Abstract
Purpose:
Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA’s Sentinel Distributed Database.
Methods:
We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15–64 years with attention deficit hyperactivity disorder or narcolepsy during 2013–2019.
Results:
We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days.
Conclusions:
These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted.
Keywords: attention deficit hyperactivity disorder, generic drugs, lack of effect, mixed amphetamine salts, narcolepsy, signal detection, switching
1 |. INTRODUCTION
Mixed amphetamine salts (MAS) are central nervous system stimulants manufactured as single-entity compounds containing d-amphetamine and l-amphetamine in a 3:1 ratio.1 The immediate-release brand product (Adderall; Teva Branded Pharmaceutical Products R&D, Inc.) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. As it was discontinued in 2010, the current reference standard (specific drug product identified by FDA for any in vivo bioequivalence testing required to support approval to market a generic drug)2 is a generic equivalent manufactured by Barr Pharmaceuticals, Inc. (subsidiary of Teva) (abbreviated new drug application [ANDA] 040422).3 The generics under this ANDA are marketed using the trade name Adderall (Teva Branded Pharmaceutical Products R&D, Inc.) or the generic name (Teva Pharmaceuticals USA, Inc.).
Certain generic immediate-release MAS had been the subject of spontaneous reports to the Drug Quality Reporting System, a subset of FDA’s MedWatch,4 describing lack of effectiveness, largely among long-term users. We aimed to examine on-label utilization and switching patterns that might suggest whether long-term users are more likely to switch away from or switch back after use of certain generics.
2 |. METHODS
We used administrative claims data from five Data Partners contributing to the FDA’s Sentinel Distributed Database,5,6 representing privately and publicly insured U.S. individuals. We identified treatment episodes from individuals aged 15–64 years with evidence of a diagnosis of ADHD or narcolepsy (Table S1) and prevalent use (utilization analyses) or ≥60-day continuous supply (switching analyses) of any immediate-release MAS during January 1, 2013, through December 31, 2019. We required continuous enrollment in health plans with medical and drug coverage in the 183 days prior to the index dispensing with allowed coverage gaps of ≤45 days. Besides the current reference standard (ANDA 040422), we selected four additional immediate-release MAS (ANDAs 202424, 040440, 040439, and 040480) (Tables S2 and S3) based on whether they had been the subject of spontaneous reports signaling lack of effectiveness. We grouped MAS by ANDA as products approved under the same ANDA are identical but might be marketed under different names or manufacturers. For the utilization analyses, we also included a group with all marketed immediate-release MAS. We included all qualifying treatment episodes, defined as days supplied in one or consecutive dispensings with an allowable gap of ≤7 days. We defined switch pattern episodes as the eligible treatment episodes evaluated for one of the switch patterns of interest. To evaluate switch pattern episodes, we required ≥60 days of continuous use with a generic under the same ANDA to ensure a minimum continuity prior to any switch. We evaluated one- and two-switch treatment patterns to identify switches to a higher dose (any ANDA), away from and back to immediate-release MAS under the same ANDA, or to those under a certain ANDA and back to products under the same or another ANDA (Table S4). We considered treatment episodes from the index dispensing until time to first switch to another ANDA (one-switch patterns), time from first switch until second switch (two-switch patterns), product discontinuation, end of available data, enrollment or study period, or death, whichever occurred earlier (Figure S1).
We described counts and proportions of individuals on immediate-release MAS under each ANDA, demographics, health characteristics and filled prescriptions often associated with MAS use and/or conditions for which these products were indicated, days supplied per dispensing and treatment episodes, number of individuals with a first and/or second switch, time to second switch, and number of censored treatment episodes. We used the Cohort Identification and Descriptive Analysis analytic tool in Sentinel (version 10.3.2)7 and custom programming in SAS version 9.4 (SAS Institute Inc.).
This was a public health surveillance activity conducted under the authority of FDA and, accordingly, not subject to Institutional Review Board oversight.
3 |. RESULTS
We identified 763 599 immediate-release MAS users with a total of 6 681 255 dispensings (Figure 1). The overall number of users increased over time during 2013–2019. Across all ANDAs, we observed a median duration of 30 days before censoring due to product discontinuation (most frequent reason for episodes ending). For other censoring reasons, we observed that median duration of treatment episode was higher for ANDA 040422 (Table S5).
FIGURE 1.
Users and dispensings of immediate-release forms of generic mixed amphetamine salts in the FDA’s Sentinel Distributed Database, from January 1, 2013, to December 31, 2019.
