This cross-sectional study evaluates regulatory decisions and health technology assessments in Australia, Canada, and the UK regarding new drugs approved by the US Food and Drug Administration in 2017 through 2020, as well as estimates the US cost per patient per year for drugs receiving negative recommendations.
Key Points
Question
Why have new drugs approved in the US not been approved or recommended for reimbursement in other countries, and how costly are these drugs?
Findings
In this cross-sectional study of all 206 new US drug approvals in 2017 through 2020, 47 drugs were refused marketing authorization or not recommended for reimbursement in other countries due to unfavorable benefit-to-risk profiles, uncertain clinical benefit, or unacceptably high price. The median US cost for these drugs was $115 281 per patient per year.
Meaning
The US may benefit from review of regulatory decisions and health technology assessments of new drugs in other countries to improve access to safe and effective treatments of sufficient value.
Abstract
Importance
Drug expenditures in the US are higher than in any other country and are projected to continue increasing, so US health systems may benefit from evaluating international regulatory and reimbursement decision-making of new drugs.
Objective
To evaluate regulatory decisions and health technology assessments (HTAs) in Australia, Canada, and the UK regarding new drugs approved by the US Food and Drug Administration (FDA) in 2017 through 2020, as well as to estimate the US cost per patient per year for drugs receiving negative recommendations.
Design and Setting
In this cross-sectional study, recommendations issued by agencies in Australia, Canada, and the UK were collected for new drugs approved by the FDA in 2017 through 2020. All data were current as of May 31, 2022.
Exposures
Authorizations and HTAs in selected countries.
Main Outcomes and Measures
All FDA-approved drugs were matched by active ingredient to decision summary reports published by drug regulators and HTA agencies in Australia, Canada, and the UK. Regulatory approval concordance and reasons for negative recommendations were assessed using descriptive statistics. For drugs not recommended by an international agency, the annual US drug cost per patient was estimated from FDA labeling and wholesale acquisition costs.
Results
The FDA approved 206 new drugs in 2017 through 2020, of which 162 (78.6%) were granted marketing authorization by at least 1 other regulatory agency at a median (IQR) delay of 12.1 (17.7) months following US approval. Conversely, 5 FDA-approved drugs were refused marketing authorization by an international regulatory agency due to unfavorable benefit-to-risk assessments. An additional 42 FDA-approved drugs received negative reimbursement recommendations from HTA agencies in Australia, Canada, or the UK due to uncertainty of clinical benefits or unacceptably high prices. The median (IQR) US cost of the 47 drugs refused authorization or not recommended for reimbursement by an international agency was $115 281 ($166 690) per patient per year. Twenty drugs were for oncology indications, and 36 were approved by the FDA through expedited regulatory pathways or the Orphan Drug Act.
Conclusions and Relevance
This cross-sectional study assessed reasons for which drugs recently approved by the FDA were refused marketing authorization or not recommended for public reimbursement in other countries. Drugs with limited international market presence may require close examination by US health care professionals and health systems.
Introduction
A new drug must be authorized by a governmental regulatory agency based on safety and efficacy evaluations before it enters the market in a country.1,2,3,4,5 In a separate process from this regulatory process, many countries have implemented public health technology assessment (HTA) strategies in response to increasing drug prices to determine the value of new treatments by conducting comparative clinical and economic analyses. National HTA agencies in countries such as Australia, Canada, and those in the UK provide recommendations on prescription drug reimbursement and contribute to price negotiations by public payers.6,7,8,9
In contrast, the US federal government does not have a centralized system to evaluate the added clinical and economic value of new drugs.10,11,12 Medicare, the largest payer of US prescription drugs, does not currently evaluate cost-effectiveness of treatments in coverage policies nor negotiate prices directly with pharmaceutical manufacturers.13,14,15 Therefore, most drugs approved by the US Food and Drug Administration (FDA) are reimbursable by public US programs despite growing evidence that high medication list prices are not associated with clinical benefits.16,17,18,19,20
With the proportion of new drugs granted approval by the FDA through expedited regulatory pathways increasing over time, more treatments have been brought to the US market based on fewer, shorter, or otherwise less robust clinical trials.21,22,23 Yet, drugs approved by the FDA through expedited pathways have been associated with higher rates of Medicare coverage compared with drugs approved through standard review.16 Simultaneously, launch prices for newly marketed prescription drugs have increased by 20% each year over the past decade with the median price reaching $180 007 in 2021.24 Centralized HTA is an approach that many other countries have implemented to balance affordability and public access to novel treatments by systemically evaluating whether drugs are appropriately priced with respect to their clinical evidence and incremental benefit.6,7,8,9
Previous studies have examined international evaluations of FDA-approved drugs to characterize trends in marketing approval concordance, therapeutic value ratings, and US expenditures on drugs not recommended for reimbursement.25,26,27,28,29,30,31 However, to our knowledge and to date, no study has categorized the reasons behind negative assessments of FDA-approved drugs across multiple international agencies and determined the US list cost of drugs not recommended by other countries. The objective of this cross-sectional study was to evaluate regulatory decisions and health technology assessments in Australia, Canada, and the UK for new drugs approved by the FDA in 2017 through 2020 and to estimate the US cost per patient per year of drugs receiving negative recommendations.
