Safety vs Price in the Generic Drug Market: Metformin

ABSTRACT

Objectives: Generic medications represent 90% of prescriptions in the US market and provide a tremendous financial benefit for patients. Recently, multiple generic drugs have been recalled due to the presence of carcinogens, predominantly N-nitrosodimethylamine (NDMA), including an extensive recall of extended-release (ER) metformin products in 2020.

Study Design: Primary pharmaceutical quality testing and database analysis.

Methods: We tested marketed metformin immediate-release (IR) and ER tablets from a wide sample of generic manufacturers for the presence of carcinogenic impurities NDMA and N,N-dimethylformamide (DMF). We examined the association of level of impurity with drug price and the impact of the 2020 FDA recalls on unit price and prescription fill rate.

Results: Postrecall NDMA levels were significantly lower in metformin ER samples (standardized mean difference = –2.0; P = .01); however, we found continued presence of carcinogens above the FDA threshold in 2 of 30 IR samples (6.67%). Overall, the presence of contaminant levels was not significantly associated with price for either IR (NDMA: R² = 0.142; P = .981; DMF: R² = 0.382; P = .436) or ER (NDMA: R² = 0.124; P = .142; DMF: R² = 0.199; P = .073) samples. Despite recalls, metformin ER prescription fills increased by 8.9% while unit price decreased by 19.61% (P < .05).

Conclusions: Recalls of metformin ER medications were effective in lowering NDMA levels below the FDA threshold; however, some samples of generic metformin still contained carcinogens even after FDA-announced recalls. The absence of any correlation with price indicates that potentially safer products are available on the market for the same price as poorer-quality products.

Am J Manag Care. 2024;30(4):161-168. https://doi.org/10.37765/ajmc.2024.89450

Takeaway Points

Generic medications represent 90% of prescriptions in the US market, but the market focuses extensively on price. Recently, however, multiple generic metformin drugs have been recalled due to poor drug quality, including the presence of carcinogens.

• We examined the price and quality after recalls of metformin and found better-quality drugs on the market at the same or lower cost.
• Making the supply chain accountable for quality will not increase the price of medications or affect access to generic drugs.

Metformin, a first-line drug used in the treatment of type 2 diabetes, was prescribed 85 million times in the United States in 2019.¹ In early 2020, independent testing of marketed generic metformin extended-release (ER) tablets in the United States revealed the presence of the known carcinogen N-nitrosodimethylamine (NDMA).^2,3 Regulation of NDMA is based on evidence of DNA mutagenicity in animal models, and NDMA is estimated to cause cancers in 1 in 100,000 patients with continued exposure above acceptable limits.^4,5 Recalls began in June 2020 with all-lot recalls from Apotex Inc and Amneal Pharmaceuticals Inc, and subsequent detection of NDMA has since led to recalls of products from 13 different labelers.² This process is global⁶ and ongoing; Viona Pharmaceuticals Inc issued a recall of metformin ER products due to detection of NDMA as recently as January 7, 2022.⁷ NDMA is hypothesized to be introduced to the metformin supply via contamination of active pharmaceutical ingredients (APIs) with NDMA precursors or factors related to film coating.^8-10

This problem is not unique to metformin; NDMA contamination has also led to extensive recalls of other drug products, including ranitidine,^11-13 angiotensin-converting enzyme inhibitors,¹⁴ and angiotensin II receptor blockers.^15-17 Nor is the problem of drug contamination exclusive to NDMA; N,N-dimethylformamide (DMF), a common solvent used in drug manufacturing, has been detected in high levels in various finished drug products.^18,19 DMF, classified as a group 2A probable carcinogen by the World Health Organization (WHO) due to animal-model evidence, is both inherently toxic and a precursor to NDMA production.¹⁹

In the context of an increasingly globalized drug supply chain—and the significant delays in regular foreign site inspections caused by COVID-19–related travel restrictions—product-level recalls provide an increasingly important complement to the FDA’s quality surveillance program, which traditionally relies heavily on inspection at the manufacturer level.^20-23 Although product-level surveys of drug quality have been published abroad,²⁴ there has been no public-facing analysis of metformin recalls in the United States. Literature on nitrosamine contamination tends to focus on either (1) analytic methods for detection of impurities or strategies for reducing their generation during drug manufacturing or (2) qualitative reviews of the regulatory issues in drug quality.^8,13,25-27