We observed 785 341 index treatment episodes with at least 60-day continuous supply for any immediate-release MAS in a total of 405 714 unique individuals, with a mean (standard deviation) age of 35.0 (11.6) years, 54.1% being females (Table S6). Most had a diagnosis of ADHD—with (0.3%) or without (98.4%) narcolepsy. Anxiety disorders (31.0%), mood disorders (29.2%), and sleep disorders other than narcolepsy (12.7%) accounted for the most frequent chronic conditions. Accordingly, at baseline, individuals often had antidepressant (36.2%) or anxiolytic (24.7%) dispensings; 22.2% had recorded a dispensing for an extended-release MAS formulation. We observed the greatest number of index treatment episodes for ANDA 040422 (n = 525 771) and the lowest for ANDA 040480 (n = 8792). Few episodes resulted in a switch to a higher dose product (range 1.9%–3.2%) (Table 1). The proportion of episodes resulting in a switch to a product under a different ANDA varied by ANDA: 42.0% of ANDA 040480 episodes resulted in a switch to another product, which contrasted with only 9.3% of the ANDA 040422 episodes. Of those with a first switch away, ANDA 040422 episodes (48.6%), ANDA 202424 episodes (43.0%), and ANDA 040439 episodes (38.1%) were most likely to end with a switch back to the same product; ANDA 040480 episodes (24.1%) and ANDA 040440 (26.8%) were the least likely. The median time [interquartile range] for this switch back ranged between 32 [29, 61] days for ANDA 040422 and 56 [30, 177] days for ANDA 040480. Among episodes that started on another ANDA and switched to an ANDA of interest, switch to ANDA 040480 was the least likely to occur (0.9%) and switch to 040422 the most likely (17.9%–18.9%). After this first switch, 46.4% of the episodes switched away from 040422 while 52.8% switched away from 040480; about one-third (range 27.1%–37.0%) switched back to the same product. These switches back had a median time of 31–32 days across all ANDAs.
TABLE 1.
Descriptive statistics of duration and time to switch for immediate-release forms of generic mixed amphetamine salts, by switch pattern, in the FDA’s Sentinel Distributed Database, from January 1, 2013, to December 31, 2019.
| First switch | Second switch | ||||
|---|---|---|---|---|---|
| Switch pattern | Switch pattern episodes, No.a | Switch pattern episodes, No. (%) | Switch pattern episodes, No. (%) | Time to second switch in days, mean (SD) | Time to second switch in days, median [IQR] |
| Switch away and switch back | |||||
| ANDA 040422 to non-040422 to ANDA 040422 | 485 437 | 45 190 (9.3) | 21 964 (48.6) | 57.7 (70.5) | 32 [29, 61] |
| ANDA 202424 to non-202424 to ANDA 202424 | 153 338 | 36 696 (23.9) | 15 769 (43.0) | 60.7 (71.3) | 33 [29, 62] |
| ANDA 040439 to non-040439 to ANDA 040439 | 51 214 | 14 083 (27.5) | 5367 (38.1) | 67.2 (74.9) | 35 [30, 83] |
| ANDA 040440 to non-040440 to ANDA 040440 | 17 185 | 5765 (33.6) | 1547 (26.8) | 78.5 (88.0) | 37 [30, 91] |
| ANDA 040480 to non-040480 to ANDA 040480 | 7287 | 3062 (42.0) | 738 (24.1) | 104.8 (104.4) | 56 [30, 177] |
| Switch to and switch back to any | |||||
| Non-040422 to ANDA 040422 to non-040422 | 207 640 | 37 240 (17.9) | 17 288 (46.4) | 61.5 (80.2) | 32 [29, 61] |
| Non-202 424 to ANDA 202424 to non-202424 | 524 014 | 31 976 (6.1) | 16 720 (52.3) | 56.9 (66.1) | 32 [29, 61] |
| non-040439 to ANDA 040439 to non-040439 | 607 676 | 24 556 (4.0) | 13 117 (53.4) | 47.8 (54.0) | 31 [29, 51] |
| non-040440 to ANDA 040440 to non-040440 | 625 227 | 14 382 (2.3) | 8382 (58.3) | 44.0 (42.6) | 31 [29, 36] |
| non-040480 to ANDA 040480 to non-040480 | 627 156 | 5337 (0.9) | 2817 (52.8) | 51.3 (41.4) | 32 [29, 60] |
| Switch to and switch back to same | |||||
| Non-040422 to ANDA 040422 to non-040422 (same) | 214 774 | 40 583 (18.9) | 12 483 (30.8) | 55.8 (68.6) | 32 [29, 59] |
| Non-202424 to ANDA 202424 to non-202424 (same) | 530 593 | 34 469 (6.5) | 12 732 (36.9) | 53.5 (59.1) | 31 [29, 59] |
| Non-040439 to ANDA 040439 to non-040439 (same) | 613 116 | 26 277 (4.3) | 8942 (34.0) | 46.0 (50.9) | 31 [29, 37] |
| Non-040440 to ANDA 040440 to non-040440 (same) | 629 184 | 15 204 (2.4) | 5187 (34.1) | 42.6 (38.6) | 31 [29, 36] |
