Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Are we there yet with biosimilars? That’s often the back-seat perspective, but this negativism is really based on “fiction” and biosimilars are rapidly gaining ground, according to Ted Okon, MBA, executive director of the Community Oncology Alliance, which advocates on behalf of community-based, nonhospital oncology clinics.

Misconceptions about biosimilars are numerous, Okon said, listing them at the recent Festival of Biologics 2021 biosimilars conference:

Physicians won’t prescribe them because they’re not as efficacious as originator products or the doctors make more money on the most expensive products

Biosimilar naming suffixes and CMS coding for them are stifling growth

Biologics are “natural monopolies” that shut out biosimilars

There have been repeated calls from the Drug Pricing Lab at Memorial Sloan Kettering Cancer Center in New York to regulate the prices of originator drugs rather than trying to make biosimilar competition do the work of trimming the soaring costs of biologics, but Okon said there’s no justification for even considering throwing in the towel on biosimilars. “I think this is just not based in fact, it’s not workable, and it’s complete fiction,” he said.

Peter Bach, MD, MAPP, and Mark R. Trusheim, MSc, 

 requiring “that biologic drug manufacturers lower their prices to affordable yet still profitable levels when their market exclusivity expires.”

Okon in his talk said that proposed policy was “price fixing” under a disguise. “I just want to say that price fixing has never worked in the long-term history of humanity,” Okon said.

Such theories and “fictions” about biosimilars distract from the true facts of the case, Okon said. “The biosimilar market is growing. Yes, it’s taking a while, but it’s growing.” Although the United States is behind Europe in terms of biosimilars approved and launched, the FDA continues to add more approvals each year—29 since 2014—and 73 additional biosimilar candidates are in clinical trials and/or under FDA review, Okon said.

Physicians continue to prescribe more biosimilars, and price competition is improving. “At COA we have a biosimilars committee, and they are committed to the growth of biosimilars. There is price competition and the market could be stronger and produce more savings,” he said.

Hospital Incentives Undermine Biosimilar Progress

However, one place that biosimilars could be absorbed and appear to be snubbed instead is in the hospital community, where financial incentives are heavily weighted in favor of biologic reference products, which means biosimilars in many cases are not even considered, Okon said. He quoted from a January 2021 report from Bernstein, the financial advisory firm, which used a recent federal drug price disclosure mandate to probe what insurers are paying hospitals for the use of reference biologics.

For example, UT Southwestern Medical Center receives $17,241 from Cigna for administering a dose of the Neulasta originator brand of pegfilgrastim, whereas Aetna pays UT Southwestern $6474 per dose. Humana pays Wake Forest Baptist Medical Center $4370 for a dose of the Prolia originator brand of denosumab, whereas United Healthcare pays Wake Forest $2209, according to the Bernstein report. As these data show, because compensation levels can sometimes be high, 30% to 43% of hospitals only carry the innovator products, Okon said 

Okon said the average markups over average selling prices on biologics are 250% although the markups are often much higher, as indicated by the Bernstein information, especially if the drugs are acquired through the 340B drug price subsidy program, which is intended to improve access to drugs for patients. Providing a scenario, Okon said it’s possible for a hospital to be paid almost $8000 for a drug whose wholesale cost is $4500, with the payer being charged over $8000 and the patient paying over $2000 out of pocket.

“You can see, especially with 340B, it makes drugs very, very economically attractive, and as a result, biosimilars are not attractive to use.”

Citing information from IQVIA, Okon said the US market for biosimilars stands at $4 billion annually. Okon called that “amazing growth.”

Growth trajectories for filgrastim biosimilars have been slow but market share growth curves for more recent biosimilars for other products, including bevacizumab, trastuzumab, epoetin, and rituximab, have been very steep, Okon noted. Similarly, price declines due to biosimilar competition are becoming steeper, too.

“It’s very, very interesting. It just took more competition,” he said.

There are culprits holding back the growth of biosimilars, he added. These include patent battles and restrictive deals that favor innovator products. Pharmacy benefit managers and payers are responsible for the latter, he said.

Although there are problems that prevent biosimilars from getting to patients, the following actions could help to improve access and lower prices, Okon said:

Prioritize and streamline the FDA approval process for biosimilars

Eliminate rebate waivers for biologics, including biosimilars

Provide 340B drug discounts to patients, not hospitals

“The bottom line is this: the biosimilar market in the United States is growing and it’s producing savings,” Okon said. “Could it be growing more? Yes. Could it be growing faster? Yes. Could it be producing more savings? Yes. But the solution is not price regulating the market. That will destroy not only the biosimilars but also the biologics market.”

