Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

China has lagged in the adoption of anticancer biosimilars, but a huge number of agents in development suggest an “incoming wave” of these agents is about to hit, according to authors of a recent 

Just 2 anticancer biosimilars were approved in China by the end of 2019, but the country has 23.9% of the global cancer burden. The turning point in China could occur very soon, the authors said, noting that 54 anticancer biosimilars representing 7 reference products are under clinical development in mainland China, 3 are involved in new drug application reviews, and 27 are in late-phase efficacy comparative studies.

These findings were included in a report of biosimilar adoption in 40 countries with 78.1% of the worldwide cancer incidence.

China’s biosimilar development engine is supercharged and running on octane, the report said.

“Indeed [in China], the number of trials of anticancer biosimilars initiated between 2016 and 2019 was 11 times higher than the number initiated between 2012 and 2015,” the authors wrote.

The report said manufacturers may be tripping over one another in the development of anticancer biosimilars in China, because there are dozens of biosimilars under development for just 5 reference anticancer products: bevacizumab (n = 17); rituximab, 13; trastuzumab, 10; cetuximab, 6; and denosumab, 4.

“To ensure coordinated effort, the government should guide pharmaceutical companies to set rational priorities for drug research and development,” the authors wrote.

In emerging biosimilar markets, there is a need for payers to develop “rational” payment plans for anticancer biosimilars, but China, has “effectively” addressed the affordability issue by using large-scale, competitive procurement bidding for drugs, the authors wrote.

They said this means of settling the affordability issue could lead to problems of not enough supply.

“Globally, we should be aware of the potential danger of adopting price competition alone as a way to attain affordability; prices must be balanced, because setting them too low could drive manufacturers out of business, leading to possible shortages of cancer drugs.”

They also said market behavior needs to be eased into a legislative framework that protects against abuses.

“Anti-competitive business practices, such as the introduction of pseudo-generics, collusion, and delaying the entry of a generic or biosimilar, should not be encouraged, as these might hamper sustainable biosimilar markets and consistent delivery of the best health care for patients. Manufacturers should also not, for the sake of affordability, yield to pressure to lower standards.”

Half of Biosimilars Globally Are Anticancer

In the 40 countries studied by investigators, 262 biosimilars in all had been approved by the end of 2019. Half of those agents were oncology biosimilars, including 63 (24%) anticancer agents and 66 (25%) cancer supportive agents.

In that total, there were 20 biosimilars for rituximab; 14 for trastuzumab; and 14, bevacizumab. These 3 anticancer agents were the most common internationally. In all, they referenced 10 originator anticancer products.

“The popularity of generating biosimilars for these 3 biological drugs is closely associated with the timing of patent expiration and likely driven by commercial interest, as these were the top 3 biological drugs for cancer by retail sale in 2018, globally,” the investigators said.

Among the 6 continents compassed in the study, Asia had the largest number of approved anticancer biosimilars (n = 33) representing 9 separate reference products; Africa had 3 approved biosimilars; and Oceana, representing Australia, New Zealand and thousands of islands, had 6. North America had 10 anticancer biosimilars at the end of 2019; and Europe, 18, according to the study.

Authors said that the availability of biosimilars in each continent was roughly equivalent to the incidence of cancer in these zones.

The authors found a strong, positive correlation between income level and biosimilar availability on the international level (correlation coefficient [CC] 0.534; 

 = .005). A CC of 0.0 shows no relationship, and a CC of 1.0 would represent a perfect positive correlation.

“Healthcare systems in high-income countries have incentives to adopt lower cost biosimilars, and governments are willing to accelerate their approval and promote their adoption through insurance coverage,” the authors hypothesized, in an effort to explain why this relationship between income and drug availability exists.

By contrast, in countries where healthcare budgets are not as robust, pharmaceutical companies have less incentive to introduce biosimilar products, the authors said. Another reason might be that lower-income countries may have less-developed intellectual capital protection laws and regulatory frameworks, they said.

“Issues such as manufacturing processes, quality control, storage, and regulatory enforcement must be properly addressed to avoid production of substandard oncology generics or biosimilars,” they added.

Huang H-Y, Wu D-W, Ma F, et al. Availability of anticancer biosimilars in 40 countries. 

Articles

China is getting the hang of producing biosimilars, and harvest time is on the near horizon, according to a new report.
 

Report: Brace for China's Late Bloom in Anticancer Biosimilars

Once physicians are comfortable with biosimilar use, they tend to adopt biosimilars exclusively, discontinuing any use of the reference biologic, according to the authors of a 

 of factors associated with biosimilar use.

 demonstrated that providers were more likely to prescribe biosimilars for patients under financial constraint, such as younger patients who do not qualify for Medicare coverage or nonwhite patients with lower incomes.

