Media attention and investor fanfare in drug development tend to focus on novel therapies. But did you know that these therapies only account for a small proportion of FDA drug approvals each year? In fact, in fiscal year 2017, there were around 20 times more generic drugs approved than novel drugs.
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 are expected to 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 burden of 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 To help with the decision-making process, the FDA has released a draft guidance, Determining Whether to Submit an ANDA or 505(b)(2) Application.
Possible Approval Pathways
If you’ve spent time in the drug development world, then you’ve probably heard the terms 505(b)(1), 505(b)(2), and 505(j). 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, of drugs that share key similarities with approved drugs but differ in potentially crucial ways, and of generic drugs.
The approval pathways for non-novel 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.
Generic Drug Marketing Applications (ANDAs)
When a sponsor submits a generic drug for marketing approval, they submit an Abbreviated New Drug Application (ANDA) instead of a full NDA. 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 any 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 preclinical 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 pursued.
505(b)(2) Marketing Applications
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 505(j). 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 an 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 strategy for 505(b)(2) approval.
The 505(b)(2) and 505(j) pathways are 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.