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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 , 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.

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eTable 1: List of Approved NMEs by Number of Review Cycles Till Approval

First Cycle Approvals (151) Abiraterone Epinastine hydrochloride disodium Formatted Table Aclidinium Eplerenone Pentetate calcium trisodium Alcaftadine mesylate Pentetate zinc trisodium Aliskiren Erlotinib hydrochloride Ambrisentan Ertapenem sodium Pimecrolimus Aprepitant Etravirine Pitavastatin Artemether; lumefantrine Exenatide Plerixafor Atazanavir sulfate Ezetimibe Pomalidomide Avanafil Fidaxomicin Ponatinib Axitinib Fingolimod Fulvestrant Prasugrel Azilsartan medoxomil Gefitinib Prussian blue (recombinant human) Raltegravir potassium hydrochloride Ibandroante sodium Ramelteon Bepotastine besilate Regorafenib Besifloxacin Imatinib mesylate Rilpivirine Boceprevir Ingenol mebutate Insulin glulisine Bosutinib Sapropterin dihydrochloride Saxagliptin Cabozantinib Kunecatechins Silodosin Canagliflozin Sitagliptin ; oxide; Capsaicin Lanreotide Citric acid Lapatinib tosylate Lenalidomide malate Ceftaroline fosamil L- Cinacalcet hydrochloride Linagliptin Telaprevir Liraglutide Telbivudine Clofarbine Lomitapide mesylate Temsirolimus Crizotinib Tenofovir disoproxil fumarate Lurasidone hydrochloride Teriflunomide Dabigatran etexilate Mecasermin (rDNA Origin) Tesamorelin acetate Dabrafenib hydrochloride Tigecycline Dalfampridine Tinidazole Daptomycin Milnacipran hydrochloride Tipranavir Darunavir Mipomersen citrate Dasatinib Mirebegron Trametinib Deferasirox Degarelix Nepafenac Ulipristal acetate Dienogest; Estradiol valerate Nilotinib Difluprednate Norelgestromin; Ethinyl estradiol Vandetanib Dimethyl fumarate Omacetaxine mepesuccinate Varenicline Doripenem Ospemifene Dutasteride Ovine hyaluronidase Vemurafenib Vilanterol; Fluticasone furoate Elvitegravir; Cobicistat; Emtricitabine; Tenofovir disoproxil fumarate Palonosetron hydrochloride Vilazodone Emtricitabine Pasireotide Vismodegib Enfuvirtide Pazopanib Entecavir Pegaptanib sodium Enzalutamide Peginesatide 2 © 2013 American Medical Association. All rights reserved.

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Second Cycle Approvals (55) Abarelix Fospropofol disodium Rifaximin Formatted Table calcium enacarbil Rivaroxaban Alfuzosin hydrochloride Hyaluronidase* (bovine) (Amphadase) Roflumilast Apixaban Hyaluronidase* (bovine) (Hydase) Rosuvastatin calcium Aripiprazole Icatibant Rotigotine Asenapine Icodextrin hydrochloride Iloperidone Sertaconazole nitrate Benzyl Indacaterol succinate Bosentan Insulin detemir Spinosad Ciclesonide Lanthanum carbonate hydrate Tadalafil Conivaptan hydrochloride Lorcaserin hydrochloride Tafluprost hydrobromide Maraviroc Mecasermin Rinfabate (rDNA Origin) Ticagrelor Deferiprone Micafungin sodium Desvenlafaxine Tolvaptan Eszopiclone Paliperidone Vardenafil hydrochloride Ezogabine Pegvisomant Voriconazole fumarate Fondaparinux sodium

Third Cycle Approvals (13) Alogliptin Febuxostat Formatted Table dimesylate Telavancin Anidulafungin Nebivolol sodium Biskalcitrate; Metronidazole; Tetracycline hydrochloride Pramlintide acetate Duloxetine hydrochloride mesylate

Fourth Cycle Approvals (2) Everolimus Tetrabenazine Formatted Table

Fifth Cycle Approvals (1) Lucinactant Formatted Table *chemically distinct based on manufacturing differences

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eTable 2: Examples of Excerpts From Publicly Available Action Letters and FDA Reviews, and Corresponding Categories of Deficiencies1

Link to 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 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.

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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 , 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.

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da.gov/drugsatfda_docs/ or intermittent nitrate therapy. However, it nda/2003/21- is expected that men with cardiovascular 368_Cialis_Approv.pdf disease will use Cialis. Some of those men will experience cardiovascular events and be given nitrates in emergency situations. You must provide information to label the effects of with and Cialis 20 mg for a period of time after Cialis dosing until no blood pressure interaction is seen.” Rosuvastin calcium “The application presented consistent 1) Uncertainty/disagreement Link: evidence of little added benefit of the 80-mg about appropriate dose http://www.accessdata.f dose over the 40-mg dose, even in patients (S,E) da.gov/drugsatfda_docs/ with homozygous familial nda/2003/21- hypercholesterolemia. This small benefit 2) Population inadequate for 366_Crestor_Approv.pd does not outweigh the risks of myopathy proposed dose/duration of f and renal toxicity apparent at this dose. therapy (S)

The numbers of patients exposed long term to rosuvastin are inadequate to provide assurance of the safety of either the 20-mg or the 40-mg proposed dose. Additional safety information is needed to permit conclusions regarding the drug’s therapeutic index, given the high incidence of rhabdoyolysis seen at the 80-mg dose.” Ranolazine “The trials in angina, however, do not 1) Uncertainty/disagreement Link: adequately characterize the relationship about appropriate dose (S,E) http://www.accessdata.f between dose and therapeutic effect da.gov/drugsatfda_docs/ sufficiently to provide labeling instructions 2) Potential risks based on nda/2006/021526_s000_ for its use. animal toxicology (e.g. Ranexa_ApprovBle.pdf It will be necessary to obtain additional carcinogenicity) (S) dose-response information.

