Surabhi Dangi-Garimella, PhD

A much-awaited talk at the 2017 AAM Biosimilars Council Conference, held in Washington DC, was by Andrew Slavitt, senior advisor, Bipartisan Policy Center and former acting administrator, CMS. Providing an overview on where the healthcare reform debate is headed, Slavitt refined the discussion to focus on drug cost and indicated the potential for biosimilars to influence the rising costs of drug products.

 that were being held by senators on the same day, where the lawmakers were to unveil new healthcare reform proposals, Slavitt predicted, “To my mind, every 10 years or so, we are due for another healthcare debate in this country. If you go back as far as Medicare and Medicaid, Medicare Advantage, Medicare Part D, Obamacare, and then of course the current battle…this could be another battle of sorts in 10 years.”

Slavitt went on to take stock of what the Affordable Care Act (ACA) accomplished, including reducing the uninsured rate, investing in healthcare cost and quality of care, and ensuring healthcare insurance for all American citizens, independent of their health or financial status. He acknowledged that the ACA did not get it all right in terms of fixing problems, including affordability of healthcare, which encompasses the absence of competition in the insurance marketplace in several states.

Slavitt said that every American should have access to affordable care, preventing healthcare-associated bankruptcy. Ensuring this can be sustained and achieved by 2020, the current focus should be:

Bipartisan legislation with complete support from 60-70% of the American public. This requires a discussion of the kitchen-table issues, he said, and an understanding of the tradeoffs faced by American families.

Implementing some of these ideas in the states over the next few years

Addressing cost and affordability of healthcare

Unlocking the innovation potential in the country in the right way

The healthcare challenge in our country, Slavitt explained, “is not the 50-year old jogger with mobile monitoring devices. The challenge is the woman who lives 2 bus stops away from a dialysis center and who may be in renal failure if she misses one of the connections.” Social determinants of health, which are outside of healthcare control, need to be addressed, he said, adding that we need to move innovation away from gadgets like Fitbit and refocus on some of these social issues.

Moving the discussion toward drug costs, he said that this problem is not forthcoming; it’s a problem we face today. “We cannot talk about affordability of healthcare in exchanges without getting into the underlying root cause.” Narrating his experiences of heading CMS, he said that, when he would talk to heads of healthcare systems or the pharmaceutical industry about keeping down or regulating the cost of care, the feedback would be:

Don’t look at me, look at them (plans, pharmacy benefit managers)

Don’t worry about the price, nobody pays it all anyway: lack of transparency is a problem

You have to spend money to make money: but this can be balanced off with real-world evidence and assigning “value” to the outcome with a specific treatment

Innovation costs money, but is price the tradeoff to make when choosing between innovation and improvements? If other industries continue to provide innovation at lower costs, why not healthcare?

“This is where biosimilars come in,” Slavitt said. He made note of changes being made by FDA Commissioner Scott Gottlieb, MD, to 

He reiterated his faith in competition, innovation, value-based ideas, and the ability for CMS to negotiate drug prices. Going back to the 

, which is being presented by Senator Bernie Sanders (I-Vermont), he said there are provisions in his bill and opportunities that are relative to generic drugs and biosimilars.

He closed by saying that the affordability questions will be ever-present, and that biosimilars and generic drugs may have a significant role to play in being part of the solution. “Being there and part of the solution while key legislations are being drafted or as people are focused on policy issues is a great place to be.”

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Providing an overview on where the healthcare reform debate is headed, Andrew Slavitt, former head of CMS, refined the discussion to highlight the potential for biosimilars to influence the rising costs of drug products.

Federal Perspective on the Biosimilar Influence on Drug Costs

During a panel on the second day of the 2017 AAM Biosimilars Council Conference, held in Washington DC, September 11-12, regulatory leaders from Pfizer and Sandoz shared their experiences with the development of their biosimilar products: epoetin alfa (Epogen) and etanercept (Erelzi), respectively.

Tracy Dianis, director, Global Regulatory Affairs Biosimilars, Pfizer Essential Health, brought up 3 key concepts with biosimilar development:

“Shifting your approach for the development program is a challenge,” Dianis said, “especially if you are trained for a long time in the development of originator molecules.”