Methods
All US regulatory data for new drugs approved by the FDA in 2017 through 2020 were collected from the online database Drugs@FDA1 and included date of initial authorization, approved therapeutic indications, application type, orphan drug designation, and expedited regulatory pathways. Drugs were matched by active ingredient to marketing authorization decisions by regulatory agencies and public reimbursement recommendations by HTA agencies in Australia, Canada, and the UK (eTable 1 in Supplement 1).
Drug regulatory decision summaries and databases by the Australian Therapeutic Goods Administration, Health Canada, the UK Medicines and Health Products Regulatory Agency, and the European Medicines Agency (EMA) were used to identify the date of initial drug marketing authorization or refusal in each corresponding jurisdiction.2,3,4,5 Marketing authorizations were compared with FDA approvals by date and regulatory agency, and reasons for refusals were tabulated. Information from both the Medicines and Health Products Regulatory Agency and EMA were included in the analysis of regulatory decisions due to the existence of European centralized and country-specific approval processes, as well as the UK withdrawal from the European Union (“Brexit”) in January 2020, which affected oversight of drugs.
Published HTA summary reports by the Australian Pharmaceutical Benefits Advisory Committee (PBAC), the Canadian Agency for Drugs and Technologies in Health (CADTH), and the UK National Institute for Health and Care Excellence (NICE) were used to identify reimbursement recommendations per drug indication, including specific reasons for negative assessments. All 3 HTA agencies issue public reimbursement recommendations based on assessment of sponsor-submitted comparative clinical and economic data for drugs that have been granted marketing authorization in their respective country. The PBAC provides recommendations for formulary listings on the national Pharmaceutical Benefits Scheme in Australia, the CADTH provides reimbursement recommendations for provincial and territorial public drug benefit programs in Canada, and the NICE provides recommendations that are implemented by the National Health Service.6,7,8
Drugs were selected for cost analysis if they were refused marketing authorization or not recommended for reimbursement for an FDA-approved indication by at least 1 drug regulatory agency or HTA agency, respectively. For these drugs, we collected the recommended dose and treatment duration from the first FDA-approved label. The treatment cost for drugs with weight-based dosing was based on median reported study participant characteristics of pivotal trials and US population averages. The cost of drugs indicated for non–long term uses, including antineoplastic agents, was calculated based on the labeled dosing duration or median clinical trial exposure from pivotal clinical trials listed in the FDA-approved label. For drugs with multiple dosing regimens, the cost was calculated based on the indication receiving a negative international recommendation (eTable 3 in Supplement 1). Using similar methods to a prior study,32 we estimated treatment costs per patient per year based on FDA-recommended dose and wholesale acquisition cost listed in RED BOOK (IBM Micromedex).
Regulatory information, health technology assessment reports, and wholesale acquisition cost were current as of May 31, 2022. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines, and descriptive analyses were conducted using Excel, version 2202 (Microsoft). Because this study relied on publicly available information, institutional review board approval and informed consent were not sought.
Results
US vs International Marketing Authorizations
A total of 206 new drugs were approved by the FDA in 2017 through 2020, of which 162 (78.6%) were granted marketing authorization by at least 1 of the regulatory agencies in Australia, Canada, or the UK as of May 2022, with a median (IQR) delay of 12.1 (17.7) months following US approval (Table 1 and eTable 2 in Supplement 1). Among the 44 FDA-approved drugs not authorized to date by any of the 4 international regulatory agencies included in this analysis, 5 were refused marketing authorization by the EMA due to unfavorable benefit-to-risk assessments. The EMA concluded that abaloparatide, betrixaban, and pexidartinib had serious safety issues that outweighed potential clinical benefits. Evidence of efficacy was inconsistent and not considered sufficient for istradefylline and emapalumab, respectively (Table 2).
Table 1. International Regulatory Authorizations of 2017-2020 FDA-Approved Drugs.
| Approval year in US | New drug approvals in US | No. (%)a | ||||
|---|---|---|---|---|---|---|
| TGA | HC | MHRA | EMA | TGA, HC, MHRA, or EMA | ||
| 2017 | 46 | 26 (56.5) | 30 (65.2) | 35 (76.1) | 33 (71.7) | 40 (87.0) |
| 2018 | 59 | 31 (52.5) | 35 (59.3) | 43 (72.9) | 44 (74.6) | 49 (83.1) |
| 2019 | 48 | 21 (43.8) | 29 (60.4) | 30 (62.5) | 33 (68.8) | 39 (81.3) |
| 2020 | 53 | 16 (30.2) | 19 (35.8) | 26 (49.1) | 30 (56.6) | 34 (64.2) |
| Total | 206 | 94 (45.6) | 113 (54.9) | 134 (65.0) | 140 (68.0) | 162 (78.6) |
Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration; HC, Health Canada; MHRA, Medicines and Health Products Regulatory Agency (UK); TGA, Therapeutic Goods Administration (Australia).
No. and proportion of FDA-approved drugs authorized by select regulatory agencies are presented as of May 31, 2022.
