中美仿制药研发申报流程
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❖New Dosage Form ▪ Tramadol orally disintegrating tablets (2005) ▪ Ondansetron oral spray (filed 2006)
505(b)(2)新药的例子
❖New Dosing Regimen ▪ Tramadol extended release tablets (2005)
505(b)(2)的意义
❖介于全创新药物和仿制药之间 ❖具有专利保护，且不存在产权纠纷 ❖和仿制药不同，无替换的要求 ❖应有突破
505(b)(2)范围
❖New Chemical Entity (rarely)：我 国1.1-1.3
❖New dosage form：我国5类 ❖New dosing regimen：我国补充申
❖New inactive ingredient that requires more than limited confirmatory studies
❖Rx OTC switch
❖New Combination Products
❖“Generic biologics”
505(b)(2)排他性
4 展望
药物经济学催生美国仿制药制度
美国社会安全制度导致政府赤字严重 SSA已经破产：如何破局？ 降低医疗费用成为必然 Hatch-Waxman法案出台 美国FDA药品注册申请：新药（两类）、仿制药和
非处方药申请
3
Company Logo
1984年后
New Drug Applications (NDAs)
请
❖New strength：我国补充申请 ❖New route of administration：我
国2类 ❖New indication：我国1.6
505(b)(2)情形
❖New active ingredient (different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of active moiety)
• Duplicate of an already approved product
• No safety/efficacy data permitted (only bioequivalence)
YES 505(b)(1)
NO 505(b)(2)
505(j)
NDA的研发和申报
505(b)(1) 新药申报资料内容
❖ 505(b)(2) eliance
▪ Merely sets conditions for certain NDAs
▪ Requires “full reports of investigations” establishing safety and effectiveness [21 USC §§ 355(b)(1)(A), (d)(1)]
美国仿制药
A generic drug product is one that is comparable to an innovator drug product ( also known as the reference listed drug (RLD) product as identified in the FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations) in dosage form, strength, route of administration, quality, performance characteristics and intended use.
These parameters were established upon the approval of the innovator drug product, which is the first version of the drug product approved by the FDA.
505(b)(2)新药的成功例子
❖ NCE ▪ Thalomid® (thalidomide) (1998)
❖Marketed unapproved drugs ▪ Levothyroxine (2000) ▪ Guaifenesin extended release (2002) ▪ Quinine sulfate (2005)
505(b)(2)新药的例子
❖New Active Ingredient ▪ Pexeva (paroxetine mesylate) (new salt) (2003)
❖New Route of Administration ▪ Emezine (prochlorperazine) (new buccal/transmucosal delivery) (NDA pending) ▪ Oral amphotericin-B (pre-clinical)
FDA 审评 仿制 药程
序
二、美国仿制药的申报、审评和研发对策
❖ 由FDA的OGD审评 ❖ 审评方式采用QbR ❖ 申报资料采用CTD ❖ 资料内容也针对问题
Office of Generic Drugs
Comparison of Receipts and Approvals of ANDA Applications
❖New Strength/Formulation ▪ Antara (micronized fenofibrate caps) (2004) (130 mg is BE to Tricor 200 mg)
❖New Formulation/Inactive Ingredient ▪ Avita (tretinoin gel) (new emollient) (1998) ▪ Abraxane (cremaphor-free paclitaxel) (2005) ▪ Oxy-ADF (oxycodone formulated to reduce drug abuse) (in development)
05) ▪ Fortical (calcitonin salmon recombinant)
(2005)
* Examples based on publicly available information
FDA
NDA
审评 过程
FDA 可以使用已有数据用于审评NDA吗？
❖ Hatch-Waxman之前,国会限制 FDA在审评 NDA X时应 用 NDA Y的数据：“No data in an NDA can be utilized to support another NDA without express permission of the original NDA holder.”[FDA “Finkel Memorandum” (1978, 1981)]
900
800
Receipts
Approvals (Full & Tentative)
中美仿制药研发和申报流程
涂家生， Ph. D. 中国药科大学药剂学教授 Tel: 025-83271305 Email: jiashengtu@ 2011.11 郑州
主要内容
1 中美关于原研药和仿制药的背景 2 美国仿制药：申报、基于问题的
审评和研发对策
3 我国仿制药申报、审评和研发 对策
❖ Hatch-Waxman 解除只适合 ANDAs：ANDA process allows “generic producer of the fully tested drug to rely on the safety and efficacy data of a prior applicant . . . .”