Dianis told the audience that Pfizer launched the epoetin alfa biosimilar program prior to the 

Biologics Price Competition and Innovation Act

 of 2009 or the formal FDA guidance being issued. Product development included statistical analysis of analytical data, preclinical studies in rats, and clinical strategies that included pharmacokinetic and pharmacodynamic studies, in addition to extra clinical studies, Dianis said.

“We had a massive quantity of data to support the analytic and qualitative data. Through our discussions with the FDA, we ended on 2 attributes: mechanism of action and inherent quality of the molecule,” she added.

Another challenge of starting early was in the non-clinical space, she explained. “We didn’t know what the requirements would be. In case of epoetin alfa, we couldn’t do animal modeling; we leaned on our experiences of [the] originator biological space and also evaluated studies conducted for the reference.”

Pfizer ended up with 2 13-week toxicology studies, but Dianis stated that applying this study design in the comparative setting was challenging. “It really required ‘flipping our mindset’ to make sure we were thinking like a biosimilar and not an originator product developer,” she said.

The product, however, continues to face challenges—it was rejected by the FDA for a 

 in June this year; the complete response letter cited issues with the potential manufacturing facility. The rejection followed a 14 to 1 recommendation by the Oncologic Drugs Advisory Committee just a month prior to approve the product.

Explaining the importance of the “totality of evidence,” she pointed to the value of highlighting data that demonstrated product biosimilarity to the reference product as well as the differences. “It is also important,” she continued “to develop a narrative on why the differences do not disqualify the existence of biosimilarity.” Teamwork should be at the core of the development program, according to Dianis, and the narrative should hold true across all the data packages submitted for FDA review. “Working in silos does not help in the biosimilar space…it requires close collaboration and needs the story to be woven through the data package.”

Dianis concluded by saying that while companies might focus their efforts in identifying and explaining new aspects of the biosimilar, traditional product development and compliance aspects retain their relevance.

Sharing the podium with Dianis was her counterpart from Sandoz, Cindy Cao, PhD, who stepped back in time to provide an overview of the regulatory approval steps faced by GP2015 (Erelzi). Prior to submission of the biologics license application on July 30, 2015, representatives from Sandoz met with the FDA for pre-investigational new drug discussions, which included conversations around a pediatric study plan as well as establishing a bridge between the US-licensed product and the EU-approved product. 

The 2 parties also discussed, and agreed on, conducting safety and immunogenicity evaluations for patients who undergo a single transition from the reference (Enbrel) to GP2015. With respect to some issues with disulfide bonding studies, they continued to have conversations with the FDA. The team had to be open and ensured that their development program was driven by science, she said.

Following an advisory committee meeting on July 13, 2016, the FDA gave the product a green light on August 30, 2016. According to Cao, the following aspects were key to Erelzi’s success story:

Early and continued discussions with the FDA:

 including important critical quality attributes

monitoring batch-to-batch variations and sharing new product development observations with the FDA

FDA’s flexibility and scientific approach

David Gaugh, RPh, senior vice president of regulatory sciences, AAM, who moderated the discussion, asked the panelists whether biosimilars are being held to higher standard than are originators.

“The reference product has had years of experience for routine manufacturing, especially in the context of statistical criteria,” Dianis responded. “In our case, even with multiple strengths, we are still very early in the process. [The FDA] are open to having the discussion, but the discussions can often be tougher because they want the product to be clean.”

Cao had a distinct perspective to share: she called biosimilar product development a moving target. “We do often observe differences over years with the reference product, but it’s not uncommon.”

Answering an audience question on differences in their experiences between the FDA approval process versus the European Medicines Agency, Dianis said that, with the epoetin alfa biosimilar, “EMA was a little more flexible than when we brought the program to the United States. Now [the differences] have evened out, but there are still some differences, statistical tiering being one of them.”

For Sandoz, on the other hand, the timings were flipped. “We filed with FDA prior to [European Union]; both authorities reviewed nearly simultaneously and our major learnings were similar with both bodies,” Cao said.

During a panel on the second day of the 2017 AAM Biosimilars Council Conference, held in Washington DC, regulatory leaders from Pfizer and Sandoz shared their experiences with the development of their biosimilar products: epoetin alfa (Epogen) and etanercept (Erelzi), respectively.

