Shortages of Essential Generic Drugs with Limited Competition

INTRODUCTION

Shortages of generic prescription drugs are a persistent challenge in the USA, limiting patient access to essential medications such as antibiotics, cancer treatments, and intravenous fluids.¹ One proposed policy solution, the Affordable Drug Manufacturing Act of 2023 (ADMA), would establish a federal Office of Drug Manufacturing to prioritize public production of off-patent drugs with limited competition, which are particularly vulnerable to shortage and more likely to experience price volatility and higher patient costs.^2–5 While certain drug classes are explicitly mentioned in the ADMA (e.g., antibiotics, insulin), it is unclear which essential medicines could provide the greatest public health benefit if prioritized for public manufacturing. We characterized drugs in shortage in the USA and identified essential generics with limited competition to inform such prioritization.

METHODS

We used the FDA Drug Shortage Database to identify drugs in shortage on November 2, 2023; we documented each drug’s route of administration and shortage duration. We classified drugs by World Health Organization (WHO) Anatomical Therapeutic Chemical category and identified those essential to public health using the 2023 WHO Model List of Essential Medicines.

We identified each drug’s market exclusivity status and manufacturers using the FDA Orange Book; the number of manufacturers per drug was summed across all drug strengths listed in shortage. We defined limited competition as 3 or fewer Orange Book–listed manufacturers, consistent with the ADMA. We excluded 1 unapproved drug (belladonna-opium), 2 discontinued or withdrawn drugs (methyldopa; cefotaxime), and 3 drugs not listed in the Orange Book (collagenase Clostridium histolyticum; parathyroid hormone; triamcinolone hexacetonide). We quantified the number of prescriptions filled in the 12 months preceding the drug’s initial shortage date using public Medicaid State Drug Utilization Data to understand the impact on a diverse, low-income patient population.

RESULTS

The 117 drugs in shortage had a median of 3 manufacturers per drug (interquartile range [IQR], 2–6) (Table 1). Overall, 109 (93%) were generic, and 78 (67%) were injectables; the most common therapeutic categories were neurologic (25%), hematologic (13%), and cardiovascular (12%). The median shortage duration was 24 months (IQR, 9–43). Sixty-five (56%) drugs were WHO essential medicines; 24 (21%) were essential generic medicines produced by 3 or fewer manufacturers.

Table 1.

Characteristics of Drugs in Shortage in the USA

Drug characteristics	All drugs in shortage (n = 117)* No. (%)	Essential generic drugs with limited competition (n = 24)† No. (%)
Manufacturers, median [IQR]	3 [2–6]	2 [2, 3]
Months in shortage, median [IQR]‡	24 [9–43]	16 [6–34]
Exclusivity status
Branded	8 (7)	–
Generic§	109 (93)	–
On WHO essential medicine list	65 (56)	–
Therapeutic class
Neurologic	29 (25)	5 (21)
Hematologic	15 (13)	–
Cardiovascular	14 (12)	5 (21)
Antimicrobial	12 (10)	5 (21)
Oncologic	11 (9)	2 (8)
Gastrointestinal	11 (9)	–
Ophthalmic	8 (7)	3 (12)
Other||	17 (15)	4 (17)
Route of administration
Injection¶	78 (67)	14 (58)
Oral	27 (23)	4 (17)
Ophthalmic	6 (5)	2 (8)
Other**	6 (5)	4 (17)

Data source: FDA drug shortage list, November 2023

^*Excludes 1 unapproved drug (belladonna-opium suppository), 2 discontinued drugs (methyldopa tablet; cefotaxime injection), and 3 drugs not listed in the Orange Book (collagenase Clostridium histolyticum ointment; parathyroid hormone injection; triamcinolone hexacetonide injection)

^†Defined as drugs with 3 or fewer active manufacturers across all drug strengths as listed in the FDA Orange Book

^‡Indicates the time interval between the date a drug’s shortage was first reported to the FDA (“Date first reported”) and November 2, 2023

^§Includes 102 generic drugs with at least one abbreviated new drug application and 7 drugs with no remaining market exclusivity but no approved generic as of December 2023

^||For all drugs: respiratory 1, urologic 3, systemic hormone 5, musculo-skeletal 4, various 4. For essential generics: respiratory 1, systemic hormone 2, urologic 1

^¶Includes drugs administered parenterally via intramuscular, intravenous, or subcutaneous injection

^**For all drugs: inhalation 1, nasal 1, rectal 1, topical 2, urethral 1. For essential generics: inhalation 1, nasal 1, rectal 1, urethral 1

These 24 essential generic drugs with 3 or fewer manufacturers were in shortage for a median of 16 months (IQR 6–34), and 14 (58%) were injectables (Table 2). In the 12 months before the shortage, these drugs had a median of 4059 Medicaid prescriptions (IQR, 696–49,317). The most used generics were erythromycin ophthalmic solution (764,390 prescriptions), fentanyl injection (282,097), lidocaine viscous oral solution (202,598), and diazepam rectal gel (111,305).

Table 2.

