2022年5月20日

海洋之神优惠大厅主站分享 | Kamali Chance博士深度解读505(b)(2) 药品批准上市路径

《联邦食品、药品和化妆品法案》(FD&C Act)第505条规定了可以提交给FDA批准的所有三种类型的新药申请：505(b)(1)、505(b)(2)、505(j)。其中，由于505(b)(2)类途径所需的申请数据相对减少，且可使用先前已获得批准的资料，因此研发费用和开发时间较创新药更少，开发风险更低，广泛受到药品开发者的青睐。

海洋之神优惠大厅主站全球监管注册业务副总裁Kamali Chance博士曾撰文对505(b)(2)类申请途径进行深度解析。

文章主要内容包括：
505(b)(2)应用案例分析
不符合505(b)(2)的情况
专利和排他性保护
通过505(b)(2)类途径进行申请的方法

Kamali Chance
海洋之神优惠大厅主站全球监管注册副总裁

  • 25年监管事务工业界经验，涵盖各类药物开发的临床前，临床和全球入市申报阶段
  • 曾助力多个药物在美国、欧盟、加拿大、中国及其他亚洲国家的成功上市
  • 曾撰写和合著了许多关于创新药和生物仿制药监管实践的文章和书籍章节
  • 拥有监管事务专业协会颁发的监管事务证书
  • 博士:北卡罗来纳大学格林斯博罗分校；硕士:北卡罗来纳大学教堂山分校
Is the 505 (b)(2) Drug Application Process Right for You?
By Kamali Chance, MPH, PhD, RAC
The 505(b)(2) section of the Federal Food, Drug, & Cosmetic Act (FD&C Act) describes the new drug application (NDA) process, which incorporates some characteristics of both NDAs and Abbreviated New Drug Applications (ANDAs)1. This application process replaces FDA’s paper NDA policy, which had allowed reliance on safety and efficacy data published in scientific literature. This section was added to the FD&C Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman), which permitted FDA to rely upon data not developed by the applicant for approval of an NDA. In October 1999, FDA issued a Draft Guidance for Industry entitled Application Covered by Section 505(b)(2) that clearly identified the application types that would be covered by this section.2
Section 505 of the FD&C Act describes all three types of new drug applications that can be submitted to FDA for approval:
  • New Drug Applications covered under FD&C Act section 505(b)(1)—This type of application contains full reports of safety and efficacy investigations as well as some of the information from studies not conducted by or for the applicant for which the applicant has obtained a right of reference.
  • 505(b)(2) New Drug Applications—This type of application relies upon “at least some of the information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference,” although some studies may have been conducted by the sponsor.
  • Abbreviated New Drug Applications covered under FD&C Act section 505(j)—This type of application includes information that shows that the proposed product is identical to a previously approved drug product in the following respects: active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use.
Protein products originally approved under the FD&C Act now also are subject to the 505(b)(2) rule as follow-on proteins. Sandoz’s Omnitrope (somatropin [rDNA origin]) NDA was submitted to FDA through this pathway and referenced Pfizer Inc.’s listed drug Genotropin (somatropin [rDNA origin]).3 Omnitrope is not a generic biologic since it is not rated by FDA as being therapeutically equivalent to Genotropin or any other human growth hormone product. In other words, this product (Omnitrope) cannot be substituted for another human growth hormone product in a pharmacy. The physician will have to write a specific prescription for Omnitrope, as for any other innovator drug. It should be noted that there is no abbreviated approval pathway for protein products licensed under section 351 of the Public Health Service Act.3
The type of information that an applicant can rely upon for which it does not have the right of reference include:
1. Published literature
If a drug application’s approval will rely upon published literature to any extent, a 505(b)(2) application [a literature-based 505(b)(2)] should be submitted. In this case, the applicant does not have right of reference to the raw data underlying the published study.
It should be noted that this only applies to referencing such information as clinical trials and animal studies that is necessary to obtain approval of the drug application, not any reference to published general information (e.g., about disease etiology, methods of analysis, etc.). However, if the applicant obtains a right of reference to the raw data, the application may be filed as a full NDA [505(b)(1)].2, 4
2. The agency’s finding of safety and efficacy for an approved drug
If a drug application’s approval relies upon the agency’s previous finding of safety and/or efficacy for a reference listed drug, a 505(b)(2) application should be submitted. This approach encourages innovation in drug development (e.g., different dosage form, strength, route of administration, etc.) of the same drug product without requiring duplication of safety and efficacy studies. The patent(s) and exclusivity rights for the approved reference listed drug are protected. This scenario would require, at a minimum, a bioequivalence study with the reference listed drug, and possibly some bridging toxicology studies or perhaps mutagenicity or genotoxicity studies if the impurity profile is different from the reference listed drug.
Examples of 505(b)(2) Drug Applications2
  • new dosage form—If the approved drug is a tablet that is taken multiple times daily, a 505(b)(2) application can be submitted for an extended release version of that product [example: Naproxen sodium extended release tablets (Naprelan)] or orally disintegrating tablets, etc.
  • strength—A drug application could request a change to a lower or higher strength of the currently approved drug product.
