Last week the US Food and Drug Administration (FDA) issued a revised draft guidance detailing its policies on mixing, diluting, and repackaging certain types of biological products outside of the scope of an approved biologics license application (BLA).

Diluting or mixing a biological product with other components, or repackaging a biological product by removing it from its approved container-closure system and transferring it to another container-closure system, in the absence of manufacturing controls, is highly likely to affect the safety and/or effectiveness of the biological product. The FDA says even minor manipulations of biologics can result in quality or safety issues due to their unique properties.

There are instances where appropriate to mix or dilute a biological product to meet the needs of specific patients. "For example, for some biological products there is no licensed pediatric strength and/or dosage form, so the product is diluted for use in pediatric patients." While there are exemptions from certain federal regulations for compounded drugs under sections 503A and 503B of the 

, these exemptions do not apply to biological products licensed under sections 351(a) or (k) of the 

In accordance, the FDA says that any biological product that is mixed, diluted, or repackaged outside the scope of an approved BLA is an "unlicensed biological product." It also does not intend to take actions for violations of section 351 of the PHS Act or sections 502(f)(1) or 582 of the FD&C Act if a state-licensed pharmacy, a federal facility, or an outsourcing facility mixes, dilutes, or repackages a biological product" in accordance with the guidance.

The guidance does not apply to investigational new drugs being studied under a new drug application or radioactive biological products.

Biologics Mixing, Diluting, and Repackaging: FDA Draft Guidance

Daniella (Dee) Latham

David T. Rubin, MD, AGAF, is a professor of medicine and section chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine. He is a fellow of the American Gastroenterological Association (AGA), which represents over 16,000 gastroenterologists worldwide and is dedicated to empowering clinicians and researchers to improve digestive health. He is also chair-elect of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, whose mission is to cure Crohn disease and ulcerative colitis, and to improve the quality of life of children and adults affected by these diseases. AGA is a member of the Biologics Prescribers Collaborative (BPC), an organization comprising medical societies whose members regularly prescribe biologic medicines. BPC strives to ensure that sound policies are in place to promote the safest possible development and use of all biologics, including biosimilars, for all patients.

David T. Rubin, MD, AGAF

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John Bujnoski is Managing Director of Pangea Advisory and Consulting, LLC, a strategic marketing consulting firm focused on the specialty biopharmaceutical and biosimilar market segments. John has extensive global biopharmaceutical industry expertise including extensive knowledge and understanding of the global market environment including pricing, market access, and reimbursement systems.

John Bujnoski

Safaraz Niazi, PhD, is an adjunct professor of biopharmaceutical Sciences at the College of Pharmacy at the University of Illinois at Chicago. 

Sarfarzaz K. Niazi

George C. Yu, JD, is a partner in the Intellectual Property group of Schiff Hardin LLP. He is an experienced patent attorney who focuses his practice focuses on patent infringement litigation and counseling and has worked in private practice and in-house positions. George has litigated patents relating to recombinant proteins, monoclonal antibodies, microarray technology, and small molecule therapeutics. George has advised companies developing novel biologics as well as biosimilars on patent strategy.

George C. Yu, JD

Coronavirus disease 2019 (COVID-19) altered the workflow in all areas of the health care and life sciences industries. The FDA was not exempt from pandemic-induced upheaval. Meetings of advisory committees, which provide the FDA with expert advice on scientific, technical, and policy matters, were often postponed, and although drugs were still reviewed and approved, significant delays occurred.

From the start of the United States’ response to the COVID-19 pandemic in March 2020 until late summer, 2 biosimilars were 

: Hulio (adalimumab) and Nyvepria (pegfilgrastim). This represented not only an improvement in patient access and affordability of life-changing medications, but also a slowdown in biosimilar approvals.

In previous years, biosimilar approvals had steadily increased. As shown in the figure, the projected trend suggested approximately 12 biosimilar approvals for 2020 and 14 for 2021.

The trend line for biosimilar approvals suggested 2020 would be another strong year for the emergence of these lower-cost therapies; however, just 2 had been approved by the midyear point.

Although other factors came into play, such as patent expirations and product development, it appeared unlikely that the total of 12 biosimilar approvals would be achieved in the final quarter of 2020, and there was even potential for this slower pace to extend into 2021.

There were other reasons why patient access did not improve as expected. Typically, once manufacturers receive biosimilar approval, many face 

 that delay products from reaching the market promptly. These court cases often are purposely filed to interfere with market access to a new product. In some cases, “

” agreements postpone market entry of a biosimilar for many 

The COVID-19 crisis extended these delays because court systems temporarily closed to prevent spread of the virus and reopenings were late or occurred only in stages. Well into 2020, virus hot spots 

 to stall judiciary system operations, adding to the time needed to achieve market access for these new therapy options.

