott was working to prepare a response to FDA
Xcytrin Motexafin gadolinium^b Pharmacyclics	Paramagnetic thioredoxin reductase inhibitor for treatment of non-small cell lung cancer with brain mestastases		Announced 12/21/2007 (Discontinued)
Xinlay Atrasentan^b Abbott	Selective endothelin-A receptor antagonist for treatment of metastatic, hormone-refractory prostate cancer		10/13/2005 (Discontinued)
Zarnestra Tipifarnib^b Johnson & Johnson	Farnesyl transferase inhibitor for treatment of newly diagnosed acute myeloid leukemia		Announced 6/30/2005 (Letter requests additional information on pivotal trial’s patient population) (Discontinued)
Zimulti (formerly Acomplia) Rimonabant^b Sanofi-Aventis	Selective cannabinoid-1 receptor blocker for use in smoking cessation		2/17/2006 (Discontinuation in all indications announced 11/2008)
^a Submission is for a new use or new formulation of product that sponsor already markets ^b New molecular entity or combination product with NME as component