Articles

Calls for price regulation and lopsided incentives are threats to biosimilar progress, Community Oncology Alliance (COA) Executive Director Ted Okon argues.

COA's Okon Takes Aim at Biosimilar Misconceptions

An Ontario, Canada, biotech company that uses tobacco plants to cultivate antibodies for biosimilar production 

 of a biosimilar pembrolizumab for the Brazilian market. Pembrolizumab (Keytruda) is a “programmed death” (PD) inhibitor that counteracts tumor cells’ ability to deactivate the immune system response to malignant cells. It is used in the treatment of melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, and stomach cancer.

PlantForm uses tobacco plants rather than animal cells to develop antibodies for use in biologics production. Antibody genes are merged with plant bacteria to “infect” the tobacco plants and cause them to produce antibodies, a process that takes about 10 days, according to company information. The company touts this as a way to avoid some of the complexities of standard production techniques that use animals and bioreactors.

PlantForm is partnering with PlantPraxis Biotecnologia and Bio-Manguinhos/Fiocruz to create the pembrolizumab biosimilar. Merck is expected to lose patent exclusivity protection for Keytruda in the United States, European Union, and Brazil in 2028, allowing a potential entry point for biosimilars. “We want to make a difference in this market by transferring an innovative technology that will bring a low cost biosimilar pembrolizumab to Brazil,” said Germana Regazzi, director of PlantPraxis.

PlantPraxis is a joint venture between PlantForm do, which is a subsidiary of PlantForm, and Axis Biotech Brazil. Bio-Manguinhos is a division of the Brazilian Ministry of Health that furthers the development of technology and production of vaccines, among other activities.

According to PlantPraxis, the pembrolizumab market is expected to reach $25 billion by 2025, making it a potentially lucrative target for biosimilar competitors. PlantPraxis is not alone in cultivating ambitions for participation in this market. 

of Sydney, Australia, announced in September 2020 that it is working to develop biosimilars for pembrolizumab and nivolumab (Opdivo), another PD inhibitor.

PlantForm has other biosimilars in development, including versions of trastuzumab and ranibizumab, which treat forms of cancer and macular degeneration, respectively.

For further reading about the development of PD inhibitor biosimilars, click 

PlantForm will use tobacco plants to develop antibodies for its checkpoint inhibitor pembrolizumab biosimilar.  

PlantForm Will Challenge Merck's Dominance for Pembrolizumab

Shanghai Henlius Biotech is one of many companies in China working to crack open the market there to biosimilar competition. However, Henlius stands out so far for some notable achievements, such as bringing the first biosimilar (rituximab) to market in China and achieving significantly rapid market penetration in the product's first several months of life. 

The company has bigger ambitions to achieve dominance not only in China but also on the world biosimilar stage, Ping Cao, company vice president of business development, explained at the recent Festival of Biologics USA meeting. 

Henlius was formed in 2010 and filed its first biosimilar investigational new drug application (HLX01, rituximab) with the Chinese National Medical Products Administration (NMPA) in 2011. The company opened its first Good Manufacturing Practices–certified factory in 2016, and HLX01 was approved in China in 2019, becoming the first biosimilar approved in China.

In July 2020, the company saw its trastuzumab biosimilar (HLX02, Zercepac) approved in the European Union. The same drug was approved a month later in China, and in December of 2020, Henlius succeeded in getting an adalimumab biosimilar (HLX03) approved in China, also.

The company decided that its first several biosimilars would be oncology products because of the relatively huge market for oncology treatment in China. That meant the company saw huge potential in rituximab, trastuzumab, and bevacizumab biosimilars. The company anticipates an FDA filing for its bevacizumab biosimilar (HLX04) in 2021.

It also anticipated strong growth for its adalimumab biosimilar, referencing the blockbuster Humira, which Cao said still has a relatively small share of the market for autoimmune diseases in China. “Autoimmune disease actually has a huge unmet need in China,” she said. Humira’s 2019 sales share in China vs its global penetration rate was 0.2%, and the estimated access rate (to adalimumab) in China in 2020 was 1.3% of patients vs a potential market of 6.7 million patients.

Global marketing of its biosimilars is an important element of the company’s growth strategy , but Henlius also wants to develop biobetters, drugs that are based on originator products but deliver better efficacy, improved safety, or other enhancements. Developing new biologics and combination therapies also is a targeted area for growth at Henlius, Cao said. 

