(UroToday.com) The 2024 GU ASCO annual meeting featured a session on the shortage of drugs for urothelial carcinoma and a presentation by Dr. Chana Weinstock discussing drug shortages, why there are recurrent issues, and what regulations can do to prevent them. Dr. Weinstock started by highlighting that drug shortages are often visible to the public, such as the press on Twitter and the New York Times. So, with regard to drug shortages, how did we get here? What is the FDA doing about this? What are some long-term solutions?
The problem with drug shortages is centered around economic factors. For example, for older drugs that are off-patent, there is downward pressure on prices and profit margins are low. Generic drugs make up >90% of US prescriptions but represent only 18% of the US drug expenditures. These issues are especially applicable to sterile injectables and biologics, given that only 1 of 17 oncology drugs on the recent shortage list was an oral medication (capecitabine).
The drug supply chain includes the (i) supplier, (ii) manufacturer, (iii) wholesaler, (iv) pharmacy/hospital, and (v) and patient/physician. For each of these stakeholders, there are potential issues that may contribute to drug shortages:
- Supplier: natural disasters and other factors may affect the supply of active pharmaceutical ingredients
- Manufacturer: costly to maintain plants, repair machinery
- Wholesaler: limited number of wholesalers, with manufacturers competing to fill bids at the lowest cost
- Pharmacy/Hospital: larger systems may stockpile drugs in advance of impending shortages
- Patient/Physicians: increase in demand due to (for example) demographics that can strain the drug supply
Dr. Weinstock then discussed the BCG shortage. BCG Is the original immunotherapy, with the findings in bladder cancer first reported in 1976, and continuing to endure as a cornerstone of medical treatment for NMIBC. TICE BCG, manufactured by Merck, is currently the only available strain in the US, secondary to several issues:
- Sanofi Pasteur discontinued production of Connaught BCG in 2017, with the FDA previously issuing a warning letter in 2012 citing 58 non-conformances related to mold
- From 2020 to 2022, Merck only slightly increased TICE BCG production
- An aging population has increased the demand
Merck does have a new plant set to open in 2025/2026, according to their website.
Another problem is that the FDA considers all BCG substrains genetically, molecularly, biochemically, and immunologically different. Since they are not the same as TICE BCG, there is no marketing approval in the US. As such, all information for strains proposed for use in the US should be submitted and reviewed by the FDA under an IND.
Next, Dr. Weinstock addressed the platinum chemotherapy shortage. Cisplatin was first approved by the FDA in 1978, followed by carboplatin in 1989, both of which are still essential in GU oncology, specifically for the treatment of bladder and testicular cancers. One manufacturer (with a large market share), placed all inventory on hold due to quality related issues in November 2022, however, they are back online as of November 2023. The result of the shortage is that some clinics are prioritizing cisplatin only for those patients with curable disease, with some larger facilities having easier access/purchasing power. The ripple effect is that there is decreased cisplatin availability, leading to carboplatin demand, and subsequent manufacturing challenges.
One of the solutions proposed by the FDA is the FDA Drug Shortage Staff, which is a program designated by the FDA to oversee and facilitate the resolution of all drug shortage situations. This group serves to support the FDA’s mission of ensuring that safe and effective drugs are available for all patients, maintaining availability while minimizing risk to patients. Dr. Weinstock then addressed what the FDA can and cannot do during drug shortage situations. The FDA can require notification by manufacturers by law under the Food and Drug Administration Safety and Innovation Act, to address disruptions, delays, and discontinuations. The FDA cannot require (i) a company to make a drug or make more of the drug, (ii) a company to report anticipated increase in demand for a drug, (iii) how much of a drug is distributed, or which purchasers are given priority, and (iv) that a given drug have a diversified supply chain.
