Why Are Generic Cancer Drugs Out of Reach for Many Patients?

An estimated nine out of 10 prescriptions filled in the United States are for generic drugs,¹ yet access to generic drugs is still out of reach for many patients with cancer, including those with hematological malignancies.

Despite the unprecedented approval of novel therapeutics to treat cancer, “there are still a lot of generic drugs that are widely used in oncology,” said S. Vincent Rajkumar, MD, the Edward W. and Betty Knight Scripps Professor of Medicine at the Mayo Clinic in Rochester, Minnesota. “For many cancers, [generics] are the backbone of treatment.”

Whether due to availability or price, many patients with cancer may not be getting access to the off-brand drugs they need, either because certain long-standing generic drugs are in short supply or because patent strategies, product hopping, or litigation delay prevent new entries from coming to market.

“These two things exactly reflect the complexity of our drug supply at this moment,” said Mariana Socal, MD, PhD, an Assistant Scientist in the Department of Health Policy and Management at Johns Hopkins Bloomberg School of Public Health.

“The complexity is that we have very expensive drugs that are expensive because of strategies that have successfully been used to avoid generic competition,” Dr. Socal said. “And, simultaneously, we have very cheap drugs that have been successful in promoting generic competitors but are often not attractive to manufacturers who often leave the market or don’t invest in good manufacturing practices.”

According to Dr. Socal, the way this complexity is playing out in the oncology specialty is emblematic of the issue, and patients and the health care system are paying the cost.

Why Short Supply

In September, the White House issued a statement in response to a current shortage of 15 cancer drugs due to manufacturing and supply chain issues.² The statement specifically mentioned a nearly halving of the supply of three essential cancer drugs: cisplatin, carboplatin, and methotrexate (both methotrexate and cisplatin are used in some formulation to treat certain blood cancers).

The White House statement mentioned several steps being taken by the US Food and Drug Administration (FDA) to improve supply. Among them, the FDA has worked with manufacturers to increase capacity and bring back companies that stopped producing generics. In addition, the FDA has allowed for the importation of some generic cisplatin from a facility outside of the United States.

In an interview with The Cancer Letter earlier this year, Richard Pazdur, MD, Director of the FDA Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases, outlined some of the underlying causes of these drug shortages.³ The most recent shortage of cisplatin was a result of quality issues at a single company’s manufacturing facility in India, which caused a “ripple effect” leading to increased demand for the cisplatin alternative carboplatin, resulting in manufacturing challenges to meet demand for carboplatin as well.

“One of the FDA’s main jobs is to patrol what they allow on the market and what is sold in the [US] market,” said George Tidmarsh, MD, PhD, an Adjunct Professor at Stanford University. “The FDA found manufacturing deficiencies at the generic [cisplatin] manufacturer and tightened its standards, and with relatively few suppliers, that led to the drug being in short supply.”

Similar issues have occurred with the manufacturing of methotrexate.

Many generics have only a small number of manufacturers because there are not large incentives to produce these drugs.

“In the typical generics cycle there is a rush to get the generic to market because the first one to market gets a period of exclusivity, up to 180 days in some cases; the others have to wait,” Dr. Tidmarsh explained. “In the [United States] it is like the wild west. If you make a generic you have multiple manufacturers battling on price, and if you have bundling—although technically illegal—that drives the price down so much that making the generic may no longer be profitable.”

A study looking at the flow of money through the pharmaceutical distribution system compared gross profit margins for branded manufacturers with generic manufacturers. In the branded market, gross margins are highest for the manufacturer (76.3%) and lower for the wholesaler (1.0%), the pharmacy (3.5%), the pharmacy benefit manager (PBM; 2.0%), and the insurer (22.2%). In contrast, in the generic market the gross margins are still highest for the manufacturer (49.8%) but are, at a minimum, quadrupled for others in the supply chain, including the pharmacy (42.7%), the wholesaler (18.5%), and the PBM (8.0%).⁴

In many European countries the government has regulatory authority over drug prices, Dr. Tidmarsh said. The government and manufacturer agree on a reasonable price for a generic that is not burdensome to the consumer, and it can be fairly profitable.

In the United States, some of the supply issues are related to manufacturers, but they are not the only ones at fault, Dr. Socal said. Another underlying issue is that more than 90% of prescription drugs in the United States are distributed through just three wholesalers—AmerisourceBergen, Cardinal Health, and the McKesson Corporation.⁵

“Evidence shows that once you hit four or five manufacturers there is a sweet spot where competition really starts and begins to successfully bring down prices,” Dr. Socal said. “The problem is we have purchasers who decide which manufacturers to buy from.”

If these three wholesalers tell a company they will buy 10% or 20% from them, there is no incentive for the manufacturer to produce more of the drug than is needed to cover its assigned percentage, Dr. Socal explained.