Its second wave of biosimilar contenders may target the cetuximab (Erbitux, rectal and head and neck cancer), ramucirumab (Cyramza, solid tumors), pertuzumab (Perjeta, breast cancer), and denosumab (Prolia/Xgeva, bone loss) markets. Henlius has biosimilars of these drugs in phase 1 development currently.

The company is seeking a rheumatoid arthritis indication for its rituximab biosimilar and, if successful, this indication would make HLX01 a bio-innovative medicine because the reference product, MabThera, has not yet been approved for this indication, Cao said. China’s NMPA has accepted a new drug application for HLX01.

Under its current indications, HLX01 was a record breaker, taking 50% of market share for new patients treated within 5 months of launch in China and surpassing market share of the originator product, MabThera, after 14 months on market, Cao said.

Although the cetuximab product candidate remains in early stage trials, Henlius has already granted commercialization rights in China to Shanghai Jingze. The company has multiple nonbiosimilar product candidates in early-stage development and antibody drug combinations in mid- to late-stage development for cancer treatment.

HLX02 (trastuzumab) was the first China-made biosimilar to gain approval in Europe, Cao said. “It has been launched in the United Kingdom, Germany, Portugal, and Spain, and used in tier 1 hospitals of Europe,” she said.

Henlius is working to increase the scale of its manufacturing operations to support its global ambitions for sales growth. It has 2 plants currently: one in Xuhui and a second in Songjian, with a total installed production capacity of 44,000 L. Both of these factories were fitted out and made operational within the past 3 years.

In Sonjiang, Henlius has a third plant in development, which Cao said when complete would rank among the largest biologics production facilities in Asia for size. This plant following phase 1 of development would have 36,000 L of production capacity, which would be increased to 45,000 L later on. Henlius currently has a manufacturing staff of 758 employees, Cao said. “For biologics, the important thing is to reduce manufacturing costs. We have our own proprietary technology to enable this mission.”

The company has its own sales team in China and is looking for partners in the rest of the world. The China sales team numbered 400 full-time employees at the close of 2020 and is projected to reach 1000 full-time workers by the end of 2021. Henlius has established relationships with 2700 upper grade hospitals and 30,000 oncologists in China, Cao said.

Shanghai Henlius Biotech began as a 2-person enterprise in 2010 and now has multiple oncology products in development and 3 biosimilars on the market. An executive discusses its business trajectory.

Shanghai Henlius Biotech Maps Out Its Biosimilars Future

Stada Arzneimittel has received European Commission approval for the bevacizumab biosimilar Oyavas and has immediately launched the product in Germany and the Netherlands.

“Launches in other European countries will follow soon, depending in part on national pricing and reimbursement clearance,” the company said in a 

The launch is in partnership with mAbxience, which is an established biosimilar supplier in Latin America.

Stada, based in Bad Vilbel, Germany, said data submitted for the European marketing authorization demonstrated that the biosimilar is equivalent to the reference product (Avastin) in terms of quality, safety, and efficacy for the treatment of colon, rectal, breast, and non–small cell lung cancers, in addition to epithelial ovarian, fallopian tube, cervical, and primary peritoneal cancers.

“Through partnerships, STADA has built a comprehensive biosimilars portfolio and pipeline, not only in oncology, but also in therapeutic areas such as autoimmune disorders, osteoporosis, and ophthalmology, as the group continues to strengthen its presence in the specialty pharma sector, said Stada CEO Peter Goldschmidt.

 to strengthen its biosimilar production capacity in Leon, Spain. 

Seeking to develop a biosimilar portfolio, Stada Arzneimittel has launched Oyavas in Germany and the Netherlands. 

Stada Launches Bevacizumab Biosimilar

A subcutaneous infliximab biosimilar (Remsima SC) candidate from Celltrion Healthcare, of Incheon, Republic of Korea, has received a recommendation for marketing authorization from European authorities. If the recommendation is accepted by the European Commission, “Remsima SC (120 mg) can be used without IV [intravenous] infusion both for new and existing rheumatoid arthritis [RA] patients,” the company said in a 

“IV administration of infliximab requires frequent hospital visits, which can pose a challenge to some patients especially given the current COVID-19 pandemic,” the company quoted RA expert Roberto Caporali as saying.

Caporali is a professor of rheumatology at the University of Milan and head of the Rheumatology Unit of Gaetano Pini Hospital, in Milan, Italy. “The direct subcutaneous induction of the SC formulation of infliximab could potentially shorten drug administration time via self-administration at home, reduce healthcare practitioner time and burden on healthcare system, as well as offering additional flexibility and convenience for patients.”