Health maintenance organization cost capitation rules also play a role in providers’ tendency to prescribe biosimilars.

Interestingly, the investigators found that biosimilar uptake was higher in provider office-based clinics versus hospitals, which they said was consistent with literature that documents higher cancer-related costs in hospital settings due to higher product costs.

One reason suggested for the hospital tendency to use higher cost drugs was that hospital providers are incentivized differently. They are more likely to be paid a percentage of hospital charges, and if reference biologics are more costly than biosimilars, they are more likely to be prescribed.

Ironically, the structure of the 340B Drug Pricing Program, which is designed to make costly medicine more accessible in areas of need, may contribute to the hospital tendency to buy more costly drugs, the investigators said. Based on these factors, the authors concluded, provider awareness and incentives “can be important levers to increase biosimilar market penetration.”

“Although frustrations over the slow pace of biosimilar introduction and adoption in the United States have led some to abandon hope that a competitive biosimilar market will produce lower prices, our study findings underscore the need for additional research on the mechanisms of uptake as promising policy targets to strengthen competition in US biosimilar markets,” the authors wrote.

Biosimilars are considered an important means of lowering medicine costs because biologics account for a significant share of overall prescription drug spending: 38% in 2015, the authors noted. Biosimilars, which are clinically equivalent to the reference drug products they imitate, represent potential savings because they compete with reference drugs and typically launch at a discount.

There are currently 26 biosimilars approved and 16 on the market in the United States.

The authors did a close study of the uptake of Zarxio, the biosimilar filgrastim to reference Neupogen. Zarxio was launched in September 2015, and by the 3-year point, the share of reimbursement claims for Zarxio versus Neupogen was 60% among office-based providers and 49% among providers at outpatient hospitals.

Uptake Began Before Significant Price Cuts

The authors noted that providers began adopting the filgrastim biosimilar before any significant reduction occurred in cost. By mid-2018 the average sales price for the biosimilar had fallen to 67% of the biologic’s ASP. This adoption trend was noted mainly among office-based providers; the hospital-based provider adoption trend more closely mirrored reductions in ASP, the authors wrote. Further, “as office-based adoption rates have continued to rise, adoption rates in the hospital setting have plateaued at around 50%.”

This observation was a clue that factors besides price play a role in the uptake of biosimilars in hospital settings, the authors concluded.

Another observation was that providers tended to prescribe the biosimilar to all patients or they used the reference brand exclusively. There was very little middle ground where prescribers prescribed both reference and biosimilar products.

“By quarter 2 of 2018, approximately 61% (742 of 1223) of providers were offering some Zarxio; of this group, 88% (651 of 742) were offering exclusively Zarxio,” The authors wrote. Just 91 providers were administering both biosimilar and reference product, and 481 were administering only the originator brand. The pattern was evident across hospital- and office-based providers.

Office based providers were 22% more likely than hospital-based providers to have adopted the biosimilar version of filgrastim.  

Chen AJ, Ribero R, Van Nuys K. Provider differences in biosimilar uptake in the filgrastim market [published online ahead of print March 25, 2020]. 

. 2020;26(5). www.ajmc.com/journals/issue/2020/2020-vol26-n5/provider-differences-in-biosimilar-uptake-in-the-filgrastim-market.

When providers get used to biosimilars, they tend to prescribe them exclusively, according to a study in The American Journal of Managed Care.

Study: Office-Based Providers Latch Onto Biosimilars

The multiple sclerosis drug Copaxone (glatiramer acetate) has seen steep erosion of market share in recent years, owing to generic competition, and maker Teva Pharmaceuticals USA is seeking to raise the bar to entry for further competition.

 in US District Court hoping to force the FDA to reclassify the drug as a biologic under the Public Health Service Act (PHS), which in turn would force new generic competitors to have their drugs approved under the biologics license pathway.

The difference, Teva argues, is that with a biologics license application, the company would be able to engage a would-be rival over potential patent infringements much earlier in the process, before the competitor’s product actually got to market and began to eat further into Copaxone’s market share.

The blockbuster Copaxone is no longer the revenue engine for Teva it once was. North American sales of the product dropped 26% from the last quarter of 2018 to the comparable 2019 quarter ($356 million vs $264 million), a decline largely chalked up to generic competition.

In its suit, Teva said an unnamed company has given notice that it intends to apply to have a glatiramer acetate product approved through the abbreviated new drug application (ANDA) pathway under the Federal Food Drug and Cosmetic Act (FD&C Act)—the pathway under which Copaxone was originally approved.