This was seen when there was a nationwide shortage of injectables. One manufacturer went down, and the others could not ramp up production fast enough to supply what was needed.

“They did not have incentive to have redundant capacity,” Dr. Socal said. “Why pay for the cost of redundant manufacturing capacity if you have a contract that outlines all you are going to ever sell over the course of a year?”

Old Problem, New Solutions?

Shortages of essential drugs are not new, said Dr. Tidmarsh, who described it as a “whack-a-mole” problem.

“As soon as people are motivated to action—because you are incensed that a child is suffering and can’t get methotrexate, which is curative in leukemia—you ramp up all efforts to produce it, and then all of a sudden a supply of methotrexate appears,” Dr. Tidmarsh said. “You sort of forget about it for a while, until the supply is gone again.”

The same is true with other drugs, he said.

Solutions won’t be simple. The US House Subcommittee on Health was recently at odds about the best way forward, with proposals ranging from suspending additional inflationary rebates for certain sterile injectables at risk of shortage, requiring the Center for Medicare and Medicaid Innovation to create a market-based pricing reimbursement policy, or awarding market exclusivity for drugs submitting shelf-life extension studies.⁶

A proposal from the Brookings Institution put forth a combination of “push” incentives designed to improve manufacturing infrastructure and “pull” incentives that would reward hospitals for taking steps to prevent shortages before they occur.⁷

In a recent study,⁸ Charles Bennett, MD, PhD, the Frank P. and Josie M. Professor of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina and an Affiliate Investigator with the Arnold Ventures Drug Access and Affordability Program at the Johns Hopkins Bloomberg School of Public Health, and colleagues proposed viewing the availability of these drugs as a public health imperative and including them in the United States’ Strategic National Stockpile (SNS). The SNS is a national repository of antibiotics, chemical antidotes, antitoxins, life-support medications, intravenous administration supplies, airway maintenance supplies, and medical and surgical items that are stored for public health emergencies, such as following an anthrax dirty bomb, nuclear reactor explosion, hurricane, or COVID-19, for example.⁹

“The idea is to identify strategies to address this problem that do not require legislation to be passed or new things to be funded or authorized,” Dr. Bennett said. “We want to work, if possible, within an existing framework.”

Another possible solution is rewarding manufacturers that have no manufacturing quality issues, Dr. Socal said.

“If you are a hospital and have three products to choose from, you often have no information to go on except for price,” Dr. Socal said. “If products had quality metrics, those could be used to justify a slightly more expensive price and would help hospitals make informed purchases.”

Blocking Competition

The second way patients may have insufficient access to generics is due to barriers that exist for delaying or blocking the release of generic or biosimilar versions of many novel targeted therapies as they move off patent.

Issues with patent strategies are not new in oncology. One of the first “blockbuster” targeted therapies for hematologic malignancies was the Bcr-Abl tyrosine kinase inhibitor (TKI) imatinib (Gleevec). Imatinib changed the outlook for chronic myeloid leukemia (CML), returning patients to an almost normal functional lifespan, but patients are on the drug for years.

Imatinib was first approved for CML in 2001,¹⁰ when its introductory price was more than $26,000 per year.¹¹ More than 20 years later, it is still used as a frontline option for CML. The drug’s initial patent was set to expire in May 2013, but the manufacturer was able to use a variety of patent extensions to extend its patent period to July 2015.

“One of the barriers that exists is that companies will generally have challenges in place at the end of a drug’s patent designed to try to prolong patent life,” Dr. Rajkumar said.

In this case, secondary patents filed on imatinib were designed to again extend its exclusivity to November 2019; however, generic manufacturer Sun Pharmaceuticals challenged those patents, and a confidential “pay-for-delay” agreement between Novartis and Sun Pharmaceuticals, the first generic company to receive FDA approval for a generic formulation of imatinib, delayed Sun’s release of the generic an additional six months after the patent’s expiration in exchange for an undisclosed amount of funds from Novartis.¹² In February 2016, Sun’s generic formulation of imatinib became available in the US market. When the drug initially came to market, it was priced similarly to its brand-name predecessor (about $140K per year vs $146K per year), although prior to marketing initiation, Sun had announced that it would price its generic at 30% lower than the price of Gleevec, the branded imatinib formulation.¹²

The generic imatinib can now be bought for about $50 per month, but that does not mean that is the price insurance companies are paying and, therefore, what the patients are paying.^13,14 The price set by the manufacturer does not always dictate the cost; it is only the first price in the supply chain path.

In a 2022 commentary published in The Lancet Haematology, Hagop Kantarjian, MD, and colleagues discussed the issue: “It is generally accepted that… the price of generic drugs is substantially reduced once four to five generic options are available. This basis is reflected in the wholesale acquisition cost of the imatinib generics. However, the average wholesale price of imatinib remained high despite the availability of 12 formulations.”

