From clinical trials to dealmaking to biosimilars launches, the biopharma landscape grows increasingly global

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Clarivate Analytics | Biopharma news and views for CPhI India 3

Three quarters in, enthusiasm is high for biopharma deals in 2018, less so for M&As 5Mylan and the FDA score a first with approval of Neulasta biosimilar 8Increasing globalization in biopharma highlights differing management styles, cultures 10Biosimilars on the rise in India; technology, capital remain challenges 12Sandoz and Biocon join forces in global biosimilar deal in immunology, oncology 14Pan-European HTA regulation garners mixed review from industry 16China becomes hot spot for early stage trials; talent scarcity brings higher costs 18

Table of contents

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Dealmaking across the biopharma industry continues to be robust – and is increasingly international. A biosimilar co-developed in India makes history. And, as always, the industry watches regulatory changes in every market, from Asia to Europe to the U.S., carefully. This collection of feature articles, compiled from BioWorld, the daily biopharma news service from Clarivate Analytics, looks at developments across the life sciences in India and around the world in 2018.

Introduction

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Three quarters in, enthusiasm is high for biopharma deals in 2018, less so for M&As By Karen Pihl-Carey, Analyst

Dealmaking for the biopharma industry has continued its steady climb through the third quarter of 2018, completing 18 percent more deals that in total are worth 25 percent more than they were this time last year. (See Biopharma deals: 2017-2018, below.) The enthusiasm wavers, however, when analyzing the world of mergers and acquisitions. While the year shows a 22 percent higher volume and a 35 percent higher value when compared with this point in 2017, the third quarter depicts a steep drop in M&A value over the first two quarters of 2018.A total of 899 biopharma deals, including licensings and collaborations, occurred in the first three quarters of 2018, according to Cortellis Deals Intelligence. Those deals were valued at $79.98 billion, and compared with 738 deals worth $60.32 billion over the same period last year.

Deal volume for the third quarter towered by 39 percent over the same timeframe in 2017 – 329 vs. 202 – even though the deal value was only 10 percent higher at $29.9 billion vs. $26.8 billion, respectively. (See Biopharma deals: 1Q-3Q, below.)

Affimed/Genentech deal best of the quarterOut of the top 10 deals for this year, all four that fell within the third quarter are focused on oncology.Leading the pack is an August agreement between Affimed NV and Roche Holding AG unit Genentech Inc. projected at signing to be worth $5.046 billion. The companies will develop and commercialize natural killer cell engager-based immunotherapeutics for solid and hematologic tumor targets worldwide. It is the second largest deal of the year behind Merck & Co. Inc. and Eisai Co. Ltd.’s $5.76 billion deal for cancer drug Lenvima completed in March. (See BioWorld, Aug. 29, 2018.)Les Laboratoires Servier SAS closed its deal in the third quarter to acquire for $2.4 billion the oncology business of Shire plc, including Oncaspar for acute lymphoblastic leukemia and Onivyde for pancreatic cancer, as well as calaspargase pegol, which could

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Biopharma deals: 2017-2018

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succeed Oncaspar and has a PDUFA date set for the fourth quarter. (See BioWorld, April 17, 2018.)A $1.7 billion deal signed in July between Immatics Biotechnologies GmbH and Genmab A/S aims to discover and develop next-generation bispecific cancer immunotherapies using Xpresident technology worldwide. And a $1.66 billion deal signed just two weeks later between Sutro Biopharma Inc. and Merck & Co. Inc. seeks to develop immunomodulating cytokine derivatives for cancer and autoimmune disorders worldwide. (See BioWorld, July 13, 2018.)Other notable worldwide deals in the third quarter include a $1.34 billion pact between Mologen AG and Oncologie Inc. to develop and commercialize lefitolimod for immuno-oncology, as well as a $1.25 billion deal between Fate Therapeutics Inc. and Ono Pharmaceutical Co. Ltd. to develop and commercialize two induced pluripotent stem cell-derived chimeric antigen receptor T cell products for cancer. The Mologen/Oncologie deal was an expansion to a first-quarter deal focused on China and other Asian countries.

M&A deal value dropsWhile more money and interest seems to rest with licensings and collaborations, the M&A landscape leaves much to be desired for the biopharma industry. The number of completed M&As has increased modestly, but the third quarter of 2018 shows the value at only $10.4 billion, lower than any of the previous six quarters. The sharp decline is in contrast to the $38.6 billion and $36.2 billion in M&A values for the first two quarters of 2018, respectively, which are the two highest of the last seven quarters. (See 1Q-3Q completed M&As, below.)