To our knowledge, no paper has attempted to quantify how metformin recalls affected the market for generic products both pharmacologically (in enduring measures of quality past the recall period) and economically (in terms of drug access and pricing). The voluntary recalls in the metformin market provide a natural experiment to test the following questions: First, did the recalls improve the quality of generic medications on the market, using NDMA and DMF contamination as a proxy for product quality? Second, did the removal of medications with higher contaminant levels from the market have an impact on price or access for consumers?

METHODS

Generic Market: Relevant Background

Generic medication production begins with synthesis of an API (Figure 1). Labelers are intermediaries in the pharmaceutical supply chain that generally purchase APIs and combine them with other ingredients (such as fillers) to create the final medication form (eg, tablets, capsules). Generally, a labeler will use a single quantity of an API from a supplier to produce a batch of medications. For example, a single barrel of an API may be used to produce a batch size of 500,000 tablets. Each batch is then used to create pills that are characterized as lots based on the dosage form. In other words, a single batch can produce several lots of medications. Labelers, however, may switch API suppliers between batches of medications, creating the possibility of batch-to-batch variation in product quality within the same labeler.

Medical distributors then purchase generic medication from many labelers and ship these products to health care systems and retail pharmacies.²⁸ Red Oak Sourcing LLC, McKesson Corp, ClarusONE Sourcing Services LLP, and Express Scripts Inc are the dominant medical distributors in the United States, controlling 91% of the market.29 Due to this production, labeling, and distribution pattern, generic products utilized by the same hospital system or the same retail pharmacy may vary over time in a manner largely opaque to both health care providers and their patients. Products within the same lot and same batch are generally considered to have the same quality; however, quality may vary within a single labeler over time because of changes to API sourcing, and quality may vary within a single distributor over time given the presence of multiple labelers.

Sampling Strategy

In October 2021, generic metformin was purchased by both Stanford Health Care and Valisure, LLC, in an attempt to capture products from a varied set of labelers. One bottle of generic metformin immediate release (IR) or ER was purchased from each available labeler for each available dosage. Products from all labelers may not be available at all times due to stocking decisions by distributors. Purchase price was recorded and normalized to a 90-tablet prescription for ease of comparison. All samples were shipped to a central facility (Valisure) for quality analysis. Valisure is an analytic pharmacy accredited by the International Organization for Standardization to perform quality testing, and several authors of this study are current employees.

Quality Assessment

In this study, quality testing assessed for the presence of the carcinogenic compounds NDMA and DMF using liquid chromatography mass spectroscopy methods previously described in literature.³⁰ (See eAppendix A [eAppendices available at ajmc.com] for a complete discussion of drug quality testing protocols.) Four metformin tablets were selected from each bottle and analyzed separately for each round of quality testing. Upper levels of acceptability were 96 ng per maximum daily dose for NDMA and 8800 µg per maximum daily dose for DMF. Cutoffs for NDMA were based on FDA guidance for acceptable daily intake based on a 1 in 100,000 cancer risk over a 70-year period.^4,31 DMF is recognized as both a group 2A carcinogen by the WHO and a potential precursor to NDMA, and the cutoff used was based on current FDA recommendations.^4,19

To determine the efficacy of product recall on improving medication quality, NDMA and DMF contaminant levels for metformin IR and metformin ER samples collected during our study in October 2021 were compared with existing data generated from metformin purchased in 2019 and previously published by Valisure.^3,18 Comparisons of contaminant levels pre- and post recall were quantified using the standardized mean difference (SMD).

Cost and Quality of Generic Metformin: Product-Level Associations

The association between levels of carcinogenic contaminants and drug price was assessed by examining samples purchased in October 2021 using separate ordinary least squares linear regression models for each NDMA and DMF and plotted on correlation plots. Pricing data were defined as the purchase price obtained by each purchaser (Stanford or Valisure), normalized to a 90-pill prescription. Variations in carcinogenic contaminant level were normalized to that expected if taking the prescription at maximum daily dose (2500 mg) to account for variation in dosages. The potential for bias from autocorrelation between initial product dosage and level of carcinogen was examined using the collinearity diagnostics function in Stata (ie, the collin command). Finally, the regression model separately controlled for purchaser, which may confound price in a product-agnostic way.

