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Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?
Open accessAbstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator–activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.
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“In 2024, the European Medicines Agency recommended revoking conditional approval for obeticholic acid based on the inability of the partially enrolled COBALT trial to show superior outcomes using obeticholic acid.24,96”
From Primary biliary cholangitis. (2024) · cites this paper as [96]
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“Concurrently, the traditional regulatory approvals based on placebo-controlled RCTs, where the elevation of liver enzymes or severe pruritus is defined as inclusion criteria, are becoming increasingly impractical, which is due to the ethical concerns of providing placebos to patients when conditionally approved drugs are available.96”
From Primary biliary cholangitis. (2024) · cites this paper as [96]
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“The issue of surrogate markers, their use in PBC and their acceptability to regulators has been a topic of significant recent controversy.35”
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Cites
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Self-citationA Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis
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“Mean baseline ALP Mean baseline ALP:ULN ratio OCA phase 2 [24] 287 ± 164 2.2 OCA phase 3 ( “ POISE ” ) [16] 326 ± 196 2.5 OCA phase 3 confirmatory ( “ COBALT ” ) [25] 490 ± 285 3.8 Bezafibrate phase 3 [17] 243 ± 114 1.8 Elafibranor phase 3 ( “ ELATIVE ” ) [21] 322 ± 151 3.1 Seladelpar phase 3 ( “…”
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Self-citationBiochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis
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“[9,10] The challenges that we now face in relation to deriving the key evidence regarding the efficacy of second-line therapies in PBC were, in fact, presaged by exactly the same challenges faced with UDCA.”
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“[1,5,37] The reasons for variability in the use of optimal therapy regimes in PBC have not been formally studied.”
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Self-citation
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Cited by
Sorted by citations
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Self-citationAdvancing care in primary biliary cholangitis: emerging insights and novel therapies
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Metadata
- Authors
- Jones, D. E. J., Beuers, U., Bonder, A., Carbone, M., Culver, E., Dyson, J., Gish, R. G., Hansen, B. E., Hirschfield, G., Jones, R., Kowdley, K., Kremer, A. E., Lindor, K., Mayo, M., Mells, G., Neuberger, J., Prince, M., Swain, M., Tanaka, A., Thorburn, D., Trauner, M., Trivedi, P., Weltman, M., Yeoman, A., & Levy, C.
- Affiliations
- Newcastle University (GB)
- Amsterdam UMC Location University of Amsterdam (NL)
- Beth Israel Deaconess Medical Center (US)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- John Radcliffe Hospital (GB)
- Freeman Hospital (GB)
- Stanford Medicine (US)
- University Health Network (CA)
- Toronto General Hospital (CA)
- St James's University Hospital (GB)
- Liver Institute Northwest (US)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Manchester Royal Infirmary (GB)
- The Royal Free Hospital (GB)
- Medical University of Vienna (AT)
- Aneurin Bevan University Health Board (GB)
- Corresponding author
- Jones, David E.J.
- Jones, Rebecca
- ORCID
- Jones, David E.J.
- Beuers, Ulrich
- Bonder, Alan
- Carbone, Marco
- Culver, Emma
- Dyson, Jessica
- Gish, Robert G.
- Hansen, Bettina E.
- Hirschfield, Gideon
- Jones, Rebecca
- Kowdley, Kris
- Kremer, Andreas E.
- Lindor, Keith
- Mayo, Marlyn
- Mells, George
- Neuberger, James
- Swain, Mark
- Tanaka, Atsushi
- Thorburn, Douglas
- Trauner, Michael
- Trivedi, Palak
- Weltman, Martin
- Yeoman, Andrew
- Levy, Cynthia
- Venue
- Hepatology
- Published
- 2024-03-22
- Volume
- 80
- Issue
- 5
- Pages
- 1291-1300
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC11486958
- OpenAlex
- W4392984296
- Cited by
- 38
- References
- 16
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 10
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by-nc-nd)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- American Association for the Study of Liver Diseases
- Gilead Sciences
- Alnylam Pharmaceuticals
- CSL Behring
- Regeneron Pharmaceuticals
- LifeArc
- Ultragenyx Pharmaceutical
- EA Pharma Co., Ltd.
- Audentes Therapeutics
- Kowa Company
- Moderna
- Amsterdam University Medical Centers
- National Institute for Health and Care Research
- ZonMw
- Eisai
- Novo Nordisk
- European Association for the Study of the Liver
- Ipsen
- Genentech
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
- Keywords
- primary biliary cirrhosis, drug approval, conditional marketing authorisation, obeticholic acid, ursodeoxycholic acid, peroxisome proliferator-activated receptor agonists, real-world data, rare diseases
- MeSH terms
- Chenodeoxycholic Acid, Cholagogues and Choleretics, Humans, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Drug Approval
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