Abstract
This study describes the process used by the US Food and Drug Administration to review potential generic drugs for Competitive Generic Therapy (CGT) designation and marketing exclusivity as well as the characteristics and outcomes of products that have sought CGT designation and exclusivity from 2017-2020.
The US Congress established the Competitive Generic Therapy (CGT) pathway in 2017 to incentivize generic entry for drugs with “inadequate generic competition,” which exists when there is only 1 or no company marketing a branded or generic product (eg, sole-source drugs), often arising when products have limited markets or are difficult to develop.1 In a 2-step process, generic applicants (ie, manufacturers) may, before or at application submission, request CGT designation and, if granted, then, on approval as a generic product, potentially become eligible for 180-day CGT exclusivity (eFigure in the Supplement).
Multiple applicants can be granted CGT designation for the same drug product (ie, active ingredient, dosage form, and strength); however, to obtain CGT exclusivity, among other requirements, an applicant must be the first approved for that product, and the reference drug must not have been protected by patents or exclusivities at application submission.1
On approval, CGT exclusivity’s 2 features encourage competition. First, CGT exclusivity-eligible generics must market within 75 days after approval or forfeit exclusivity; second, until the exclusivity-eligible applicant “triggers” exclusivity by marketing, the US Food and Drug Administration (FDA) can approve other applicants for the same product who can then initiate marketing. However, on exclusivity trigger, the FDA cannot approve other applications for the same product until exclusivity is exhausted.
This study describes the characteristics and outcomes of products that have sought CGT designation and exclusivity.
Methods
This was a cross-sectional study of generic drug applications received by the FDA with CGT designation requests between September 26, 2017, and August 25, 2020; only CGT requests with grant or deny decisions were included (eFigure in the Supplement). Multiple products in a single application, eg, diltiazem 60-mg or 90-mg capsules, are considered distinct products for CGT. Products’ marketing and regulatory statuses were assessed on April 12, 2021.
Because multiple applicants can be granted CGT designation for the same product (eg, “applicant A” and “applicant B” each receive designation for diltiazem 60-mg capsule), product-applicant pair data are reported (“diltiazem 60-mg capsule–applicant A” is a single product-applicant pair). Also, unique products are reported because only the first approved product-applicant pair is granted CGT exclusivity (if applicant A’s diltiazem 60-mg capsule is approved first, applicant B cannot receive exclusivity for the 60-mg strength).
“Complex” products that are difficult to develop owing to attributes such as formulation (eg, injectable suspension) or route (eg, metered-dose inhalation) are less likely to have generic versions and are highlighted.2
Descriptive statistics were calculated using Python version 3.9 (Python Software Foundation).
Results
Of 2724 generic applications (including those not CGT-eligible), 283 (10.4%) requested CGT designation (89 applicants for 292 unique products). Overall, 429 product-applicant pairs, 92 for complex products, requested CGT designation; of the 429 pairs, 320 (74.6%) were granted CGT designation (Table) and 109 (25.4%) were denied designation either because requests were not made in accordance with statutory time frames (61.5%) or because there was adequate competition (38.5%).
Table. Characteristics and Outcomes of CGT Designation Requests Received From September 2017 to August 2020a.