In addition to regulatory and judicial barriers, the overwhelming workflow within health systems also played a role in limiting access to new therapies. When health care facilities are in crisis mode, many components of the reimbursement and education processes, each of which is vital for biosimilar uptake, are hindered. 

Pharmacy and therapeutics (P&T) committees are necessary for ensuring new therapies will be included in the health care facility formulary. From the start of COVID-19, P&T meetings were often conducted virtually or 

 on evaluating emerging therapies for COVID-19 treatment, leaving little time for consideration of other formulary additions. With so much focus on COVID-19, little time was allocated to much else.

Within hospitals, the same was true regarding in-service education for physicians. With a need to educate physicians on current protocol, diagnostics, and treatment surrounding COVID-19, there was not much time left to educate on biosimilar therapies and novel agents.

“Lunch and learn” programs were likely on hiatus during the pandemic due to social distancing requirements, understaffing, and a strain on funding. Gathering professionals into a conference room could not be prioritized over keeping everyone safe.

Typically, many facilities partner with manufacturers to supply marketing materials and food to lunch and learns, and a clinical staff member presents on the topic at hand. As manufacturer field teams were grounded, less information reached the health care providers. Most nonessential visits were prohibited to prevent unnecessary risk of virus spread. These grounded professionals included sales representatives who provide information about new products, field reimbursement specialists who assist in getting products approved by the health plans, and medical science liaisons who can discuss new products on a higher level. These professionals were not as physically active as the pandemic unfolded and virtual methods of interaction were implemented.

If new therapies, including biosimilars, were not approved by the FDA, litigated promptly in the courts, cleared for formulary placement, or explained to physicians, it is unlikely patients were learning much about them. Especially when it comes to biosimilars, patients need to be aware of their potential options and the associated benefit of cost savings. With COVID-19, the nation entered a time of financial instability and loss of health care coverage, and these new therapy options became even more important for safe and affordable health care.

Coronavirus disease 2019 altered the workflow in all areas of the health care and life sciences industries, and the FDA was not exempt from pandemic-induced upheaval.

The Pandemic's Multilevel Effect on Patient Access

Amanda DeMarzo, PharmD, MBA, PACS, is the associate director of Patient Access with the National Board of Prior Authorization Specialists, an affiliate of the Accreditation Council for Medical Affairs, based in Oradell, New Jersey. She focuses on how to improve the current health care system as a whole through improved training, widespread certification, and advanced technology for better patient outcomes. She developed a passion for patient-centered care and shared decision making during patient-facing roles over the last 8 years.

Amanda DeMarzo, PharmD, MBA, PACS

The House of Representatives has approved the bipartisan 21st Century Cures legislation, which includes funding for innovative research and provisions to speed up the drug approval process.

By a vote of 392-26, the House approved the 21st Century Cures Act. The House had passed an earlier version of the bill in July 2015 but continued to revise and update it, releasing the most recent draft of the bill last week. These updates included provisions for mental health, substance abuse, and child and family services.

Members of both political parties have been vocal in their support of the legislation, often citing its passage as a top priority during the lame-duck Congressional session. Prior to the election, Senate Majority Leader Mitch McConnell, R-Kentucky, had said it “could end up being the most significant piece of legislation we pass in the whole Congress." 

House of Representatives Approves Bipartisan 21st Century Cures Legislation

Christina Mattia

Gregory Schimizzi, MD, is a co-convener of the Biologics Prescribers Collaborative (BPC) and the cofounder of Carolina Arthritis Associates, PA, in Wilmington, NC.  He has been a licensed and board-certified rheumatologist in private practice for 30 years. He co-founded, and previously served as president, of the Coalition for State Rheumatology Organizations (CSRO). He has also previously served as president, and a member of the executive board, at the North Carolina Rheumatology Association. Dr Schimizzi completed his undergraduate and medical school studies at Wayne State University in Detroit and completed his fellowship training at the University of California at Irvine.

Gregory Schimizzi, MD

Providers and health care institutions are going to need a lot more real-world data on how patients respond to various biosimilars and switches between biosimilars and reference products, according to a varied panel of private practice, academic hospital, and group purchasing organization experts in a discussion at the Community Oncology Alliance virtual Community Oncology Conference 2021.

“If we can solve the issue of real-world evidence and data and supply that, I think that will support the use of biosimilars moving forward,” said Sandeep Parsad, PharmD, MBA, BCOP, assistant director of pharmacy at University of Chicago Medicine (UCM).