Dr. Kantarjian and colleagues cited an example of one generic imatinib that has a wholesale acquisition cost of about $6,900 but an average wholesale price of $131,200.¹⁵

A similarly frustrating situation has occurred with the long-anticipated generic form of lenalidomide, according to Giada Bianchi, MD, an Assistant Professor at Harvard Medical School.

“In multiple myeloma, lenalidomide is frequently used throughout induction and maintenance,” Dr. Bianchi said. “Patients often receive it early on and may stay on it for several years, if not decades.”

Lenalidomide was first approved in 2005.¹⁶ According to Dr. Bianchi, there was great anticipation of the generic form of lenalidomide as a way of possibly offsetting some of the burden that patients and their families bear related to the cost of treatment. However, it took 17 years for a generic form of lenalidomide to be marketed in the United States, and this availability is “volume-limited” until 2026.¹⁷

Several generic manufacturers were forced to reach legal agreements with Celgene, the manufacturer of branded lenalidomide, as a result of patent litigation related to the submission of the abbreviated new drug application (ANDA) for a generic version of Revlimid (lenalidomide capsules) in the United States, which Celgene alleged infringed on Bristol Myers Squibb’s patented, proprietary Risk Evaluation and Mitigation System (REMS) called RevAssist, as well as patents on lenalidomide itself, violating the Hatch-Waxman Act. According to Dr. Bennett, the manufacturer of Revlimid currently has 27 patents for lenalidomide. Four are for Active Pharmaceutical Ingredients, five are for product-related parts of the drug, and the rest are for the REMS distribution program.

The undisclosed “pay-for-delay” settlement allowed seven generic manufacturers to sell generic lenalidomide at restricted volumes, “described as a mid-single-digit percentage” of the brand name’s monthly volume until 2026 in exchange for an undisclosed amount of payment to each generic manufacturer.^12,18

What Does That Mean for Patient Access?

“I can start patients on generic lenalidomide, and payments are slightly lower for a month or two, but then the generics hit their sales maximum, and there is no more generic drug available; then I have to prescribe Revlimid,” Dr. Rajkumar said. “This is very different from what is happening in Europe, Canada, or the United Kingdom. There, once a generic drug is available, prices fall, and the generic takes over market share. In almost all other countries, lenalidomide costs about $100 per month. In the United States, Revlimid is $17,000 a month.”

Additionally, because the generic manufacturers have a limited market share available, they have no incentive to lower the price of the generic because the patented drug still controls 80% of the market, Dr. Rajkumar said.

Barriers to Use of Available Generics

Even once generics are available, there may be barriers to their uptake, including perceptions about safety and efficacy.

“The FDA can approve a generic that is equivalent to the original patented product, but it is in the FDA’s authority to decide what kind of evidence is needed to show the product’s equivalence,” Dr. Rajkumar said.

Dr. Bianchi said that clinicians often have a sense of comfort using drugs they are familiar with, and in good faith tend to believe that the generic form will work similarly to the drug that was proven in clinical trials.

Among the FDA’s requirements are that generics have the same active ingredient as the brand-name drug and show evidence that this active ingredient is the same; that the generic drug is the same strength, the same type of product (eg, tablet or injectable), and the same route of administration; that it has acceptable inactive ingredients; and that it is manufactured under the same strict standards as the brand name.¹⁹

“It is certainly possible that some side effects or allergic reactions could be triggered by additives that are present in a generic drug but are not contained in the formulary drug,” Dr. Bianchi said. “If that happens and can be clearly documented, then a note needs to be added to the prescription to ensure patients are only dispensed the nongeneric form of drug.”

However, in a review article published in The Lancet Oncology in 2016, Dr. Bennett and colleagues reported that no safety outbreaks among generic oncology drugs had been reported in developed countries.²⁰

In general, Dr. Rajkumar believes that there is trust in the generic formulations.

Another barrier to increased use of generic drugs in oncology is the rapid pace of innovation. By the time one novel therapy comes off patent, another “second-generation” form of the drug could have taken its place.

Second-generation TKIs dasatinib, nilotinib, and bosutinib are considered more potent than imatinib and are active against imatinib-resistant CML.

“It is important to have thought-leaders speak up and say that you can get the same survival paying $500 or $600 a year for imatinib, and there is no reason to spend more on something like nilotinib or dasatinib,” Dr. Rajkumar said.

Instead of trials looking at whether nilotinib produces better progression-free survival than imatinib, researchers need to examine whether using nilotinib after generic imatinib stops working still captures the whole benefit, Dr. Rajkumar said.