In the first three quarters of 2017, a total of 77 M&As valued at $55.65 billion were completed. That compares with the 99 completed M&As valued at $85.1 billion in the first three quarters of 2018. While year-over-year 2018 showed a 35 percent higher value in completed M&As, the third quarter contributed only about 12 percent of the total.Three M&As completed in the third quarter stand out, falling in the number eight and nine spots of the top 10 this year. They include Roche’s $2.4 billion acquisition of Foundation Medicine in July, and Advent International’s $2.3 billion acquisition of Sanofi SA’s generics business Zentiva in September. (See BioWorld, June 20, 2018.)Some other notable M&As include PTC Therapeutics Inc.’s $945 million acquisition of gene therapy company Agilis Biotherapeutics Inc. in August, Novo Nordisk’s $800 million acquisition of smart insulin developer Ziylo Ltd., also in August, and Roche’s $780.94 million acquisition of immuno-oncology specialist Tusk Therapeutics Ltd. in September. (See BioWorld, July 23, 2018, Aug. 20, 2018, and Oct. 1, 2018.)

Most deals from North America, oncology-focusedIn line with the typical findings from prior quarters, the majority of deals were completed by North American-based companies. Broken down by principal company headquarters, there were 160 deals done from those based in the U.S. or Canada, 98 from those based in Europe, and 60 from those based in Australia/Asia. When looking at completed M&As during the third quarter, the breakdown was 19 for U.S./Canada-based companies, 12 for European companies, and two for Asian companies.

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In terms of therapeutic area, M&As completed during the third quarter were across the board, with the most, six of them, concerning companies focused on cancer. Oncology also led the way for licensings and collaborations, with 86 deals during the third quarter focused on cancer therapeutics,

and the next highest number of deals, 29, focused on neurology/psychiatric therapies. The rest of the deals were spread evenly across several different therapeutic areas, including infection, endocrine/metabolic and dermatologic therapies. s

– BioWorld Insight, October 15, 2018

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Mylan and the FDA score a first with approval of Neulasta biosimilar By Mari Serebrov, Regulatory Editor

Mylan NV has accomplished what others have failed to do – get FDA approval for a Neulasta biosimilar. The licensing of Fulphila (pegfilgrastim-jmbd), co-developed with Biocon Ltd., of Bangalore, India, also scores a first for the FDA, which has been playing catch-up with the EMA’s head start on the biosimilar path. Although the EMA has authorized 43 biosimilars since 2006, it has yet to approve a biosimilar to Amgen Inc.’s Neulasta, which is used to treat neutropenia in patients on chemotherapy in certain types of cancer.In another first, the FDA didn’t hold an advisory committee meeting on Fulphila, even though it was the first biosimilar referencing Neulasta. The agency generally convenes an advisory committee for the first proposed biosimilar to a given reference biologic, especially if there are novel scientific or regulatory questions that need to be discussed.“The FDA did not hold an advisory committee meeting for this product, because we determined that the application did not raise issues that needed discussion,” FDA spokesman Jeremy Kahn told BioWorld.While Fulphila can claim several firsts, it is not the first pegfilgrastim biosimilar approved in a regulated market. Apobiologix, a division of Toronto-based Apotex Inc., claimed that honor last week when Health Canada approved its Lapelga.Apotex was the first in line to snag FDA approval for a pegfilgrastim biosimilar, with the agency accepting its application in December 2014. But whatever happened with the application remains between the agency and the privately held company, as Apotex has been mum on the subject.Getting approval for a biosimilar to Amgen’s long-acting G-CSF drug hasn’t been an easy task for anyone. After greenlighting Sandoz Inc.’s Zarxio (filgrastim) as the first U.S. biosimilar in 2015, the FDA accepted Sandoz’s application for a Neulasta biosimilar later that year, but then handed the company a complete response letter (CRL). Coherus Biosciences Inc.’s candidate, submitted in 2016, met the same fate last year.

Several months after accepting Mylan’s biosimilar application in February 2017, the FDA gave the Hertfordshire, U.K., company a CRL relating to a pending update of chemistry, manufacturing and controls data following modifications made to the facility that would be used to manufacture the biosimilar. At the time, Biocon said the letter was not expected to affect commercial launch timing in the U.S., which Mylan had predicted would occur late this year or early next year. (See BioWorld Today, Oct. 11, 2017.)

