The Center for Biosimilars Staff

BioCND, a South Korean biopharmaceutical company, 

 that it will begin clinical development in Korea of ranibizumab, a biosimilar of Genentech’s Lucentis® injection for patients with wet age-related macular degeneration (wAMD), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME).

Globally, other companies have already begun clinical development of ranibizumab.  

In January 2016, California-based Pfenex completed Phase I and II trials on PF582, its ranibizumab product.  Munich-based Formycon AG and bioeq GmbH 

 that they had begun enrollment for a Phase III study involving FYB201, Formycon’s biosimilar of Lucentis.  Intas Pharmaceuticals also 

 its Lucentis biosimilar, Razumab, in India in June of last year.

Articles

BioCND to Develop Lucentis Biosimilar

the top eight barriers to the development and access of biosimilars are highlighted. Drug quality, safety and the population health needs, a deep knowledge of biosimilar development, as well as joint effort of the manufacturers and their will to share the critical development data are some of the primary concerns:

Changes to the manufacturing process of biosimilars compared to their original counterpart aren’t advised, but changes are somehow inevitable as the manufacturing data for the reference product is not accessible for the biosimilar manufacturers, as it is property of the innovator manufacturer, even after the patent expiry. Modifications can also be made to improve the quality, efficiency and reliability of the manufacturing process or the end product. These changes may lead to structural differences, resulting in efficacy modifications and with potential insurgence of adverse effects, i.e., immunogenicity. In these cases, further non-clinical and clinical evaluations might be needed to evaluate the product, depending on the extent of modifications.

The extrapolation across indications is a concept pointing that, when the clinical data for a biological drug is generated for one therapeutical indication, they can be extrapolated to other indications, taking into account, for the drug efficacy and safety, of the overall information gained from the comparability exercise.

In the context of biosimilars, extrapolation from one indication to another may be considered if biosimilarity to the reference product has a comprehensive comparability, including efficacy, safety and immunogenicity, suitable to detect clinically relevant differences, in particular if the mechanism of action of the active substance and the target receptor(s) is the same. In Europe, this concept has been successfully implemented with biosimilars of EPO, filgrastim and infliximab.

 product involved, it is important to consider other factors that can be potentially immunogenic, such as the variation in the glycosylation pattern, denaturation or aggregation, the presence of impurities in the solution, dose, route of administration, treatment duration and genetic characteristics of patients. Hence, the immunogenicity of a biosimilar must always be deeply investigated.

Manufacturers need to plan an extended post-market surveillance, that is very important to grab the immunogenic phenomenon, as well as efficacy in the different diseases. The biosimilar guidelines state that the 

 plan should be included in the data submitted for the registration of a biosimilar.

Products approved for the same indication can be considered 

and used for the said indication. This is not to be confused with the term 

, which refers to the product that can be used in lieu of another during the same therapeutical treatment.

Generic drugs are usually considered therapeutically equivalent with their reference products. In these cases, substitution is permitted. As already underlined, biotechnological drugs are distinct from chemical drugs and it’s difficult that two biologic drugs could be exactly the same. It is widely agreed by a broad consensus of the scientific, regulatory and industry communities, that biotechnological drugs have the potential to present unique risks when switched, without involving the prescribing physician. 

WHO has proposed the Biological Qualifier scheme, applicable to all biological substances assigned INN’s, which can be adopted on a voluntary basis by any Regulatory Authority. This scheme will assign a code of four letters at random to complement the INN for a biological compound and it will uniquely identify directly or indirectly the manufacturer and manufacturing site of the active substance in a biological product.

Efficacy and safety are the primary concerns. Since the active substance of a biosimilar is not identical to the active substance of the reference product, the regulatory requirements for approval of generics are inadequate to demonstrate the quality, efficacy, and safety of biosimilars.

The clinicians often look at clinical data to determine the efficacy and safety of a drug. For biosimilars, in some cases, the clinical data can be reduced, if the comparison of structural and functional characteristics is comprehensive. Moreover, in some Countries, problems have been reported on biological drugs which are erroneously called biosimilars, due to the inconsistent use of the terminology. Sometimes, clinicians are just not well informed about the scientific concept regarding the development and licensing of biosimilars. This can lead to the fear of their use for some of proposed indications, especially for those for which no specific clinical trials have been performed, but data are extrapolated based on the efficacy and safety for other indications.