The recommendation for authorization came from the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA). The recommended Remsima SC dosage for patients newly initiated on infliximab or with new RA diagnoses is an injection at week 0 followed by injections at weeks 1, 2, 3, and 4. Every 2 weeks after, patients would receive maintenance therapy. For patients with a history of treatment with infliximab, Remsima SC would be administered 8 weeks after the final administration of intravenous infliximab.

“If the recommendation of the EMA is accepted by the European Commission, Remsima SC could be used without IV infusion for newly initiated patients as well as patients currently on infliximab treatment,” explained HoUng Kim, PhD, head of the Medical and Marketing Division at Celltrion.

The company estimated that potential savings would be $29 million over 1 year from Remsima SC and IV induction vs IV infliximab alone based on a model enrolling British patients with RA. The potential savings without IV induction would have been $19 million.

 in a high-concentration, citrate-free version of adalimumab. 

Late last year, Celltrion announced plans to 

on a $453.3 million biopharmaceutical plant near its base of operations in Incheon. 

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a thumbs up for a subcutaneous (SC) infliximab biosimilar candidate from Celltrion.

CHMP Gives Remsima SC a Positive Recommendation

It’s not easy to break into the insulin market, and for that reason the public should not expect a flood of insulin biosimilars producers, said a panel of experts on biologics manufacturing at the Festival of Biologics USA.

Insulin is a biologic that is very difficult to consistently produce at high purity in large volumes that would be necessary for distribution, and very few manufacturers have the resources to perfect this process and convince regulators that they can get it right, the panelists said.

Further, the United States is an intensely litigious country for biologics producers, and would-be biosimilar contenders may encounter a barrage of legal opposition from entrenched producers, they said. In the United States, Eli Lilly, Novo Nordisk, and Sanofi produce and distribute an estimated 90% of the insulin.

This relative monopoly has given rise to extraordinary inflation in the cost of insulin products. A report from Mayo Clinic in 2020 observed an 

 in the cost of a vial of Humalog (insulin lispro, Eli Lilly) between 1999 and 2019 ($21 vs $332, respectively).

The United States has attempted to clear a pathway for the introduction of insulin biosimilars. In 2020, the 

351(k) Biologics License Application process

 under the Public Health Service Act became available for insulins and growth hormones, allowing these products to be approved as biosimilars. 

There are no biosimilar insulins so far, although in mid-2020, Biocon and Mylan succeeded in getting an insulin glargine (Semglee) approved under the generic 505(b)(2) New Drug Application pathway and are seeking to have it designated a biosimilar. The panel discussion at Festival of Biologics USA included the participation of 

 vice president and head of Global Regulatory Affairs for Biocon.

Many companies have attempted to bring rival insulin products through the review process in Europe and have failed because the pharmacokinetics of these products are extremely difficult to match precisely with originator products, Ramanan said. “That’s barrier number 1. Barrier number 2 is we need to have economies of scale, and that requires a large capital investment, and not many companies have that to combine with the science. This limits the number of players that are coming in beyond the ones that are truly committed.”

Biocon is one of the success stories, having insulin products approved in more than 60 countries. “It took us a very long time, but now we have that institutional knowledge,” Ramanan said.

 an expert on pharmaceutical marketing who serves as a professor and chair of Brac University in Dhaka, Bangladesh, agreed that manufacturers have difficulty meeting the regulatory expectations for quality. “Regulators are encouraging companies to invest in continuous processing, so that would mean they have the technical mastery over the process. This is easier to say than to do,” she said.

Process validation is another source of regulatory rejections of insulin product applications, she said. Process validation refers to efforts to confirm that drug product of a standard quality can reliably be produced consistently over time.

Insulins are not complex drugs and, in fact, involve a simple amino acid sequence, Ramanan noted. “However, it is not easy to produce insulins of high purity at extremely large scale. That is what scientific capabilities require.” This makes producing insulin biosimilars a challenge, and it’s another reason why the market is not flooded with competitor products, Ramanan said. 

“It’s a production manufacturing challenge at scale. The world consumes many times more insulin than monoclonal antibodies,” which are the standard form of biosimilars commonly available in the United States, said 

 panel moderator and managing director of SBLehrer, an expert on biosimilar commercialization.

The insulin producer competition in the United States remains scanty, and for this reason, prices are unlikely to come down anytime soon, Ramanan said. Another structural problem in the marketplace is the heavy patenting that originator companies do to protect themselves against competition. “It prevents competition and it keeps the price higher for decades,” Kabir said. Multiple versions of insulin products are needed to really tamp down the price curve, she said.