Launch plansThat optimism proved true, as Mylan said it is preparing to launch Fulphila in the “coming weeks,” bringing the first U.S. competition to Neulasta, which produced nearly $4.7 billion in global sales last year, according to Cortellis.It will be an at-risk launch, since Mylan is in a patent dance with Thousand Oaks, Calif.-based Amgen over two patents claiming methods of purifying proteins used in manufacturing biologics. In keeping with the Biologic Price Competition and Innovation Act, the companies are scheduled to conduct fact and expert discovery through 2019 with a trial expected around midyear, Leerink Partners LLC analyst Geoffrey Porges said. However, he noted, Mylan and Amgen are trying to resolve the litigation through court-sponsored mediation.Regardless of whether there’s a trial or a settlement, Porges said he views the “manufacturing patents as weak protection for Amgen, and we are not surprised to see Mylan launch at risk against them.”Besides being the first Neulasta biosimilar approved in the U.S., Fulphila would be one of only a handful of biosimilars to launch in the country. Some of those biosimilars have found it difficult to gain quick traction against a long-established innovator. But Fulphila could benefit from a reimbursement change in the 340B drug discount program, which accounts for about 30 percent of Neulasta’s U.S. sales.

Potential 340B benefitUnder the revisions the Centers for Medicare and Medicaid Services made to 340B reimbursement this year, biosimilars qualify as a “new and innovative technology” that are reimbursed at average sales price (ASP) plus 6 percent for two to three years, while the innovator will be reimbursed at ASP minus 22.5 percent.

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“This is a key financial incentive for rapid uptake for the biosimilar in 340B-participating hospitals,” Leerink Partners LLC analyst Ami Fadia said.That incentive could work against Fulphila in the long term, though. Once its two- to three-year window as a new and innovative technology closes, it will be reimbursed like the innovator. And like the innovator, it will have to compete with newer biosimilars that are still in their favorable 340B reimbursement period, Fadia said.Even in the near-term, the 340B incentive could be offset somewhat by Amgen’s Neulasta Onpro, which represents about 62 percent of U.S. Neulasta sales, said Salim Syed, a Mizuho Securities USA LLC analyst. “While it’s not clear if this 62 percent is equally spread across channels, Amgen has previously communicated that many of the large 340B institutions have switched to the Onpro system,” he added.

The competitionPart of Amgen’s strategy to prepare for Neulasta biosimilar competition was to convert at least half of the treated population to Neulasta Onpro, a next-generation medical device combo product that’s more convenient for patients as it eliminates a return visit to the provider for an injection the day after chemo. That strategy “could prove sticky for some physicians and centers and lessen the degree of revenue erosion compared to historical precedents,” Porges said.Jefferies LLC analyst Michael Yee said Amgen has “swapped around 60 percent of utilization to the more simple Onpro device.” He expected that the other 40 percent of Neulasta sales could decline by 10 percent due to market share loss or price erosion, if Mylan prices Fulphila at a 20 percent to 25 percent discount. Mylan has yet to provide pricing guidance; some of the first biosimilars to launch in the U.S. offered only a 15 percent discount off the list price.

Meanwhile, Amgen likely is working closely with many big customers and locking in contracts to ensure a consistent supply and reliability of product, Yee said, adding that it takes time for many hospitals and big customers to change formularies.

The Neulasta market could get more competitive in November if Coherus’ biosimilar is approved on its PDUFA date. Other biosimilars, from Sandoz and Amneal Pharmaceuticals Inc./Adello Biologics LLC, could come to market in two to three years – just as Fulphila loses its 340B reimbursement advantage.

Fulphila is the second biosimilar from the Mylan/Biocon team. In December, the FDA approved the partners’ Ogivri, a biosimilar to Roche Holding AG’s breast cancer therapy, Herceptin (trastuzumab). Under the partnership, Mylan has exclusive commercialization rights for Fulphila in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights in the rest of the world. (See BioWorld, Dec. 4, 2017.)

In addition to the good news about Fulphila, Mylan and Biocon had a bit of déjà vu when they recently received a CRL on their Lantus (insulin glargine, Sanofi SA) follow-on, which is being developed as a 505(b)(2) drug in the U.S. The letter was expected, as the companies already had agreed to provide the agency with additional clinical data in support of a manufacturing site change from Bangalore to Malaysia, Julie Knell, senior director for Mylan’s global product communications, told BioWorld.

“Together, Mylan and Biocon are already executing on all required activities we had agreed upon with FDA,” Knell said, adding that the partners don’t anticipate any impact to the timing of the product’s approval and launch. s

– June 6, 2018

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East or West?

Increasing globalization in biopharma highlights differing management styles, cultures By Chermaine Lee, Staff Writer

The recent M&A deal between Japan’s 237-year-old Takeda Pharmaceutical Co. Ltd. and Irish firm Shire plc has attracted massive attention, not just because of the mammoth size of the deal but also the tug of war among the Japanese company’s shareholders, a group of which made a failed attempt to block the deal during Takeda’s general meeting earlier this year. (See BioWorld, May 8, 2018.)It is likely no coincidence that the deal is led by the first ever non-Japanese CEO of Takeda, Christophe Weber, who has said he believes the acquisition will allow Takeda to become an “agile, R&D-driven global pharmaceutical company,” according to his open letter to shareholders. And it’s an indication that the increasing globalization of the biopharma industry highlights different management styles and company strategies.

