Jackie Syrop

Three European Union (EU) biopharma industry groups have issued a 

 urging prescribing physicians to exercise caution when considering switching patients from reference biologics to biosimilars. The industry groups—European Biopharmaceutical Enterprises, the European Federation of Pharmaceutical Industries and Associations, and the International Federation of Pharmaceutical Manufacturers & Associations&mdash;state that physicians are the individuals best placed to assess their patients and potential treatments and whether and how to switch a biological product for another one. Physicians should balance risk and uncertainties against the availability of evidence on a case-by-case basis, the group strongly recommends. The 3 groups industry groups represent member biopharma companies who have billions in revenue at stake when more biosimilar products are approved.

The position paper notes that to qualify for approval, a biosimilar should be compared in terms of quality, safety, and efficacy with its reference product alone—there is no regulatory authority requirement for biosimilars to the same reference product to be compared with each other. Therefore, this type of data may not be available to refer to when evaluating a switch between 2 biosimilars to the same reference product, the group cautions.

The position paper reminds physicians of the complex nature of biological molecules, which are being used to treat patients who have multifaceted, chronic diseases, and concludes that there are 2 scenarios in which switching from a reference product to a biosimilar (or between any products within a similar group of related products) is 

When the initial treatment choice (reference product or biosimilar) loses efficacy or when there are tolerability issues, switching to a similar product within the same group of related products is not recommended because these products are expected to have similar clinical efficacy and safety to each other, without incremental clinical benefit to the patient.

If the physician feels that, on balance, a switch is likely to compromise the patient’s future treatment options (eg, with an alternate biologic therapy), a switch is not advisable. However, little is known about the consequences of multiple exposures to the same group of related products and the consequences on immunogenicity of future treatments with biologics.

Gillian Woollett, PhD, senior vice president at Avalere Health, has a different perspective. In an 

, she argues that the regulatory agency in Europe, the European Medicines Association, does not have an interchangeability designation; national health authorities there allow switching, as yet without safety issues. Woollett notes that Dutch, Finnish, German, and Norwegian regulators analyzed 10 years of switching studies and concluded that it is unlikely and very difficult to substantiate that 2 products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch. “I would argue that as a scientific matter, once your product is deemed biosimilar it is already interchangeable,” she says.

Switching studies that would be required by the FDA to show interchangeability can be cumbersome and expensive, and are likely to contribute to a higher entry bar for biosimilar developers. The cost of biosimilar development can be $250 million or more, while the cost of generic drug development is typically $1 million to $4 million. Without flexibility, no biosimilar will ever be designated as interchangeable by the FDA, Woollett advises.

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European Industry Groups Urge Caution on Biosimilar Switching

Amgen has filed a legal action in California state court against Bay Area biosimilar maker Coherus Biosciences, Inc, 

 that since 2014 Coherus has engaged in a “massive conspiracy” to steal trade secrets for Amgen’s reference biologic pegfilgrastim (Neulasta). The drug, a pegylated form of recombinant human granulocyte colony-stimulating factor, is indicated to reduce the incidence of infection in patients with non-myeloid malignancies who are receiving myelosuppressive anticancer agents. Coherus’ biosimilar to pegfilgrastim (CHS-1701) is currently scheduled for a June 9, 2017, regulatory hearing at the FDA concerning its approval.

The lawsuit asserts that Coherus induced multiple Amgen employees to breach confidentiality agreements regarding Amgen’s pipeline in order to gain proprietary knowledge, allegedly receiving such information on “stolen” USB drives. This included sensitive Amgen standard operating procedures, lab notebook pages, validated analytical methods, method development reports, specifications, documents reflecting process optimization work, cost calculators, and pricing and contracting strategies. Amgen is seeking restitution and damages. The 

 former Amgen employees, including Howard S. Weiser, currently executive director at Coherus, as having violated trade secrets.

Coherus categorically rejected the allegations as baseless and accused Amgen of using the lawsuit to prevent potential competition from the biosimilar product, should it be approved. Danny Lanfear, president and CEO of Coherus, said the action is without merit and the company would defend against it vigorously. “Coherus believes this lawsuit is best understood as an effort by Amgen to use baseless litigation in an effort to delay Coherus as a competitor in the pegfilgrastim market,” he said in a 

Lanfear went on to deny that his company needed Amgen’s proprietary information to compete or be successful, adding that he is proud of Coherus’ novel clinical development strategy and novel clinical study designs—none of which were ever performed at Amgen and are not Amgen’s intellectual property. Barclays analysts said the alleged violations occurred well after Coherus developed CHS-1701.