Essential Generic Drugs in Shortage with Limited Competition

Drug name and strength*	Route of administration	FDA-approved manufacturers	Common use	Annual Medicaid prescriptions†	Shortage duration (months)
Albuterol   2.5 mg/0.5 mL	Inhalation	2	Asthma or COPD	70,775	12
Alprostadil   250 ug, 500 ug, 1000 ug	Urethral	1	Erectile dysfunction	0	12
Cefixime   400 mg	Oral	2	Bacterial infections	8476	21
Chloramphenicol   1 g/10 mL	Injection	1	Bacterial infections	0	6
Cyclopentolate   5 mg/mL, 10 mg/mL, 20 mg/mL	Ophthalmic	3	Pupil dilation	23,069	35
Desmopressin   10 ug/0.1 mL, 0.1 ug/mL, 1.5 mg/mL	Nasal	3	Central diabetes insipidus	3597	31
Lidocaine in dextrose   0.4 g/100 mL, 0.8 g/100 mL	Injection	2	Cardiac arrhythmia	2015	72
Diazepam   5 mg/mL	Rectal	2	Seizures or anxiety	111,305	16
Digoxin   250 ug/mL, 100 ug/mL	Injection	3	Cardiac arrhythmia	398	28
Dopamine   0.8 mg/mL, 1.6 mg/mL, 3.2 mg/mL, 40 mg/mL	Injection	3	Shock or heart failure	1376	71
Epinephrine   0.1 mg/mL	Injection	2	Cardiac arrest	1525	138
Erythromycin   5 mg/g	Ophthalmic	3	Bacterial eye infection	764,390	15
Fentanyl   50 ug/mL	Injection	3	Analgesia	282,097	142
Fludarabine   25 mg/mL	Injection	3	Leukemia	140	17
Fluorescein   100 mg/mL, 250 mg/mL	Injection	3	Eye imaging	218	6
Hydrocortisone sodium succinate   50 mg/mL, 100 mg/mL, 125 mg/mL	Injection	1	Various uses‡	42,486	7
Isoniazid   100 mg, 300 mg	Oral	3	Tuberculosis	44,031	5
Lidocaine (viscous)   20 mg/mL	Oral	2	Pain in mouth or pharynx	202,598	5
Nitroglycerin   5 mg/mL, 10 mg/100 mL, 20 mg/100 mL, 40 mg/100 mL	Injection	2	Angina or heart failure	3194	0
Penicillin G benzathine   600000 [iU]/mL	Injection	1	Bacterial infections	64,454	6
Propranolol   1 mg/mL	Injection	2	Cardiac arrhythmia	25	0
Rifapentine   150 mg	Oral	1	Tuberculosis	4521	43
Valproate   100 mg/mL	Injection	3	Seizures	795	34
Vinblastine   1 mg/mL	Injection	2	Various cancers	5534	1

Abbreviations: iU, international units; mg, milligrams; mL, milliliters; COPD, chronic obstructive pulmonary disease

^*Drug strengths listed in the FDA Drug Shortage Database as of November 2, 2023

^†Quantity of prescriptions reimbursed through Medicaid 12 months before the initial drug shortage date posted on the FDA Drug Shortage Database

^‡Clinical uses include adrenal insufficiency, asthma, septic shock, thyroid storm, severe COVID-19, and other conditions

DISCUSSION

One in five drugs on the FDA’s shortage list are essential generic medicines with 3 or fewer manufacturers. Many drugs had been in shortage for over a year, suggesting that the US supply chain has difficulty rapidly resolving shortages. Most generics were injectable medications, consistent with previous analyses and reinforcing the need for robust supply chains for sterile injectable therapies.⁶ Prescriptions for many drugs were filled only a few times by Medicaid patients, even before the initial shortage; this included drugs to treat infectious diseases like tuberculosis, which are not used widely but are crucial for the patients who need them and in the event of wider outbreaks. These findings suggest that drugs with a greater number of pre-shortage Medicaid prescriptions may warrant greater attention in efforts to prioritize drugs for public manufacturing. Limitations of this study include its cross-sectional design and the potential overestimate in the number of manufacturers actively marketing each drug.

Current market dynamics have been insufficient in maintaining a reliable supply of many essential medications in the USA, emphasizing the need for policy reforms to improve manufacturing capacity and market availability at fair prices. In addition to the ADMA, various strategies to mitigate drug shortages have been proposed, including greater supply chain oversight and quality-based payment adjustments to drug purchasers.⁷ Should policymakers seek to maximize the public health impact of the ADMA and other policy proposals, similar prioritization procedures as we have outlined may ensure drug shortages are effectively addressed.

Funding

This work was funded via a grant from Arnold Ventures. Dr. Kesselheim is also supported by a grant from the Commonwealth Fund. The funder had no role in the design or 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.

Data Availability

Data analyzed during this study can be provided by the authors upon request.

Declarations:

Conflict of Interest:

Dr. Rome and Kesselheim’s work is also supported by grants from the National Academy for State Health Policy, the Colorado Division of Insurance, the Oregon Department of Consumer and Business Services, the Washington State Health Care Authority, and the Elevance Health Public Policy Institute. Mr. Martin reports receiving a challenge prize from the PhRMA Foundation for contributions to a publication on Medicare drug price negotiation. Dr. Kesselheim reports serving as an expert witness for a large group of state attorneys general and payors related to generic drug pricing.