安渡分享 | Kamali Chance博士深度解读505(b)(2) 药品批准上市路径

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.

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.

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)).

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.

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

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