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Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012

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Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012 Supplementary Online Content Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri K, Lanthier ML, Sherman RE. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA. doi: 10.1001/jama.2013.282542. eTable 1. List of Approved NMEs by Number of Review Cycles Till Approval eTable 2. Examples of Excerpts From Publicly Available Action Letters and FDA Reviews, and Corresponding Categories of Deficiencies This supplementary material has been provided by the authors to give readers additional information about their work. © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 1: List of Approved NMEs by Number of Review Cycles Till Approval First Cycle Approvals (151) Abiraterone acetate Epinastine hydrochloride Pemetrexed disodium Formatted Table Aclidinium bromide Eplerenone Pentetate calcium trisodium Alcaftadine Eribulin mesylate Pentetate zinc trisodium Aliskiren Erlotinib hydrochloride Perampanel Ambrisentan Ertapenem sodium Pimecrolimus Aprepitant Etravirine Pitavastatin Artemether; lumefantrine Exenatide Plerixafor Atazanavir sulfate Ezetimibe Pomalidomide Avanafil Fidaxomicin Ponatinib Axitinib Fingolimod Pralatrexate Azacitidine Fulvestrant Prasugrel Azilsartan medoxomil Gefitinib Prussian blue Bedaquiline Hyaluronidase (recombinant human) Raltegravir potassium Bendamustine hydrochloride Ibandroante sodium Ramelteon Bepotastine besilate Iloprost Regorafenib Besifloxacin Imatinib mesylate Rilpivirine Boceprevir Ingenol mebutate Romidepsin Bortezomib Insulin glulisine Ruxolitinib Bosutinib Ivacaftor Sapropterin dihydrochloride Cabazitaxel Ixabepilone Saxagliptin Cabozantinib Kunecatechins Silodosin Canagliflozin Lacosamide Sitagliptin phosphate Sodium picosulfate; Magnesium oxide; Capsaicin Lanreotide Citric acid Carfilzomib Lapatinib Sorafenib tosylate Carglumic acid Lenalidomide Sunitinib malate Ceftaroline fosamil L-Glutamine Tapentadol Cinacalcet hydrochloride Linaclotide Teduglutide Clevidipine Linagliptin Telaprevir Clobazam Liraglutide Telbivudine Clofarbine Lomitapide mesylate Temsirolimus Crizotinib Lubiprostone Tenofovir disoproxil fumarate Crofelemer Lurasidone hydrochloride Teriflunomide Dabigatran etexilate Mecasermin (rDNA Origin) Tesamorelin acetate Dabrafenib Memantine hydrochloride Tigecycline Dalfampridine Methylnaltrexone Tinidazole Daptomycin Milnacipran hydrochloride Tipranavir Darunavir Mipomersen Tofacitinib citrate Dasatinib Mirebegron Trametinib Deferasirox Nelarabine Trospium chloride Degarelix Nepafenac Ulipristal acetate Dienogest; Estradiol valerate Nilotinib Valdecoxib Difluprednate Norelgestromin; Ethinyl estradiol Vandetanib Dimethyl fumarate Omacetaxine mepesuccinate Varenicline Doripenem Ospemifene Velaglucerase alfa Dutasteride Ovine hyaluronidase Vemurafenib Eltrombopag Oxaliplatin Vilanterol; Fluticasone furoate Elvitegravir; Cobicistat; Emtricitabine; Tenofovir disoproxil fumarate Palonosetron hydrochloride Vilazodone Emtricitabine Pasireotide Vismodegib Enfuvirtide Pazopanib Vorinostat Entecavir Pegaptanib sodium Enzalutamide Peginesatide 2 © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Second Cycle Approvals (55) Abarelix Fospropofol disodium Rifaximin Formatted Table Acamprosate calcium Gabapentin enacarbil Rivaroxaban Alfuzosin hydrochloride Hyaluronidase* (bovine) (Amphadase) Roflumilast Apixaban Hyaluronidase* (bovine) (Hydase) Rosuvastatin calcium Aripiprazole Icatibant Rotigotine Asenapine Icodextrin Rufinamide Atomoxetine hydrochloride Iloperidone Sertaconazole nitrate Benzyl alcohol Indacaterol Solifenacin succinate Bosentan Insulin detemir Spinosad Ciclesonide Lanthanum carbonate hydrate Tadalafil Conivaptan hydrochloride Lorcaserin hydrochloride Tafluprost Darifenacin hydrobromide Maraviroc Taliglucerase alfa Decitabine Mecasermin Rinfabate (rDNA Origin) Ticagrelor Deferiprone Micafungin sodium Tiotropium bromide Desvenlafaxine Miglustat Tolvaptan Eszopiclone Paliperidone Vardenafil hydrochloride Ezogabine Pegvisomant Voriconazole Fesoterodine fumarate Pregabalin Fondaparinux sodium Ranolazine Third Cycle Approvals (13) Alogliptin Febuxostat Sodium Oxybate Formatted Table Alvimopan Lisdexamfetamine dimesylate Telavancin Anidulafungin Nebivolol Treprostinil sodium Biskalcitrate; Metronidazole; Tetracycline hydrochloride Pramlintide acetate Duloxetine hydrochloride Rasagiline mesylate Fourth Cycle Approvals (2) Everolimus Tetrabenazine Formatted Table Fifth Cycle Approvals (1) Lucinactant Formatted Table *chemically distinct based on manufacturing differences 2 © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 