❖RxOTC Switch ▪ Alavert (loratadine) (2002)
505(b)(2)新药的例子
❖“Generic Biologics”
▪ Omnitrope (rHGH) (2006) ▪ Glucagen (glucagon recombinant) (1998) ▪ Hyaluronidase (various approvals 2004-
1. Index 2. Summary 3. Chemistry, Manufacturing and Control 4. Samples, Methods Validation Package and
Labeling 5. Nonclinical Pharmacology and Toxicology
Patent Issues ▪ 505(b)(2) drugs can have Orange Book-listed patents, and enjoy 30-month stay protection against generic competitors ▪ But, 505(b)(2) NDAs may also be blocked by patents on Reference Drugs
6. Human Pharmacokinetics and Bioavailability
7. Microbiology ( for anti-microbial drugs only)
8. Clinical Data
9. Safety Update report ( typically submitted 120 days after the NDA’s submission )
▪ By whom? ▪ On what?
❖Reliance and Exclusivity
▪ Market vs. Data Exclusivity ▪ Safety/Efficacy Data vs. CM&C data
❖FDA Process for Determining Reliance
▪ Who, when and how?
Exclusivities available for 505(b)(2) products ▪ NCE Exclusivity (5 years) ▪ New Product Exclusivity (3 years) ▪ Orphan Drug Exclusivity (7 years) ▪ Pediatric exclusivity extensions (6 months)
▪ Phantom ANDA
❖FDA Draft Guidance for Industry (1999)
❖FDA Response to Citizen’s Petition (2003)
❖ 可以降低研发的费用和审评力量的浪费
505(b)(2)的关键: 可靠性
❖What is “Reliance”
Generic drug applications are termed “abbreviated” in that they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
10. Statistical 11. Case Report Tabulations 12. Case Report Forms 13. Patent Information 14. Patent Certification
505(b)(2): 历史过程
❖Hatch Waxman法案：1984 ❖Parkman Letter
• “Full Reports” of Safety and Efficacy Investigations
• Applicant has right of reference to essential
investigations?
Abbreviated New Drug Applications (ANDAs)
505(b)(2)新药的例子
❖New Dosing Regimen ▪ Tramadol extended release tablets (2005)
505(b)(2)的意义
❖介于全创新药物和仿制药之间 ❖具有专利保护，且不存在产权纠纷 ❖和仿制药不同，无替换的要求 ❖应有突破
505(b)(2)范围
❖New Chemical Entity (rarely)：我 国1.1-1.3
❖New dosage form：我国5类 ❖New dosing regimen：我国补充申
❖New inactive ingredient that requires more than limited confirmatory studies
❖Rx OTC switch
❖New Combination Products
❖“Generic biologics”
505(b)(2)排他性
4 展望
药物经济学催生美国仿制药制度
美国社会安全制度导致政府赤字严重 SSA已经破产：如何破局？ 降低医疗费用成为必然 Hatch-Waxman法案出台 美国FDA药品注册申请：新药（两类）、仿制药和
非处方药申请
3
Company Logo
1984年后
New Drug Applications (NDAs)
请
❖New strength：我国补充申请 ❖New route of administration：我
国2类 ❖New indication：我国1.6
505(b)(2)情形
❖New active ingredient (different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of active moiety)
• Duplicate of an already approved product
• No safety/efficacy data permitted (only bioequivalence)
YES 505(b)(1)
NO 505(b)(2)
505(j)
NDA的研发和申报
505(b)(1) 新药申报资料内容
❖ 505(b)(2) eliance
▪ Merely sets conditions for certain NDAs
▪ Requires “full reports of investigations” establishing safety and effectiveness [21 USC §§ 355(b)(1)(A), (d)(1)]
美国仿制药
A generic drug product is one that is comparable to an innovator drug product ( also known as the reference listed drug (RLD) product as identified in the FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations) in dosage form, strength, route of administration, quality, performance characteristics and intended use.
These parameters were established upon the approval of the innovator drug product, which is the first version of the drug product approved by the FDA.