Biosimilars can lead to significant cost reductions, not only for the final recipients, but also for governing authorities who have reimbursement policies for the pharmaceuticals. Each Regulatory Authority has its own guidelines for the comparability of biosimilar to its reference product. These differences make hard for the manufacturing companies to reduce the productive costs of these products, as they may have to establish different comparison in different countries.

Quality, safety, and knowledge are critical.

What Are the Eight Barriers to Biosimilar Development?

A notably larger percentage of US physicians say they intend to prescribe biosimilars in the coming three years. However, fewer would allow pharmacy-level substation of these drugs for their patients than just six months ago, and they are weighting more factors into their choice of potentially prescribing biosimilars at all, as reported by InCrowd, a provider of real-time market intelligence to the life sciences and healthcare firms.

new biosimilars prescribing intentions report 

showing that 84% of physicians across five subspecialties in which biologics prescribing is significant -- dermatology, endocrinology, gastroenterology, oncology and rheumatology -- surveyed in September 2016 said they expect to prescribe, assume they will prescribe, or look forward to prescribing more biosimilars in the next 3 years -- up from 70% in February 2016. The figure reflects a decrease in those physicians who would only prescribe biosimilars if they were forced to do so, or there were specific patient conditions that warranted a move away from the originating biologic -- from 26% in February to 16% in September.

However only 17% of total physicians surveyed in September said they would not prohibit biosimilars substitutions on their prescriptions for the originator biologic, down from 28% in February. Verbatims echoed their increased caution. "At this time I would not be amenable to switching a patient from a stable medication without significant data to prove complete compatibility," said one rheumatologist. "I would wait and let other doctors experiment on their patients," said an oncologist."

In addition, among the top 10 most important factors in deciding to prescribe a biosimilar, physicians now are placing greater emphasis on thought leader opinions and professional organization guidelines -- now at 55%, from 46% in February -- as well as patient acceptance of biosimilars, up to 49% from 40%.

"Data reflect that during this time when biosimilars are of strong interest to insurers and health care systems for cost control, physicians are not rushing to issue a blank check for their substitution, and are keenly aware of their need to thoughtfully consider any such use," said Diane Hayes, president and co-founder of InCrowd.

The September survey on US physician prescribing intentions with biosimilars also showed:

Given the choice, roughly the same percentage of physicians - 35% in September compared with 36% in February -- plan to prescribe original biologics first and foremost.

The majority of physicians are still looking for discounted pricing if they're going to prescribe biosimilars -- 59% would prescribe a biosimilar over the originator at 15% discount, 77% at 25% discount -- figures that remained roughly the same in the past six months. 

A notably larger percentage of US physicians say they intend to prescribe biosimilars in the coming three years.

Six Months Makes a Difference: Physicians' Attitudes About Biosimilars

What are the top five issues connected with biosimilars that pharmacists should know? Erika Lietzan, JD, associate professor at the University of Missouri School of Law, provided some legal guidance for pharmacists and physicians during a 2015 Wolters Kluwer Clinical Drug Information webinar.

Biosimilars will most likely be branded, and physicians will be prescribing by brand name. These branded products are not substitutable, according to Lietzan. As a result, pharmacists will be dispensing the product as prescribed. “I don’t perceive any particular challenges for pharmacists dispensing these products; the prescriber will write a script, and the pharmacist will dispense what was written,” Lietzan said.

Insurers may require that the biosimilar — rather than the reference product – be dispensed, as biosimilars will likely cost approximately 15% to 20% less than the reference product. “A physician might write a script for the reference product, and the pharmacist might discover that the insurance covers only the biosimilar, so that may entail some back-and-forth [with the physician],” Lietzan said.

FDA has proposed that the names of all biosimilar agents contain four-letter suffixes to ensure that the branded drug can be distinguished from the biosimilar version in instances of manufacturing changes or adverse events.