Table 2. Reasons for International Marketing Authorization Refusals of 2017-2020 FDA-Approved Drugs.
| Active ingredient | FDA-approved indication | FDA approval date | International marketing refusal date (agency) | Reasons for international refusal of marketing authorization |
|---|---|---|---|---|
| Abaloparatide | Osteoporosis | Apr 28, 2017 | Jan 7, 2019 (EMA) |
|
| Betrixabana,b,c | Venous thromboembolism prophylaxis | Jun 23, 2017 | Sep 20, 2018 (EMA) |
|
| Emapalumaba,d,e | Primary hemophagocytic lymphohistiocytosis | Nov 20, 2018 | Jan 7, 2021 (EMA) |
|
| Istradefylline | Parkinson disease | Aug 27, 2019 | Jan 6, 2022 (EMA) |
|
| Pexidartiniba,d,e | Symptomatic tenosynovial giant cell tumor | Aug 2, 2019 | Oct 28, 2020 (EMA) |
|
Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration.
Approved by the FDA through the special regulatory program priority review.
Approved by the FDA through the special regulatory program fast track.
Discontinued by the manufacturer.
Approved by the FDA with orphan drug designation.
Approved by the FDA through the special regulatory program breakthrough therapy.
Applications submitted to international regulatory agencies for 5 other FDA-approved drugs were withdrawn by their respective pharmaceutical sponsors prior to final review. The EMA held negative provisional opinions on copanlisib, edaravone, ivosidenib, and plazomicin at the time of application withdrawal due to a lack of sufficient evidence to prove clinical efficacy. Of note, edaravone received marketing approval from Health Canada prior to application withdrawal from EMA review. Health Canada noted concerns with proposed product labeling for lasmiditan prior to the application cancellation by the respective sponsor. Health Canada also identified deficiencies in the clinical data submitted for emapalumab, and the sponsor withdrew its marketing authorization application from Canada a few weeks after the EMA’s marketing refusal.
Betrixaban was discontinued by its manufacturer for independent business reasons in April 2020, but the other 9 drugs remain available on the US market. Emapalumab and pexidartinib, which have both been refused authorization by the EMA, were granted approval by the FDA under expedited regulatory pathways and the Orphan Drug Act (Table 2). Four of the 5 drugs withdrawn from international regulatory review were approved by the FDA under at least 1 expedited regulatory pathway, the Orphan Drug Act, or both (eTable 2 in Supplement 1).
Health Technology Assessments
Among the FDA new drug approvals from 2017 through 2020, 105 drugs have been formally assessed by at least 1 HTA agency (PBAC, CADTH, NICE) to guide drug coverage decisions by publicly funded payers in their respective countries. Negative reimbursement recommendations have been issued for 42 drugs for at least 1 of the following reasons: (1) uncertain clinical benefit, (2) small comparative clinical benefit, (3) comparative safety concerns, and (4) lack of cost-effectiveness at the proposed price. Most drugs receiving negative reimbursement recommendations have orphan drug designation in the US and were approved by the FDA under at least 1 expedited review pathway (Table 3). Among the 42 drugs that received a negative recommendation from the PBAC, CADTH, or NICE, 17 were designated as breakthrough therapy, 8 were granted accelerated approval, 18 were designated as fast track, and 30 underwent priority review by the FDA. Notably, 19 of the 42 drugs (45.2%) were indicated for use in treatment of cancer.
Table 3. Characteristics of 2017-2020 FDA-Approved Drugs Not Recommended for Public Reimbursement by Health Technology Assessment Agencies.
| Drugs with an FDA-approved indication not recommended for reimbursement by PBAC, CADTH, or NICE (n = 42) | No. (%) |
|---|---|
| FDA approval year | |
| 2017 | 13 (31.0) |
| 2018 | 16 (38.1) |
| 2019 | 8 (19.0) |
| 2020 | 5 (11.9) |
| Anatomical therapeutic chemical classification | |
| Antineoplastic agents | 19 (45.2) |
| Nervous system drugs | 9 (21.4) |
| Alimentary tract and metabolism products | 5 (11.9) |
| Other | 9 (21.4) |
| Application type | |
| New drug application | 32 (76.2) |
| Biologics license application | 10 (23.8) |
| FDA orphan drug designation | |
| Yes | 26 (61.9) |
| No | 16 (38.1) |
| FDA expedited review | |
| Priority review designation | 30 (71.4) |
| Fast track designation | 18 (42.9) |
| Breakthrough therapy designation | 17 (40.5) |
| Accelerated approval | 8 (19.0) |
| Any expedited process | 30 (71.4) |
Abbreviations: CADTH, Canadian Agency for Drugs and Technologies in Health; FDA, US Food and Drug Administration; NICE, National Institute for Health and Care Excellence (UK); PBAC, Pharmaceutical Benefits Advisory Committee (Australia).