Coherus is also developing a biosimilar of Amgen’s rheumatoid arthritis treatment 

Amgen Lawsuit Against Coherus Alleges Misappropriation of Neulasta Trade Secrets 

 Valeant’s new biologic brodalumab (Siliq) on February 15, 2017, for the treatment of moderate to severe plaque psoriasis, but did not follow the agency’s own 

 on naming new and previously approved biologics and biosimilars with a 4-letter suffix “devoid of meaning” to be attached at the end of the nonproprietary name. For example, Amgen’s filgrastim (Neupogen) is to be changed to filgrastim-jcwp.

Siliq, a monoclonal antibody, is the first novel biologic to be approved since the January 12, 2017, release of the FDA’s finalized guidance on nonproprietary naming of biologic products. The guidance explains that the suffixes are needed to create a distinguishable naming element for biologics and biosimilars in order to facilitate pharmacovigilance and accurate identification by prescribers and patients, and to help decrease unintentional substitution of products not deemed interchangeable.

It was thought that the approval of Siliq might be the first novel biologic approved with the suffix because the FDA guidance had been finalized a month earlier than the drug’s approval. However, Siliq was 

 because the final guidance was issued at a point in the review of the drug’s application that the FDA said did not allow enough time for the agency to designate a proper name that includes a suffix as described in the guidance.

 In the interest of public health, the FDA did not want to delay the approval of Siliq in order to license the product with a designated proper name, according to an agency spokesman, and therefore issued the approval with only the designated proper name and no suffix. However, the FDA clarified that it intends to work with Valeant to implement the naming convention described in the final guidance for Siliq.

The FDA may also be waiting for an approval from the Office of Management and Budget (OMB) approval of the information collected under the final guidance before implementing the suffix requirement on novel products.

 Some stakeholders have asked the OMB to block the implementation of the naming guidance because the FDA ignored the costs of implementing the new naming system. The naming guidance, including the post-marketing changes of names to comply with the guidance, has met with 

 from drug sponsors including Novartis and AbbVie, which said the naming convention would not support safe prescribing and pharmacovigiliance. The American Society of Health-System Pharmacists also spoke against the plan as burdensome for every segment of healthcare, including hospitals, payers, and providers, and CVS Health said the FDA’s guidance could have a potentially deleterious effect on the marketplace and a chilling effect on the development of affordable and accessible biosimilars.

1. Cipriano M. Where’s the suffix? Valeant’s Siliq approved without four-letter identifier. 

Siliq Approved Without a Suffix

 that Biocon and Mylan can manufacture and sell the companies’ trastuzumab biosimilar to Roche’s biologic cancer treatment trastuzumab (Herceptin globally; Herclon and Bicletis in India) for the treatment of early breast cancer and metastatic gastric cancer—2 new indications that can now be added to an earlier approval of the biosimilar for treatment of metastatic breast cancer.

According to a previous court ruling, the companies could market their biosimilar trastuzumab only for treatment of metastatic breast cancer and could not use data from Roche’s Herceptin package inserts to market and guide treatment for the biosimilar in cancer indications that the reference drug is used for. The court was hearing an appeal by Biocon, and its partner Mylan, 

 an interim order restricting them from marketing trastuzumab for the additional indications. The Delhi high court ruling now allows the companies to use Roche’s product data in their biosimilar product’s package inserts. Roche had opposed some paragraphs from the product inserts about the additional indications and objected to their use of clinical tests conducted by Roche as being the biosimilar makers’ own data.

The Delhi high court decision stated that until there are any further court decisions, Biocon and Mylan are permitted to manufacture and sell biosimilar trastuzumab under their brand names for all 3 cancer indications “on the basis of the product inserts which have been approved by the competent authority.” Biocon counsel Pratibha Singh said the court has once again confirmed that there is no data exclusivity in India. Biocon founder Kiran Mazumdar Shaw said she hoped the order set a precedent for future such issues, and that the decision will pave the way for greater access to affordable biosimilar trastuzumab for cancer patients in India.