“Due to the litigious nature of the US market, even before a company finishes a clinical study, there is litigation already ongoing,” said panelist 

ice president of Global Regulatory Affairs for Gan & Lee Pharmaceuticals USA

. Therefore, a company needs significant resources to endure these battles and finally get its product to market.

Despite the expansion of the 351(k) licensing pathway, US regulatory efforts to enlarge the insulin product pipeline have been “lagging,” Dave said. “The decision-making right now is really in the hands of the pharmacy benefit managers in the United States.”

Taking all structural conditions into account, Dave said he anticipates that only a “limited” number of companies will develop insulin biosimilars.

Even if the problem of too few competitors can be solved, there isn’t much hope for price reduction. The benefit for patients and health care systems from having insulin biosimilars will not be as dramatic as has occurred for generic drugs, where deep discounts have been achieved, Dave said.

Biosimilars involve costly biologics manufacturing, and biosimilar developers will not be willing to enter market at deep discounts to the originator products. Combining the scarcity of players in the market and the unwillingness to discount products, the problems of low competition and high prices are very likely to persist, he said.

For an article about legislation introduced to grant automatic interchangeability for insulins, click 

Insulin is not a complex drug, but churning it out in massive quantities at high levels of purity is one of the main hurdles inhibiting biosimilar competition, panelists said. 

Panel: Insulin Biosimilar Competition May Be Scant at Best

It is tough enough to get manufacturers to take the plunge and develop biosimilars for even-lucrative drugs that address major diseases, so what are the chances of seeing biosimilars developed for orphan drugs? Very slim, said a panel of experts who spoke at the Festival of Biologics USA conference.

Orphan drugs address conditions that affect relatively small patient populations, and it is difficult to recruit patient populations large enough for clinical trials needed to prove that experimental drugs are going to be efficacious. The expense of development and the small patient base for these agents translate into very high prices, which it is why it is desirable to have lower-cost biosimilar versions.

But with orphan drugs, biosimilar developers face almost the same set of difficulties that originators do. “When you’re talking about biosimilars, this can be considered even more challenging,” said 

 executive director of Global Biosimilars Regulatory Affairs and Regulatory and Research and Development Policy at Amgen.

Biosimilar companies need samples of originator drugs so they can develop their own versions of these agents, but with orphan drugs, access to drug samples is heavily controlled, she said. After that come the clinical trials, and, again, recruiting patients is difficult and time consuming. Patients may not want to participate in clinical trials with a biosimilar candidate if they know that their rare condition is already in stable condition on the originator drug, which further narrows the already small pool of available trial candidates, Christl said.

It may therefore be helpful if regulators are flexible in their demands for evidence used to support orphan drug development and willing to consider alternative means of demonstrating bioequivalence between biosimilar candidates and reference products. “But where should you look for flexibilities from the regulatory and scientific side?” Christl asked. “Can you conduct studies, maybe, in healthy individuals?”

Regulatory approvals that are more reliant on molecular characterization than clinical trials might also be possible, she said. Along the way, it’s important to ensure that patients and providers are confident in the process used to establish biosimilarity. “We need to find ways that are right, from a scientific perspective, to answer the question, to maintain the confidence in those regulatory pathways and what regulators are doing when they’re approving a biosimilar,” she said.

Whatever happens, standards for approving biosimilars cannot be lowered for the sake of making it easier to have affordable medicines, said panelist 

 who served 8 years with the FDA, most recently as acting deputy director of Therapeutic Biologics and Biosimilars. “The FDA has an approval standard, and any product it approves has met that standard. There may be different pathways to that same end point. It may be that one product is approved based on more analytical data—tighter analytical data—and a different pharmacodynamic end point.”

The desire for less costly versions of originator drugs for orphan diseases is just as strong in Europe, said 

director of Biosimilar Policy and Science for Medicines for Europe, an industry group for generics and biosimilars producers. “The price tags are really high, so it’s a problem for patients and for health care systems if there is no prospect of competition ever.”

“In the orphan space in Europe, we are up for a very big overhaul of the regulation and legislation around this. I’m expecting that there will be quite a substantial amount of discussion, not only scientific, but bringing the science and the regulatory processes to serve that purpose and meet those objectives,” she said.

In Europe there have been incentives and other support granted to encourage the development of even originator drugs for orphan diseases, and the question is whether biosimilars will emerge for orphan drugs without the same incentives that were offered to originator companies, Maréchal-Jamil said. “Less than 11% of those orphan biologics have biosimilar candidates in development at the moment, so that gives a little bit of a perspective on the difficulty for biosimilar developers to overcome the risks that are set in front of us at the moment.”