| Non-040480 to ANDA 040480 to non-040480 (same) | 628 595 | 5600 (0.9) | 1516 (27.1) | 49.2 (41.2) | 31 [29, 57] |
| Switch to higher strength (regardless of the generic brand) | |||||
| ANDA 040422 to higher strength (any immediate-release MAS) | 525 771 | 16 505 (3.1) | – | – | – |
| ANDA 202424 to higher strength (any immediate-release MAS) | 181 693 | 4381 (2.4) | – | – | – |
| ANDA 040439 to higher strength (any immediate-release MAS) | 62 363 | 1278 (2.1) | – | – | – |
| ANDA 040440 to higher strength (any MAS IR) | 21 143 | 392 (1.9) | – | – | – |
| ANDA 040480 to higher strength (any MAS IR) | 8792 | 167 (1.9) | – | – | – |
Abbreviations: ANDA, abbreviated new drug application; IQR, interquartile range; MAS, mixed amphetamine salts.
Number of valid treatment episodes evaluated for a switch.
4 |. DISCUSSION
This descriptive analysis of switching patterns for generic immediate-release MAS, grouped by ANDA, among U.S. individuals aged 15–64 years with ADHD or narcolepsy and ≥60 days of continuous use of MAS with the same ANDA did not suggest increased switching away or back after use of the selected generics. Consistent with their number of dispensings, we observed a larger proportion of episodes with ANDA 040480 switching to a new ANDA without switching back and the opposite pattern for those with ANDA 040422. Similarly, we observed higher proportions of episodes switching to ANDA 040422 and lower proportions of episodes with switches to ANDA 040480. Switches away after a first switch and time to second switch appear consistent across all ANDAs regardless of number of dispensings.
Negative views about generics as compared to their branded equivalents are likely associated with higher side effect reporting and lower adherence.8,9 Although Adderall has been discontinued, the reference standard is marketed using both the brand and generic name. Thus, some individuals might still believe they are being dispensed the brand name. Therefore, we did not rely on the generic brand, using ANDA instead. Strengths of the FDA’s Sentinel Distributed Database for active surveillance include the availability of large cohorts with individually linked data containing demographic, diagnostic, and dispensing information. The selected Data Partners, which included four national commercial health insurers and a single state Medicaid, contributed to the large number of episodes, even after requiring ≥60 days of continuous use. Limitations relate to the fact that the Sentinel data consists of outpatient administrative pharmacy claims; because MAS are classified as a Schedule II substance,10 this should have not affected our estimates. Also, despite our inclusion of one state Medicaid, our sample might not be generalizable to uninsured persons. As per the characteristics of the signal, certain individuals had been on a specific immediate-release MAS for some time prior to switching. Therefore, we required ≥60-day supply before any switch of interest. Thus, we allowed the inclusion of different supply periods, and, therefore, we introduced misclassification of exposed time for the first switch. As the aim was to detect potential differences in switching patterns that might suggest lower switchback rates or higher switch away rates for certain immediate-release MAS as compared to the current reference standard and other ANDAs for which analyses in MedWatch have not signaled lack of effectiveness, time to second switch provides more relevant information. Finally, these data cannot be used to confirm a bioequivalence issue. The nature of this assessment—where we could not consider factors such as market share, pharmacy selection of generic(s) to stock, prescriptions dispensed at a different pharmacy, and patient and/or provider preferences—does not allow us to confirm whether the observed patterns, which appear to correlate with the number of dispensings, are mostly due to product availability in the pharmacies. While our results did not suggest increased switching away or switching back after use of the generics of interest, continued post-marketing surveillance is warranted.
Supplementary Material
Key Points.