This could enable the rival to get the product on market before Teva could bring suit for infringement, Teva argues. If the rival were forced to file a biosimilar approval application, it would have to enter a “patent dance” prior to launch, which could delay market entry by years.  

FDA Shuns Teva’s Request for Biological Status

Teva contends that when, on March 23, 2020, the FDA converted the licensure for 

 previously approved under the FD&C Act to biologics products licenses under the PSA, the FDA should have given Copaxone that new status also, but didn’t.

Until 2019, chemically synthesized polypeptides were excluded from the definition of biologics under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), which meant Copaxone was excluded.

That’s no longer the case, and Teva argues the product now fully meets the FDA’s stated definition of a biologic. However, the company contends the FDA has ignored its pleas to reclassify the product, right up until March 23, when the BPCIA biologics pathway transition occurred, reclassifying many protein-based products under the PHS licensure protocols. Teva filed its suit the next day.

“Under the BPCIA’s transition mandate, FDA should have deemed the Copaxone [FD&C Act approval] to be a “license” under the PHS,” Teva wrote. “Even if chemically synthesized polypeptides were not categorically 

, Copaxone met the length and specificity requirements set forth in FDA’s definition of 

Teva and the rival company have been unable to come to terms over the exchange of information that might enable Teva to formulate and exert its legal position, according to the suit.

Meanwhile, the rival company has given notice that it will soon file an ANDA for its product under the FD&C Act and has asked Teva to withhold asserting its patent rights over the marketing of that drug.

Teva has declined that request and, to date, the companies have “not been able to negotiate the information exchange necessary to consider such a covenant,” Teva wrote.

“If that manufacturer files an ANDA, it will not be required to notify [Teva], and [Teva] will not be able to assert their process patents against that manufacturer based on the submission to FDA,” Teva wrote in its suit.

Teva contends that having to make a claim of actual infringement would lead to delay and higher cost than litigating a case of “artificial infringement,” such as that posed by a biosimilar application, which would involve no tangible damages because the litigation would occur prior to product launch.

Teva has demanded that the court declare that Copaxone is a biological product under the BPCIA and that it be added to the list of former FD&C Act products that will be deemed biological products under the PHS.

Teva Pharmaceuticals USA has filed suit in an attempt to use the expanded biologics licensure pathway as a way to hold back a potential competitor.

Teva Tries to Block a Rival by Forcing It Through the Biosimilar Application Process

It will be both interesting and curious to see how drugs fare as they transition to a new biologics licensing pathway under the Biologics Price Competition and Innovation Act (BPCIA), according to Stacie L. Ropka, PhD, JD, a patent attorney with Axinn, Veltrop & Harkrider LLP, in Hartford, Connecticut.

The transition that occurs this week allows certain biologics previously approved as small molecule formulations to be licensed as biologics for the first time. This group includes insulin and human growth hormone.

Some believe the complexity of biologics and the patent thickets that surround their manufacture will present a significant obstruction that hinders competition, although regulators believe the new pathway consolidates protein-based agents under 1 licensing classification and will provide efficiencies and more competition for scarce or prohibitively costly agents, such as insulin.  

The Basalgar form of insulin glargine was approved for US distribution in 2015, and it was marketed at a discount to Lantus, the dominant insulin glargine at the time. The follow-on was approved via the 505b(2) pathway for roughly similar existing drugs. Now, Basalgar will enjoy a different type of status under the biologics pathway in the BPCIA.

“It was approved as a follow-on, not a biosimilar, not a generic, and not an interchangeable. Really, when it migrates over, it’s going to be a standalone product,” said Ropka, in an interview with The Center for Biosimilars

.  Standalone products are so called because they do not depend on prior approved formulations.

Basalgar will automatically be deemed to be licensed as a biologic under the new pathway, without the burden of needing clinical evidence or going through the approval process, and the independent status may help it to stand out from Lantus.

For novel biosimilars, the process is more complicated, Ropka noted.  

The new biologics from the expanded class must be approved under the so-called abbreviated 351(k) pathway of the Public Health Service Act, which enables manufacturers to get their drugs approved “based on a less-than-full complement of product-specific preclinical and clinical data,” according to the 

“First of all, you’re going to have to be approved as a biosimilar, which is a little more rigorous of a pathway,” Ropka said. “And then you’re going to be branded as a biosimilar.”

In some people’s minds, a biosimilar is a lesser medicine than its reference product, so it may not be accepted. “It may not make it onto formularies as readily or it may not be as readily accepted,” Ropka said.  

