First to Market or 505 (b)2 CMC Considerations IPAC-RS/UF Orlando Inhalation Conference Orlando, Florida Prasad Peri, Ph.D., Branch Chief, ONDQA, FDA March 19, 2014 1
Topics for discussion Introduction Brief overview of FDA drug approval pathways List of Approved Drug Products for Oral Inhalation CMC considerations for 505(b) and 505(b)(2), and combination drug products Summary 2
Drug Development Three types of drug development applications 505(b)(1) Contains full reports of investigations of safety and effectiveness 505(b)(2) Information required to rely (at least in part) on studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. 505(j) Proposed product is identical to a previously approved product 3
Drug Development NDA vs. ANDA NDA process: Sec. 505 (b) of FD&C Act Adequate manufacturing and controls to ensure identity, strength, quality, and purity (QUALITY) Safety under conditions of labeled use (SAFETY) Substantial evidence of efficacy under conditions of labeled use (EFFICACY) ANDA process: Sec. 505 (j) of FD&C Act Same active ingredients as listed drug Same strength, route, and dosage form as listed drug Bioequivalence to listed drug Same labeling as listed drug Exceptions for exclusivity claims 4
NDA 505(b)(1) of the FD&C Act Application used for approval of a new drug (for clinical use) whose active ingredient has not previously been approved. Requires extensive data to establish. Safety and effectiveness of the drug for the proposed uses Production methods are adequate to ensure identity, strength, quality, purity of the drug Proposed labeling is appropriate and contains all necessary information 5
CMC Information Required in a NDA for 505(b)(2) 21 CFR 314.50(d)(1) The application is required to contain a full description of the chemistry, manufacturing, and controls (CMC) information. Drug Substance: Physical and chemical characteristics, manufacturer, method of synthesis and purification, process controls, specifications, and stability Drug Product: Components, composition, specifications for each component, manufacturer, description of manufacturing and packaging procedures, in-process controls, specifications, and stability 21 CFR 314.54 Procedures for submission of an application requiring investigations for approval of a new indication for, or other change from, a listed drug. Refers to information required under 314.50 that must be submitted for 505(b)(2) applications (these include full CMC) 6
Partial List of US Approvals for MDIs Riker Labs/3M Medihaler Epi 1956-Epinephrine Medihaler Iso 1956-Isoproterenol Alupent: 1973-metaproterenol sulfate (BI) Proventil: 1981-albuterol (3M/Schering) Ventolin: 1981-albuterol (GSK) Aerobid: 1984-flunisolide (Roche/Forest) Atrovent: 1986-ipratropium bromide (BI) Albuterol: 1995-IVAX/Teva Albuterol: 1996-Pliva Combivent: 1996-albuterol/ipratropium (BI) Albuterol: 1996-Armstrong Pharmaceuticals Albuterol: 1997-GenPharm Proventil HFA: 1996-albuterol sulfate (3M/Schering) QVAR HFA: 2000-beclomethasone dipropionate 3M Ventolin HFA: 2001-albuterol sulfate (GSK) Proair HFA: 2004-albuterol sulfate (Ivax/Teva Global) Atrovent HFA 2004-ipratropium bromide (BI) Flovent HFA: 2004-fluticasone propionate (GSK) Aerospan HFA: 2006-flunisolide (Acton) Advair HFA: 2006-fluticasone propionate/salmeterol (GSK) Xopenex HFA: 2005-levalbuterol tartrate (Sepracor/Sunovian) Symbicort: 2006-budesonide/formoterol Alvesco: 2008-ciclesonide Nycomed/Sunovion Dulera: 2010- mometasone furoate/formoterol fumarate Schering/Merck Extracted from Drugs at FDA http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 7