Six of the 42 drugs received negative reimbursement recommendations from 2 HTA agencies: caplacizumab, fostamatinib, neratinib, ozanimod, prucalopride, and tafamidis meglumine. Twenty-four drugs were not recommended by the PBAC, 10 drugs were not recommended by the CADTH, and 2 drugs were not recommended by the NICE (Table 4). The most common reason for a negative reimbursement recommendation was an uncertain clinical benefit, which was described in summary reports for 39 of the 42 drugs. The HTA agencies often cited a lack of mature data, limitations in comparative evidence, and weaknesses in trial design, which created uncertainty around critical questions regarding the net benefit of these drugs. Lack of cost-effectiveness was also frequently described as a reason for a negative reimbursement recommendation in 29 of the 42 drugs due to unacceptably high incremental cost-effectiveness ratios, which indicated that manufacturer-proposed prices were overinflated in relation to demonstrated therapeutic benefit. For 26 drugs, the HTA agencies cited both uncertain clinical benefit and lack of cost-effectiveness as reasons for not recommending public payer reimbursement. Small comparative benefit was acknowledged in a minority of cases, for which the reviewing HTA agency remained unconvinced regarding clinical significance and long-term benefit. Safety concerns were described in assessments for 4 drugs where adverse events were higher than with the reference comparator and were considered substantial enough to outweigh potential clinical benefit.
Table 4. Reasons for Negative Reimbursement Recommendations by International HTA Agencies of 2017-2020 FDA-Approved Drugs.
| Active ingredient | Indication(s) not recommended for reimbursement | Reason(s) for negative reimbursement recommendation (HTA agency) |
|---|---|---|
| Acalabrutiniba,b,c,d | Chronic lymphocytic leukemia or small lymphocytic lymphoma | Uncertain clinical benefit, comparative safety concerns, not cost-effective at proposed price (PBAC) |
| Alpelisibb | Hormone receptor–positive, ERBB2-negative, PIK3CA-mutated, advanced or metastatic breast cancer | Uncertain clinical benefit, comparative safety concerns, not cost-effective at proposed price (CADTH) |
| Amifampridinea,b,d | Lambert-Eaton myasthenic syndrome | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Apalutamideb,e | Metastatic, hormone-sensitive prostate cancer | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Burosumaba,b,d,e | X-linked hypophosphatemia in pediatric patients | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Cannabidiolb,e | Lennox-Gastaut syndrome | Not cost-effective at proposed price (PBAC) |
| Caplacizumaba,b,e | Acquired thrombotic thrombocytopenic purpura | Uncertain clinical benefit, not cost-effective at proposed price (PBAC, CADTH) |
| Cemiplimabb,d | Metastatic or locally advanced cutaneous squamous cell carcinoma | Uncertain clinical benefit (PBAC) |
| Cerliponase alfaa,b,d | Neuronal ceroid lipofuscinosis type 2 disease | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Deutetrabenazinea | Chorea associated with Huntington disease | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Enasideniba,b,e | Relapsed or refractory acute myeloid leukemia with an IDH2 mutation | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Erenumab | Chronic migraine | Uncertain clinical benefit (PBAC) |
| Ertugliflozin | Type 2 diabetes as adjunct to diet and exercise | Uncertain clinical benefit (CADTH) |
| Fostamatiniba | Chronic immune thrombocytopenia | Uncertain clinical benefit (CADTH), not cost-effective at proposed price (CADTH, NICE) |
| Galcanezumab | Episodic migraine | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Gilteritiniba,b,e | Relapsed or refractory FLT3 mutation–positive acute myeloid leukemia | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Glasdegiba,b | Previously untreated acute myeloid leukemia in adults aged ≥75 y or not eligible for intensive induction chemotherapy | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Larotrectiniba,b,c,d | Advanced or metastatic low-frequency NTRK fusion tumors in adult patients | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Letermovira,b,d,e | Prophylaxis of cytomegalovirus infection or disease | Uncertain clinical benefit (PBAC) |
| Midostaurina,b,d,e | Aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Migalastata,b,c,e | Fabry disease | Uncertain clinical benefit (PBAC) |
| Mogamulizumaba,b,d | Relapsed or refractory cutaneous T-cell lymphoma | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Neratinib maleate | Extended adjuvant treatment of early-stage ERBB2-positive breast cancer | Uncertain clinical benefit (CADTH), small comparative clinical benefit (PBAC), comparative safety concerns (PBAC) |
| Nirapariba,b,d,e | Platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer | Uncertain clinical benefit, comparative safety concerns (PBAC) |
| Ocrelizumabb,d,e | Primary progressive multiple sclerosis | Uncertain clinical benefit (PBAC) |
| Ozanimod | Relapsing-remitting multiple sclerosis | Uncertain clinical benefit, not cost-effective at proposed price (CADTH, NICE) |
| Ozenoxacin | Impetigo | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Pemigatiniba,b,c,d | Previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Pitolisanta,b,e | Excessive daytime sleepiness in adults with obstructive sleep apnea | Uncertain clinical benefit, not cost-effective at proposed price (NICE) |
| Polatuzumab vedotina,b,c,d | Relapsed or refractory diffuse large B-cell lymphoma | Uncertain clinical benefit (PBAC) |
| Prucalopride | Chronic idiopathic constipation | Uncertain clinical benefit (PBAC, CADTH) |
| Risdiplama,b,e | Spinal muscular atrophy type 3b in adult patients or types 1, 2, or 3 in pediatric patients | Uncertain clinical benefit (PBAC) |
| Sacituzumab govitecanb,c,d,e | Unresectable, locally advanced or metastatic triple negative breast cancer | Not cost-effective at proposed price (PBAC) |
| Safinamide | Parkinson disease | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Selinexora,b,c,e | Relapsed and/or refractory multiple myeloma | Uncertain clinical benefit (PBAC) |
| Sodium zirconium cyclosilicate | Hyperkalemia | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Solriamfetola | Excessive daytime sleepiness in adults with obstructive sleep apnea | Uncertain clinical benefit, not cost-effective at proposed price (NICE) |
| Tafamidis megluminea,b,d,e | Transthyretin amyloid cardiomyopathy | Uncertain clinical benefit (NICE), not cost-effective at proposed price (PBAC, NICE) |
| Talazoparibb | Germline BRCA-mutated, ERBB2-negative locally advanced or metastatic breast cancer | Uncertain clinical benefit, not cost-effective at proposed price (PBAC) |
| Telotristat ethyla,b,e | Refractory carcinoid syndrome diarrhea | Uncertain clinical benefit, not cost-effective at proposed price (CADTH) |
| Tucatiniba,b,d,e | ERBB2-positive metastatic breast cancer | Not cost-effective at proposed price (PBAC) |
| Zanubrutiniba,b,c,d | Waldenström macroglobulinemia | Uncertain clinical benefit (PBAC) |
Abbreviations: CADTH, Canadian Agency for Drugs and Technologies in Health; FDA, US Food and Drug Administration; HTA, health technology assessment; NICE, National Institute for Health and Care Excellence (UK); PBAC, Pharmaceutical Benefits Advisory Committee (Australia).
