A common reason drugs are removed from the market after receiving regulatory approval is due to safety concerns that were not revealed during the clinical trials. However, there are several other reasons why approved pharmaceuticals are removed from the market.
Less convenient for patients than competitors:
Example: Exubera
Background: Exubera was rapidly acting inhaled insulin administered prior to eating. It was designed to provide a needle-free alternative for patients Type 1 and 2 diabetes. It had the advantage of being able to be stored at room temperature and not having the variable absorption times seen with subcutaneous injections among patients with different amounts of subcutaneous fat. The product was designed by Nektar Therapeutics, with Pfizer providing manufacturing and marketing. It received FDA approval in 2006 as well as by the EMA.
Contributing factors:
- A physician and patient education campaign was launched to assist with adoption, but this did not alleviate several issues.
- The inhaler was considered too cumbersome to use, which contributed to the poor sales when it was removed from the market in 2007:
- Lack of dose control.
- Different units from the subcutaneous (sc) version caused confusion.
- Still needed to give basal insulin via sc injections, so it was not a complete replacement.
- Lower bioavailability of inhaled vs sc (requires more insulin to obtain the same effect).
- The metabolic control was not better than sc version and came at a higher cost.
- Required lung function tests, which added the burden of additional doctor appointments.
- Hidden costs of product support: training sales reps, answering questions, and reporting requirements.
- The choice to withdraw this also led other developers of inhaled insulin to halt their process (Eli Lilly & Novo Nordisk).
- There were considerable improvements in subcutaneous insulin delivery mechanisms by that time, such that the need to switch to a more convenient option was not as strong as it was in the past.
- Clinical trial population may not reflect interests of general patients on account of the participation criteria.
Sources:
- https://ir.nektar.com/news-releases/news-release-details/nektar-reports-pfizer-introduce-exubera-us-comprehensive
- https://pmc.ncbi.nlm.nih.gov/articles/PMC2769732/
- https://www.rxlist.com/exubera-drug.htm#side_effects
- https://www.ema.europa.eu/en/medicines/human/EPAR/exubera
- https://patents.google.com/patent/JP2006077032A/en?q=(exubera)&assignee=Nektar+Therapeutics
Rare disease patient population limited sales:
Example: Glybera (alipogene tiparvovec)
Background: Glybera was a one-time gene therapy for familial lipoprotein lipase deficiency, a rare disease, paired with severe pancreatitis episodes despite dietary restrictions. It involved multiple intramuscular injections of an AAV vector containing a functional LPL gene. It was shown to increase breakdown of fats and it received marketing approval in 2012 by EMA that was authorized for 5 years. In 2017, uniQuire biopharma elected to not renew the authorization due to lack of demand.
Contributing factors:
- Cost burden:
- Very few patients received it and there was insufficient demand to keep up with the infrastructure and manufacturing costs as well as patient safety surveillance.
- Average of $50,000 USD per vial and the average patient takes approximately 19 vials (dependent on the patient’s weight).
- Approximately $1.4 million USD per patient
- There was the question of how payors/insurance companies would pay for it: all up-front, annuity-style, and cost effectiveness comparison with currently available treatments:
- High price but it is only relevant for a small patient population, so the overall effect on their budget would not be that high for payors.
- Part of the high cost was directed towards the development costs in addition to the current manufacturing costs.
- Ultimately, it was a business decision to use the funds for their other programs.
Sources:
- https://www.ema.europa.eu/en/medicines/human/EPAR/glybera
- https://www.sec.gov/Archives/edgar/data/1590560/000110465917024899/a17-11623_1ex99d1.htm
- https://www.nature.com/articles/nbt0315-217
- https://www.reuters.com/article/us-health-genetherapy-price/exclusive-first-gene-therapy-drug-sets-million-euro-price-record-idUSKCN0JA1TP20141126/
Combination of inadequate demand, inconvenience for patients & physicians, and lack of superiority over competitors:
Example: Bexxar (tositumomab)
Background: Bexxar was a radioimmunotherapy drug (combination of a murine monoclonal antibody targeting the CD20 antigen and the radioactive isotope iodine-131) developed by GlaxoSmithKline. It was approved in 2003 by the FDA for patients with non-Hodgkin’s lymphoma that had failed rituximab therapy.
Contributing factors:
- Efficacy: In 2011, it was demonstrated that this therapy did not have superiority over the standard of care (CHOP chemotherapy).
- Logistics: This involved radioactive iodine administration which had to be done at nuclear medicine facilities or academic medical centers. This complicated the referrals because oncologists could not administer directly and lacked the financial incentives to navigate the process.