“To ensure continued safety of a biological product, appropriate pharmacovigilance necessitates that FDA have the ability to track adverse events to a specific manufacturer (and as appropriate, site or lot for a particular biological product) and that surveillance systems be able to detect safety signals throughout the lifecycle of a product so that the Agency and the manufacturer can act swiftly and in a targeted manner to identify and address a problem,” the FDA wrote in its draft guidance. However, FDA has encountered many objections to this proposal. The Federal Trade Commission (FTC), for example, said in late October that the FDA draft guidance on biosimilar naming may hinder competition, and FTC recommended that the agency consider alternatives.

Pharmacists may need to provide adverse event information connected with biosimilars to physicians, who will submit reports to the FDA, or they will submit the report themselves. “One issue will be getting the adverse event reporting right [whether it’s the pharmacist or the physician reporting to FDA].  It is going to be really important to provide as much [information] as possible about the product the patient took and, especially, if the nonproprietary name is being used, to remember the suffix,” Lietzan said.

Because biosimilars — including Zarxio, the first FDA-approved biosimilar drug – are likely to be specialty drugs, they may be dispensed by specialty pharmacies.

“Maybe there will be some issues related to the use of specialty pharmacy down the road, but it’s hard to know what they will be,” Lietzan said. “A lot of products are physician-administered, so the issue isn’t specialty pharmacy vs. ordinary pharmacy; it’s dispensing by a specialty pharmacy vs. patients obtaining it from the hospital pharmacy.”

Top 5 Biosimilar Facts for Pharmacists

The biopharma industry has the opportunity to change lives--and possibly the world--with the creation of biosimilars. Patients get more treatment options, with more access to global medicines and new revenue streams to the marketing authorization holders (MAHs) who bring products to market.

With many patents of branded biologics expiring, the biosimilars industry holds incredible growth potential, with a September 2015 report predicting revenues from such products will grow to $

, up from $2.5 billion in 2014. While biosimilars are approved as highly similar versions of already authorized biologics, MAHs will have to convince regulators, payers, physicians and patients that they are as safe and effective as their originators when used in the real-world.

To convince these various stakeholders, MAHs will need to generate comprehensive and convincing data to support the safety and effectiveness of their products. A key component of that process is the evaluation of real-world evidence to augment data generated by the analytical studies, animal studies and clinical studies that can fill the evidence gap for decision-makers. Real-world evidence generation strategies should be part of the post-approval plan from the outset with early planning taking into account how to accommodate the unique interests of all relevant stakeholders.

Once regulatory approval is obtained, regulatory agencies are mainly concerned about safety issues, including delayed risks, while clinicians and patients have interests in both clinical effectiveness and safety, as well as how the risks and benefits of one treatment compare with another, particularly for patients who switch from the originator biologic.

Payers’ interests will be similar to physicians and patients, but they will consider these issues through the lens of economic risk-benefit considerations and how use of the biosimilar impacts related medical care.

MAHs may also want to consider how the interests of these stakeholders vary across different markets. For example, while the National Health Service in the U.K. provides coverage from "cradle to grave," in the US, the average duration of coverage by private health insurance for an adult member under age 65 is about 2.5 years, thus delayed risks and benefits may be less important to stakeholders in those markets that do not provide lifetime coverage, 

Economic considerations are also important to patients and healthcare providers, since in some countries, including China and India, patients directly bear the costs of pharmacotherapy. These economic considerations must be balanced with benefits achieved in broader population access to these life-altering treatments. Crafting an evidence generation strategy targeting the needs of all of these varied players will help MAHs assemble a more convincing body of high-quality data to support the real-world safety and effectiveness of their products.

Convincing data to support the safety and effectiveness is key.

Looking to 2017: Market Access for Biosimilars 

Sanofi is investing $80 million in biopharma JHL Biotech as part of a strategic collaboration to develop biologics for the Chinese and potentially other international markets, as reported by 

Genetic Engineering and Biotechnology News

. Under terms of the agreement Sanofi will also pay the Taiwan-based startup $21 million up front for exclusive rights to a proposed Rituximab biosimilar, along with options to other specified JHL pipeline products.