“The real trial isn’t nilotinib versus imatinib, it is imatinib followed by nilotinib versus imatinib,” Dr. Rajkumar said. “If you give 10 years of generic imatinib and then have to use nilotinib, which could be a generic form by that time, do you still capture the whole benefit? Is the benefit of a few months achieved by giving nilotinib early worth the cost paid?”

Newer formulations of a drug that provide some benefit compared with the original—even if it is marginal—fall into another strategy used to avoid generic entry called product hopping or evergreening. Product hopping may occur when a company reformulates their brand-name drug and encourages physicians to prescribe the new formulation. In some cases, the old drug formulation is removed from the market.²¹

The manufacturer of pembrolizumab, Merck, is currently looking to patent a new subcutaneous formulation of the drug. Patents on pembrolizumab are set to expire in 2028.²² Although a subcutaneous version of the drug may be preferred by patients looking to avoid long intravenous infusions, it could also be more complicated to dose.²³ Currently being studied in clinical trials, if the subcutaneous formulation is effective, it could replace the intravenous version of the drug—and any biosimilars developed after the patent expires. Merck is just one of a handful of manufacturers looking to develop subcutaneous formulations of immune checkpoint inhibitors.

Other strategies for delaying generic competition include authorized generics produced by the brand company, pay-for-delay tactics where the brand company pays the generic competitor to delay entry, litigation efforts, or simply buying out the generic competitors.¹⁷

Potential Solutions

Similar to the generic drug shortage issue, there is no one solution that will stimulate healthy competition in the generic and biosimilar markets.

Widely, there is a push to regulate the cost of drugs in the United States at large. The Inflation Reduction Act was one step toward this goal. The act will require companies that raise their drug prices faster than the rate of inflation to pay Medicare a rebate. Additionally, it authorizes Medicare to negotiate directly with drug manufacturers to lower the price of 10 single-source drugs identified in a list that was disseminated on September 1, 2023.^24,25

Dr. Bennett said, “only one cancer drug, Imbruvica, is included in this list of 10 drugs, and the negotiated price will not go into effect until 2026.”

The Mark Cuban Cost Plus Drug Company is attempting to disrupt the status quo by selling certain drugs directly to patients with a prescription. On its website, the company admits to marking up the drug 15% plus a small pharmacy fee to cover costs.²⁶ However, Dr. Bennett noted, “only seven oral generic oncology drugs are sold by Cost Plus Drug—abiraterone, anastrozole, imatinib (100 mg and 400 mg), letrozole, methotrexate, and tamoxifen.”

“The only catch is that patients are going to have to pay cash and are not able to use insurance,” Dr. Rajkumar said. Though if patients have high-deductible insurance plans, the out-of-pocket cost savings may be worth it. “This shows that even in cases where lower-priced generic alternatives exist, that does not mean that the patient will be able to access [them].”

Dr. Rajkumar also supported an idea put forth by Aaron Kesselheim, MD, JD, MPH, of Harvard University, that supports the FDA offering reciprocal approval to generics approved in Europe or Canada and a so-called single-window pathway for approving generic medicines for use in multiple countries.²⁷

There are also calls to reform patent laws that are used to exploit the system, although Dr. Socal said patent reform is likely to be “very difficult.” The Initiative for Medicines, Access, and Knowledge recently published data showing that, on average, 74 patents are granted on each of America’s 10 top-selling drugs, and about two-thirds of these patent applications were filed after the drug was approved by the FDA.²⁸

“Major pharmaceutical companies have significant financial incentive to delay the inevitable competition in the market once the primary patents expire. Drugmakers prepare for these looming patent expirations by filing or amassing hundreds of patents (‘patent thickets’),” the report’s authors wrote. “The strategy of securing additional patents extends their monopoly power far beyond the 20 years of patent protection intended under the law for an invention.”

There are also calls for the FDA to establish a clear time window for generic entry and to streamline the review of ANDAs for generics, biosimilars, or new drugs that rely on research from an existing reference drug.

“The House Oversight Committee report in 2021 stated that the 14 largest drug companies in the world spend more on ‘enriching investors and executives than on research and development,’” Dr. Bennett said. He added that the report concluded that Congress engages in five specific actions: “allow Medicare negotiation; restrain price increases and cap out-of-pocket costs; address anticompetitive practices on patents and targeting providers to prescribe patented drugs instead of generics; address anticompetitive ‘pay-for-delay’ agreements; and ensure transparency of research and development costs and support innovative research.”

Dr. Bennet noted that “the 2022 Inflation Reduction Act has begun to address two of these recommendations: Medicare price negotiation and restraining price increases.”

The system poses a complex challenge, with multiple factors involved, according to Dr. Rajkumar.

“These are things that need congressional, legislative, [and] regulatory type changes to enable the public to have access to these lower-cost generic drugs,” he said.

Leah Lawrence is a freelance health writer and editor based in Delaware.

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