Cost and Quality of Generic Metformin: Market-Level Trends

To determine the impact of product recall on drug access and price at the market level, we used the Medicaid State Drug Utilization Data to examine metformin ER product sales quantity and unit prices before and after the recalls.³² This data set reports all prescriptions filled through Medicaid drug programs in all 50 states at the National Drug Code level by fiscal quarter. Importantly, this data set reports the number of prescriptions filled by labeler and product codes within each quarter, allowing the differentiation between recalled and unrecalled products when examining time trends. The data set also reports total reimbursement in US$, which can be used to calculate unit price. FDA-announced recalls of metformin ER began on June 11, 2020.² This included all-lot recalls of products from the labelers Amneal, Apotex, and Lupin Pharmaceuticals, Inc, and partial-lot recalls of products from 3 other labelers (Marksans Pharma Ltd, Lupin, and Teva Pharmaceuticals USA, Inc). Our study examined data from quarter 1 through quarter 4 of 2020 and compared products from recalled and unrecalled labelers. Labelers were considered recalled only if subject to all-lot recalls, as lot-level data are not available in this data set.

Statistical Analysis

All statistical analyses mentioned here and the creation of the resultant figures were completed using Stata 16 (StataCorp LLC).

RESULTS

Product Sampling

In October 2021, we obtained metformin IR products from 9 of 21 labelers in the Medicaid database, representing 63.9% of claims filled under the Medicaid program during 2021, and we obtained metformin ER products from 9 of 21 labelers in the Medicaid database, representing 98.2% of claims filled under the Medicaid program during 2021 (Table 1). Acquisition of samples from other labelers was limited by availability from distributors contracted with Stanford and Valisure.

Quality Assessment

In general, contaminant levels between replicates of the same sample were highly congruent, with SD averaging 7 ng for NDMA and 2.5 µg for DMF levels. For metformin IR in 2021, mean NDMA levels were 15 ng (95% CI, 4-32 ng) and mean DMF levels were 19.9 µg (95% CI, 11.9-27.9 µg) (Table 2). For metformin ER in 2021, mean NDMA levels were 8.6 ng (95% CI, 1-16 ng) and mean DMF levels were 14.6 µg (95% CI, 4.4-24.8 µg). In total, 2 of 30 (6.67%) metformin IR products and 0 of 26 (0.00%) metformin ER products contained NDMA levels above the FDA acceptable daily intake limit of 96 ng/day. Labelers with samples with NDMA levels above this limit comprised 10.6% of metformin IR claims filled under the Medicaid drug programs in 2021. No samples tested contained DMF levels above the current standard.

For metformin IR products purchased prior to the FDA-announced recalls, mean NDMA levels were 15 ng (95% CI, 5-25 ng) and mean DMF levels were 64.5 µg (95% CI, 8.8-120.0 µg). Changes in levels of carcinogens before and after recall were not significant for NDMA (SMD = 0.02; P = .92) but were significant for DMF (SMD = –14.0; P = .03). For metformin ER products purchased prior to the FDA-announced recalls, mean NDMA levels were 264 ng (95% CI, 50-477 ng) and mean DMF levels were 63.3 µg (95% CI, 21.3-105.2 µg). Changes in levels of carcinogens before and after recall were significant for NDMA (SMD = –2.0; P = .01) but not significant for DMF (SMD = –1.92; P = .07) (Table 2).

Cost and Quality of Generic Metformin: Product-
Level Associations

Metformin IR contaminant levels were not significantly associated with 90-tablet prescription price (Figure 2; for regression results see eAppendix Table 1). This lack of association held true for both NDMA (R² = 0.142; P = .981) and DMF (R² = 0.382; P = .436). Similarly, metformin ER contaminant levels were not significantly associated with 90-tablet prescription price for either NDMA (R² = 0.124; P = .142) or DMF (R² = 0.199; P = .073). Initial sample dosage was confirmed not to be collinear with other examined variables, including contaminant levels and price.