Roche had challenged Biocon/Mylan’s ability to market trastuzumab in India for the additional indications. The companies had litigated the use of Roche’s clinical trial data on the safety and efficacy of trastuzumab to treat early breast cancer and metastatic gastric cancer, with Roche’s attorneys arguing that the data were being used by Biocon and Mylan to “pass off” their brands as equally safe and effective without conducting their own clinical trials. For their part, Biocon and Mylan attorneys argued that the data used in the companies’ latest package insert were publicly available and not exclusive to Roche.

A statement from Roche said the Delhi high court’s decision meant that critical information about the clinical studies of Herceptin would be included on the packaging of biosimilars “even though there continues to be no evidence in the public domain that the companies producing these products have conducted the studies required for biosimilars.” The company also 

 it was important to ensure that physicians and patients were not “misled into believing these medicines will provide the same benefit and safety experience” as Hercepin. Roche intends to continue challenging companies that fail to present data outlined in the Indian biosimilar framework.

The decision is expected to give the Biocon/Mylan trastuzumab biosimilar greater access to a Rs-300-crore (about $45 million) market in India.

New Delhi High Court Allows Marketing of Biocon-Mylan Biosimilar of Trastuzumab

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation (CDER), urged members of Congress to pass the reauthorizations of the Biosimilar User Fee Act (BsUFA) and the Generic Drug User Fee Act (GDUFA). Woodcock 

 before the House Energy and Commerce Committee on March 2, 2017.

Congress has already agreed upon details of the reauthorizations, but they need to be finalized before the end of September 2017 for the FDA to continue receiving funding to ensure timely review of biosimilars and generics over the next 5 years. “Many of our most important drugs are biological products,” Woodstock said. “It is important for the public health of the US population to have access to safe, effective, and affordable biological products. Biosimilars can provide more treatment options for patients, and possibly lower treatment costs, enabling greater access for more patients.” According to Woodcock, 64 biosimilars in development are expected to provide competition for 23 biologics.

Rigorous review and approval standards are essential to earn physicians’ and patients’ confidence in biosimilar and interchangeable products, Woodcock explained, and they are key to the success of the biosimilar program. The FDA cannot achieve these goals without adequate funding in place.

While FDA has made significant progress in creating and implementing the biosimilar program, there is more work to do and challenges that must be addressed, Woodcock said. The ability to hire the right staff is key to ensuring timely review of new biosimilars, and the agency is committed to recruit and retain the critical scientific, technical, and professional talent needed to address complex and often novel scientific and legal issues involved in biosimilar review, she added. But the lack of additional staffing to handle the increased workload for biosimilar review has affected review performance, she told members of Congress. For example, in 2015, the FDA was able to schedule only 50% of initial advisory meetings within the 90-day meeting goal. While 2016 saw an improvement, the agency continued to face challenges and was unable to meet some performance goals.

In the FDA’s discussions with industry, biosimilar producers said they would like to see more meetings and faster turnaround of Agency advice in the reauthorized BsUFA. “BsUFA I provided critically needed funding for FDA to implement the beginning of a successful biosimilars program,” said Woodcock. “BsUFA II will allow the FDA to continue building this program and make improvements where needed.” She said the new pathway for biosimilar and interchangeable products has the potential to offer a significant contribution to the public health of many Americans by increasing access to more affordable biologics. “At FDA, we are working hard to ensure this positive impact can be realized,” she concluded. “We are optimistic and energized about the future of biosimilars.”

FDA's Director of Drug Evaluation Urges Congress to Pass the BsUFA Reauthorization

The United States and the European Union (EU) 

 that they have agreed to mutually recognize each other’s pharmaceutical manufacturing inspections, an agreement that is likely to mean less duplication of inspections and thus lower costs for both the EU and United States.

Under the Pharmaceutical Annex to the 1998 US-EU Mutual Recognition Agreement, US and EU regulators can utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical and active pharmaceutical ingredient manufacturing facilities. In addition to lower costs and reducing duplication of inspections, the agreement will allow regulators to devote more resources to other parts of the world where there may be greater risk.

 “The Mutual Recognition Agreement is an important step in working collaboratively and strategically with key partners to help ensure that American patients have access to safe, effective and high quality drugs,” said FDA associate commissioner for global regulatory policy, Dara Corrigan.

