An Abbreviated New Drug Application (ANDA) contains data which is submitted to the FDA for the review and potential approval of a generic drug product whereas a New Drug Application (NDA) is the application through which sponsors formally propose the approval of a new pharmaceutical drug. Media attention in drug development tends to focus more on novel therapies than generic drugs. However, new drugs only account for a small portion of FDA approvals each year. In 2020, the FDA approved or tentatively approved 948 ANDAs, including 72 first generics and only approved 53 novel drugs, either as new molecular entities (NMEs) under NDAs, or as new therapeutic biologics under Biologics License Applications (BLAs). Historically each year, there are around 20 times more generic drugs approved than novel drugs approved.
Classifying Your Drug
The distinction between a novel drug and a generic drug is relatively straightforward. A novel drug is one that contains an active ingredient that has not yet been approved. Once a drug is approved, it is known as an innovator drug. A generic drug is essentially a duplicate of an approved drug. There may be differences in the way a generic and innovator drug look (e.g., size, shape, color), but they should share the same active ingredients, strength, safety, effectiveness, and quality characteristics. But what about a drug that contains the same active ingredient(s) as an approved drug but still differs in ways that could impact how the medication works? Is this considered to be a novel drug, a generic drug, or something all its own? Is the same proof for safety and effectiveness required for this drug as for an innovator drug? The implications of these questions are far-reaching and impact not only key drug development decisions but also the regulatory pathways through which these drugs are approved. To help with the decision-making process, the FDA has released a draft guidance called “Determining Whether to Submit an ANDA or 505(b)(2) Application.”
Approval Pathways: 505(b)(1) NDA, 505(j) ANDA, & 505(b)(2) NDA
There are three approval pathways for NDAs and ANDAs which are: 505(b)(1) NDA, 505(j) ANDA, and 505(b)(2) NDA. These refer to the particular parts of Section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act which respectively covers the approval of innovator drugs, generic drugs, and drugs that share key similarities with approved drugs but differ in other potentially crucial ways. The approval pathways for non-innovator drugs are abbreviated and are meant to encourage a quicker time to market. They allow applicants to use existing knowledge instead of performing a full collection of safety and efficacy studies themselves, as would be required for an innovator drug.
Abbreviated New Drug Applications (ANDAs)
When a Sponsor submits a generic drug for marketing approval, they submit an ANDA instead of a full 505(b)(1) NDA. Generic drug applications are called “abbreviated” because they do not require new pre-clinical (animal) and clinical (human) data to establish safety and effectiveness. In an ANDA, the applicant is claiming that their drug is a duplicate of an already-approved drug. Within the ANDA, the innovator drug, commonly referred to as the “Reference Listed Drug” (RLD), is specified. Because the FDA has already approved the RLD to be safe and effective, the goal of an ANDA is to demonstrate “sameness” with the RLD. Sameness is demonstrated via a bioequivalence assessment. According to Section 505(j)(8)(B)(i) of the FD&C Act, a generic drug is determined to be bioequivalent to the listed drug if the rate and extent of absorption of the generic drug do not show a significant difference from those of the RLD. Also, there must not be a significant difference when administered at the same molar dose and under similar experimental conditions. In short, drugs approved under an ANDA must be therapeutically equivalent to the RLD. This means that if an ANDA-approved drug is swapped with the RLD, patients should experience the same clinical effect and safety profile. The active ingredient, dosage form, route of administration, and strength must all be the same, and the product labeling is usually the same. In addition, the sameness requirement also extends to the inactive ingredients in a generic drug product. Inactive ingredients that are not considered exception excipients (such as preservatives, buffers, and antioxidants) must be qualitatively and quantitatively (Q1/Q2) the same as those in the RLD. Because a generic drug is intended to act as a duplicate of the RLD, no new safety or efficacy studies are performed and only small confirmatory studies are allowed to support the ANDA. If additional pre-clinical or clinical data are needed to support safety or efficacy, then the ANDA route is not appropriate and a 505(b)(2) NDA should be used.
505(b)(2) New Drug Applications (NDAs)
Section 505(b)(2) of the FD&C Act allows the FDA to approve marketing applications for non-innovator drugs that do not otherwise qualify for approval under a 505(j) ANDA. Under this statute, the approval may rely in whole or in part on published literature and/or on the FDA’s findings of safety and/or effectiveness for a previously approved drug. Certain findings and data submitted in support of a 505(b)(2) NDA will stem from investigations that were not conducted by or on behalf of the applicant and for which the applicant has not obtained a right of reference. Changes to approved drugs that would require a 505(b)(2) NDA include differences in dosage form, strength, route of administration, formulation (i.e., excipients), dosing regimen, active ingredient (e.g., different salt or enantiomer), or indication (i.e., repurposed drugs). Applications for a new combination product would also be included, even if the individual active ingredients have been previously approved. Changing a drug from a prescription indication to an over-the-counter indication would also require a 505(b)(2) NDA. Additional information may be found in the FDA draft guidance, “Applications Covered by Section 505(b)(2).” Because the goal of a 505(b)(2) application is to present a complete body of evidence to demonstrate that the drug is safe and effective, if there are aspects of the drug that cannot be adequately supported by published literature, then the applicant is responsible for conducting appropriate investigations to bridge the formulations. These investigations may include nonclinical or clinical studies or a combination of both. Data from these bridging investigations are then submitted to the FDA for review as part of the NDA. It is important to develop a strong strategy for 505(b)(2) approval. The NDA review includes:
- Medical Review(s)
- Chemistry Review(s)
- Environmental Assessment
- Pharmacology Review(s)
- Statistical Review(s)
- Microbiology Review(s)
- Clinical Pharmacology/Biopharmaceutics Review(s)
- Risk Assessment and Risk Mitigation Review(s)
The 505(b)(2) NDA and 505(j) ANDA pathways are both intended to provide an efficient means for approving non-innovator drug products by harnessing existing information to support the approval package. Each of these abbreviated pathways includes its own nuances and regulatory requirements. Understanding which pathway applies to your drug is critical for making good drug development decisions and ensuring that your product gets approved and on the market in a timely manner. Allucent has experience with both ANDAs and 505(b)(2) application support and can help choose the right approval pathway for your drug development program. Contact one of our senior consultants for 505(j) ANDA, 505(b)(1) NDA, or 505(b)(2) NDA support.