Differing valuesFor a long time, pharmaceutical giants seemed to belong to the Western world – from Roche Holding AG in Switzerland to Merck & Co. Inc. in the U.S. But as M&A deals between the East and the West are on the increase, the Asian scene is taking shape.An industry survey by L.E.K. Consulting revealed that more than one-fifth of respondents believed the China market is a high priority for international biopharmaceutical firms. About 90 percent of the companies expressed interest in Asian expansion and 86 percent wanted to expand in China specifically.“The majority of the higher-value [over $20 billion] M&A transactions continue between U.S. and European entities. But there is increasing M&A activity by companies in Eastern or emerging markets to buy targets in the U.S. and Europe,” Nitin Naik, vice president of global life sciences at Frost & Sullivan, told BioWorld.For instance, China outbound M&A deals surged 97 percent in deal value and 10 percent by number of deals in 2017, according to a report from consulting firm PwC.

But, while changes brought by M&A deals may often be expressed only in figures, changes in management can have a ripple effect at those biopharmaceutical companies, especially when cultural clashes are involved.“Language barriers clearly contribute to complexity but are among the least of the issues in these cross-border situations,” Stephen Sunderland, partner at L.E.K. Consulting, told BioWorld. “Of just as great importance are the different perspectives that Chinese and Western counterparts can share in interpreting even the same facts.”He cited the example of a Chinese biopharma firm having plenty of distribution partners. “The firm itself will see that as a broad and deep commercial platform, whereas their Western counterparts will be concerned that the very same network might create compliance issues.”When it comes to leadership and management, Eastern and Western leaders are observed to have different sets of qualities. A research paper at business school INSEAD, by Anupam Agrawal and Caroline Rook, found that Southeast Asian leaders are likely to be recognized for good vision as well as design and alignment, while Western leaders were rated lower on both. The West is also considered to have a lower resilience to stress compared to those in the Middle East and Southeast Asian.While that does not necessarily signify the prevalence of those leadership qualities in East and West, it can indicate the two worlds’ different expectations of management.The East, in the decision-making process, typically focuses more on collective benefits, hierarchy, harmony and introspection, while the West attaches greater importance to matters such as speed, feedback and discord from differing opinions.The qualities sought in a good member of staff can also vary across cultures. As part of acquiring linguistic and cultural fluency in language and behavior, East Asians will often have to reach beyond their usual ways to speak up and even dominate conversations – assertive qualities valued in Western culture.

Respecting the differencesAs one outcome of globalization, some Asian biopharmaceutical companies will parachute in

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Westerners for senior management roles, while at counterpart Western firms, Eastern talent will be recruited to make decisions.Naik said that Eastern biopharma talent can bring a lot of value, such as a “disciplined approach to problem-solving – like not rushing to make things fit if they really cannot. Western CEOs can use this value to assess long-term impact on investments to maximize portfolio value for the business approach.“In the biopharmaceutical development landscape, process is equally or more important than product,” Naik added. “So, while speed to market is crucial, Eastern companies value ‘inclusive growth’ where employees share and document knowledge.”As China’s pharmaceutical sector matures, the nation’s companies will also improve their management approaches and priorities, according to Sunderland, “whether that’s an increasing premium placed on innovation from faster commoditization of off-patient drugs, or heavier safety oversight or scrutiny and

consolidation driving better quality in development, manufacturing and supply, or delayering in distribution driving transparency and efficiency, or more public market shareholders at earlier stages in company development demanding economic returns and profitable growth.”For the Western CEOs or management staff that are parachuted into an Eastern biopharmaceutical firm, Naik offered this advice: “Most Eastern companies feel strongly about their science, so it’s critical that both cultures are able to respect these differences in their mindsets.”Behind the generalized cultural qualities, each staffer’s exclusivity should not escape the radar. The INSEAD research paper noted it “is important for global leaders to recognize cultural preferences of leadership styles in different nations, but also to pay attention to the individual uniqueness of people beyond their culturally determined cognitions and behaviors.” s

– September 28, 2018

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BioAsia 2018

Biosimilars on the rise in India; technology, capital remain challenges By T.V. Padma, Staff Writer