Potential testicular toxicity, manifest as impaired fertility in rats in study AT- 413616-R-86-43285-PO-RFM. The available data are inadequate to determine whether this was a chance finding or evidence of testicular toxicity to ranolazine. While no clinical signs of male reproductive toxicity were reported, this is not surprising or reassuring, as adequate assessment of this toxicity typically requires targeted clinical evaluation.”

2 © 2013 American Medical Association. All rights reserved.

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Rasagiline mesylate Examination of your NDA database reveals 1) Adverse events: Link; a rate of 5.8 tumors/1000 patient- years of Neoplasm (S) http://www.accessdata.f exposure, considerably greater than that da.gov/drugsatfda_docs/ seen for other Parkinson’s treatments for nda/2006/021641s000_ which we have data. Azilect_APPROV.pdf

Conivaptan HCl “The number of subjects receiving 1) Population too small to Link: conivaptan at the systemic exposures characterize drug safety (S) http://www.accessdata.f associated with the dose and dosing regimen da.gov/drugsatfda_docs/ proposed for marketing are inadequate for 2) Uncertainty/disagreement Formatted: Not Expanded by / Condensed by nda/2005/021697s000_ the evaluation of the safety of conivaptan. about appropriate dose (S,E) Formatted: Not Expanded by / Condensed by Vaprisol_ApprovBLE.p Formatted: Not Expanded by / Condensed by df The lowest effective dose of intravenous Formatted: Not Expanded by / Condensed by conivaptan in the treatment of Formatted: Not Expanded by / Condensed by nonhypovolemic hyponatremia has not been Formatted: Not Expanded by / Condensed by established nor has the optimal dosing Formatted: Not Expanded by / Condensed by regimen.” Formatted: Not Expanded by / Condensed by Mecasermin rinfabate “Provide the chemistry, manufacturing, and 1) CMC alone (C) Formatted: Not Expanded by / Condensed by Link; control information as requested below…” Formatted: Not Expanded by / Condensed by http://www.accessdata.f Formatted: Not Expanded by / Condensed by da.gov/drugsatfda_docs/ nda/2005/021884_s000_ Formatted: Not Expanded by / Condensed by Iplex_ApprovBle.pdf Formatted: Not Expanded by / Condensed by Decitabine “When inspectors compare the source 1) Data Integrity (E) Formatted: Not Expanded by / Condensed by Link: documentation with the case report forms Formatted: Not Expanded by / Condensed by http://www.accessdata.f and data listings, they uncovered multiple Formatted: Not Expanded by / Condensed by da.gov/drugsatfda_docs/ instances where patients’ data were Formatted: Not Expanded by / Condensed by nda/2006/021790s000_ inconsistent.” Formatted: Not Expanded by / Condensed by Dacogen_Approv.pdf Formatted: Not Expanded by / Condensed by Iloperidone “The remaining three studies (3000, 4000, 1) Population not Formatted: Not Expanded by / Condensed by Link: and 30050 included a mix of appropriate for intended use Formatted: Not Expanded by / Condensed by http://www.accessdata.f schizoaeffective and schizophrenic (E) Formatted: Not Expanded by / Condensed by da.gov/drugsatfda_docs/ patients. In our analysis, we have focused nda/2009/022192s000_ on the patients with schizophrenia. We 2) Inadequate efficacy Formatted: Not Expanded by / Condensed by Approvable.pdf consider schizoaffective disorder a distinct compared to standard of care Formatted: Not Expanded by / Condensed by entity that would require a separate (E) Formatted: Not Expanded by / Condensed by development program. Formatted: Not Expanded by / Condensed by 3) Safety population Formatted: Not Expanded by / Condensed by Patients, with only 64 treated for at least 6 inadequate for proposed Formatted: Not Expanded by / Condensed by months and only 22 for at least 1 year. dose/duration of therapy (S) Formatted: Not Expanded by / Condensed by These exposures are far below the Formatted: Not Expanded by / Condensed by minimum requirements for relevant doses Formatted: Not Expanded by / Condensed by according to ICH standards for a Formatted: Not Expanded by / Condensed by 2 © 2013 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Formatted ... Formatted ... Formatted ... Formatted chronically used drug. Thus, we ask that ... you obtain additional exposures within Formatted ... this iloperidone dose range of20-24 Formatted ... mg/day. You would need at least 1000 Formatted ... additional patients exposed, and the Formatted ... chronic use would need to meet the Formatted ... minimum standard of at least 300 for 6 Formatted ... months and at least 100 for 1 year Formatted ...

Formatted ... First there is some evidence that iloperidone Formatted is substantially inferior to existing ... Formatted alternative treatments, although we do not ... consider this entirely established, The Formatted ... agency has, in the recent past, taken the Formatted ... relative effectiveness of new psychiatric Formatted ... drugs compared to currently available drugs Formatted ... into consideration when making overall risk Formatted ... benefit decisions about new psychiatric Formatted ... drugs. The overall principle is that markedly Formatted ... inferior performance on the treatment of an Formatted ... acute schizophrenia episode presents a risk Formatted to patients “ ... Formatted ... Formatted ... Formatted ... 1 Additional data on these and other approved products are accessible on the web at drugs@fda. Formatted ... This may include FDA reviews and action letters. Formatted ... Formatted ... 2 S=safety deficiency, E= efficacy deficiency, C=CMC deficiency, S,E=both safety and efficacy Formatted ... deficiencies Formatted ...

Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... Formatted ... 2 © 2013 American Medical Association. All rights reserved.

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