JHL will take the lead in product development, registration, and manufacturing, while Sanofi will shoulder commercialization efforts in the Chinese market. JHL could receive milestones of up to $236 million, plus royalties.

Sanofi said the partnership is in line with its commitment to invest in the development of high-quality biologic therapeutics for the Chinese market. “JHL has quickly developed leading capabilities in the development of biologics and I am confident that our alliance will positively impact lives of patients in areas of high unmet medical needs in China,” commented JeanLuc Lowinski, president of Sanofi China and svp of Sanofi Asia.

JHL Biopharma carries out preclinical and early-stage development of biosimilars at its JHL Center of Excellence in Taiwan, and earlier in 2016 opened its commercial-scale manufacturing facility for biosimilars and monoclonal antibodies, in Wahun, China. The Wahun site represents 

the world’s first KUBio™ modular biopharmaceutical manufacturing facility

 with single-use bioprocessing technology. Last month JHL inked a manufacturing services agreement with Singapore-based Aslan Pharmaceuticals, under which it will work with Aslan on process development and manufacturing of the latter’s IL-4/IL-13-blocking fully human mAb, ASLAN004, for clinical trials.

Biosimilars in Development for Chinese Market Via Sanofi Partnership

South Korea’s Celltrion Inc., has said the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization to its Truxima (rituximab), a biosimilar to Roche’s Rituxan, which is indicated for blood cancer. The recommendation, 

 is based on data from various studies that showed Truxima is bioequivalent to its reference drug Rituxan in safety and efficacy. 

Market authorization usually follows the recommendation two to three months later, which was made by experts who reviewed efficacy and safety data of the drug. The EMA’s approval is equally effective in 27 European Union members and three European Economic Area countries - Norway, Iceland and Lichtenstein. 

The recommendation for Truxima is applied to all indications of its reference drug, which include non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. 

Truxima was approved in Korea last month. The manufacturer aims to receive approval in Europe early next year and to plan to submit a New Drug Application (NDA) with the U.S. counterpart FDA in the first half of next year. 

“We are working to launch Truxima in Europe with an anticipated milestone of regulatory approval early next year. The milestone will serve as an opportunity to reaffirm our vision to play as a first mover in the market and achieve 10 trillion won ($8.42 billion) in sales within 10 years and join the the top 10 list of global biotech companies,” said Celltrion president Kim Hyung-ki. 

A biosimilar to Roche’s Rituxan, Truxima (rituximab) is indicated for blood cancer.

Celltrion's Biosimilar Granted Marketing Approval Recommendation

The legal war for CRISPR gene-editing technology is heating up, with several biotechs joining forces to coordinate the defense and enforcement of key patents. An invention management deal has been struck by CRISPR Therapeutics, Intellia Therapeutics, Caribou Biosciences and ERS Genomics covering the CRISPR/Cas9-related intellectual property owned by the University of California, Emmanuelle Charpentier and University of Vienna, according to 

The Broad Institute and Editas Medicine, which draws its IP from the Broad, disagrees. While the University of California's Jennifer Doudna published the landmark 2012 study showing CRISPR's gene-editing potential, The Broad believes its researcher Feng Zheng made the crucial scientific step which demonstrated CRISPR could be applied to human DNA. Under now-changed patent rules, The Board was awarded the initial patent. 

UC is challenging that decision by the U.S. Patent Office through a process known as "interference." The first and only oral arguments in the case were held earlier this month and a decision is likely sometime next year.

"Intellia, CRISPR Therapeutics, Caribou and ERS view this agreement as enhancing the efforts to protect our shared intellectual property rights and support the ongoing development of our product candidates, as well as those of our corresponding partners and licensees," Novak said. 

Per the deal, each of the co-owners (i.e. UC, Charpentier or the University of Vienna) grants so-called cross-consents to "all existing and future licenses based on the rights of another co-owner." The agreement unites the biotechs aligned with UC into a more cohesive group opposing the Broad and Editas. Yet even if the Broad wins, the impact to the biotechs themselves may less damaging than first appearances. 