The more fortunate Basalgar will be deemed to be licensed under the 351(a) pathway for the approval of innovator products. “It could become the reference product—oddly enough, for Lantus.”

It is hoped that more insulin products emerge as a result of this new pathway for biologics formerly approved as small molecule drugs, but there may be greater challenges to approval and launch that may be daunting for manufacturers, legal experts have noted. For example, the evidence needed for a biologics application may be more difficult to accrue.

Ropka noted that the “patent dance” that has been a feature of most biologics launch efforts will apply also to the newly added group of biologics. In a patent dance, the biosimilar developer and the reference product innovator engage over existing patents that protect exclusivity. This can be a lengthy and costly process that may defeat attempts to bring a product to market or delay its arrival on market by many years.

For chemical-based, small molecule drugs, the patent thicket is much smaller by comparison owing to the less complex nature of these agents, and developers have been aided by the FDA’s 

, which includes exclusivity information along with product formulation data.

For biologics now under the new pathway, “You’re going to have to do your patent dance litigation instead of the Orange Book,” Ropka said.

What may be of some assistance to product developers is the 

, which is an FDA compendium of information on approved biologics. The database has been upgraded to a searchable online database, and the FDA has plans to include exclusivity information, something Ropka said may improve the appeal of bringing drugs to the market under the biologics pathway.

The patent dance “adds another challenge to making a business decision to develop” a biosimilar, she said. However, “clients do use the Orange Book as one bit of information when they’re making their decisions on what molecule to pursue, and I could see a Purple Book patent listing providing the same sort of certainty, Ropka added. “‘This is the universe of patents that I could face. And I can do some early analysis to decide how I feel about facing that patent portfolio.’”

Life under the new biologics pathway will be easier for some drugs than others, notes Stacie L. Ropka, PhD, JD, a patent attorney with Axinn, Veltrop & Harkrider LLP, in Hartford, Connecticut.

New Biologics Pathway Could Be Daunting for Biologics Developers

The FDA has approved a 420-mg multidose vial of Samsung Bioepis’ trastuzumab biosimilar Ontruzant, which is yet to be launched in the United States.

Ontruzant is indicated for the adjuvant treatment of 

-overexpressing breast cancer, metastatic breast cancer, and metastatic gastric cancer or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease.

 as a 150-mg single-dose vial by the FDA in January 2019 across all indications for the reference product, Herceptin.  

In the United States, Ontruzant, when launched, would compete with 4 other trastuzumab biosimilars, Herzuma, Trazimera, Ogivri, Kanjinti, as well as Herceptin. Herzuma was launched this month; Trazimera in February 2020; Ogivri in December 2019; and Kanjinti, the first biosimilar trastuzumab to launch, in July 2019.

Amgen reported fourth quarter 2019 US revenues of $79 million for Kanjinti, up from $39 million in the previous quarter. The product launched at a 15% discount to Roche-Genentech’s Herceptin, which has annual sales of roughly $7 billion and costs about $70,000 for a full course of treatment.

In tandem with the Ontruzant announcement, Samsung Bioepis said the biosimilar will be marketed and distributed in the United States by Merck, which intends to spin off products from its biosimilars business, including Ontruzant, into a new independent, publicly traded company. This spinoff is expected to occur in the first half of 2021, and until that time Merck will handle the commercialization of Ontruzant.

The European Commission approved Ontruzant 150 mg in November 2017. The 420-mg vial was approved for sales by the European Medicines Agency in March 2019.

The FDA has approved a multidose vial of Samsung Bioepis’ trastuzumab biosimilar Ontruzant, which was first approved as a 150-mg single-dose vial in January 2019 and has yet to reach the US market in either form.

Ontruzant Trastuzumab 420-mg Multidose Vial Approved by FDA

 and other agents are likely to slow down, if not stall, as coronavirus disease 2019 (COVID-19) wends its course, said Jim M. Koeller, MS, a professor of pharmacotherapy with the Graduate School of Biomedical Studies at UT Health in Austin, Texas.

“The clinical trials will be the easiest thing to put on hold. I don’t see a new trial starting until some of this stuff levels out,” he said in an interview with The Center for Biosimilars

. “We’re still talking about supplies of masks and gowns.”

Similarly, new agents that become available for use following FDA approval will likely not find their way into circulation within medical institutions because the resources needed to conduct the extensive internal reviews by pharmacy and therapeutics committees simply are not available at this time, he said.

What’s more likely is that hospitals and clinics will devote their energies to attending to the patients expected to become sickened by COVID-19. In addition, clinical trial activity will be downsized for weeks, possibly months, until conditions normalize, he said.