Providers are going to need convincing, particularly as the choices among biosimilars become more numerous, the panel said. In the oncology space, biosimilars as therapeutic drugs are fairly new, although in supportive care these have been used much longer. And it is often stated that oncologists, especially, become more circumspect in the disease setting about the choice of agents, preferring to go with a well-established originator brand that both they and the patient may have come to trust. To encourage more switching to biosimilars, more evidence is going to be the tool for that, said E. Randolph “Randy” Broun, MD, a blood and marrow transplant specialist with Oncology Hematology Care (OHC), of Cincinnati, Ohio.

“I think data are really lacking in this area. Physicians are going to want data to understand that these truly are biosimilars that are interchangeable and they’re not shortchanging their patients by doing this, even under pressure from payers,” he said.

There’s an important distinction to be made, he said. At his practice, at least, biosimilars are a concept that physicians are very familiar with and they now use these agents in many settings and are comfortable with them. But their confidence in biosimilars can be strained when multiple versions of a single reference product start to appear and they are tasked with making the right choices for their patients.

“Once we have 8 different Herceptins (trastuzumab), are they all the same? Is it reasonable to simply pull a different one off the shelf for a patient who got something different 3 months ago? That will be a barrier, I believe. And you’re only going to solve that with a lot of data that are very convincing that these things are perfectly interchangeable,” Broun said.

Cardinal Health has recognized the value in using biosimilars, as their discounts, particularly when many are available on the market, can be significant, and became proactive with its participating physician practices to cultivate an understanding of these agents that would translate into greater use, according to Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars for Cardinal Health.

Parsad said the same goes for her institution. “We took a very purposeful approach to meeting with physicians and nursing staff to talk about the regulatory requirements for approval and demonstrate how biosimilars are similar to reference products, how they have a high standard for safety and quality,” she said.

When it approves a biosimilar, the FDA certifies that it is as safe and effective as the original biologic, and that it has been rigorously evaluated, but the FDA doesn’t give it automatic interchangeable status, meaning pharmacists would be free to substitute the biosimilar with a reference product without informing the physician. Additional requirements are needed for that. It has been hard to explain to physicians that that shouldn’t stop them from prescribing biosimilars, Parsad said. “We felt that was a bit of a bump for us. This is what I’ve heard as well with other colleagues around the country, that physicians do prefer that they are informed when there is a decision whether we should switch or not from the reference product to the biosimilar. But I feel like it went fairly smoothly once there was this very open dialogue.”

It was more of a challenge to develop policies about switching from reference products to biosimilars and in what instances this should occur, she said. A lot of issues arose, such as whether patients should be asked for fresh consent before they are prescribed a biosimilar after having been on a reference product, and if a patient’s condition is stable on a reference product, is it really wise to “rock the boat” and prescribe a biosimilar? And further, following a new diagnosis of metastatic disease, should patients be started on a biosimilar instead of the reference product?

“We had to really work through this saying this is something that we believe as an organization. We believe in the literature, we believe in the data, and we would like to move forward. So, we’ve gotten past that hump,” Parsad said. 

All that said, UCM still wants to see more real-world evidence that shows biosimilars can stand the test of time outside of clinical trials performed in limited numbers of patients for the purposes of FDA approval, she said.

Oskouei agreed. “The conversation has definitely evolved with a desire for more real world evidence and studies around biosimilar to biosimilar switching. With 5 trastuzumab biosimilars on the market now for example, and more in the pipeline, this dynamic is becoming something that providers must navigate.”

At OHC, providers are now using biosimilars in practically 100% of situations when it comes to trastuzumab, rituximab, and supportive care products, such as growth factors for the control of neutropenia in patients treated with chemotherapy products, Broun said. But the practice has found it more manageable to administer a single brand of biosimilar overall except in instances where payers demand something different. “Actually, the ones that give us the most trouble as far as the payers are concerned are the growth factors. Every insurance company seems to have their favorite [pegfilgrastim], and so we stock 3 or 4 of those and we have to sort of interchange them.” 

It would be nice if payers were more lenient about the choice of biosimilars, panelists said. For example, Parsad noted that the administrative work that goes into payer authorizations could be used on something more beneficial, such as patient education and support. “We’re dealing with it as best we can, but it’s unfortunate,” she said.

These issues resemble growing pains for a relatively new option in medicine that is already proving its value, said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center in Louisiana, who served as panel moderator. “The US market is still in its infancy. We just need to let it mature. Biosimilars have been, at least for our organization, a great way to help provide some cost savings to the system and to the patient.”

Next-stage biosimlar acceptance will stand on the strength and availability of real-world data as more of these biologics are launched, a Community Oncology Alliance (COA) conference panel said.

COA Panel Says Confidence Rests on Real-World Data

Tony Hagen is senior managing editor for The Center for Biosimilars

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