Cost and Quality of Generic Metformin: Market-Level Trends

In quarter 1 of 2020, Amneal Pharmaceuticals and Apotex produced 12.2% of examined metformin ER prescriptions filled under Medicaid drug programs (Figure 3). By quarter 4 of 2020, after the FDA-announced recalls, utilization of metformin ER for those labelers decreased to 0.3%. During this same period, fills from other labelers increased by 24.1% and total metformin ER prescription fills increased by 8.9%. Further, unit price for nonrecalled metformin ER products decreased by 19.61%, from $13.05 per 90-pill prescription to $10.49.

DISCUSSION

The Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch-Waxman Act, created a new pathway for generic versions of branded medications to receive FDA approval.³³ This effort was so successful that generic medications, then only 19% of the US market, came to represent 90% of US prescriptions by 2020.³⁴ Generic medications provide significant savings for patients when compared with branded alternatives: One industry estimate suggests that generic medications saved $313 billion in 2019 alone.³⁴

Cost savings have been the generic drug market’s primary benefit, with generic manufacturers entering the market by offering a lower price than their competitors,^35,36 while quality has traditionally been treated as a binary: approved or not approved.

The FDA is the primary regulatory body overseeing quality of drugs sold in the US market. Over the past several decades, the US Government Accountability Office has documented how globalization of the generic medication supply chain has created novel challenges for the federal agency; 70% of active ingredients sold in the US are now manufactured abroad.^20-23 A central component of the FDA’s quality assurance of drug manufacturers is site inspections. Tools key to effective oversight—unannounced quality inspections, for example—become untenable when inspectors must communicate with these foreign establishments to apply for visas or coordinate interpreters.^37,38 Further, COVID-19 travel restrictions have constrained the number of foreign inspections, which had already been in documented decline for several years prior.¹⁷

In this context, together with frequent news reports of product recalls, concerns have developed about the quality of the generic medication supply in the US market.^37-39 Beliefs about the lack of integrity of generic medications are echoed by health care professionals.^40,41 A 2009 survey showed that up to one-fourth of physicians expressed negative views of generic medications or avoided prescribing them as first-line therapies,⁴² and many pharmacists may avoid filling generic medications they deem ineffective or unsafe.⁴³ Although more recent data, published in 2016, showed physician trust to be improving,⁴⁴ a key factor in continuing this trend will be assuring the public that there are robust systems in place to ensure product quality.⁴⁵

Two findings are notable from our study in this regard. First, we found that FDA-announced manufacturer recalls were effective in reducing the levels of carcinogenic impurities in the generic metformin drug supply. NDMA levels in examined metformin ER products were significantly less than those identified prior to the recalls in 2020. Second, there was no evidence from a population level that these recalls significantly limited metformin prescription fills or increased unit price; the recall of products from certain labelers was offset by an increase in fills of other products. This latter finding is consistent with that of a prior study of metoprolol utilization within the FDA’s Sentinel System database, which found that a large portion of users switched from generic to branded or authorized generic formulations after FDA-announced recalls.⁴⁶

Nonetheless, by sampling and retesting the metformin IR and ER supply, we discovered that products remain on the market with NDMA levels above the FDA acceptable daily intake. Further, we broadly detected the presence of the carcinogen DMF, which the WHO and International Agency for Research on Cancer classified as a group 2A probable human carcinogen in 2018. Since this decision, the FDA has not reevaluated regulation of DMF. Further, the initial recall of metformin ER was prompted by a petition based on independent quality analysis of drug products rather than ongoing quality screening by the FDA or industry,^2,18 suggesting the need for more systematic and comprehensive drug quality testing protocols by the FDA³⁸ and across the market.³⁹ Further, there have been reports of NDMA accumulation over time in stored metformin products, with 12 weeks being an important inflection point, suggesting that some products with undetectable levels at one time point may accumulate contaminants at a later time point.⁴⁷