| CGT designation request and designation outcome (product-applicant pair level) | Eligibility for CGT exclusivity (unique product level) | Marketing of products with CGT exclusivity (unique product level) | |||||
|---|---|---|---|---|---|---|---|
| Product-applicant pairs with CGT designation request (n = 429) | Product-applicant pairs with CGT designation granted (n = 320) | Product-applicant pairs with CGT designation approved as generic product (n = 114) | Unique generic products with CGT designation approved by FDA (n = 86) | Unique generic products with CGT designation approved by FDA with eligibility for CGT exclusivity (n = 63) | Products with eligibility for CGT exclusivity that triggered the 180-d period by marketing within 75 d (n = 63) | Time to market for products with eligibility for CGT exclusivity, median (IQR) [range], d (n = 54) | |
| Total product-applicant pairs or unique products, No./No. (%)b | 429/429 (100) | 320/429 (74.6) | 114/320 (35.6) | 86 (100) | 63/86 (73.3) | 54/63 (85.7) | 2.5 (0-9.5) [0-70] |
| Product type, No. (%) | |||||||
| Complexc | 92 (21.4) | 77 (24.1) | 21 (18.4) | 18 (20.9) | 9 (14.3) | 9 (14.3) | 10 (3-34) [1-69] |
| Not complex | 336 (78.3) | 243 (75.9) | 93 (81.6) | 68 (79.1) | 54 (85.7) | 45 (71.4) | 1 (0-8) [0-70] |
| Current regulatory status, No. (%)d | |||||||
| Approved | 164 (38.2) | 114 (35.6) | 114 (100) | 86 (100) | 63 (100) | 54 (85.7) | 2.5 (0-9.5) [0-70] |
| Under FDA review | 146 (34) | 122 (38.1) | NA | NA | NA | NA | NA |
| Complete response lettere | 100 (23.3) | 72 (22.5) | NA | NA | NA | NA | NA |
| Tentatively approvedf,g | 11 (2.6) | 7 (2.2) | NA | NA | NA | NA | NA |
| Withdrawn by applicant | 8 (1.9) | 5 (1.6) | NA | NA | NA | NA | NA |
| Therapeutic area (top 10), No. (%)h | |||||||
| Infectious disease | 47 (11) | 33 (10.3) | 11 (9.6) | 9 (10.5) | 7 (11.1) | 4 (6.3) | 7 (3-12.3) [0-19] |
| Endocrinology, diabetes, and metabolism | 44 (10.3) | 29 (9.1) | 6 (5.3) | 6 (7) | 5 (7.9) | 4 (6.3) | 10.5 (0-23.3) [0-30] |
| Psychiatry | 40 (9.3) | 30 (9.4) | 14 (12.3) | 12 (14) | 12 (19) | 11 (17.5) | 1 (0-1) [0-5] |
| Oncology | 35 (8.2) | 25 (7.8) | 3 (2.6) | 3 (3.5) | 1 (1.6) | 1 (1.6) | 6 (6-6) [6-6] |
| Neurology | 25 (5.8) | 19 (5.9) | 5 (4.4) | 5 (5.8) | 2 (3.2) | 2 (3.2) | 3 (3-3) [3-3] |
| Cardiovascular disease | 24 (5.6) | 20 (6.3) | 11 (9.6) | 8 (9.3) | 8 (12.7) | 8 (12.7) | 3 (0-8) [0-8] |
| Dermatology | 22 (5.1) | 21 (6.6) | 7 (6.1) | 4 (4.7) | 2 (3.2) | 2 (3.2) | 18.5 (10.8-26.3) [3-34] |
| Genetic disorders | 22 (5.1) | 15 (4.7) | 9 (7.9) | 7 (8.1) | 3 (4.8) | 2 (3.2) | 32 (16.5-47.5) [1-63] |
| Analgesia | 21 (4.9) | 16 (5) | 10 (8.8) | 10 (11.6) | 6 (9.5) | 5 (7.9) | 69 (2-70) [0-70] |
| Hematology | 21 (4.9) | 14 (4.4) | 6 (5.3) | 5 (5.8) | 3 (4.8) | 2 (3.2) | 6.5 (6.3-6.8) [6-7] |
| Route of administration, No. (%) | |||||||
| Oral | 278 (64.8) | 196 (61.3) | 79 (69.3) | 57 (66.3) | 48 (76.2) | 42 (66.7) | 1 (0-8) [0-70] |
| Intravenous/injectable | 89 (20.7) | 66 (20.6) | 13 (11.4) | 11 (12.8) | 7 (11.1) | 4 (6.3) | 3 (1.5-4.5) [0-6] |
| Topical | 29 (6.8) | 28 (8.8) | 10 (8.8) | 6 (7) | 2 (3.2) | 2 (3.2) | 18.5 (10.8-26.3) [3-34] |
| Ophthalmic | 13 (3) | 11 (3.4) | 4 (3.5) | 4 (4.7) | 3 (4.8) | 3 (4.8) | 34 (34-51.5) [34-69] |
| Transdermal | 12 (2.8) | 12 (3.8) | 6 (5.3) | 6 (7) | 2 (3.2) | 2 (3.2) | 1.5 (1.3-1.8) [1-2] |
| Other | 8 (1.9) | 7 (2.2) | 2 (1.8) | 2 (2.3) | 1 (1.6) | 1 (1.6) | 3 (3-3) [3-3] |
Abbreviations: CGT, competitive generic therapy; FDA, US Food and Drug Administration; NA, not applicable.