 “I think people who are under treatment currently will continue to get treatment. It’s unlikely that new patients will go on trial protocols before we figure out what’s going on,” Koeller said.

The University of Texas MD Anderson Cancer Center, which encompasses UT Health, is the largest cancer treatment center in the United States and has an extensive body of ongoing clinical trial activity.

Although some major drugmakers such as Eli Lilly and Co and Bristol Myers Squibb (BMS) recently hit the pause button on starting new clinical trials, there has been a scarcity of guidance filtering down to investigators from trial sponsors about how they wish ongoing trials to proceed, Koeller said. “The emails have gone silent.”

Eli Lilly, which has been developing an insulin biosimilar, has delayed most new clinical studies and halted enrollment in most ongoing studies. Treatment, however, will continue for patients already enrolled.

“The severe burden on healthcare systems caused by this pandemic has also impaired the ability of many research sites to start new studies or enroll new patients,” the company said in a statement Monday, March 23. “At the same time, Lilly recognizes that for patients already enrolled in clinical trials, discontinuation would disrupt their treatment and potentially diminish the societal value of the research information to which they are contributing. Therefore, we will maintain ongoing studies, but with study-by-study consideration."

For its part, BMS has decided to allow new patient enrollment if sites can demonstrate the ability to recruit and manage patients effectivity and in compliance with protocol. However, BMS is not activating new study sites.

 or not initiate treatment for patients with signs of COVID-19 until the symptoms resolve.

A Sandoz spokesperson said the company is monitoring its clinical trials programs closely, aided by a real-time system established in 2018 that culls information at the individual-patient level and enables the company to rapidly implement contingency changes. “As of now, we have kept the majority of our trials operating amid the COVID-19 situation,” said Allison Schneider, director of communications.

Not just patients but also clinicians and investigators are preoccupied daily with figuring out how to work under such conditions as COVID-19 has created, obtain food, and look after family members, Koeller said. As hospitals start to see a deluge of patients affected by COVID-19, resources available for normal activities will become scarce.

Many decisions have yet to be made about how ongoing clinical trials can be conducted in these conditions, such as whether family members may accompany patients on trials for onsite care. “There are a lot of things changing by the minute,” he said.

Late last week, the FDA issued clinical trial guidance indicating that modifications to clinical trials may be acceptable if they are well reasoned and well documented. The unusual conditions brought about by COVID-19 allow for such departures from previously approved protocol, the FDA said, although at the end of the process, investigators will need to produce reliable evidence. Koeller notes that some patients may simply lose their eligibility to participate in trials, given infection with the new coronavirus.

The National Cancer Institute (NCI), which conducts a multitude of clinical studies, also has issued advice to allow flexibility needed to continue clinical trials. “We continue to closely monitor NCI-supported clinical trials to help address the needs of investigators to implement accommodations to maintain continuity of care for their patients who are being treated on trials as much as possible,” the NCI said.

Accommodations such as allowing patients to receive treatments from local providers who are able to maintain trial protocols, such as examinations and tests, are allowable, the NCI said.

“The activities provided by the local healthcare provider must be conducted under the oversight of the responsible investigator in accordance with the protocol and with assurances that processes are in place to report all required information to the responsible investigator who is responsible for ensuring that the data are entered into the data management system for the trial,” the NCI 

As coronavirus disease 2019 (COVID-19) causes medical systems to bog down from a host of related issues, a UT Health expert said clinical trials likely will be powered down and hospitals will put consideration of newly available agents on hold.

Slowdown Anticipated for Clinical Trials, New Agent Adoption 

 patients received medicinal agents through the FDA’s expanded access program, which allows access to premarket drugs in cases of unmet need, but none have received access to biosimilars under this program, according to the FDA.

The FDA does not rule out access to biosimilars, either those in development or those already approved, through the expanded access program, although there is a strict set of criteria that must be met for patients to qualify. These include no acceptable alternative agents, no available clinical trials, a life-threatening condition, and risks of taking the agent are not unreasonable in the context of the disease or condition to be treated.

The question about using the expanded access program for access to biosimilars arose during a series of talks recently about patent thickets created around innovator products and the challenges posed to manufacturers of biosimilars in navigating these legal obstacles to get to market. Much of the appeal of using biosimilars through expanded access as opposed to the originator agents could conceivably derive from the cost-benefit ratio. Biosimilars are typically brought to market at lower cost than reference drugs. For patients facing financial toxicity, a biosimilar at a lower cost or available free of charge could be appealing.

Biosimilars are developed so that they are highly similar to original, or reference, products and have no meaningful clinical differences. Immunogenicity studies may be required for a biosimilar to achieve the ranking of “interchangeability” with the respective reference product; interchangeability is a designation indicating the agent can be substituted for the reference product at the pharmacy counter without consultation with the prescribing physician.