HYDERABAD, India – Companies are increasingly willing to invest in biosimilar development and manufacturing in India, despite a spate of regulatory hurdles and a shortage of capital that remain visible.A case in point is Germany-based Merck KGaA, which plans to invest in a $16 million facility in Mumbai, to expand distribution and manufacturing in the country. The new facility is likely to be set up by the end of 2019, Merck Life Sciences CEO Udit Batra, told BioWorld, on the sidelines of the annual Indian biotechnology industry conference BioAsia.On Feb. 21, Merck announced $47 million in additional investments “to build a robust manufacturing distribution platform in Asia over a span of two years,” a company release said. That follows a $95 million investment in life sciences in Nantong, China, announced in November 2016. At the time, Batra said: “Our investments in the important Asian markets of South Korea, India and China ensure that our customers have ready access to the products needed to develop new therapies and biosimilars that accelerate access to health for people everywhere.” Speaking at the BioAsia 2018 conference, Batra said the penetration of biosimilars is low in India, despite similar levels of purchasing power as some comparable emerging economies and wider availability of the products. “The need for biosimilars is clear in India and there are large commercial opportunities for biosimilars in India,” Batra said. The Indian market for biosimilars is rapidly growing and projected to grow at 35 percent per year from $310 million in 2015 to $1.35 billion in 2021, Batra said.As with other biosimilars makers, Merck is looking to position its portfolio to ride the wave of growth. The company’s wide portfolio of biosimilars and range of processing technologies and services is helping the company exploit the US$64 billion to $65 billion pharmaceutical market in India.

Batra said that more Indian firms could enter into tie-ups to avail themselves of some of the latest technology trends in biosimilars, such as single-use technology. Single-use systems (SUS), which are becoming increasingly popular in pharmaceutical and biosimilars production, are disposed of after use, compared to traditional processing systems that are cleaned and reused.Single-use technologies offer several advantages – reduced consumption of water and chemicals; lower energy costs; little or no cleaning; and minimized space requirements. Many companies have adopted that platform for its ease of adapting to new product development and the flexibility in adjusting to varying product supply and demand. In 2017, Bangalore-based Stelis Biopharma Pvt. Ltd. entered a collaboration with the Milliporesigma group at Merck, under which Merck will provide training and support in single-use technology at Stelis plants that have experience in process development from cell lines to commercial manufacturing.While Merck is ready to distribute its technology and services more widely, access to such technologies requires the right regulatory framework and quality standards, which in turn require proper training in process development, he added. “The skills for bioprocessing under good manufacturing practices are not available in India.”There are other services offered to biosimilar testing. For example, Bioreliance Corp., of Rockville, Md., which was acquired by a Merck subsidiary, Sigma-Aldrich, in 2012, offers an array of end-to-end assays and services to support biosimilar development, from initial product characterization to full comparability studies which involve a range of analytical assays for the drug’s properties and comparing them with the original biologic molecule.Another challenge the Indian biosimilars industry has to deal with is a shortage of capital, which Batra called “a big problem.” Other speakers at BioAsia also considered the problems of India’s emerging biosimilars industry. The Minister of Industries and Commerce of Telengana State K. T. Rama Rao acknowledged that the Indian government needs to incentivize R&D and

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Mumbai-based Cipla Ltd.; Bangalore-based Biocon Ltd.; Hyderabad-based Dr. Reddy’s Laboratories Ltd. and Hetero Drugs Ltd.; and Ahmedabad-based Zydus Cadilla. In a huge fillip to India’s nascent biosimilars industry, in December 2017, the U.S. FDA granted Mylan NV and India-based partner Biocon Ltd. approval for their biosimilar of Roche Holding AG’s cancer drug, Herceptin (trastuzumab). It is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer. (See BioWorld, Dec. 18, 2017.)In January, Indian drugmaker Hetero launched a biosimilar of Abbvie Inc.’s blockbuster, Humira (adalimumab), to treat rheumatoid arthritis and other autoimmune disorders. s

– March 5, 2018

act as an enabler to companies that are transitioning from chemicals to biologics. Hyderabad, where the conference was held, is the capital of Telengana State. There are also problems of regulation.“We are still struggling with the regulatory framework for biologics in the country,” Sanjiv Navangul, managing director at Janssen Pharmaceuticals, said during a session on the future of biologics in India.Biologics have yet to find a place in India’s health policy, noted Jawed Zia, country president of Novartis India Ltd.The conference deliberations come amid concerted efforts by the Indian government to back domestic companies looking to become world-class biosimilar manufacturers. The number of companies in India with biosimilar portfolios is growing and includes

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opinion this month from the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommending the approval of Semglee, an insulin glargine developed in collaboration with Mylan. (See BioWorld, Dec. 18, 2017.)The CHMP’s positive opinion will be considered by the European Commission, which is expected to provide a decision on the approval of Semglee in April.Arun Chandavarkar, the CEO and joint managing director for Biocon, cited the firm’s significant investments, together with Mylan, in global scale manufacturing and R&D. As an early mover in the biosimilars space, Biocon has already successfully launched its trastuzumab and bevacizumab biosimilars in India, insulin glargine in Japan, and rh-insulin, insulin glargine and biosimilar trastuzumab in a few emerging markets. Last month, Brazil regulators cleared the trastuzumab biosimilar.The recent FDA approval was particularly significant as it marked the first trastuzumab biosimilar to be given the green light in the U.S. That progress should expedite the approval in other markets, including Australia, Canada and the EU, where the biosimilar is under review. Ogivri’s reference drug, Herceptin (Roche Holding AG), had U.S. sales of more than $2 billion for the 12 months ending Sept. 30, according to health care analytics company IQVIA.