- Cost: Due to the lack of superiority and complex logistics, usage of the product declined significantly and the developer elected to discontinue manufacturing in 2014, leading to the official withdrawal by the FDA.
- Ultimate reason for market withdrawal in 2014: too few patients were receiving it to keep up with manufacturing and safety monitoring expenses.
Sources:
- https://openmedscience.com/the-rise-and-fall-of-iodine-131-tositumomab-bexxars-story/
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125011s0126lbl.pdf
- https://www.federalregister.gov/documents/2013/10/23/2013-24840/glaxosmithkline-llc-withdrawal-of-approval-of-the-indication-for-treatment-of-patients-with-relapsed
- https://www.medscape.com/viewarticle/834879?form=fpf
- https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1070497/full
Inadequate clinical benefit after accelerated approval:
Example: Lartruvo (olaratumab)
Background: Olaratumab was an IgG1 monoclonal antibody that targeted the platelet derived growth factor receptor alpha, with the intended effect of inhibiting downstream pathways supporting cell proliferation and tumor micro-environment. Eli Lilly developed it as a combination treatment with doxorubicin for soft tissue sarcoma.
Contributing factors:
- This is an exception to the typical progression through Phase III trial completion, because it received accelerated approval by the FDA in 2016 for patients with advanced soft-tissue sarcoma who were not eligible for surgery or radiation. This decision was predicated on the results of the Phase II study that showed an increase in the median survival time, compared to doxorubicin alone.
- Lack of clinical benefit: The Phase III trial did not confirm the Phase II results of increased survival times, so Eli Lilly decided to discontinue it in 2019.
Sources:
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8293854/
- https://reference.medscape.com/drug/lartruvo-olaratumab-1000101
- https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-lartruvotm-olaratumab-combination
- https://www.federalregister.gov/documents/2020/07/17/2020-15516/eli-lilly-and-co-announcement-of-the-revocation-of-the-biologics-license-for-lartruvo
Competitor products improved after approval:
Example: Exviera/Viekira Pak (dasabuvir)
Background: Exviera was an antiviral medication used for chronic hepatitis C infections that was administered in combination with Viekirax and occasionally ribavirin. It inhibited the enzyme responsible for RNA replication of the virus. It was approved by the FDA in December 2014 and by the EMA in January 2015
Contributing factors:
- Competitor products that have been approved after Exviera (direct-acting antiviral combinations) were more convenient and effective for patients, leading to the decision by AbbVie to discontinue it for commercial reasons.
- The competing products made Exviera obsolete within a few years of approval.
- The EMA removed marketing authorization in September 2024 following AbbVie’s decision to pull the product.
Sources:
- https://www.ema.europa.eu/en/medicines/human/EPAR/exviera
- https://www.ema.europa.eu/en/documents/product-information/exviera-epar-product-information_en.pdf
- https://news.abbvie.com/2016-07-25-AbbVie-Receives-U-S-FDA-Approval-of-Once-Daily-VIEKIRA-XR-dasabuvir-ombitasvir-paritaprevir-and-ritonavir-for-the-Treatment-of-Genotype-1-Chronic-Hepatitis-C
- https://www.drugs.com/pro/viekira-pak.html
- https://www.federalregister.gov/documents/2023/09/05/2023-19013/merck-sharp-and-dohme-llc-et-al-withdrawal-of-approval-of-35-new-drug-applications
Limited marketing claims:
Example: Zemdri (plazomicin)
Background: Plazomicin was a next-generation antibiotic for multi-drug resistant infections, specifically for complex urinary tract infections that had few other treatment options. It was developed by Achaegon and approved by the FDA in 2018 (only for cUTIs, it did not approve it for bloodstream infections).
Contributing factors:
- There was a lack of sufficient evidence to support the bloodstream infection indication by the FDA, which reduced the broader commercial uptake of the product.
- Achaogen was unable to commercialize it well enough to keep up with costs, leading to it filing Chapter 11 bankruptcy in 2019.
- Part of this commercialization failure is due to broader budget and reimbursement models not favoring newer antibiotics in addition to some prescriber preferences for better established antibiotics.
- Cipla USA acquired Zemdri and resumed marketing the product, although the commercialization difficulties remain.
Sources:
- https://revive.gardp.org/why-are-new-antibacterials-failing-as-commercial-products/
- https://www.nature.com/articles/s41599-024-03452-0
- https://www.sec.gov/Archives/edgar/data/1301501/000156459019023628/akao-8k_20190620.htm
- https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210303Orig1s000SumR.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/210303Orig1s005ltr.pdf
Disclaimer: This article is intended for educational and informational purposes only and does not constitute medical, regulatory, legal, or investment advice. Opinions expressed are my own.