505(b)(2)新药的成功例子
❖ NCE ▪ Thalomid® (thalidomide) (1998)
❖Marketed unapproved drugs ▪ Levothyroxine (2000) ▪ Guaifenesin extended release (2002) ▪ Quinine sulfate (2005)
505(b)(2)新药的例子
❖New Active Ingredient ▪ Pexeva (paroxetine mesylate) (new salt) (2003)
❖New Route of Administration ▪ Emezine (prochlorperazine) (new buccal/transmucosal delivery) (NDA pending) ▪ Oral amphotericin-B (pre-clinical)
FDA 审评 仿制 药程
序
二、美国仿制药的申报、审评和研发对策
❖ 由FDA的OGD审评 ❖ 审评方式采用QbR ❖ 申报资料采用CTD ❖ 资料内容也针对问题
Office of Generic Drugs
Comparison of Receipts and Approvals of ANDA Applications
❖New Strength/Formulation ▪ Antara (micronized fenofibrate caps) (2004) (130 mg is BE to Tricor 200 mg)
❖New Formulation/Inactive Ingredient ▪ Avita (tretinoin gel) (new emollient) (1998) ▪ Abraxane (cremaphor-free paclitaxel) (2005) ▪ Oxy-ADF (oxycodone formulated to reduce drug abuse) (in development)
05) ▪ Fortical (calcitonin salmon recombinant)
(2005)
* Examples based on publicly available information
FDA
NDA
审评 过程
FDA 可以使用已有数据用于审评NDA吗？
❖ Hatch-Waxman之前,国会限制 FDA在审评 NDA X时应 用 NDA Y的数据：“No data in an NDA can be utilized to support another NDA without express permission of the original NDA holder.”[FDA “Finkel Memorandum” (1978, 1981)]
900
800
Receipts
Approvals (Full & Tentative)
中美仿制药研发和申报流程
涂家生， Ph. D. 中国药科大学药剂学教授 Tel: 025-83271305 Email: jiashengtu@ 2011.11 郑州
主要内容
1 中美关于原研药和仿制药的背景 2 美国仿制药：申报、基于问题的
审评和研发对策
3 我国仿制药申报、审评和研发 对策
❖ Hatch-Waxman 解除只适合 ANDAs：ANDA process allows “generic producer of the fully tested drug to rely on the safety and efficacy data of a prior applicant . . . .”
❖RxOTC Switch ▪ Alavert (loratadine) (2002)
505(b)(2)新药的例子
❖“Generic Biologics”
▪ Omnitrope (rHGH) (2006) ▪ Glucagen (glucagon recombinant) (1998) ▪ Hyaluronidase (various approvals 2004-
1. Index 2. Summary 3. Chemistry, Manufacturing and Control 4. Samples, Methods Validation Package and
Labeling 5. Nonclinical Pharmacology and Toxicology
Patent Issues ▪ 505(b)(2) drugs can have Orange Book-listed patents, and enjoy 30-month stay protection against generic competitors ▪ But, 505(b)(2) NDAs may also be blocked by patents on Reference Drugs
6. Human Pharmacokinetics and Bioavailability
7. Microbiology ( for anti-microbial drugs only)
8. Clinical Data
9. Safety Update report ( typically submitted 120 days after the NDA’s submission )
▪ By whom? ▪ On what?
❖Reliance and Exclusivity
▪ Market vs. Data Exclusivity ▪ Safety/Efficacy Data vs. CM&C data
❖FDA Process for Determining Reliance
▪ Who, when and how?
Exclusivities available for 505(b)(2) products ▪ NCE Exclusivity (5 years) ▪ New Product Exclusivity (3 years) ▪ Orphan Drug Exclusivity (7 years) ▪ Pediatric exclusivity extensions (6 months)
▪ Phantom ANDA
❖FDA Draft Guidance for Industry (1999)
❖FDA Response to Citizen’s Petition (2003)
❖ 可以降低研发的费用和审评力量的浪费
505(b)(2)的关键: 可靠性
❖What is “Reliance”
Generic drug applications are termed “abbreviated” in that they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
10. Statistical 11. Case Report Tabulations 12. Case Report Forms 13. Patent Information 14. Patent Certification
505(b)(2): 历史过程
❖Hatch Waxman法案：1984 ❖Parkman Letter
• “Full Reports” of Safety and Efficacy Investigations
• Applicant has right of reference to essential
investigations?
Abbreviated New Drug Applications (ANDAs)