case studies and filing process

1. Overview of regulatory applications for generic drugs Rohitthanage Roll no 24 28/5/2010

2. 3 largest markets ThrEE of ThEworld’SlargESTpharmacEUTicalmarkETS are the United States (U.S.), the European Union (EU), and Japan. Drug manufacturers spend a tremendous amount of time, money and effort ensuring that drug approval applications meet the necessary regulatory requirements for approval Nonetheless, the application process continues post approval with the ongoing reporting requirements necessary for implementing changes to an approved application. The U.S. and the EU have made efforts to reduce regulatory reporting burdens. On the other hand, Japan tends to require more detail for reporting changes and has excessive review times for approval of certain modifications

3. Mutual recognition procedure National procedure RMS CMS Uk MHRA Dossier report is send italy Get MAA grant Feels satisfactory Start manufacturing as per guidelines Grant approval

4. Decentralized procedure Simultaneous dossier submission to all countries A combination of MRP and national procedure 210 days Query ??? Rms reviews If there is a dispute between Member States, the points under dispute can be referred to the EMEA for arbitration. 8000 pounds cms cms cms cms Query rms 10000 pounds

5. Centralized procedure Community authorization procedure compulsory for Drugs from biotechnology processes, such as genetic engineering; advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines; intended for the treatment of HIV/Aids, cancer, diabetes, neurodegenerative disorders, autoimmune diseases and other immune dysfunctions, or viral diseases; orphan medicines If emea and EC approve u can market it in all eu participant countries

6. Sec. 310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses ANDA DESI OTC 356 h effective 502j Monograph applicable DESI NOOH in 21 CFR 310, section 502 of the Code of Federal Regulations. Drugs listed in this section are categorically considered new drugs. In other words, these products cannot be marketed under the OTC monograph pathway. Suitability petition Market till notice result 505b(1) 505b(2) Other methods: monograph deviation Time method

9. Proposed Change: two intermediate strengths 0.0375% and 0 .075%

11. Proposed change: Tablets to Oral Solution

13. The 505(b)(2) applicant may qualify for 3 or 5 years of market exclusivity, depending on the extent of the change to the previously approved drug and the type of clinical data included in the NDA. This distinguishes a 505(b)(2) from an ANDA, where exclusivity can be held for only 180 days. A 505(b)(2) application may also be eligible for orphan drug or pediatric exclusivity. A product approved via the 505(b)(2) pathway may receive an “AB” substitutability rating in the Orange Book. Thus, from a therapeutic substitution perspective and under state formulary laws, the 505(b)(2) applicant is not disadvantaged relative to a generic (ANDA) drug

14. Article 10 of Directive 2001/83/EC where the bioavailability studies cannot be used to demonstrate bioequivalence; the results of tests and trials must be consistent with the data content standards required in the Annex to the Directive 2001/83/EC as amended by Directive 2003/63/EC. These applications will thus rely in part on the results of pre-clinical tests and clinical trials for a reference product and in part on new data.”

15. Stability Batches BE Requirements - e.g. Sustained Release Product US: EU / Australia: Fasted and/or Fed Fasted + Fed + Steady State

16. Even after this there are many hurdles PSURs Type 1 A/B Variations Type 2 A/B Variations Coordination with Agencies prior-approval, CBE (immediate), CBE-30 and annual report Type IA variations are minor changes Notify Admin changes Changes that can be implemented within 14 days of notification. Type IB variations are more scientific minor changes and implicit approval is granted within 30 days of notification. Prior-approval (major change):Substantial potentialto adversely affect the identity, strength, quality, purity, or potency of a product moderate change CBE Minor change annual Type II variations are major changes

17. changes that have upcome Analytical validations Readability tests impurity Stability changes Residual solvents organic inorganic characterization genotoxic Eg acetone solvent. Degradation changes

18. GMP deficiencies found in indian companies in 2006

19. Now this is the product I wish to market naproxcinoid , a pro-drug of naproxen Dsnt increase bp And has gastrointestinal profile than naproxen with the same efficacy.

20. is metabolized to the NSAID naproxen + nitrate butanediolmononitrate (BDMN) subsequent downstream metabolites [gamma-hydroxybutyric acid (GHB) and butanediol (BD)]. BDMN is the moiety responsible for donating nitric oxide (NO). I have done 35 studies also NO is thought to stimulate GI protective factors that are negatively affected by NSAIDs, such as mucus production, secretion of bicarbonate and increased blood-flow in the gastric mucosa I can further extended application to hypertensive patients also

21. To show improved gastrointestinal safety, conducted three (3) endoscopy studies in (2) healthy subjects and (1) osteoarthritis patients. Note that just prior to the Advisory meeting NicOx had asked to withdraw the ulcer claim. The studies are presented in the following table:

23. in general, fdarecommends study durations of at least 6 months; The prescription proton pump inhibitors currently marketed for this indication, esomeprazole, lansoprazole, and the naproxen/lansoprazole combination product, were supported by studies of 3 months and 6 months duration Thus, the reviewer noted that studies 0002 and 0027 did not use endpoints or duration consistent with studies used for approval of PPI's. Study 0005 was reviewed with the caveat that it was only 6 weeks (not months) duration. The comparison of incidence of ulcers in this short study gave a point estimate (naproxcinod/naproxen) of 0.70 (95% CI, 0.48, 1.03) p=0.07. The results were not significant and the difference was judged to be not clinically meaningful. I emphasized in the text above that the FDA used criteria that were used for PPI product approval. NicOx didn't want treatment but just wanted labeling that showed show an improvement.

24. The reviewer from FDA's Division of Gastroenterology Products outlined the following study criteria used for approval (emphasis mine) of products (e.g., PPIs) for the reduction of NSAID -induced ulcers: I emphasized in the text above that the FDA used criteria that were used for PPI product approval. Ididn't want treatment but just wanted labeling that showed show an improvement. Naproxcinod represents an additional treatment option for physicians and OA patients, combining the proven efficacy and safety of naproxen with an NO-donating moiety that mitigates some of the known side effects of NSAIDs. Naproxcinod is less likely to increase BP than NSAIDs, which may be of particular importance to OA patients with pre-existing hypertension. The overall benefit/risk profile of naproxcinod 750 mg bid and 375 mg bid is positive and supports its use for the relief of the signs and symptoms of OA.” As I summarized above, FDA’s analysis of the BP data indicated that naproxcinod was not sufficient to

25. Here is the broader issue for us in the 505(b)(2) world: we are developing improvements to existing products and in order for them to be a commercial success we must be able to promote the difference from what is often the generic RLD. In order to be able to legally promote a difference, the data must be on the label. What studies are sufficient to be included in the label? Do the data need to show clinically meaningful difference (an objective standard) or simply statistically different? Does the answer to the latter question depend on which section of the label we want to have modified? I’m uncomfortable leaving questions unanswered at the end of this posting, but the general answer is, it depends on each circumstance.

26. Thank you for your patient hearing