In the process of developing a biosimilar to obtain FDA approval and to launch the product on market, a substantial quantity of the agent may be accumulated that might reach its expiration date between the time the product receives the FDA stamp of approval and the time the sometimes formidable legal hurdles are overcome to do a product launch, noted Bruce Leicher, a legal advisor and former senior vice president and general counsel for Momenta Pharmaceuticals. Leicher served as the moderator during the series of talks in early March at the World Biosimilar Congress USA 2020 at the Festival of Biologics USA in San Diego, California.

“There’s a lot of product that may actually be OK that could go to waste. The question is, would it be infringing” on the originator’s patents to offer this product to patients through the expanded access program? he asked rhetorically.

In an interview, Noelle Sunstrom, CEO and founder of NeuClone, a biopharmaceutical company with a broad pipeline of biosimilar candidates based in Redfern, Australia, opined that in cases where financial toxicity was presented as a reason for seeking a biosimilar through the expanded access program, “it would have to be for very severe disease instances where there are no other viable treatment options except for the unaffordable originator.”

“It would also require the biosimilar company to have a commercial supply available as well as a nominated price that would warrant exceptional access,” she said. “Who would be able to decide what biosimilars would qualify for this?”

She noted that the FDA’s expanded access program is traditionally intended for patients with diseases for which all other alternatives have been exhausted except an investigational product that may hold some degree of benefit. If the FDA has approved the product, then “it’s now a question of legal proceedings as to when it can begin being sold to patients,” Sunstrom said.

In response to a media query, the FDA did not rule out the possibility that financial toxicity would be weighed by the agency as a potential reason given by a patient for seeking access to a biosimilar that hasn’t yet been launched versus its reference product. Instead, the FDA pointed to its standard criteria, described above, and said those would have to be met for access to be granted.

In the expanded access decision process, the FDA makes a decision whether expanded access will be allowed, but that decision also is made by the company that produces the drug. A company has a right to decide for itself whether it wants to make a product available outside of the clinical trials process.

Speaking about expanded access in a presentation at the Festival of Biologics, Christopher Robertson, a professor of law and associate dean for research and innovation at the University of Arizona School of Law in Tucson, said the expanded access dilemma for these development companies has traditionally been “should they be laser focused on getting through the FDA process and getting to market, where they can get reimbursement for potentially thousands of patients over decades in the future, versus providing access to 1 or 5 or 20 patients now.”

Companies must take care not to compromise the long-term prospects for a drug candidate. Traditionally, companies have had to worry that granting access to drugs in development outside of clinical trials would make patients less willing to enroll in clinical trials for these drugs, because they might end up with placebo instead of the experimental, active agent.

Another issue is that outcomes for patients receiving drug through expanded access are not intended to be factored into approval decisions, but the FDA may make exceptions to this rule, which means that there is potential liability for a company that makes product available that is associated with a patient outcome that is concerning for the FDA. “There ends up being a series of repercussions, market-based challenges, that Congress really can’t fix if bad news comes out of expanded access,” Robertson said.

Assuming those hurdles are not insurmountable for biosimilars in development and other experimental agents, there’s still the question of whether doctors and patients even know of the expanded access program or the agent in question and have the time and wherewithal to apply for access, Robertson said.

“The expanded access program really begins with the doctor and patient. And it begins with the doctor and patient typically approaching a company who has to decide whether it wants to provide product in this setting. Then the company and the doctor approach the FDA together for permission,” Robertson said.

“Physicians often don’t know about the existence about drugs that are early in the development process, or that preapproval is even possible. It still requires some effort by the physician to go out of his or her normal practice pattern to pursue expanded access or right to try,” he said. Right to try is a reference to a federal law and multiple state laws that allow access to drugs in phase I development without FDA approval.

Much depends on the size of the company and its ability to respond to expanded access requests, Robertson said. “In some situations, there are no additional units of a drug that they’re in a position to provide outside of clinical trials…And who even picks up a phone when a physician calls to gain access? You see huge companies creating expanded access programs, and they have the staff and training to do that, but for smaller companies it ends up being a challenge.”

Legal and industry experts ponder whether expanded access to biosimilars is a way around patent thickets that slow the launch of approved biosimilars.
 

Is Expanded Access a Route to Biosimilars Mired in Litigation?

Numerous aspects of the COVID-19 pandemic could be disruptive to the success of clinical trials, and in fresh 

, the FDA has acknowledged that deviations from trial protocol may be necessary. It said these updated guidelines would help to ensure the safety of participants, maintain good clinical practices, and minimize risks to trial integrity.