Approved by the FDA with orphan drug designation.
Approved by the FDA through the special regulatory program priority review.
Approved by the FDA through the special regulatory program accelerated approval.
Approved by the FDA through the special regulatory program breakthrough therapy.
Approved by the FDA through special regulatory program fast track.
Cost
Estimated US drug costs per patient for abaloparatide, emapalumab, istradefylline, and pexidartinib, which have all been refused marketing authorization by an international regulatory agency, were $27 854, $92 868, $20 887, and $208 930, respectively (eTable 3 in Supplement 1). Betrixaban was also refused marketing authorization but is no longer on the US market.
The estimated annual median US treatment cost of the 42 FDA-approved drug indications receiving negative reimbursement recommendations from at least 1 international HTA agency was $123 432 per patient, with 25 drugs each having an estimated cost exceeding $100 000 (eTable 3 in Supplement 1). The treatment with the highest estimated cost was cerliponase alfa, an intraventricularly injected enzyme indicated for use in a rare pediatric neurological disease, at $755 898 per year. Cerliponase alfa was not recommended for reimbursement in Australia due to uncertainty regarding survival benefit and an unacceptably high proposed price, which was likely impossible to demonstrate cost-effectiveness. Ozenoxacin had the lowest US cost of $312 for a 5-day treatment course and was not recommended for reimbursement in Canada due to lack of quality comparative evidence to other topical antibiotics. It was also determined that the clinical benefits of ozenoxacin were unlikely to justify the price premium proposed. The US drug costs of the 19 antineoplastic agents receiving negative international HTA reimbursement recommendations ranged from $49 871 to $487 693 per patient. Additionally, the 8 treatments granted accelerated approval by the FDA based on surrogate end points ranged in estimated cost from $102 292 to $359 329 per patient.
Discussion
Among the 206 new FDA approvals in 2017 through 2020, we identified 5 drugs that have been refused marketing authorization internationally due to efficacy or safety concerns. An additional 42 FDA-approved drugs received negative recommendations by at least 1 HTA agency in Australia, Canada, or the UK as of May 2022 based on concerns of net clinical benefit or economic value, indicating that the drugs should not be reimbursed by public health care programs. Most of the drugs refused marketing authorization or not recommended for public reimbursement internationally were initially approved by the FDA under the Orphan Drug Act or at least 1 expedited regulatory pathway. We also found that the median US cost of drugs not recommended for approval or reimbursement in other countries was greater than $100 000 per patient per year. To our knowledge, this is the first study to evaluate the reasons behind international marketing authorization refusals and negative reimbursement recommendations from multiple international agencies for drugs recently approved by the FDA.
This analysis identified the median delay for international marketing authorization following US FDA approval to be approximately 1 year, which is consistent with trends identified in previous studies.26,27,28 Almost 80% of drugs approved by the FDA and at least 1 regulatory agency were approved first in the US (eTable 2 in Supplement 1). Previous studies have found that manufacturers often prioritize marketing authorization by the FDA and the EMA over other regulatory agencies,30,33 so the 44 drugs identified in this study that have not yet been approved for use in an international market may be pending review. However, there are 30 drugs currently on the US market that have been approved by the FDA for more than 2 years but remain unauthorized by any of the international regulatory agencies included in this study. These include 4 drugs that have been refused marketing authorization by the EMA (Table 2) and 4 other drugs that were withdrawn by the sponsor from final application review by international regulatory agencies, all of whom held provisional negative opinions at the time of withdrawal.