  • route of administration—This could include a change from an intravenous to an oral route of administration, etc.
  • formulation—An application could propose a drug product containing a quality or quantity of an excipient(s) different from that of the reference listed drug (e.g., novel excipient). Studies required for this application type are beyond those required for generic drug applications (e.g., bioequivalence confirmatory studies5). The additional studies that may be required include safety studies on the novel excipient and its interaction with the remaining drug product ingredients.
  • dosing regimen—This application type would include a change from the currently approved dosing regimen (e.g., from every four hours to once per day).
  • active ingredient—This type of drug application would include a different salt, ester, complex, chelate, clathrate, racemate or enantiomer of the active ingredient of an already approved drug product containing the same active moiety. One example would be the approval of the drug product Pexeva (Paroxetine mesylate), which is a different salt form of Paxil (Paroxetime hydrochloride), via the 505(b)(2) route.
  • new molecular entity/new chemical entity— For new molecular entities such as different salt or ester forms of the approved active in a reference listed drug, the new drug sponsor can rely upon safety and efficacy data from both the reference listed drug and literature. Bridging safety studies may be required. For NCEs, even drugs with similar pharmacologic effects (pharmaceutically equivalent) may be eligible for consideration in the approval of a new drug.
  • combination product—A new combination product would include one or both of the active ingredients that previously had been approved individually. If only one of the actives was approved previously, the sponsor can rely partially on the efficacy and safety data for that active. However, additional clinical studies will need to be conducted to show the combination’s safety and efficacy.
  • indication—If applying for a new indication of a previously approved drug product, the innovator company should file a supplemental NDA. Other applicants who do not have the right of reference to the innovator/reference listed drug can file a 505(b)(2) application and ask the agency to rely upon a previous finding of safety and/or effectiveness for the innovator product.
  • Rx/OTC switch—A request is submitted to change the prescription (Rx) status of an already approved prescription drug to over-the-counter (OTC) status for marketing approval. The product’s safety profile is reviewed by the agency, which looks at US and worldwide adverse event data. Consideration is given to how long the product has been on the market and how extensively it has been used. Label comprehension studies may be required. Normally, the applicant requests the Rx to OTC switch; however, health insurers and even FDA have been known to initiate the switch (e.g., Claritin).
  • OTC monograph—A 505(b)(2) drug application is submitted for a nonmonograph indication or a new dosage form of a product described in an OTC monograph (21 CFR 330.11).
  • naturally derived or recombinant active ingredient—In this case, the active ingredient is the same as that in a reference listed drug, but it is derived from animal or botanical sources or recombinant technology. Clinical studies would be required to show that the active ingredient has the same drug impact (pharmacokinetic/ pharmacodynamic) as the one in the reference listed drug.
  • bioinequivalence— If the rate and/or extent of absorption are different from those of the reference listed drug (e.g., exceed standards for bioequivalence), a 505(b)(2) drug application can be submitted. Additional clinical studies may be required to document the new drug product’s safety and efficacy (e.g., a controlled- release drug product that is bioinequivalent to a reference listed drug may qualify). This change would be reflected in product labeling. It should be noted that if the proposed drug product is an exact duplicate of the reference drug product, a 505(j) application should be submitted.
The Following Do Not Qualify for 505(b)(2) Status2
  • A drug application that is a duplicate of a reference listed drug should be submitted for approval under section 505(j) (ANDA route) of the FD&C Act (also see 21 CFR 314.101(d)(9)). However, a 505(b)(2) application can be submitted for a change in a drug product that also may be eligible for consideration under suitability petition guidelines under Section 505(j)(2)(C) of the FD&C Act.
  • A drug application for a product where the only difference from the reference listed drug is that the extent and/or rate of absorption of the active ingredient(s) or delivery to the site of action are less than for the reference listed drug (21 CFR 314.54(b)(1)).
Patent and Exclusivity Protections
Patent/exclusivity certifications must be filed for 505(b)(2) applications for any references to a listed drug.2,6 Existing patents and/or exclusivities can delay the approval of a 505(b)(2) application. A 505(b)(2) application also can be eligible for patents and exclusivities:
  • A 505(b)(2) application can be eligible for three years of exclusivity under the Hatch-Waxman Act, if one or more clinical studies were essential for product approval and these studies were conducted or sponsored by the applicant [21 CFR 314.50(j); 314.108(b)(4) and (5)].