For coverage on the regulatory environment for biosimilars from Festival of Biologics USA, click 

Potential developers of orphan drug biosimilars face daunting challenges to get these drugs approved and onto market, said a panel of experts. 

Are Orphan Drug Biosimilars Too Costly and Difficult to Produce?

In the court of expert opinion, clinical efficacy studies for evaluating biosimilar equivalence to reference products increasingly stand in a gray area. Many experts agree they are not sensitive enough in comparison with other tests to provide convincing evidence of biosimilarity, but regulators in the United States and Europe still hold onto their right to require these tests for biosimilar approval. The United Kingdom’s recent decision not to require these tests, therefore, is “revolutionary,” said 

 who leads Regulatory Affairs Policy at Sandoz and spoke at the Festival of Biologics USA conference.

“This is the way the future will look, so we will see more complex biologicals, which can be developed as biosimilars, without the need for these very large efficacy studies, and the evidence to ensure the safety and effectiveness of biosimilars will be collected by other means,” such as pharmacokinetic studies, Schiestl said.

Such regulatory changes can significantly improve the landscape for biosimilar development and acceptance, panelists at the conference agreed, but too much divergence between national policies can be a hindrance, as it adds complexity, said 

Biosimilar Policy and Science for Medicines for Europe, an industry group for generics and biosimilars producers. “Complexity is never really linked to access or availability in the end. That is just an additional hurdle.”

But it’s important to note that biosimilar approvals are based on the “totality of evidence,” and although the data that regulators will require may be voluminous and diverse, it is certainly not “one size fits all,” panelists said. In other words, US and European regulators are willing to be flexible in their requirements for individual biosimilar applications.

“I think we’re going to see the FDA and the European Medicines Agency be more open, and hopefully that will influence other regulators about what types of data and studies are really necessary to demonstrate biosimilarity," said 

Christl previously headed up the therapeutic biologics division at the FDA, and drawing on that experience, she said the FDA has tended not to provide micro-level, rigid guidance about biosimilar approval requirements simply because it makes sense to stay flexible so that it’s possible to adapt to changing needs and situations.

“You can target the data you need to look at—are there clinically meaningful differences between the products?—and look across the spectrum of different scientific studies, whether they are in the analytical space, looking at functional data or pharmacodynamic end points, vs those traditional clinical end points. I expect that the FDA is going to keep moving forward with that same type of approach,” she said.

Perceptions about what data are essential for biosimilar characterization may change, but ultimately one of the hurdles that must be crossed is the acceptance factor among providers and patients. They’re the ones who need to be convinced, ultimately, that biosimilars are safe and efficacious, so the requirements for regulatory review have to be tailored, somewhat, in that regard, said 

 who served 8 years with the FDA, most recently as acting deputy director of Therapeutic Biologics and Biosimilars. 

“There’s a real push-and-pull that regulators are grappling with around these issues," she said. "On the one hand, there’s a desire, and I think appropriately, to have efficiencies wherever we can and to really harness the flexibility that’s built into the 351(k) biosimilars approval pathway, and to exercise that flexibility appropriately. On the other side of that coin is that we also have patients and health care providers who need to be driving uptake and utilization of these products for that piece of this puzzle to be successful.” Temkin is now in private practice with King & Spalding in Washington, DC.

Insulin products, which are now approved under the Biologics Price Competition and Innovation Act, could help open the door for simplification of regulatory requirements, such that gaining FDA approval for substituting these biosimilars with established brands will be put on an easier gradient, said 

 of Axinn, Veltrop & Harkrider. “I’m sincerely hoping that because insulin is so well understood and such a simple protein, the FDA will be able to work with those who are seeking an interchangeable designation so that the immunogenicity clinical trials, which seem to drive up the cost of development for follow-on biologics, will not be required.”

That, in fact, is the direction the FDA wants to go, Temkin said. “My understanding is that the elimination of that requirement will save many, many months and potentially millions and millions of dollars from the development of biosimilar and interchangeable insulins, which can hopefully catalyze some additional development of those products.”

Regulators want built-in flexibility, and that benefits biosimilar developers, but there can be a price for this amount of latitude, panelists said.

Biosimilar Experts Debate Divergence in Regulatory Standards

Brexit, the United Kingdom’s official exit from the European Union after nearly half a century, has brought new challenges for the biopharmaceutical industry and, for those based in the United Kingdom, the potential for regulatory reforms that enhance their business opportunities, according to Maria Manley, LLM, a London-based partner with Sidley Austin and a widely respected expert on the life sciences.