Industry Regulatory Experts Share Learnings From the Biosimilar Approval Process

 the tumor necrosis factor (TNF) inhibitor adalimumab-adbm (Cyltezo) injection for subcutaneous use in patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis.

Developed by Boehringer Ingelheim (BI), this is the second adalimumab (Humira, Abbvie) biosimilar to be approved in the United States, nearly a year after 

 (Amjevita, Amgen) was approved by the FDA in September 2016.

The most serious adverse events with adalimumab-adbm include infections and malignancies. The FDA has included a serious boxed warning for serious and sometimes fatal infections, including tuberculosis, bacterial sepsis, invasive fungal infections, and infections from other opportunistic pathogens. TNF blockers also increase the risk of lymphomas and other malignancies, particularly in young children and adolescents, according to the product label.

Abbvie, which has a multi-billion dollar market for the reference product, had filed a 

 against BI in a Delaware federal court earlier this month claiming that BI will infringe on 74 of its patents for adalimumab in its development of this product.  

The approval for adalimumab-adbm comes a year after the first adalimumab biosimilar, by Amgen, was approved in September of 2016.

Competition Strengthens for Humira Market With Approval of Second Biosimilar

With multiple biosimilars to infliximab (Remicade) in the US market, Janssen Biotech, which developed the reference product, has taken steps to block the marketing of at least one of these in the United States. Last week, the company 

 in a US District Court to prevent Korea-based Samsung Bioepis from selling its infliximab biosimilar in the United States.  

According to Janssen, the Korean company violated 3 of its manufacturing process patents, a claim that Samsung Bioepis disputes: “We are confident we do not infringe Janssen’s patents,” the company said in a statement, adding, “We will take all necessary measures against Janssen’s attempts to violate patient rights and deny patient access to effective, lower cost treatment options.”

Infliximab-abda (Renflexis), developed by Samsung Bioepsis/Merck, was 

 by the FDA just about a month ago. This tumor necrosis factor (TNF) inhibitor has been indicated for various inflammatory conditions, including Crohn’s disease (adult and pediatric), ulcerative colitis, rheumatoid arthritis (combined with methotrexate), ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

Janssen's objections are with the same patents as it did with Celltrion’s infliximab biosimilar, Inflectra. The current 

 claims that Samsung Bioepis “short-circuited the patent dispute resolution process” as noted in the Biologics Price Competition and Innovation Act (BPCIA), specifically the information exchange and good-faith negotiations between the plaintiff and the defendant.

Janssen claims that “Bioepis short-circuited the BPCIA’s patent dispute resolution process by withholding the information necessary for Janssen to assess infringement.”

The lawsuit further accuses Samsung Bioepis of serving the notice of commercial marketing much earlier than when it is allowed to legally do so, which is after approval of the abbreviated Biologics License Application.

Infliximab brings in close to $5 billion in sales for Janssen, and the company is definitely worried about the drop in revenue as a result of the biosimilar competition.

With multiple biosimilar products in the pipeline, Samsung Bioepis’ 6 initial offerings are focused on immunology, oncology, and metabolic diseases.

The company plans to proceed marketing Renflexis in the United States as planned.

Janssen Moves to Block Marketing of Renflexis in Suit Against Samsung Bioepis

The Senate today confirmed Scott Gottlieb, MD, as FDA commissioner by a margin of 57 to 42 votes. The vote came along party lines, with Democratic Senators criticizing Gottlieb’s intertwined connections with the pharmaceutical industry and his opposition to FDA’s risk evaluation and mitigation strategies.

Gottlieb’s predecessor, Robert Califf, MD, who led the FDA for less than a year, has previously 

Welcoming Gottlieb’s nomination, Rep. Greg Walden (R-OR.), chairman of the House Energy and Commerce Committee, and Rep. Michael C. Burgess (R-TX), 

 in a statement, ““We are at a critical juncture in the effort to help accelerate the discovery, development, and delivery of new cures and treatments, and Scott will be an important ally in that journey.”