The number of users of generic mixed amphetamine salts products increased over time during 2013–2019.
Overall, switching appeared to correlate with the number of dispensings.
Few individuals increased dose after at least 60 days of use.
Of those individuals who, after at least 60 days of use, switched to a generic product under an Abbreviated New Drug Application of interest, about half switched back to their prior product after a month.
Results from this descriptive analysis did not suggest increased switching away or switching back after use of the generics of interest.
ACKNOWLEDGMENTS
The authors thank Drs. Daniel Bak, Andrew Mosholder, Edward Kim, and Howard Chazin (FDA) for their contributions to the study design. We also thank the institutional partners that provided the data used in the analysis: CVS Health Clinical Trial Services, an affiliate of Aetna, a CVS Health Company, Blue Bell, PA; HealthCore/Elevance Health, Wilmington, DE; Humana Healthcare Research Inc., Louisville, KY; OptumInsight Life Sciences Inc., Boston, MA; Vanderbilt University Medical Center, Department of Health Policy, Nashville, TN, through the TennCare Division of the Tennessee Department of Finance & Administration, which provided data.
FUNDING INFORMATION
The Sentinel program is funded by the U.S. Food and Drug Administration through the Department of Health and Human Services. This project was supported by Task Order 75F40119F19002 under Master Agreement 75F40119D10037 from the U.S. Food and Drug Administration (FDA).
Footnotes
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest. Employees of the FDA contributed as coauthors to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The FDA had the opportunity to review the final manuscript but did not have the right to either prevent publication or direct it to a specific journal; approved the study protocol including statistical analysis plan and reviewed and approved this manuscript. The FDA had no role in data collection, management, or analysis.
ETHICS STATEMENT
This study was conducted within the Sentinel System and represents a public health activity under the auspices of the U.S. Food and Drug Administration. Activities conducted within Sentinel are not under the purview of institutional review boards.
Preliminary results of this work were presented at 38th International Conference on Pharmacoepidemiology & Therapeutic Risk Management, August 24–28, 2022. Copenhagen, Denmark.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
REFERENCES
- 1.US Food and Drug Administration. Adderall, Teva Branded Pharmaceutical Products R&D, Inc. US labeling. 2022. [Google Scholar]
- 2.US Food and Drug Administration. Referencing approved drug products in ANDA submissions guidance for industry. Accessed April 18. 2020 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/referencing-approved-drug-products-anda-submissions-guidance-industry
- 3.US Food and Drug Administration. Abbreviated new drug application (ANDA): 040422. DEXTROAMP SACCHARATE, AMP ASPARTATE, DEXTROAMP SULFATE AND AMP SULFATE. Original approval. Accessed May 27. 2002 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/040422.PDF [Google Scholar]
- 4.US Food and Drug Administration. MedWatch: the FDA safety information and adverse event reporting program. Accessed June 17. 2022 https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program
- 5.Platt R, Brown JS, Robb M, et al. The FDA Sentinel Initiative—an evolving national resource. N Engl J Med. 2018;379(22):2091–2093. [DOI] [PubMed] [Google Scholar]
- 6.Brown JS, Mendelsohn AB, Nam YH, et al. The US Food and Drug Administration sentinel system: a national resource for a learning health system. J Am Med Inform Assoc. 2022;29:2191–2200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gagne JJ, Popovic JR, Nguyen M, et al. Evaluation of switching patterns in FDA’s sentinel system: a new tool to assess generic drugs. Drug Saf. 2018;41(12):1313–1323. [DOI] [PubMed] [Google Scholar]
- 8.Desai RJ, Sarpatwari A, Dejene S, et al. Comparative effectiveness of generic and brand-name medication use: a database study of US health insurance claims. PLoS Med. 2019;16(3):e1002763. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Colgan S, Faasse K, Martin LR, Stephens MH, Grey A, Petrie KJ. Perceptions of generic medication in the general population, doctors and pharmacists: a systematic review. BMJ Open. 2015;5(12):e008915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Office of the Federal Register (OFR) of the National Archives and Records Administration (NARA) and the U.S. Government Publishing Office (GPO). FederalRegister.gov. Code of Federal Regulations. Title 21 Chapter II Part 1308 Schedules 1308.12 Schedule II. Accessed May 27. 2022 https://www.ecfr.gov/current/title-21/chapter-II/part-1308/subject-group-ECFRf62f8e189108c4d/section-1308.12 [Google Scholar]
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