2: Examples of Excerpts From Publicly Available Action Letters and FDA Reviews, and Corresponding Categories of Deficiencies1 Link to drug action Excerpt of FDA document describing Assigned category of Formatted Table letter or review deficiencies deficiency2 Rufinamide “You have submitted results of 8 controlled Link: trials that appear, by design, capable of 1) Uncertainty/disagreement http://www.accessdata.f demonstrating the effect of an antiepileptic about appropriate dose (S,E) da.gov/drugsatfda_docs/ drug, but results are inconsistent, leave the nda/2008/021911s000_ appropriate dose unclear, and with one 2) Inconsistent results in Approvable.pdf exception, show either no, or numerically different trials or at different very small effects. While the studies do study sites (E) suggest that rufinamide has activity, we see no good basis for identifying the useful range of doses and even the evidence of efficacy is not reasonably assured.” Nebivolol “A highly statistically significant and dose- 1) Potential risks based on Formatted ... Link: http://www.access related increase in benign and malignant animal toxicology e.g. data.fda.gov/drugsatfda_ Leydig cell tumors was observed in male carcinogenicity (S) docs/nda/2007/021742s0 mice. The findings appear with exposure 00_APPROVable.pdf only several times the clinically attained blood levels. This effect may be endocrinologically mediated. Other possibly endocrinologically mediated effects were also seen in long-term toxicology studies of rats-reductions in adrenal and ovary weights, dystocia, and interference with cyclicity. If an endocrine mechanism can be established and if this mechanism is not relevant to human use, e.g., because it is not active at clinical doses, the mouse findings may not be of concern. It will therefore be necessary for you to establish the mechanism by which nebivolol is responsible for these findings and demonstrate that these findings are not relevant in humans.” Febuxostat “Due to the finding that exposure to Uloric 1) Adverse events: Link: appeared to increase the risk of cardiac Cardiovascular (S) http://www.accessdata.f thromboembolic events compared to da.gov/drugsatfda_docs/ placebo, or allopurinol, the sponsor was 2) Adverse events: nda/2009/021856s000_S asked to either provide further comparative Hemostasis (S) umR.pdf controlled clinical safety data or to reanalyze the original database and 3) CYP enzyme studies not demonstrate that the apparent signal of done (S) increased risk is not predictive of clinically 2 © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 important differences. Due to the finding of hemorrhagic adverse events and elevated INRs in patients on Uloric and warfarin in the original database for the application, and questions concerning the reliability of the results of a pharmacokinetic study that specifically looked at warfarin interaction with Uloric, the sponsor was asked to further evaluate the potential for concomitant administration of warfarin and Uloric to result in haemorrhagic adverse events… Due to an absence of data to evaluate the induction potential of Uloric on human CYP P450 enzymes, the sponsor was asked to perform a study to provide this data either in vitro or in vivo.” Atomoxetine “Although we believe that no important 1) QT prolongation studies hydrochloride effect on the QT interval was demonstrated not done or inadequate (S) Link: at mean plasma levels at or below about http://www.accessdata.f 2000 ng/ml, there are relatively few data at 2) Population inadequate for da.gov/drugsatfda_docs/ or above these levels, and, as a result, we proposed dose/duration of nda/2002/21- cannot reach a definitive decision at this therapy (S) 411_Strattera_Approv.p time about whether there is or is not an df effect of atomoxetine on the QT interval at these higher levels, and, if there is, what the plasma level threshold for such and effect might be. For this reason you will need to prepare a comprehensive report in which you address the question of the relationship between higher level of atomoxetine and the duration of the QT interval. We also note that there is a paucity of long- term safety data in poor metabolizers (PM) in your database (13 PMs treated at a therapeutic dose for at least 6 months and 1 such patient treated for at least 1 year). Please submit additional long-term safety data in these patients…” Tadalafil Link: “We agree that use of Cialis should be 1) Population not appropriate http://www.accessdata.f contraindicated for patients on continuous to reflect intended use (E) 2 © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 da.gov/drugsatfda_docs/
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