The FDA and the European Medicines Agency (EMA) were collaborating since May 2014 on evaluating how they each inspect drug manufacturers and assess the risks and benefits of mutual recognition of drug inspections. The FDA observed 14 of the EU’s Joint Audit Programme, a cooperative evaluation in which 2 EU nations audit the regulatory authority of another EU country and will be observing more this year. The EMA has mutual recognition GMP agreements in place with several countries including Switzerland, Japan, and Canada.

The mutual recognition agreement was originally part of the Transatlantic Trade and Investment Partnership discussions conducted under President Barack Obama.

 A major point of negotiation for both the FDA and EMA was the question of trade secret information because inspections usually involve specifications of manufacturing equipment and processes that are proprietary.

The text of the mutual recognition agreement is available 

Brennan Z. US and EU forge landmark agreement to mutually recognize drug manufacturing inspections. Regulatory Affairs Professionals Society website.  

http://www.raps.org/Regulatory-Focus/News/2017/03/02/27001/US-and-EU-Forge-Landmark-Agreement-to-Mutually-Recognize-Drug-Manufacturing-Inspections/

. Published March 2, 2017. Accessed March 2, 2017.

Brennan Z. Updated: TTIP on thin ice not likely to delay US-EU mutual GMP recognition deal. Regulatory Affairs Professionals Society website. 

http://raps.org/Regulatory-Focus/News/2017/02/22/26936/Updated-TTIP-on-Thin-Ice-Not-Likely-to-Delay-US-EU-Mutual-GMP-Recognition-Deal/

. Published February 22, 2017. Accessed March 2, 2017.

US and EU Agree on Mutual Recognition of Drug Manufacturing Inspections

Melbourne, Australia-based Mesoblast Limited 

 promising data from a phase 2 trial of the company’s novel stem cell therapy for patients with rheumatoid arthritis (RA), which shows its therapeutic benefits continued 9 months after administration of a single intravenous (IV) dose.

The stem cell infusion of Mesoblast’s allogeneic Mesenchymal Precursor Cells (MPC)-300-IV was administered to 48 RA patients resistant to anti-Tumor Necrosis Factor (TNF) agents. A single IV dose of 2 million MPC/kg of MPC-300-IV was well tolerated and demonstrated a durable improvement in clinical symptoms, physical function, and disease activity relative to placebo over the follow-up period.

Approximately a third of RA patients develop resistance to TNF agents; others patients do not respond to the drugs or experience adverse events when using them. Second-line drugs such as Rituxan are not as effective as the anti-TNF agents and are associated with serious side effects.

The phase 2 study patients had active RA, were on a stable regimen of methotrexate, and had an inadequate prior clinical response to at least 1 anti-TNF agent. Of the 48 patients, 30 (68%) had previously received 1 to 2 biologic agents. Patients were randomized to a single IV infusion of 1 million MPCs/kg, 2 million MPCs/kg, or placebo. Patients were evaluated using the American College of Rheumatology (ACR) 20/50/70 measurement to assess clinical response and improvement in signs and symptoms of RA in terms of 20%, 50%, or 70% improvement from baseline. The study also used the ACR-N scale to assess mean or median magnitude of benefit, assessed health/disability with the HAQ-DI measure for functional status, and applied the DAS28 scale to measure RA disease activity in order to judge improvement.

The safety profile over 39 weeks was comparable among placebo and both MPC treatment groups, with no cell-related serious adverse events. Both MPC doses tested outperformed placebo at week 39 in each of the ACR20/50/70 responses. The 2 million MPCs/kg dose was found to be the most effective over 39 weeks; that dose also achieved the maximal ACR-N score earlier (at 12 weeks) and exhibited a more robust durable effect.

Mesoblast CEO Silviu Itescu said the company’s MPC therapies have demonstrated virtually no toxicity, and had generated no negative immune response. The cells also appear to be targeted, intrinsically moving toward sites of inflammation and embedding in tissue, he said. Receptors on the cells’ surface are activated by every major cytokine that is important in progressive RA, including TNF, interleukin (IL)-1, IL-6, and IL-17. Itescu believes MPC-300-IV has an edge on the biologics inhibiting TNF-alpha or other key targets because it is getting to the heart of the inflammation and disease, not just knocking back the immune system.

Although larger phase 3 studies are needed to validate these results, the data are intriguing in that they suggest what optimized and targeted regenerative medicines could potentially accomplish to address the unmet medical need among anti-TNF—resistant RA patients.