The challenges that may arise during the current coronavirus outbreak include quarantines, site closures, travel limitations, and interruptions to the supply chain for the investigational product, the FDA noted. There is also the risk that clinical personnel or patients may become infected with COVID-19.

“These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory and diagnostic testing,” the FDA said.

The FDA added that patient safety should remain a top concern of investigators. Further, they should make assessments and decisions that are in accord with the specific circumstances in each instance that may require a modification of study conduct.

Those decisions may involve whether to continue use of the investigational product in patients who have been participating in the trial, continue trial recruitment, or change patient monitoring. “In all cases it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them,” the FDA said.

Following consultation with the clinical investigators, institutional review boards, and independent ethics committees, trial sponsors may decide that for an individual patient, the best course of action may be to continue the trial regimen and thereby protect the patient’s safety, welfare, and rights.

“Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial,” the FDA said.

In the event that trial participants are unable to come to the investigational site for scheduled visits, phone contact and virtual visits are acceptable alternatives when feasible and necessary, and patient safety will not be compromised. Alternative locations for treatment may also be considered, the FDA said, adding that if it becomes impossible to continue to supply a patient with investigational product, the patient may require additional safety monitoring.

“The need to put new processes in place or to modify existing processes will vary by the protocol and local situation. For example, this assessment could include consideration of whether it is appropriate to delay some assessments for ongoing trials, or, if the study cannot be properly conducted under the existing protocol, whether to stop ongoing recruitment, or even withdraw trial participants,” the FDA wrote.

The agency noted that under normal conditions, changes to trial protocol are typically not implemented before review and approval by institutional review boards and independent ethics committees, and in some cases by the FDA. If adhering to this standard is not possible, investigators should engage with these authorities as soon as possible when trial protocol changes are anticipated as a result of COVID-19, the guideline states. Changes should be documented and amendments to trial protocols reported.

The guidance states that for all trials affected by the COVID-19 epidemic, full documentation of trial changes or disruptions should be recorded, along with analyses and discussions “that address the impact of implemented contingency measures on the safety and efficacy results reported for the study.”

In guidance issued specifically in response to the COVID-19 pandemic, the FDA has advised that clinical trial protocol modifications may be made but must be documented and reported as promptly as possible. The FDA notes that trial participants may be sickened by COVID-19, supplies of investigational drugs may be interrupted, and quarantines and closings may make on-site patient visits impossible.

FDA Issues Contingency Guidance for Trials Affected by COVID-19

The FDA’s decision to discontinue pharmaceutical site inspections abroad appears destined to exacerbate shortages of critical drugs, including biologics, said Imron T. Aly, a patent attorney at Schiff Hardin, which represents numerous India-based manufacturers of small- and large-molecule drugs, in an interview with The Center for Biosimilars

. “At a time when you’d rather have things expedited, having the FDA pull its inspections in India, in particular, is slowing things down,”

 last week that it would stop routine overseas inspections of food, drugs, and medical devices until April, citing the worldwide spread of COVID-19. Instead, the agency said it would rely on border inspections of products and examinations of product data from manufacturers.

Manufacturers in India, which supply 18% of the active pharmaceutical ingredients (APIs) used in the US drug supply, are “extremely concerned” about the move, as it stands to harm manufacturing operations and plans for new manufacturing or drug development activity, Aly noted.  

A case in point is Biocon, a Bengaluru, India—based company that hopes to achieve a $1-billion revenue target in biologics by 2022. It is the only Indian pharmaceutical company with 2 biosimilars on the US market: Fulphila (pegfilgrastim) and Ogivri (trastuzumab).

Compounding the problem is that earlier this month, supply chain problems led India to restrict the export of 26 APIs and the medicines and vitamins made from them. These include paracetamol; antibiotics such as tinidazole and erythromycin; the hormone progesterone, which is used in the contraceptive pill; and vitamins B12, B1, and B6.

Further, Indian pharmaceutical companies obtain almost 70% of the APIs for their products from China, particularly Hubei province, the epicenter of the COVID-19 outbreak. The interdependence of markets and fears that India may not be able to provide medicines for its own population of 1.3 billion people contributed to the decision by India’s authorities to tamp down on exports.  

“We see the pharmaceutical supply chain exported out of China under significant pressure,” Jim DeYonker of Centrient Pharmaceuticals, which has manufacturing facilities in India, told the 

“In addition to a manpower shortage due to more and more provincial governments adopting a mandatory 14-day quarantine policy for returning workers, the transportation and logistics apparatus is also getting clogged up due to various travel restrictions and difficult access to ports,” DeYonker said. The same article noted Indian media reports that traders were hoarding APIs and that prices for medicines were already surging.