A verdict would probably force the biotechs on one side or the other to negotiate new licenses from the winning party, according to 

. That would cost money and could entail royalties for any future products that make it to market. Biotechs on each side should be able to continue their march towards human testing of CRISPR. 

Key patents for gene-editing technology are at stake.

CRISPR Biotechs Create IP Pact: More Legal Battles Ahead?

In February 2017, the European Medicines Agency (EMA) plans to test the added value and feasibility of tailored scientific advice for the development of biosimilar medicines.

The pilot is open to all companies seeking scientific advice for the development of a biosimilar medicine, and planned to run until six scientific advice requests have been completed, with maximum one scientific advice request accepted per month, per the 

. The objective of the pilot is to give developers of biosimilars advice for conducting studies/tests based upon qualitative, analytical, and functional data already available for the product, and to support the recommended biosimilars development within European Union (EU) guidelines.

Per the EMA, any type of biosimilar will be accepted in the pilot.

Companies that would like to take part in the pilot will have a pre-submission meeting during which the suitability of the data package is reviewed. The EMA’s Scientific Advice Working Party will need an extra month in addition to normal scientific advice timelines to review the requests accepted in the pilot.

Breadth and depth of established data will determine study approach.

EMA Plans Pilot for Biosimilars Developers 

Global and China Biologics and Biosimilars Sales Market Report 2020

, the burgeoning pressure on healthcare system has caused the regulators across the globe to look for suitable therapeutic options. Biologic drugs are commonly used for treatment of various diseases but they are costly and their alternative options are difficult to find. Biosimilars have come forth as new modality having lesser cost with equivalent therapeutic efficacy like biologics.

They are introduced in market after patent expiry of biologics and Europe became the first market to allow commercialization of biosimilars. European Commission (EC) passed legislation in 2004 creating approval pathway (Directive 2001/83/EC Directive 2004/27/EC) for biosimilars. European Medicines Agency (EMA) approved first biosimilar in 2006, since then several biosimilars have been introduced in European market owing to applicability in numerous indications and higher cost arbitrage. In this way, European nations are expected to relieve burden from their healthcare system with the help of biosimilars.

Safety and efficacy are main concerns with biosimilars; EMA requires head-to-head comparison for ensuring pharmacological parameters. Ensuring similarity or high similarity in bioanalytical way decreases market winding time. Consequently, clinical trials could be conducted with higher confidence levels to ensure patient safety. Many biosimilars belonging to different categories for different indications has been introduced in past years. 

They have been able to erode profit margins of biologics in past decades. Wide acceptance could also be observed leading to higher prescription for biosimilars as compared to biologics. This scenario shows that biosimilars developers will have lots of commercialization opportunities in European market.

Biosimilars have been introduced for several disease categories offering myriad of options to the patients. Cancer supportive therapies have large consumer base due to which associated biosimilars are in high demand. Filgrastim and Erythropoietins biosimilars are one of the widely used products in European market. These well-established segments have numbers of products as compared to other disease categories. Biosimilar monoclonal antibodies are in high demand as they have high safety and efficacy along with minimized side effects. Their cost is also lesser as compared to biologic monoclonal antibodies. 

Besides this, biosimilar insulin has also been introduced which have capability to generate significant revenues. Biosimilar insulin has created as new segment due to which more biosimilar products are expected to enter in coming years. In this way, European biosimilars market shows diverse categories and opportunities to venture in newly developed segments.

Extrapolation of biosimilars is allowed after establishing significant comparability with reference biologics. Depending on quality profile they are approved by EMA and biosimilar developers have to submit Risk Management Plan (RMP). This measure ensures that biosimilars entering in European market are harmless. Biosimilar developers from developing countries find it difficult to enter in European market as their fall short of EMA's standards. On the other hand, outsourced biosimilars products showing compliance with EMA's norms are allowed for commercialization. In this way, biosimilar developers from under developing countries find Europe as a suitable market place.

Their competitive prices and highly developed manufacturing capabilities have also contributed in growth of European biosimilars market.

New report: biosimilars outlook for 2020.