Following passage of the Inflation Reduction Act of 2022, Medicare will have the authority to negotiate prices of select drugs in the US beginning in 2026.34 International reference pricing and maximum fair pricing have been formally proposed as means by which Medicare can negotiate “reasonable” prices.35,36 The present analysis found that the US drug cost for treatments not marketed or recommended for reimbursement by international markets often exceeded $100 000 per patient per year. For example, tafamidis is a specialty cardiology drug with an estimated annual US treatment cost of $238 163 per patient. Tafamidis was not recommended for reimbursement in both Australia and the UK due to unacceptably high pricing and uncertain clinical evidence. The CADTH recommended reimbursement only if specific clinical and economic criteria were met, including a 92% reduction in price. A cost-effectiveness analysis of tafamidis from the US health care sector perspective similarly recommended a 92.6% price reduction to meet standard cost-effectiveness thresholds.37
Instead of reference pricing, some believe the US should move toward a value-based reimbursement system using similar approaches implemented internationally with HTA agencies.10,11,38 With annual US prescription drug spending expected to increase,39 reimbursement criteria such as comparative clinical benefit and cost-effectiveness may be considered to address issues of health care affordability and access. While cost-effectiveness analyses may be useful in drug coverage decisions, variability in interpretation can exist among different HTA agencies for the same drug indication, as found in this study and in previous evaluations.40,41,42 Factors such as differences in clinical practice, HTA methods, and perspective on treatment value can contribute to differing recommendations for formulary policies across countries. Additionally, health technology assessments must continually be updated as new evidence becomes available by the evaluating agency and following negotiations with the drug sponsor. For example, the PBAC rejected brolucizumab 3 times from listing on the national Australian prescription formulary as first-line treatment of subfoveal choroidal neovascularization in November 2019, March 2020, and July 2020 over comparative safety concerns. Brolucizumab was resubmitted to the PBAC by the manufacturer in March 2021 at a 5% price reduction and was subsequently recommended for coverage as a second-line option.
Strengths and Limitations
Due to the differences in criteria used for regulatory approval and public payer reimbursement recommendations, we evaluated decisions made by regulatory and HTA agencies for each country (eTable 1 in Supplement 1). While marketing authorization is conferred based on assessment of drug safety and efficacy by a regulatory agency, recommendations for reimbursement are typically based on evaluations of comparative effectiveness and value. Another strength of the study included the estimation of US treatment costs based on current drug labeling and list prices.
This study had several limitations, including collection of date of marketing authorization vs date of marketing authorization application submission. Therefore, drugs not yet approved by international markets may still be pending decision. Additionally, HTA agency recommendations were assessed instead of national formulary status. Because nonformulary drugs can be obtained internationally through various mechanisms (eg, Exceptional Access Program in Ontario, Cancer Drugs Fund of England), HTA reports were used to gain a comprehensive understanding of the analyses and reasoning behind reimbursement recommendations. Furthermore, it is also possible for a single drug to receive both positive and negative reimbursement recommendations from an HTA agency due to indication-specific review processes. We attempted to account for these differences by estimating treatment costs based on the specific indication identified in negative reimbursement recommendations. However, the wholesale acquisition cost may not be fully representative of actual costs to US health care payers.
International market presence, defined through both marketing authorization and public payer coverage, can serve as an important indicator of a drug’s clinical value. While we acknowledge the many complexities involved in assessing treatment value,43 including the effect of cultural, societal, and governmental perspectives, drugs not approved or recommended for reimbursement internationally may be perceived as having lower clinical value or excessive cost. This study identified 36 novel drugs approved by the FDA under an expedited regulatory pathway or the Orphan Drug Act that were not recommended in other countries due to concerns with efficacy, safety, or cost-effectiveness. It has been argued that drugs for which there is unclear clinical benefit, such as those granted expedited marketing authorization in the US based on surrogate end points, should be discounted in cost accordingly with the level of uncertainty.44 Future analyses should evaluate US utilization, pricing disparities, and clinical outcomes of FDA-approved drugs with limited international market presence. Further research is needed to elucidate the differences in perceived value of specific drugs among various countries, including the US.
Conclusions
This cross-sectional study demonstrated that more than one-fifth of the new drugs approved by the FDA in 2017 through 2020 were either refused marketing authorization or not recommended for reimbursement in Australia, Canada, or the UK as of May 2022 due to unfavorable benefit-to-risk profiles, uncertain clinical benefit, or unacceptably high price. Ongoing review of international regulatory authorization refusals and formulary recommendations can support safe and cost-effective clinical decision-making by US health systems and payers.