  • Five years of exclusivity may be granted if the drug product contains a new chemical entity [21 CFR 314.50(j); 314.108(b)(2)].
  • Orphan drug exclusivity (21 CFR 314.20-316.36) and pediatric exclusivity (section 505A of the Act) also apply to 505(b)(2) drug applications.
How to Begin the 505(b)(2) Application Process
It is highly recommended that the 505(b)(2) applicants request a meeting with the appropriate FDA division before an official drug application is filed for review. This could be a pre-IND or pre-NDA meeting, depending upon clinical study status. Meeting with the agency early in the planning process can help:
  • establish a good working relationship with the particular FDA division
  • get input from potential reviewers to guide the robust protocol development to address all agency’s concerns.
  • avoid unnecessary studies that the applicant may have been considering
  • determine the issues of importance to the particular division that should be addressed, perhaps as a different arm of one clinical trial as opposed to conducting a different trial
  • gain early acceptance of the number of pivotal studies, if any, or perhaps of confirmatory bioequivalence study by the drug approval division
  • gain early acceptance of the appropriate reference listed drug by the division the applicant may have identified; this information would be crucial if the applicant is planning any comparative studies with the reference listed drug
In general, early agreements with the division can save the applicant time, from concept development through drug approval. Best of all, the agency does not charge for these meetings.
Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products outlines FDA requirements for making meeting requests and includes information on what should be included in the briefing (information) package. The following information generally is required:7
  • identification of any application components for which the applicant will rely upon FDA’s finding of safety and effectiveness of a previously approved drug product; identity of the reference listed drug.identification of any studies the applicant does not own or has the right to reference (includes any preclinical or clinical studies) from published literature
  • identification of proposed bridging studies for the approval of the 505(b)(2) application
  • for a 505(b)(2) application for a New Chemical Entity, identification of a pharmaceutically equivalent drug, if the application will rely upon any data from the pharmaceutically equivalent drug; provide certifications for patents listed for the pharmaceutically equivalent drug
  • identification of any patents and/or exclusivities (per FDA’s Orange Book) that claim the reference listed drug or the use of drug in the proposed 505(b)(2) drug application
  • if seeking marketing exclusivity for the 505(b)(2) drug product, include information required under 314.50(j), e.g., if approval is sought for a new patient population, identify clinical studies that will be the basis for the new exclusivity
  • if seeking approval for a new indication for a reference listed drug, certification to that effect is required per (21 CFR 314.54(a)(1)(iv)
  • information on any Bioavailability /Bioequivalence (BA/BE) study conducted or planned comparing the proposed drug product to the reference listed drug
  • information on any proposed studies that may be necessary to support changes to the reference listed drug (i.e., studies using the new dosage form, dosing regimen change, new patient population, etc.); often, appropriate bridging studies may meet FDA requirements for safety and efficacy in addition to what exists in literature
and/or previous finding of safety and efficacy by the agency for the reference listed drug
Conclusion
 
It should be noted that the standards required to gain approval of a drug via the 505(b)(2) route are the same as those that apply to 505(b)(1) applications. The difference is that the 505(b)(2) applicant can rely upon studies conducted by others (literature-based), for which the applicant has not obtained a right of reference, and also can request reliance upon FDA’s safety and efficacy findings for the reference listed drug.
REFERENCES
1. Federal Food, Drug, and Cosmetic Act as amended by the FDA Modernization Act of 1997.
2. FDA Guidance for Industry: Applications Covered by Section 505(b)(2). This guidance is available at www.fda.gov/cder/guidances.
3. www.fda.gov/cder/drug/infopage/somatropin/default.htm
4. 21 CFR Part 314.54. Procedure for submission of an application requiring investigations for approval of a new indication for, or other change from, a listed drug.
5. Limited confirmatory testing is explained in further detail in 54 Federal Register 288872, 28880 (10 July 1989) and 57 Federal Register 17950, 17957-58 (28 April 1992).
6. “Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule,” Federal Register. Vol. 59, No.190, Monday, 3 October 1994, page 50338. Also found under 21 CFR 314.107 Effective date of approval of a 505(b)(2) application.
7. FDA Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products. This guidance is available at 222.fda.gov/cder/guidances.