India spurring biosimilar growth“Many Indian generic companies are investing in and developing their capacity to manufacture biosimilars,” Malini Aisola, a member of the All India Action Drug Network, told BioWorld. “This underscores a trend towards biosimilars in the South Asian country.” According to the Generics and Biosimilars Initiative Journal, India’s first biosimilar, a hepatitis B vaccine, was approved and marketed in 2000. That puts the country about 15 years ahead of the U.S. in terms of regulatory acceptance of similar biologics. But Aisola noted that there is a need for stronger support and regulation from the authorities to make biosimilars accessible.“The priority of course should first be access to Indian people. We are supportive of developing local capabilities to manufacture biosimilars to meet the

Pricing will continue to vary considerably by product’

Sandoz and Biocon join forces in global biosimilar deal in immunology, oncology By David Ho and Cornelia Zou, Staff Writers

Less than two months after picking up a big win with the FDA approval for Mylan NV-partnered Herceptin biosimilar Ogivri (trastuzumab-dkst), India’s Biocon Ltd. inked a deal with another leader in biosimilar development, Sandoz Inc., a division of Novartis AG, to develop, manufacture and commercialize multiple products in the areas of immunology and oncology. Besides addressing the next wave of global biosimilar opportunities, a key goal of the partnership is to provide the foundation for both parties to expand their portfolios. Under the terms, the companies will share the responsibility for end-to-end development, manufacturing and obtaining global regulatory approvals for a number of products. “This collaboration aims to help patients worldwide gain access to a range of high-quality, affordable immunology and oncology biologics,” Michelle Bauman, head of product communications for Sandoz, told BioWorld. “The early stage biosimilar assets that are part of this agreement complement our existing portfolio in immunology and oncology.”Worldwide commercialization responsibilities will be divided and each company’s strengths will be leveraged for specific markets. Sandoz will take the lead in commercialization for North America and the EU region, while Biocon will take charge of commercialization for the other markets around the world. Both companies involved will operate under a global cost and profit-share arrangement.Kiran Mazumdar-Shaw, chairperson and managing director for Biocon, said she believes the Sandoz partnership will help the Indian biosimilar leader scale up its capabilities for an “end-to-end” play in the global biosimilars space.Bengaluru-based Biocon is entering the latest partnership fresh from some recent triumphs generated by its earlier work with Mylan. In addition to the Ogivri approval, Biocon received a positive

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different approaches to introduce the products to more markets.“As we do in other countries, pricing of biosimilars will continue to vary considerably by product, market and channel, and depending on the level of competition,” said Sandoz’s Bauman. “But we know price is only one aspect driving uptake, and as we enter new geographies, we’ll continue to focus on building confidence through education.” s

– January 31, 2018

health care needs which are currently out of reach of the majority of Indians,” said Aisola. “The potential of Indian biosimilars, with the appropriate regulation, is to bring to market lower-cost medicines,” she added. “This is unlike big pharma companies that market biosimilars without the necessary and adequate price reductions needed to make them affordable.”Sandoz acknowledged that aspect in the increasing adoption of biosimilars but is determined to try

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on Wednesday. Research has to be better aligned with medical needs and high prices reined back to promote sustainability of Europe’s publicly funded health care systems, she said.The regulation “will improve the access of European citizens to medicines and new health products.”Cabezon Ruiz pointed a finger at new cancer drugs, saying that despite prices increasing up to 10-fold, only 15 percent of products have been shown to increase survival by more than five years. While the drugs may have met the safety and clinical efficacy standards required by the EMA to get to market, they have not all proved to be cost-effective.The current system in which member states carry out their own HTA evaluations results in time consuming and costly duplication. But it also means there is a lost opportunity “to improve the available clinical evidence, to direct the priorities of research to the medical needs of patients, to improve the quality of research and, ultimately, access to medicines,” Cabezon Ruiz said.In particular, she said there needs to be more evidence of the cost effectiveness of medical devices.