Targeted Regenerative Meds Hold Promise for RA Patients Resistant to anti-TNF Agents

Allergan likely won’t do much with biosimilars beyond the company’s current involvement in projects involving 4 cancer-drug biosimilars developed in partnership with Amgen, according to Allergan CEO Brent Saunders. In an 

 with Bloomberg on February 22, 2017, Saunders also predicted that many pharmaceutical companies will eventually retreat from the biosimilars business because the market will not be able to support the large number of molecules that will soon be approved.

Several biosimilars have been marketed or are in advanced stage clinical trials, including those for Rituxan, Herceptin, Avastin, Humira, Enbrel, Remicade, and Lantus. Amgen, Allergan, Boehringer Ingelheim GmbH, Pfizer Inc, AstraZeneca PLC, Merck & Co Inc, Biogen Inc, and Novartis AG have all made substantial investments or have partnerships for developing biosimilars. In addition to these companies, there are Chinese, Indian, and Korean competitors, including Samsung Biologics Co Ltd.

It is not easy to predict how quickly biosimilars will be adopted because the market for biosimilars is unsettled. One important factor is continuing patent litigation, which has prevented the marketing of several approved biosimilars. In the United States, for instance, only 2 of the 4 approved biosimilars have been marketed.

The other big concern is that none of the approved biosimilars has yet been deemed interchangeable with the reference product by the FDA, preventing the potential substitution of biosimilars for reference products without the approval of prescribers. States, meanwhile, are preparing for interchangeability—the senate in New Mexico has 

 that will allow pharmacists to substitute a physician-approved biosimilar for its reference drug. The bill now awaits a House vote.

The bigger drug developers, with their larger marketing and legal budgets, stand an advantage over the smaller ones in the legal process. Additionally, because the bigger companies will get to market first, late entrants may need a drastic price cut to compete. Such discounting is “great for society, but it’s bad for business,” said Saunders. He warned that the biosimilar business will end up looking very much like the standard generic drug business but with much higher legal, research and development, and manufacturing costs.

Will the Biosimilars Bubble Burst Even Before It Expands?

, practicing rheumatologist Angus B. Worthing, MD, advises that it’s more important than ever that the FDA forge ahead with biosimilar drug review, where the safety stakes are high but additional FDA-approved therapies can have real value and impact for American patients. Physicians prescribing biosimilars need to know the new biosimilars are not only affordable, but also entirely safe for our patients, and this is possible only if there is a sufficiently large workforce at the FDA, he concludes.

Biologics are powerful but complex therapies, life-changing treatments for diseases such as rheumatoid arthritis (RA), ulcerative colitis, psoriasis, and several forms of cancer. The problem is, they are also prohibitively expensive, and even patients with health insurance coverage struggle to afford them. That is why it is more important than ever that the FDA adhere to its dual mandate—to promote patient access while ensuring consumer safety, Dr Worthing states. It’s a delicate balance to strike, especially in biosimilar drug review, an area of potentially high safety stakes and high value and patient impact.

More than 52 million Americans have rheumatic diseases, and having access to approved biologic therapies is critically important because these treatments can dramatically improve long-term patient outcomes, says Dr Worthing. “These drugs are highly effective, helping my patients to manage pain, avoid long-term disability, and lead healthy, full lives.” He adds that patients and clinicians welcome the introduction of biosimilars because they have the power to increase competition and eventually lower the cost of biologics. The first FDA-approved biosimilar treatment of rheumatic diseases went on the market in 2016 (Inflectra, a biosimilar to the reference infliximab drug, Remicade), and other biosimilars for treatment of rheumatic diseases are currently undergoing FDA review—good news for patients who struggle to access and afford the biologic therapies they need to manage their conditions, Dr Worthing writes.

Biosimilars hold great promise but they come with high stakes because of their complexity. Even small changes in the manufacturing process can lead to ineffectiveness or dangerous interactions with the patient’s immune system, Dr Worthing explains. “It is imperative that there be full transparency in biosimilar naming, labeling, and post-market surveillance practices, as well as a robust FDA workforce to support the biosimilars review and regulatory process,” he concludes. Physicians must know precisely what they are prescribing and patients must know what they are taking. Distinct names, clear labeling, and consumer-friendly dispensing practices must be priorities. While the FDA has made some good progress on this front, Dr Worthing writes, it must now issue and implement final industry guidances.