Columns present data for each step of the CGT process (eFigure in the Supplement). Applicants first request CGT designation for a drug product (column 2); the FDA then adjudicates these requests for each drug product-applicant pair, granting or denying CGT designation (column 3); when ready, the FDA then approves products for which CGT designation was granted (as shown in previous column) (column 4). The second phase of the process is eligibility for CGT exclusivity. The unit of analysis switches from product-applicant pairs to unique products because CGT exclusivity is granted at the unique-product level (ie, only the first approved applicant[s] per product can be eligible for CGT exclusivity). Column 5 shows unique products with CGT designation that were approved; the subset of these approved with eligibility for CGT exclusivity is in column 6. The third phase is the trigger or forfeiture of CGT exclusivity. Column 7 shows the number of unique products that marketed within the CGT-exclusivity’s statutory limit of 75 days and triggered the 180-day period. Column 8 summarizes the median time to market for products that were eligible for and triggered CGT exclusivity.
Row percentages, with the denominator changing with each column depicting steps of the CGT process. All other percentages are column-based and use the denominator (n) shown in the column headers.
Complex generic products have complex active ingredients, dosage forms, routes of administration, or are drug-device combinations; examples include inhalers, topical products, and extended release injectables. While evidence is limited, findings indicate the CGT program could help incentivize competition for difficult to develop complex drugs with patient-friendly formulations, such as sprays and patches, rather than traditional tablets. Among the complex products, some of the active ingredients and formulations approved with eligibility for CGT exclusivity include buprenorphine patch, dihydroergotamine mesylate nasal spray, and loteprednol etabonate ophthalmic gel.
The “product-applicant” status is shown for each product that had a CGT designation request by each applicant, as of April 12, 2021. A given generic application can include multiple drug products, and multiple applicants can request/receive CGT designation for the same drug product. From a regulatory standpoint, the FDA issues a single regulatory action to each application; thus, multiple products reviewed under 1 application would have the same regulatory status. For consistency in data presentation, this analysis was performed at the product-applicant pair level instead of the application level.
A complete response letter is a written communication to an applicant from the FDA usually describing all of the deficiencies that the FDA has identified in the generic drug application that must be satisfactorily addressed before it can be approved.
If the generic drug application meets the substantive requirements for approval but cannot be finally approved by FDA because of unexpired patents or exclusivities, the FDA issues a tentative approval to the applicant. Thus, final approval of the generic drug product is delayed until the patent or exclusivity issues are resolved and the FDA issues an approval letter after any necessary additional review of the generic drug application. A tentative approval does not allow the applicant to market the generic drug product in the US.
These product-applicant pairs received tentative approvals for reasons other than a blocking CGT exclusivity; other reasons might include unexpired patent(s) on the listed drug product or other (non-CGT) exclusivities.
For selected therapeutic areas, some of the active ingredients and formulations approved with eligibility for CGT exclusivity include the following (this is not a comprehensive list). For infectious disease products: albendazole tablet, daptomycin intravenous powder, and metronidazole infusion; for cardiovascular products: digoxin solution and mexiletine capsule; for psychiatric products: amphetamine sulfate tablets and thiothixene capsules.
Of the 320 product-applicant pairs granted CGT designation, 114 product-applicant pairs (35.6%), for 86 unique products, had been approved at the time of analysis. Among those 86 unique generic products, 63 (73.3%) were eligible for exclusivity at approval.3 Of these 63 products, 54 (85.7%) marketed within a median of 2.5 (IQR, 0-9.5) days of approval; the remaining did not market within 75 days of approval, forfeiting exclusivity.
Of the 114 approved product-applicant pairs with CGT designation, 51 pairs accounting for 23 unique products were not eligible for exclusivity at approval because another applicant for the product was approved first (30/51 [58.8%]) or because the reference drug had unexpired patents or exclusivities at generic application submission (21/51 [41.2%]) (patent/exclusivity had been resolved at generic approval).
Discussion
A sizable fraction of generic applicants requested CGT designation, and many drugs approved with CGT exclusivity eligibility marketed within 2.5 days after approval, which can benefit the health care system and patients.
CGT generics enhance previously inadequate competition, and generics typically decrease drug prices.4 Although several competing generics are needed to achieve floor prices, 30% reductions can occur with 1 competing generic, potentially increasing patient access to affordable drugs.5 Moreover, because CGT encourages an additional manufacturer for a sole-source drug product, it may limit indiscriminate drug price increases.6
Limitations include not analyzing if generics approved with CGT exclusivity affect drug prices, and findings cannot be generalized to other types of FDA applications.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
eFigure. FDA Process for Applicants to Request Competitive Generic Therapy Designation and Receive CGT Exclusivity on Generic Drug Products
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. FDA Process for Applicants to Request Competitive Generic Therapy Designation and Receive CGT Exclusivity on Generic Drug Products