Adding another layerPharma may have railed against HTA since it was first introduced to the system by the U.K.’s National Institute for Health and Care Excellence, following its formation in 1999. However, with HTA now a regular feature across Europe, the industry is broadly in favor of a system for conducting single assessments.“It makes sense to join forces to provide one, high-quality clinical assessment for use across Europe,” said Nathalie Moll, director general of the European Federation of Pharmaceutical Industries and Associations. “This will support better decision-making and ultimately benefit all patients,” she said.However, Moll is not pleased that the European Parliament did not back the EC’s original proposal that member states be required to use joint HTA assessments in their national pricing and reimbursement processes, leaving the door open for countries to conduct their own “complementary assessments.”As Moll noted, member states would have a duty to ensure joint clinical assessments are “of high quality and fit for national use.” Given that, “it should follow [member states] have confidence in their own work

Pan-European HTA regulation garners mixed review from industry By Nuala Moran, Staff Writer

The European Parliament has voted in favor of a new regulation on health technology assessment (HTA), a significant step toward creating a pan-European system for conducting cost-effectiveness appraisals.The aim of the legislation is to end duplicate national assessments undertaken to determine the added value of new drugs and medical devices.Soledad Cabezon Ruiz, member of the European Parliament (MEP) who steered the proposal through, likened it to the HTA equivalent of the EMA.There were mixed reactions from industry, with pharma welcoming the prospect of a single appraisal to replace the string of national assessments their products currently undergo. But there is concern the European Parliament had watered down a proposal which would have required all member states to use the joint HTAs, and stop conducting their own.The med-tech sector, on the other hand, would come under the scope of comprehensive HTA for the first time and is more resistant, making the case that it should not fall within the scope of HTA until implementation of other new EU regulations relating to the sector is complete.Currently, more than 50 national HTA bodies are operating in the EU, using different methodologies and requiring companies to provide varied types of evidence to show their products offer greater medical benefits and to support pricing and reimbursement decisions. That is distorting market access, impeding uptake of innovative therapies and medical devices and constraining economic growth, according to the European Commission (EC), which drew up the regulation.The regulation is deliberately framed around ending perceived distortions in the EU single market, to avoid any accusations the EC is stepping into national health care policy, which under the EU principle of subsidiarity is entirely the jurisdiction of member states.“The Commission’s proposal was a timely proposal,” Cabezon Ruiz said, opening the debate

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already answered by the new medical device and in vitro diagnostic regulations that are currently being implemented,” MTE said in a statement.There needs to be a clear distinction between the role of CE marking and HTA and there should be “an appropriate phase-in” of medical technology into the new HTA regulatory framework, once the medical device and in vitro diagnostic regulations are fully implemented and operational, MTE said.The regulation next goes to the third arm of the EU, the European Council, for consideration by national ministers.The proposed pan-EU system for HTA will build on the existing voluntary network, Eunethta, which is funded by the EC. The network has been in operation since 2009, providing the framework for national HTA bodies to work together on joint assessments. The regulation envisages the EC continues to fund Eunethta as the body coordinating joint HTA. s

– October 5, 2018

and that of their peers,” she said.Only by guaranteeing the use of joint HTAs and avoiding unnecessary duplication can patients really benefit from the increased consistency, speed, transparency and quality of assessments, Moll said.The risk in allowing “complementary assessment” is that rather than reducing complexity, the legislation introduces a fourth layer of pan-European HTA, to add to EMA scrutiny, national HTA and pricing and reimbursement.The regulation clearly states joint HTAs would remain distinct from pricing and reimbursement decisions, so member states can have no concerns about subsidiarity, said Moll.The industry body Medtech Europe (MTE) had lobbied hard for amendments to the legislation, which it views as more relevant to pharma and not necessarily appropriate for medical technologies.“Any new regulation should not create an extra layer of assessments, nor duplicate any elements

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The increasing number of trials, and shift from foreign to domestic sponsors, illustrates the dramatic changes that the regulatory reforms have wrought.Some of the more significant changes Zhu outlined are as follows:• Improved quality, after instituting clinical trial data self-assessments and on-site inspections• Faster timelines due to streamlined review and approval procedures such as a pre-IND meeting with the Center for Drug Evaluation (CDE), a 60-day notification-based CTA review, an expedited pathway for unmet medical needs and rare disease and conditional approvals• More clinical trial sites, after permitting hospitals to do an online filing with the NMPA (and removing the CCP accreditation step)• Global integration following International Council of Harmonization (ICH) membership and acceptance of overseas dataAnd the changes keep on coming. Nearly every Friday, the NMPA announces changes to the regulations, leaving regulatory affairs experts to pore over the details each weekend.During a panel, local Chinese executives working for MNCs lamented how difficult but necessary it is to provide context to headquarters about the weekly regulatory announcements. Difficulties arise when those at HQ rely on Google translate to keep up to speed. But translations fail to capture the gray areas the authorities intentionally leave open to interpretation – so that they can test different ways to actually execute changes on the ground.