In an interview with The Center for Biosimilars

, Manley discussed the complex regulatory and business restructuring adaptation to the new Brexit landscape, the significance for biosimilars producers, and the British government’s goals for this new arrangement.

“A lot of pharmaceutical companies had to make significant changes to the way they were operating in the United Kingdom and in the European Union,” she said. For example, companies that wanted to continue marketing their products in the European Union had to make sure the corporate entities holding European “marketing authorization” for products were properly domiciled, “so they had to transfer their marketing authorization from the UK entity into an EU entity.” Packaging labels had to be changed, too, and clinical trials had to be managed differently, among other changes.

Although it was costly and complicated for the corporate sector, Brexit meant certain advantages also. “It led to a free trade agreement with no tariffs and no quotas,” and an accord was reached on product certification and good manufacturing practice (GMP) inspection between the United Kingdom and European Union. “The acceptance of natural recognition of GMP inspection and certification are obviously very important to the industry because they avoid duplication and extensive cost,” she said.

The United Kingdom’s final departure from the European Union, which it joined in 1973, took effect December 31, 2020.

When the United Kingdom was a member of the European Union, goods could travel between Europe and the United Kingdom without taxation or quotas. That hasn’t changed.

Now, people may no longer move freely across EU and UK borders when choosing where to live and work. Visas will be required.

The Republic of Ireland remains an EU country, and Northern Ireland, which is part of the United Kingdom, will continue to follow many EU rules.

Through Brexit, the United Kingdom became free to set its own trade policy and negotiate deals with other countries.

What still represents a problem for companies that do business across national boundaries is the Northern Ireland Protocol, a subsection of Brexit that allowed Northern Ireland, which is part of the United Kingdom, to continue following some EU rules. This affected the movement and border checks of goods from Great Britain into Ireland. “Two sets of legislation apply: one to what we call Great Britain [Wales, England, Scotland], and another one to Northern Ireland, and this is a complete nightmare to the industry,” Manley said.

Despite the stress and complexity of Brexit, there has been minimal effect on the supply of drugs, and this is partly because the United Kingdom has temporarily acknowledged marketing authorizations previously granted to drugs in the European Union, which makes it possible for continued distribution in the United Kingdom. “Affected companies have a period of 1 year to submit the essential [clinical/regulatory] baseline data to the regulatory body, the Health Research Authority, and to establish a presence in the United Kingdom if they didn’t have it, and that is until January 2023,” Manley said.

Protecting the interests of the pharmaceutical sector in the United Kingdom was paramount because not only do patients need continuity of quality health care, but the life sciences sector in the United Kingdom employs 260,000 individuals and contributes $41 billion annually to the local economy, Manley said. “Having been an essential EU partner for so many years, the United Kingdom needs to make sure that they offer a legal environment that stimulates both innovation and also investment.”

There remains close alignment between the UK and EU regulatory systems for biological products, according to Manley. However, the United Kingdom and its Medicines and Healthcare products Regulatory Agency (MHRA) have simplified the legal framework for biologics and biosimilars companies to apply for marketing authorization. In the United Kingdom, the new guidance and legislation make animal toxicology studies unnecessary for biologics developers, as these studies are rarely considered necessary, and comparative clinical efficacy studies will not be required unless there are very good reasons for doing them.

The new approval pathway for biologics is designed around accelerating the progress to market for experimental innovative medicines, and further, the United Kingdom has signaled that regulators “would be eager and willing to accept real world evidence in support of regulatory submissions. That’s quite an interesting new pathway, because it also involves other stakeholders who are crucial for having effective market access, which are the payers and other entities we have in the United Kingdom who assess the cost-effectiveness of a product,” Manley said.

Another feature of Britain’s now-independent medicines approval process is the “rolling review” that UK regulators employed to do a controversially rapid assessment of the Pfizer/BioNTech COVID-19 vaccine (Comirnaty) in 2020. UK countries became the first in the world to begin vaccinations with Comirnaty, and in defense of the rapid approval process, UK regulators insisted that it never got ahead of the availability of confirmatory data.

Rolling review “is meant to reduce the risk of failure at the final stage and to ensure that the application is moving as fast as possible and addressing any potential issue that the regulators may have,” Manley said. This review is available for any new active substance, including biosimilars and other biologics.

Also defining the UK system of approvals is the Accelerated Access Collaborative (ACC), which is a multistakeholder partnership (patients, industry, payers, regulators) to speed up patient access to innovative new treatments. This was established prior to Brexit, but “the ACC is now the umbrella organization for support of UK health innovation, particularly focusing on medicinal products, including biologics and biosimilars,” Manley said.