The ripple effects from these events are sure to reach the United States, Aly said. “I think we’re guaranteed drug shortages. We just don’t know how soon they’re going to be experienced here. From everything we’re hearing, there are going to be shortages within a matter of 2 months.”

The 26 APIs that India is withholding are a subset of total pharmaceutical products shipped to the United States, and so the FDA policy on inspections raises serious questions about whether the speed and efficiency of imports can be maintained, Aly said.

“Inspections at the border have been rarely used, so Indian manufacturers have big concerns about how that’s going to happen. We’re talking about crates of product that get imported here, and depending on what it is that the FDA is testing or how, there might be disputes about whether that crate of material is allowed to enter or not, when it normally wouldn’t have been an issue because the plant would have been cleared [via a site inspection in India]. So, there’s a lot of uncertainty about how this is going to impact the drugs that can get released from India.”

FDA inspections have been a very important part of the FDA clearance system in India since 2008, when the FDA established the India Office for the purpose of ensuring medical product and food safety.

The importance of foreign inspections was highlighted in a December 2019 

 by Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER). Woodcock noted that from 2012 to August 2019, 83% of India’s manufacturing facilities were found to be nondeficient, versus 98% in Europe, 93% in the United States, and 90% in China.

“India had a lower percentage of acceptable outcomes than other countries and regions,” the CDER report said. Standards are identical for foreign and domestic drug manufacturers.

For firms that have received warning notices, having their imports to the United States approved following remediation of the deficiency requires an onsite reinspection, according to the FDA.

In 1991, China-sourced drug ingredients made up only 0.3% of India’s bulk drug imports, according to the 

. But as India’s manufacturers switched to making formulations, that percentage climbed much higher.

In India, “about two-thirds of the raw materials for drugs come from China, and that’s just as true for biosimilars as it is for small molecules, so it’s definitely going to be an issue that creates slowdowns, creates delays, and it’s a matter of when that will be,” Aly said.

This year, India’s government and pharma industry have been collaborating on plans to step up API manufacturing in the country to reduce the perceived threat to drug supplies and national health.

Schiff Hardin patent attorney Imron T. Aly works with India-based manufacturers of biologics and says supply chain problems are anticipated shortly in the United States, based on FDA inspection policy and sourcing issues.

FDA Overseas Inspection Policy Is Concerning, Says Biosimilars Patent Attorney 

Three months after its FDA approval, a fourth trastuzumab biosimilar has been launched. Teva Pharmaceuticals USA and Celltrion Healthcare announced the market availability of Herzuma (trastuzumab-pkrb), an injectable biosimilar with the same indications as the Herceptin reference product.

The biosimilar arrival on market follows launches of other biosimilars for trastuzumab by Pfizer (Trazimera), Mylan/Biocon (

), Amgen/Allergan (Kanjinti). An additional trastuzumab biosimilar approved but not yet launched is Samsung Bioepis’ Ontruzant.

Herzuma is indicated for the treatment of breast cancer in the adjuvant setting, metastatic breast cancer, and metastatic gastric cancer.  

The wholesale acquisition cost (WAC) for Herzuma 150 mg is $1402.50 and HERZUMA 420 mg is $3927, which is a 10% discount to the WAC of Herceptin, Teva and Celltrion said in a 

. They said actual costs for Herzuma are expected to be lower because WAC does not account for rebates and further discounts that may apply.

“We are proud to make Herzuma available to patients in the United States living with HER2-positive breast and gastric cancers, and their providers,” said Brendan O’Grady, executive vice president, North America Commercial, Teva.

Teva and Celltrion also are partners on a biosimilar for rituximab, whose reference product is Rituxan. Teva and Celltrion’s version, Truxima, was approved November 28, 2018, and was launched in November 2019. The product also was being offered at a 10% discount to the list price of reference product. Truxima was made available at $845.55 for a 100-mg vial and $4227.75 for a 500-mg vial.

Although the reference rituximab also carries indications for inflammatory diseases including rheumatoid arthritis, Celltrion 

 and received approval only for adults with CD20-positive, B-cell non-Hodgkin lymphoma (NHL) either as monotherapy or in combination with chemotherapy.

Pipeline Report: Oncology Biosimilars to Advance in 2020

Pfizer Touts Lower WAC of 3 Oncology Biosimilars as It Launches Rituximab Product

Teva Pharmaceuticals USA and Celltrion Healthcare have launched the fourth trastuzumab biosimilar, Herzuma, at a 10% discount to the cost of reference product Herceptin.