Hurdles still remain While many of the changes are welcomed by the industry, other issues have cropped up as well.Attendees recounted that they struggle to find talent that can manage early stage clinical trials. Mabspace Biosciences Co. Ltd.’s CEO, Xueming Qian, said salaries for chief medical officers working in China can be 30 percent to 40 percent higher than similar counterparts in the U.S.“You have to entice the experienced people to bring their careers and families to China,” said Qian.Fangning Zhang, a McKinsey consultant, reiterated that “the talent war is top of mind for everyone. The biggest pain is retention.” But she said not enough

ChinaTrials 11

China becomes hot spot for early stage trials; talent scarcity brings higher costs By Shannon Ellis, Staff Writer

SHANGHAI – The verdict is in. The regulatory reforms that China kicked off in 2015 have opened the floodgates to an unprecedented number of early phase clinical trials being conducted in China.This year to date, 838 clinical trials are underway in China, according to data presented by Jason Zhu, CEO for contract research organization PPC, at the ChinaTrials 11 event. Back in 2015, when the State Council gave the CFDA (now the National Medicinal Products Administration, or NMPA) permission to conduct wholesale reforms of the regulatory system, there were only 338 trials ongoing.In the five years before the reforms, from 2009 to 2015, the number of trials inched up by a third. But compared to the two years following the reforms, the number of trials has more than doubled.It follows that the vast majority of those new studies are early stage trials. In 10 years, the number has gone from 134 phase I studies to more than 400.Not so long ago, multinational corporations (MNCs) dominated the IND clinical trial category. In 2009, the top three were Novartis AG, Bayer AG and Pfizer Inc. The first local pioneers to enter the top 10 were Hutchison Medipharma, a subsidiary of Hutchison China Meditech Ltd., and Jiangsu Hansoh Pharmaceutical Co. Ltd. in 2014.But today, the list of top 10 clinical trials sponsors is led by local firms. Jiangsu Hengrui Medicine Co. Ltd. is the most dominant, with more than 40 trials ongoing.In second place, Novartis lags far behind with fewer than 20 trials. Going down the list, companies from spots three to seven are largely tied: Beigene Ltd., Chia Tai Tianqing Pharmaceuticals Holdings Co. Ltd., Lee’s Pharmaceuticals Ltd. and Sichuan Kelun Pharmaceutical Co. Ltd., with more than 15 trials each.Rounding out the bottom of the list are Astrazeneca plc, Roche Holding, Qilu Pharmaceutical Co. Ltd. and Luye Pharma Group.

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obtain approval from a hospital ethics committee and the NMPA as a cumbersome process. Few hospitals are equipped to have an independent ethics review of a clinical trial and sorely lack capacity. That can lead hospital ethic committees to drag their feet until more experienced government reviewers weigh in.“An [ethics committee, or EC] will issue approval after the NMPA says they have no comments or wait until all comments have been received. If the EC issues approval but the drug authorities do not, they feel awkward,” shared Limin Wen, head of clinical development at Fosun Kite Biotechnology Co. Ltd.Helen Jiang, vice president and chief medical officer at Qingfeng Medicine, added, “I hope the NMPA will be more aggressive and we can do the EC and NMPA review in parallel like other countries.”Lastly, China’s strict rules governing the collection and usage of human genetic resources remains a thorny problem, especially for MNCs. One audience member asked how China continues to have those regulations, unlike other countries, even though they are a signatory to the global rules such as the ICH. The response was swift from the moderator: ICH admittance does not preclude following existing domestic laws. s

– November 12, 2018

attention is being paid to tackle that problem.The result is salaries that are spiraling ever upward. Where once the benefit to doing clinical development in China was lower costs, higher salaries are eroding that advantage.Timelines are another area where further improvement is needed. While the time it takes to initiate clinic trials has been whittled down to seven months (vs. 12 months-plus in the past), China still takes far longer than other markets such as Australia.For the 60-day notification process to be successful, sponsors find it is crucial to have a pre-IND meeting first to communicate with the authorities. One panelist shared that asking for a face-to-face meeting can take a very long time, but written responses have been quick.“You cannot rely on rounds of comments from the NMPA,” said Jason Yang, chief medical officer and senior vice president of clinical development at Cstone Pharmaceuticals Co. Ltd. “You need to have an executable protocol for pre-IND. Few companies have the talent capable of doing that. A lot of companies will be washed out. Many will not be competitive in this process, which might be the intention of regulators.”Other pain points continue to beleaguer the industry. Many experts view the two-stage requirement to

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