Partial List of US Approvals for DPIs (All are 505 (b) (1)) First US marketed DPI was Fison s Spinhaler (1970) -cromolyn sodium Ventolin Rotacaps: 1988-albuterol sulfate Flovent Diskus (fluticasone) Serevent (salmeterol) Diskus: US approved in 1997 Pulmicort Turbuhaler: 1997-budesonide Relenza Diskhaler: 1999-zanamivir Advair Diskus: 2000-fluticasone/salmeterol Foradil Aerolizer: 2001-formoterol fumarate Spiriva Handihaler: 2004-tiotropium bromide Asmanex Twisthaler: 2005-mometasone furoate Exubera: 2006-insulin (recombinant human) Pulmicort Flexhaler: 2006-budesonide Foradil Certihaler: 2006-formoterol fumarate Aridol: 2010-mannitol Arcapta Neohaler: 2011-indacaterol maleate Extracted from Drugs at FDA 8
US Approvals for Inhalation Solutions-Albuterol-1 Albuterol(sulfate) Ventolin: GSK 1987, 1992 Proventil: Schering Plough 1987 Mylan Specialty: 1992, Copley, Actavis: 1995, Hi-Tech Pharma: 1998, 1999, Nephron: 1997, 2004, Bausch and Lomb: 1998, 2000, Roxane: 2001, Teva: 1999, Wockhardt EU 1999 Apotex: 2007, Watson: 2003, 2007 Landela Pharm RiteDose Corp Extracted from Drugs at FDA 9
US Approvals for Inhalation Solution and Suspension-2 Brovana (Arformoterol tartrate): Sunovian 2006 505 (b) Pulmicort Respules (Budesonide) AstraZeneca: 2000 505 (b) Teva, Apotex, Watson, Sandoz Extracted from Drugs at FDA 10
US Approvals for Inhalation Solutions-3 Atrovent (Ipratropium bromide): 1993 Dey, Actavis, Teva, Apotex, Pharmascience, Nephron, Ritedose, Baush and Lomb, Roxane, Watson, Landela Perferomist (formoterol fumarate): Dey 2007, 505 (b)(2) Levalbuterol HCl: Sepracor 2001 505 (b)(2) Watson, Dey, Cipla, Mylan, Teva Extracted from Drugs at FDA 11
US Approvals for Inhalation Solutions-4 Duoneb 505 (b)(2), 2001 Albuterol/Ipratropium bromide-dey Pharma (Mylan) Teva, Nephron, Sandoz, Watson, Apotex, Cipla, Ritedose Corp Extracted from Drugs at FDA 12
Albuterol Sulfate Label Case Study Proventil HFA 505 (b) Ventolin HFA 505 (b) ProAir HFA 505 (b)(2) 1996 2001 2004 HFA 134a, ethanol, Oleic acid HFA 134a, ethanol, HFA 134a 12 Weeks 565 subjects (193 Proventil HFA, 186 CFC, 186 placebo) Two 12 weeks 610 subjects (99 Ventolin HFA, 101 CFC, 97 placebo) (91 Ventolin HFA, 100 CFC, 95 placebo) 6 weeks 116 subjects (58 ProAir, 56 marketed Albuterol, 58 Placebo) Extracted from Package Inserts for Proventil HFA, Ventolin HFA, and ProAir HFA 13
CMC Considerations for Combination Drug Products We expect to see in vitro CMC-related data (e.g., dose delivery, aerodynamic particle size distribution by cascade impaction) that clearly demonstrate that, for the duration of the clinical studies, each strength of the combination drug product is pharmaceutically similar to the single ingredient monotherapy drug products. Typically these data should be provided for our evaluation via the IND, prior to the commencement of your phase III clinical studies. Draft MDI DPI Guidance document 14
Comparison of the NDA Documentation In the picture above, the volume that Charles Thiel (left) is holding is the original NDA for the epinephrine MDI. On the right, Robert Moris, one of the inventors of the HFA-134a albuterol formulation, is standing with his back toward the 193 volume (400 pages per volume) NDA for the product! The HFA-134a beclomethasone dipropionate MDI is twice as efficient as its CFC counterpart. Patients need only half as much drug for an effective dose. Courtesy: Charles Thiel 15
Conclusions Section 505(b)(1) is submitted with a complete data set of CMC, clinical, and non-clinical data. Section 505(b)(2) of the FD&C Act permits an applicant to rely (at least in part) on studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. Complete CMC information must be submitted for the drug substance(s) and the drug product to support the quality of the proposed drug product for marketing 16
Thank You Any questions, comments, concerns: NewDrugCMC@fda.hhs.gov 17