eTable 1. Sources of International Drug Regulatory Decisions and Public Reimbursement Recommendations
eTable 2. Dates of US and International Regulatory Authorization of 2017-2020 New FDA-Approved Drugs
eTable 3. Calculation Inputs for Costs of Drugs Not Recommended for Approval or Reimbursement by International Agencies
eReference
Data Sharing Statement
References
- 1.Drugs@FDA: FDA-approved drugs. US Food & Drug Administration . Accessed January 3, 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
- 2.Australian prescription medicine decision summaries. Australian Government Department of Health and Aged Care . Accessed January 3, 2023. https://www.tga.gov.au/australian-prescription-medicine-decision-summaries
- 3.Drug product database: access the database. Health Canada . Accessed January 3, 2023. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html
- 4.Products. Medicines & Healthcare products Regulatory Agency . Accessed January 3, 2023. https://products.mhra.gov.uk/
- 5.Medicines. European Medicines Agency . Accessed January 3, 2023. https://www.ema.europa.eu/en/medicines
- 6.Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (PBAC). Australian Government Department of Health and Aged Care . Updated September 2016. Accessed January 3, 2023. https://pbac.pbs.gov.au/
- 7.Reimbursement review reports. Canadian Agency for Drugs and Technologies in Health . Updated January 3, 2023. Accessed January 3, 2023. https://www.cadth.ca/reimbursement-review-reports
- 8.NICE guidance. National Institute for Health and Care Excellence . Accessed January 3, 2023. https://www.nice.org.uk/guidance
- 9.Janoudi G, Amegatse W, McIntosh B, Sehgal C, Richter T. Health technology assessment of drugs for rare diseases: insights, trends, and reasons for negative recommendations from the CADTH common drug review. Orphanet J Rare Dis. 2016;11(1):164. doi: 10.1186/s13023-016-0539-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lakdawalla D, Neumann PJ, Wilensky GR, et al. Health technology assessment in the US—a vision for the future. February 9, 2021. Accessed January 3, 2023. https://healthpolicy.usc.edu/research/health-technology-assessment-in-the-u-s-a-vision-for-the-future/
- 11.Pearson S, Nichols L, Chandra A. Policy strategies for aligning price and value for brand-name pharmaceuticals. Health Aff. Published online March 15, 2018. [Google Scholar]
- 12.Kesselheim AS, Avorn J, Sarpatwari A. The high cost of prescription drugs in the United States: origins and prospects for reform. JAMA. 2016;316(8):858-871. doi: 10.1001/jama.2016.11237 [DOI] [PubMed] [Google Scholar]
- 13.NHE fact sheet. Centers for Medicare & Medicaid Services . December 14, 2022. Accessed January 3, 2023. https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData/NHE-Fact-Sheet
- 14.Chambers JD, Cangelosi MJ, Neumann PJ. Medicare’s use of cost-effectiveness analysis for prevention (but not for treatment). Health Policy. 2015;119(2):156-163. doi: 10.1016/j.healthpol.2014.11.012 [DOI] [PubMed] [Google Scholar]
- 15.Social Security Act: Subpart 2—Prescription Drug Plans; PDP Sponsors; Financing. Social Security Administration . Accessed January 3, 2023. https://www.ssa.gov/OP_Home/ssact/title18/1860D-11.htm
- 16.Shaw DL, Dhruva SS, Ross JS. Coverage of novel therapeutic agents by Medicare prescription drug plans following FDA approval. J Manag Care Spec Pharm. 2018;24(12):1230-1238. doi: 10.18553/jmcp.2018.24.12.1230 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sachs RE, Donohue JM, Dusetzina SB. Confronting state Medicaid drug spending pressures. JAMA. 2020;324(18):1831-1832. doi: 10.1001/jama.2020.19325 [DOI] [PubMed] [Google Scholar]
- 18.Vokinger KN, Hwang TJ, Daniore P, et al. Analysis of launch and postapproval cancer drug pricing, clinical benefit, and policy implications in the US and Europe. JAMA Oncol. 2021;7(9):e212026. doi: 10.1001/jamaoncol.2021.2026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Vokinger KN, Hwang TJ, Grischott T, et al. Prices and clinical benefit of cancer drugs in the USA and Europe: a cost-benefit analysis. Lancet Oncol. 2020;21(5):664-670. doi: 10.1016/S1470-2045(20)30139-X [DOI] [PubMed] [Google Scholar]
- 20.Saluja R, Arciero VS, Cheng S, et al. Examining trends in cost and clinical benefit of novel anticancer drugs over time. J Oncol Pract. 2018;14(5):e280-e294. doi: 10.1200/JOP.17.00058 [DOI] [PubMed] [Google Scholar]
- 21.Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176. doi: 10.1001/jama.2019.20288 [DOI] [PubMed] [Google Scholar]
- 22.Kesselheim AS, Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ. 2015;351:h4633. doi: 10.1136/bmj.h4633 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Mitra-Majumdar M, Gunter SJ, Kesselheim AS, et al. Analysis of supportive evidence for US Food and Drug Administration approvals of novel drugs in 2020. JAMA Netw Open. 2022;5(5):e2212454. doi: 10.1001/jamanetworkopen.2022.12454 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rome BN, Egilman AC, Kesselheim AS. Trends in prescription drug launch prices, 2008-2021. JAMA. 2022;327(21):2145-2147. doi: 10.1001/jama.2022.5542 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kashoki M, Hanaizi Z, Yordanova S, et al. A comparison of EMA and FDA decisions for new drug marketing applications 2014-2016: concordance, discordance, and why. Clin Pharmacol Ther. 2020;107(1):195-202. doi: 10.1002/cpt.1565 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Lythgoe M, Krell J, Warner JL, Desai A, Khaki AR. Time intervals between U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) new cancer therapy approvals. J Clin Oncol. 2021;39(15):1575. doi: 10.1200/JCO.2021.39.15_suppl.1575 33600210 [DOI] [Google Scholar]