One approach to prevention and mitigation of drug shortage is early notification, which is key according to Dr. Weinstock. The FDA can assist and expedite inspections and reviews, and encourage smart distribution. Other tools include (i) identifying new manufacturing sites, new raw material sources, and extending expiration dates on drugs when safe to do so, and (ii) temporarily exercising regulatory flexibility regarding importation from other countries. Indeed, through ongoing dialogue/work with industry, the number of prevented shortages has generally grown since 2014:
In contrast, new drug shortages have remained generally flat since 2012:
Specific to FDA actions related to the BCG and platinum chemotherapy shortages, Dr. Weinstock highlighted the FDA Guidance on NMIBC from 2018. This stated that there should be a uniform definition of “prior BCG”, and that 5 of 6 doses of initial induction + either 2 or 3 doses of maintenance therapy, or 2 of 6 doses of a second induction is deemed “adequate BCG.” Additionally, the FDA has stated that patients with less than adequate prior BCG may be enrolled in the same cohort as those with adequate prior BCG. For these trials, randomization is recommended, given the heterogeneity of this patient population, stratifying patients by amount of prior BCG, and using sensitivity analyses to control for differences in prior exposure to BCG.
In November 2021, the FDA held an open public workshop on NMIBC. Among the pre-workshop survey responses (n = 255), 92% of participants identified developing alternatives to BCG as a priority, and 24% said that the BCG shortage affected trial enrollment. The workshop also discussed alternative control arms in BCG naïve high risk NMIBC, such as the intravesical chemotherapy doublet gemcitabine + docetaxel (ie. ECOG BRIDGE trial), and the Tokyo BCG strain (fully accrued S1602 trial, awaiting results).
For the cisplatin/carboplatin shortage, the FDA expedited the review of a new carboplatin generic drug, as well as encouraged/convinced companies that had discontinued production to voluntarily bring them back on the market (resulting in 1 additional company for cisplatin, and 2 additional companies for carboplatin). Additionally, they have implemented temporary importation of products. Moreover, potentially affecting the demand in GU oncology is the recent FDA approval of enfortumab vedotin + pembrolizumab in metastatic urothelial carcinoma, given that the combination does not use platinum, with a >1 year median overall survival improvement versus the platinum doublet.
With regard to future directions, Dr. Weinstock highlighted what is needed for enduring solutions to the drug shortages:
- Companies required to have risk management plans in place under the FDASIA, given that it is important to consider all scenarios and have backup plans
- Redundancy in manufacturing and suppliers, encouraging industry to have components and supplies at the ready for critical drugs
- Have more capacity, additional manufacturers making critical drugs at risk for shortage
- “We have got to fix the core economics if we’re going to get this situation fixed” – Dr. Robert Califf, FDA Commissioner, May 11, 2023
Additional solutions include (i) industry-wide economic incentives to foster technological upgrades to shore up manufacturing of critical drugs, establish price stability, long-term contracts; (ii) proposal to maintain a buffer reserve of essential oncology drugs (ie. front line and curative drugs), ie. a 6-month supply rotated periodically into the commercial market to avoid drug expiration, waste; (iii) continue to encourage external dialogue and advocacy efforts including Friends of Cancer Research, ASCO, BCAN, in addition to many others.
Dr. Weinstock concluded her presentation by discussing drug shortages, why there are recurrent issues, and what regulatory can do to prevent them with the following take-home points:
- Platinum and BCG shortages are multifactorial but relate to downward pricing pressures on older drugs and related manufacturing challenges
- FDA Drug Shortage Staff works with companies to mitigate shortage solutions, with early shortage notification being required through FDASIA legislation
- The FDA has worked with the GU oncology community regarding trial design issues in the era of the BCG shortage
- Continued advocacy and encouragement is important
Presented by: Chana Weinstock, MD, Team Leader GU Oncology, U.S. Food and Drug Administration, Silver Spring, MD
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
Related content: Drug Shortages: Why Are They a Recurrent Issue and What Can Regulatory Do to Prevent Them? - Chana Weinstock