Congress can support these efforts, he notes, by ensuring adequate funding to enhance and expedite the FDA’s review of biosimilar therapies and to issue industry guidance. This is a goal that can be achieved if Congress creates a dedicated program for biosimilar review with its own source of funding, similar to what exists for prescription drugs, generics, and medical devices. In addition, Congress should also quickly reauthorize the Biosimilar User Fee Act, under which the FDA is allowed to collect user fees on biosimilar products in order to fund the review process. The law will expire in September 2017.

Finally, the incoming administration must enact hiring reforms to help the FDA hire qualified reviewers, Dr Worthing recommends, because right now it is too difficult to find highly qualified employees. The 21

 Century Cure Act authorized decision makers to make a change in this process, he says, and there are many ways the new administration could tackle this issue. For example, federal agencies can use market surveys of salaries in related competing industries where FDA candidates might currently work in order to better align pay rates that will attract the best talent with expertise to study biologics.

Innovative and efficient onboarding of experts in the complex field of biologic therapies must be a top priority in the years ahead if biosimilars are to reach the many patients who would benefit from these therapies, Dr Worthing concludes. “We can have the best of both worlds, providing patients with state-of-the-art treatments and manageable prices. It is imperative that our policymakers dedicate more time and resources towards biosimilar policy at the FDA to realize that goal.”

FDA Should Forge Ahead on Biosimilar Drug Reviews: A Rheumatologist's Opinion

 a 2-year contract in which Harvard Pilgrim will pay less for Amgen’s biologic drug etanercept (Enbrel) if patients score below certain levels on measurements of 6 criteria. The contract represents another action by Harvard Pilgrim is to reimburse based on value to the patient, and not solely on volume of medicine sold, according to the insurer. Enbrel is approved for the treatment of moderate to severe rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis.

The 6 criteria measured include patient compliance, switching or adding drugs, dose escalation, and steroid interventions that can serve as a global measure of the positive impact on Harvard Pilgrim members. “If patient scores are below a specified level, Harvard Pilgrim will pay less for Enbrel because its real-life effectiveness will have been lower,” the company states. The insurer said that tracking patient adherence to the drug is the only outcomes-based contract of its kind in the market for the treatment of moderate to severe RA. “Real-world performance of new medicines frequently differs from the well-controlled clinical trial setting, and we know that historically only about a third of patients on Enbrel and others in this class meet all 6 criteria,” said Harvard Pilgrim chief medical officer Michael Sherman. By linking the ultimate cost of Enbrel to its real-world clinical efficacy, the contract puts the focus on the patients, he said.

Amgen’s statement said the agreement with Harvard-Pilgrim aims to demonstrate the value of using Enbrel to effectively treat patients, and provides powerful evidence to be considered by formulary decision-makers in the future. The action may signal that Amgen is ready to negotiate with other health insurers to gain some kind of preference for Enbrel over etanercept biosimilars that are likely to be marketed in the future.

 The FDA approved Novartis/Sandoz’s etanercept biosimilar Erelzi in August 2016, but Amgen’s court case against Novartis/Sandoz has put Erelzi’s launch in limbo, with the patent fight likely to last into 2018.

 A company spokesperson said its work with value-based contracts and partnerships “is about rewarding medicines that deliver value and solutions to patients,” and not a reaction to expected competition from Enbrel biosimilars.

Amgen has previously negotiated a pay-for-performance agreement with Harvard Pilgrim for its cholesterol-lowering drug evolocumab (Repatha), which allowed Amgen an exclusive role in the insurer’s formulary in return for a discount and future rebates if Repatha did not perform as expected.

Harvard Pilgrim is a Wellesley, Massachusetts-based not-for-profit health services company with 2.7 million customers.

1. Palmer E. Amgen strikes Enbrel “outcomes” contract with Harvard Pilgrim. 

 Website. Available at http://bit.ly/2kTQ3re. Published February 22, 2017.Accessed February 23, 2017.

2. Palmer E. Sandoz head: Enbrel biosimilar Erelzi won’t launch before 2018, delayed by legal battle. 

 Website. http://bit.ly/2jMIPR9. Published January 25, 2017. Accessed February 23, 2017.