- 27.Barua B, Westcott W, Vo VN. Timely access to new pharmaceuticals in Canada, the United States, and the European Union. Fraser Institute . May 13, 2021. Accessed January 3, 2023. https://www.fraserinstitute.org/studies/timely-access-to-new-pharmaceuticals-in-canada-the-united-states-and-the-european-union
- 28.Rawson NSB. Canadian, European and United States new drug approval times now relatively similar. Regul Toxicol Pharmacol. 2018;96:121-126. doi: 10.1016/j.yrtph.2018.05.002 [DOI] [PubMed] [Google Scholar]
- 29.Hwang TJ, Ross JS, Vokinger KN, Kesselheim AS. Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study. BMJ. 2020;371:m3434. doi: 10.1136/bmj.m3434 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hwang TJ, Kesselheim AS, Tibau A, Lee CC, Vokinger KN. Clinical benefit and expedited approval of cancer drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia. JCO Oncol Pract. 2022;18(9):e1522-e1532. doi: 10.1200/OP.21.00909 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Egilman AC, Wallach JD, Dhruva SS, Gonsalves GS, Ross JS. Medicare spending on drugs and biologics not recommended for coverage by international health technology assessment agencies. J Gen Intern Med. 2019;34(11):2319-2321. doi: 10.1007/s11606-019-05149-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.DeMartino PC, Miljkovic MD, Prasad V. Potential cost implications for all US Food and Drug Administration oncology drug approvals in 2018. JAMA Intern Med. 2021;181(2):162-167. doi: 10.1001/jamainternmed.2020.5921 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Zeukeng MJ, Seoane-Vazquez E, Bonnabry P. A comparison of new drugs approved by the FDA, the EMA, and Swissmedic: an assessment of the international harmonization of drugs. Eur J Clin Pharmacol. 2018;74(6):811-818. doi: 10.1007/s00228-018-2431-7 [DOI] [PubMed] [Google Scholar]
- 34.Inflation Reduction Act of 2022, HR 5376, 117th Cong (2021-2022). Pub L No. 117-69. Accessed January 3, 2023. https://www.congress.gov/bill/117th-congress/house-bill/5376
- 35.Elijah E. Cummings Lower Drug Costs Now Act, HR 3, 117th Cong (2021-2022). Accessed January 3, 2023. https://www.congress.gov/bill/117th-congress/house-bill/3
- 36.Rand LZ, Kesselheim AS. International reference pricing for prescription drugs in the United States: administrative limitations and collateral effects. Value Health. 2021;24(4):473-476. doi: 10.1016/j.jval.2020.11.009 [DOI] [PubMed] [Google Scholar]
- 37.Kazi DS, Bellows BK, Baron SJ, et al. Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy. Circulation. 2020;141(15):1214-1224. doi: 10.1161/CIRCULATIONAHA.119.045093 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Neumann PJ, Ollendorf DA, Cohen JT. Value-based drug pricing in the Biden era: opportunities and prospects. Health Serv Res. 2021;56(6):1093-1099. doi: 10.1111/1475-6773.13686 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Keehan SP, Cuckler GA, Poisal JA, et al. National health expenditure projections, 2019-28: expected rebound in prices drives rising spending growth. Health Aff (Millwood). 2020;39(4):704-714. doi: 10.1377/hlthaff.2020.00094 [DOI] [PubMed] [Google Scholar]
- 40.Salas-Vega S, Bertling A, Mossialos E. A comparative study of drug listing recommendations and the decision-making process in Australia, the Netherlands, Sweden, and the UK. Health Policy. 2016;120(10):1104-1114. doi: 10.1016/j.healthpol.2016.08.006 [DOI] [PubMed] [Google Scholar]
- 41.Fischer KE, Heisser T, Stargardt T. Health benefit assessment of pharmaceuticals: an international comparison of decisions from Germany, England, Scotland and Australia. Health Policy. 2016;120(10):1115-1122. doi: 10.1016/j.healthpol.2016.08.001 [DOI] [PubMed] [Google Scholar]
- 42.Spinner DS, Birt J, Walter JW, et al. Do different clinical evidence bases lead to discordant health-technology assessment decisions? an in-depth case series across three jurisdictions. Clinicoecon Outcomes Res. 2013;5:69-85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Neumann PJ, Garrison LP, Willke RJ. The history and future of the “ISPOR value flower”: addressing limitations of conventional cost-effectiveness analysis. Value Health. 2022;25(4):558-565. doi: 10.1016/j.jval.2022.01.010 [DOI] [PubMed] [Google Scholar]
- 44.Kaltenboeck A, Mehlman A, Pearson SD. Strengthening the accelerated approval pathway: an analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Institute for Clinical and Economic Review . April 26, 2021. Accessed January 3, 2023. https://icer.org/wp-content/uploads/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-ICER-White-Paper-_-April-2021.pdf
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Sources of International Drug Regulatory Decisions and Public Reimbursement Recommendations
eTable 2. Dates of US and International Regulatory Authorization of 2017-2020 New FDA-Approved Drugs
eTable 3. Calculation Inputs for Costs of Drugs Not Recommended for Approval or Reimbursement by International Agencies
eReference
Data Sharing Statement