An important task for the incoming leader of the FDA is to meet the Trump administrations goals of speeding up the drug approval process and also to implement the provisions of the 

. The challenges would be to bring about these changes on a very tight budget.

Meanwhile, several organizations, including the American Society of Clinical Oncology (ASCO) and the American College of Rheumatology (ACR) have expressed their support for Gottlieb’s confirmation.   

“As a physician and cancer survivor, Dr Gottlieb knows firsthand that safe and effective cancer treatments must move from the lab to the patient as quickly as possible. We are hopeful that Dr Gottlieb will serve as a passionate advocate for the public’s health,” said Daniel F. Hayes, MD, FACP, FASCO, president of ASCO, in a statement.

In his statement congratulating Gottlieb, Sharad Lakhanpal, MBBS, MD, president of ACR said, “The FDA continues to play a critical role in lowering biologic drug costs as it works to bring safe, effective, and lower-cost biosimilar alternatives to the marketplace. Therefore, it is imperative that FDA have the funding and resources it needs to expedite biosimilar drug approvals, hire and retain qualified staff, issue guidance, and perform adequate post-market surveillance.

“We look forward to working with Commissioner Gottlieb, Congressional leaders and the Trump Administration to bolster the FDA’s important work on biosimilars to ensure more Americans can access safe, effective and life-changing therapies.”

Senate Confirms Scott Gottlieb as FDA Commissioner

Amgen has gained a European marketing authorization for its biosimilar version of Abbvie’s anti-inflammatory drug adalimumab (Humira), making it the first European license for a biosimilar to adalimumab. Amgen’s product will be 

Biosimilar adalimumab is approved for the following inflammatory conditions in adults:

Severe active ankylosing spondylitis (AS)

Severe axial spondyloarthritis without radiographic evidence of AS

Moderate-to-severe chronic plaque psoriasis

Moderate-to-severe hidradenitis suppurativa

Non-infectious intermediate, posterior and panuveitis

Moderate-to-severe Crohn's disease and moderate-to-severe ulcerative colitis

It is also approved for the following pediatric conditions:

Moderate-to-severe Crohn's disease (ages 6 and older)

Severe chronic plaque psoriasis (ages 4 and older)

Enthesitis-related arthritis (ages 6 and older)

Polyarticular juvenile idiopathic arthritis (ages 2 and older)

The approval comes from results of 2 phase 3 studies conducted in moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis patients, each of which met their primary endpoint with no clinically meaningful differences to adalimumab, including safety and immunogenicity data.

Approval from the European Commission (EC) means Amgen can now market the drug across 28 countries across Europe. Other European Economic Area member nations, including Norway, Iceland and Liechtenstein, will take corresponding decisions based on the EC decision.

Called adalimumab-atto (Amjevita) in the United States, Amgen gained FDA approval in September 2016. However, pending legal issues have prevented market launch.

Global sales of Humira crossed $16 billion in 2016.

Amgen Gains EC Approval for Biosimilar to Adalimumab 

Mylan has entered a global settlement with Genentech Inc and F. Hoffman-La Roche Ltd on a patent for trastuzumab (Herceptin), which will provide the company with global licenses for its trastuzumab biosimilar.

Under the global license, Mylan can now commercialize its product around the globe, except in Japan, Brazil, and Mexico. Today’s announcement ensures that the US market will see the first biosimilar to trastuzumab, once Mylan’s biologics license application—filed in collaboration with Biocon&mdash;is approved by the FDA. The Biosimilar User Fee Act for trastuzumab is September 3, 2017. The 2 companies have co-developed 5 other biologics.

“There is an unmet need for access to more affordable versions of biologic products such as trastuzumab. We look forward to enhancing access to this important treatment option, which complements our comprehensive cancer care offerings, in the U.S. and around the world,” 

While Mylan has already been marketing the product in 14 emerging markets around the globe, the US and European markets would provide the most value—Roche reported sales of nearly $4.5 billion in 2016 alone. Just 

 the New Delhi high court ruled in favor of Mylan being able to sell the trastuzumab biosimilar in India for additional indications using Roche’s package inserts for Herceptin.