Although challenging for the United Kingdom, separating its medical products regulation from the European Union’s has engendered optimism that systems are in place to spur investment and enable Britain to “retain the position of one of the best life sciences platforms in the world,” and this involved the United Kingdom listening to what the industry was saying about its difficulties, Manley said.

“They’ve been extremely good in realizing that if the market of the European Union was going to be challenging, the rest of the world was available. We’re looking toward being more global, trying to avoid duplication, reducing the time for procedures, and making it very attractive to the industry. We also have a pool of technology—whether genomics, artificial intelligence, or first class scientists—which is there to stimulate this innovation. And obviously, if we’re successful with this, there would be more drug development investment in the United Kingdom.”

A key development that sets the United Kingdom apart from the European Union is the way Britain has responded to an EU stance that the market for medicine is not sufficiently competitive and doesn’t fully address the needs of patients for access and affordability. In Europe, fears are rising that pricing and other data disclosure requirements will be broadened and intellectual property rights diminished. The United Kingdom via the trade and cooperation agreement (TCA) established for Brexit has styled itself as a haven from these potential changes.

“There is concern by the industry that the market exclusivities for orphan drugs and pediatrics medicines which are currently in place may change and may be reduced by the European Commission in the years to come, while the United Kingdom has made sure, in the negotiation of the TCA, that companies get the possibility to depart from Europe, in the sense that they keep a very high level of protection of those rights,” Manley said. “The United Kingdom has also confirmed that they want to protect the confidential nature of commercial pricing discussions with companies.”

A renowned expert on the life sciences industry in the United Kingdom provides an insightful look at Brexit and the importance for the pharmaceutical sector. 

The Brexit Rollout From the Biosimilars Perspective

AbbVie, maker of the blockbuster originator product Humira (adalimumab), has filed suit against biosimilar developer Alvotech of Iceland for unlawful receipt of trade secrets related to production of its very successful high-concentration (HC) formulation of adalimumab. In Europe, the HC formulation has achieved 

 of the adalimumab market while in the United States it’s roughly 70%.

AbbVie alleges a former employee, Rongzan Ho, stole proprietary adalimumab manufacturing information from his offices at AbbVie in 2018 and took that information with him to Alvotech, where he was allegedly employed on development of the adalimumab HC biosimilar AVT02, for which Alvotech is now attempting to gain regulatory approval in both the United States and Europe.

The AbbVie suit was filed March 19, 2021, in the US District Court for the Northern District of Illinois. In response to a request for comment made by The Center for Biosimilars

, Alvotech said it "strongly disputes AbbVie's allegations of wrongdoing relating to AVT02" and would "vigorously defend" itself.

. “Instead of investing the necessary time and resources to independently develop the manufacturing process for its biosimilar, Alvotech embarked on an unlawful plot to surreptitiously take AbbVie’s confidential and proprietary trade secrets related to the confidential large scale manufacturing process for Humira in order to develop and manufacture its copycat product.”

AbbVie claims Ro tried 3 times to transfer the trade secrets to his private email account but was blocked twice by a security program. On the third try, Ro managed to fool the system into unblocking his transmission. AbbVie says Ho was a team leader of upstream manufacturing at AbbVie and left the company in February 2018.

The company says Ro claimed on his exit forms that he was going to Alvotech “mainly to learn single-use bioreactors and other new technologies.” In fact, AbbVie says, Ro took the disputed information with him to Alvotech in order “to develop and implement the manufacturing of” AVT02 in competition with the concentrated adalimumab formulation that AbbVie has successfully used to retain and grow market share in the face of growing international competition.

In response to the suit, Alvotech noted that AbbVie waited over 3 years from the date of alleged trade secret theft before filing suit and didn't name Ro as a defendant. "This lack of urgency causes Alvotech to question the motivation behind the case. Indeed, Alvotech believes that the case may be part of a larger AbbVie strategy to delay an emerging competitor from providing patients with a lower-cost alternative to AbbVie's Humira high-concentration product," Alvotech said. 

 in global 2020 revenues, and all of the competition currently is in lower-concentration adalimumab, which is increasingly less preferred by patients and providers. The HC, citrate-free version involves less pain for patients.

AbbVie also contends that in May 2020, Alvotech hired 2 other AbbVie employees with “intimate knowledge” of the adalimumab manufacturing process.

In November 2020, Alvotech announced that the FDA and European Medicines Agency had 

 biologics license applications for AVT02.

The company claims in a suit that a former employee transferred high-concentration adalimumab trade secrets to his laptop and took those to a new job with Alvotech.