Our analysis provides evidence that increasing drug quality can be accomplished without significantly increasing generic medication cost or limiting medication access. First, our regression analyses demonstrated that levels of carcinogenic impurities were not significantly associated with acquisition cost, suggesting that high-quality products may be obtained at low cost if a reliable mechanism exists for identifying them and incentivizing their purchase. Second, examination of time trends for medication utilization and price found that dispensing volumes of total metformin products did not significantly decrease following recalls of contaminated products (ie, a net increase of metformin ER fills was observed over the study period), nor did costs of metformin increase in the Medicaid program over this period (ie, a net decrease of unit price of metformin ER was observed). Although these aggregate trends do not account for epidemiological shifts in metformin demand or other time-associated confounders unrelated to FDA-announced recall, these data suggest that drug shortages or price inflation may not have been significant consequences of the metformin recalls, even when a substantial portion of the initial market share was recalled.

Limitations

Our study was not sufficiently powered to examine variation in quality within each labeler over time. Generic medication production begins with synthesis of APIs. Labelers generally outsource production of APIs, and they may switch ingredient suppliers between batches of medications. Therefore, medication quality from a given labeler may vary significantly from batch to batch, which was not investigated. Results for NDMA and DMF levels are means of 4 dosage units from each lot, and SDs represent variability within manufacturing batches and a snapshot of quality across companies for the product sampling period.

Second, modeling health risks of NDMA and DMF is based on incomplete understanding of toxicological risk. Regulatory bodies agree that there exists no safe exposure to genotoxic compounds, even if acceptable daily intake thresholds may be practical.^31,48 Regulatory decisions regarding NDMA and DMF are based on evidence from in vitro or animal studies demonstrating their potential to cause metastatic tumors in multiple organ sites⁴⁹ as well as epidemiological evidence of the carcinogenicity of NDMA and DMF in humans based on cohort studies and meta-analyses of case control studies.^50-52 Thus, although it is clear that NDMA and DMF pose a risk to human health, how best to quantify the impact of various levels of contaminants is uncertain. Further, patients who have diabetes and take metformin may have taken multiple other medications with NDMA contamination (ranitidine, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors⁵³).

Last, our ecological study of metformin ER drug utilization and price was limited to data available in the Medicaid State Drug Utilization Data.²⁶ Although this database is extensive, it may not detect all medication shortages. Similarly, it is difficult to distinguish impacts of medication shortages from changes in demand due to evolving epidemiological need for metformin products.

CONCLUSIONS

The rate of the carcinogenic contaminant NDMA in the metformin prescription drug supply appears to be significantly reduced after recall of contaminated products; however, medications currently on the market may still vary widely in quality. Meanwhile, product price set by labelers is not a significant determinant of quality, so the market cannot continue to compete on price and assume quality is equivalent.⁵⁴ Finally, there is no evidence to say that prior recalls resulted in either shortages or price inflation, suggesting that safer products may be available on the market for the same price as poor-quality products.

Author Affiliations: Clinical Excellence Research Center, School of Medicine, Stanford University (BT, AM, KAS), Stanford, CA; Valisure, LLC (AH, KK, DL, JN, SW), New Haven, CT; Graduate School of Business, Stanford University (KAS), Stanford, CA.

Source of Funding: None.

Author Disclosures: Ms Hudspeth, Dr Kucera, Mr Light, and Ms Williams are employees of Valisure, LLC, an independent testing laboratory. Mr Light and Ms Nailor are stockholders in Valisure, and Mr Light is also a board member of Valisure and has received a speaker honorarium from Stanford University Medicine grand rounds. Dr Schulman is an unpaid member of the Civica Rx Scientific Advisory Board. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (BT, KK, DL, AM, KAS); acquisition of data (BT, AH, JN, SW, AM, KAS); analysis and interpretation of data (BT, AH, DL, JN, SW); drafting of the manuscript (BT, DL, JN, SW); critical revision of the manuscript for important intellectual content (BT, AH, DL, SW); statistical analysis (BT, AH); provision of patients or study materials (BT); obtaining funding (AM); administrative, technical, or logistic support (AH, KK, AM, KAS); and supervision (KK).

Address Correspondence to: Kevin A. Schulman, MD, Clinical Excellence Research Center, School of Medicine, Stanford University, 453 Quarry Rd #117B, CAM Building, Palo Alto, CA 94304. Email: kevin.schulman@stanford.edu.

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