Mylan's Settlement With Genentech and Roche Opens US Market for Trastuzumab Biosimilar

Senators in New Mexico have passed a bill that will allow pharmacists in the state to substitute biosimilar products in place of the original or reference product, similar to what they currently are allowed to do with generic drugs.

 that the state Senate voted 39-0 in favor of Senate Bill 180, which promises to give flexibility and control costs for some of the most expensive, and effective, biological products being used to treat a plethora of conditions—from cancer to rheumatoid arthritis to irritable bowel syndrome. The next step is approval of House Bill 260, now with the House Business and industry Committee in New Mexico.

The argument rests on drug costs. Between 2014 and 2016, the state-run Medicaid program saw a huge increase in the biological drug spend, which they associated with a 5% increase in state-funded plan members who were using adalimumab (Humira) and etanercept (Enbrel). The 2-year period saw a 52% increase in plan costs for those 2 drugs. Overall, state-run plans spent $13.3 million on anti-inflammatory agents in the year 2015—a 20% increase from 2014.

With budget impact in focus, lawmakers in New Mexico will debate whether pharmacists can substitute these expensive antibodies for cheaper “replicates,” and whether this substitution can lower consumer cost. This would require the blessings of the prescribing physician, who has the authority to write “no substitution” on the prescription.

The biosimilar approval process has been slow in the United States, with numerous legal and regulatory barriers preventing product application and launch. To date, just 1 biosimilar to adalimumab has been 

—Amgen’s Amjevita&mdash;but patent lawsuits will push product launch to 2018. Another product, manufactured by Sandoz, has 

 its abbreviated Biologics Licensed Application or aBLA.

Sandoz has also developed a biosimilar to etanercept (etanercept-szzs, Erelzi), but faces patent claims by Amgen, the developer of the original product.

Biosimilar competition will hopefully subdue the skyrocketing price of these biologicals. Abbvie, the manufacturer of Humira, has steadily raised the price of this antibody by over 70% in just a few years ($49,000 annually before discounts and $27,665 after discounts), likely due to broadening indications of the drug. Amgen has followed a similar route with Enbrel, which costs $4000 for a 30-day supply.

New Mexico Senate Passes Bill for Biosimilar Substitution 

Amgen has been sued by Genentech, a Roche company, for withholding information on its biosimilar to Genentech’s bevacizumab (Avastin), thereby creating a barrier for filing a potential patent infringement lawsuit.

, Genentech states that Amgen has violated the Biologics Price Competition and Innovation Act (BPCIA) as it develops the biosimilar to bevacizumab. Genentech expected access to Amgen’s manufacturing information of the biosimilar to determine whether the manufacture or sale of the product would infringe on Genentech’s patents. The company also wants sufficient time for a legal intervention, if need be, before the biosimilar is launched in the market.

The lawsuit, filed in a US District Court in Delaware, claims that Amgen is refusing to share relevant “confidential information” with Genentech’s consultants, beyond the Abbreviated Biologics License Application (aBLA), which would allow an infringement analysis. Per the BPCIA statute, Genentech expected to have not just the copy of the aBLA for review, but additional information that describes the steps used to manufacture the biosimilar product—in this case, bevacizumab&mdash;within 20 days of filing the aBLA on January 4, 2017. This would allow Genentech to provide Amgen with a list of patents within 2 months of receiving information from the company.

The complaint also accuses Amgen of improperly withholding consent for 4 experts to review their aBLA, which “violates subsection (l)(1)(C) of the BPCIA.”

Genentech would like its 60-day window for providing its list of patents to Amgen to begin only after Amgen provides all the required information. The company also seeks to prevent marketing of Amgen’s biosimilar till it meets all obligations per the BPCIA.

Amgen has witnessed this “patent dance” before, with one of its own products, epoetin alfa (Epogen). Amgen had then sued the biosimilar manufacturer, Hospira, for noncompliance with the BPCIA.

The competition for the high stakes involved with this multi-billion dollar industry has resulted in companies tapping into loopholes left by the fairly new rules around biosimilars. Amgen is already involved in a case with Sandoz that will decide whether a biosimilar applicant can completely opt out of the BPCIA information exchanges, and if so, what information would the originator company end up with. Another argument is over the 6-month obligatory 

 for biosimilar manufacturers after they have informed the originator about its biosimilar product.