Gillian Woollett

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece… Show more

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece considers the efficiencies that could be achieved within the biosimilar approval process. In clinical trials for biosimilars, clinical efficacy endpoints have been shown to be less sensitive measures of biosimilarity than biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential biosimilars and reference products do not add information that is useful for regulatory purposes. Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control processes in place for all biologics, including biosimilars. The expectation for multiple-switch studies for US interchangeability designation should be reconsidered immediately, and the category should be eliminated in the future. As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic testing of EU and US reference products is unnecessary. Manufacturers and regulators could take greater advantage of existing real-world evidence. Streamlining biosimilar development would enable biosimilar development of more and a wider variety of biological drugs, accelerating biosimilar development without impacting patient safety or effectiveness. Show less

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to-date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the… Show more

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to-date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products. Consequently, the comparative analytical assessment and the head-to-head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future. Show less

Biologics are increasingly vital medicines that significantly reduce morbidity as well as mortality, yet access continues to be an issue even in apparently wealthy countries, such as the USA. While patient access is expected to improve with the introduction of biosimilars, misperceptions in a significant part based on terminology continue to make a sustained contribution by biosimilars difficult. Patients are and will continue to suffer needlessly if biosimilars continue to be impugned… Show more

Biologics are increasingly vital medicines that significantly reduce morbidity as well as mortality, yet access continues to be an issue even in apparently wealthy countries, such as the USA. While patient access is expected to improve with the introduction of biosimilars, misperceptions in a significant part based on terminology continue to make a sustained contribution by biosimilars difficult. Patients are and will continue to suffer needlessly if biosimilars continue to be impugned. Consequently, it is increasingly urgent that semantics are clarified, and in particular, the implication that interchangeable biologics are better biosimilars dismissed. This paper distinguishes between the real differences between biologics that matter clinically to patients and discusses the actual meaning of a US Food and Drug Administration designation of interchangeability for a biosimilar product. This will help highlight where there is need for further Food and Drug Administration education and which stakeholders likely need that education the most. Show less

The Food and Drug Administration’s decision to approve a long-acting insulin called Semglee (insulin glargine-yfgn) as the first interchangeable biologic licensed for the U.S. market represents a major step forward to greater competition and access for patients. What it means in practice, however, depends on where you sit.

The principles of comparability assessments have been accepted globally as offering sensitive and reliable tools with which to evaluate potential changes to biologics that may arise either through processing changes or through the creation of a copy (biosimilar) by a different sponsor. The comparability approach has evolved through systematic advances in four areas: clear and convergent guidelines for evaluation of potential changes to biologics; risk-based systems of weighting analytical data;… Show more

The principles of comparability assessments have been accepted globally as offering sensitive and reliable tools with which to evaluate potential changes to biologics that may arise either through processing changes or through the creation of a copy (biosimilar) by a different sponsor. The comparability approach has evolved through systematic advances in four areas: clear and convergent guidelines for evaluation of potential changes to biologics; risk-based systems of weighting analytical data; progressive improvements in analytical methods; and advanced understanding of post-translational modifications. Routine regulatory expectations for clinical equivalence data are being reevaluated, as they seldom contribute to the assessment of similarity. Similarly, we show that requirements to compare biosimilars and locally sourced versions of their reference products are of questionable scientific value and represent a double standard by comparison with the invariable acceptance of the clinical profiles of novel biologics without reference to their sources. The consistent application of evidentiary standards for comparability to all biologics offers an opportunity for regulators to curtail their own assessments of new biosimilars and instead to recognize comparability assessments made in another jurisdiction (reliance), thereby gaining important efficiencies in the regulatory review of biosimilars and improving the competitiveness of the biosimilars market. Such consistency can also enhance the confidence of all stakeholders, especially patients and their providers, in all biologics. Show less

As life sciences companies sprint toward COVID-19 vaccines and therapies, we consider who has the authority to make the call on their availability at the Food and Drug Administration (FDA) and the US Department of Health and Human Services (HHS). Traditional delegations to FDA do not change the statutory authority granted to the Secretary of HHS.

The current development paradigm for biosimilars required by regulators in highly regulated jurisdictions is derived from the development of novel drugs and is unnecessarily burdensome and inefficient. It requires the accumulation of data from analytical, nonclinical (including in vivo studies in some jurisdictions), and clinical studies (including powered efficacy studies in most cases); this paradigm is known as ‘totality of evidence’ (ToE) and does not admit a conclusion of biosimilarity… Show more

The current development paradigm for biosimilars required by regulators in highly regulated jurisdictions is derived from the development of novel drugs and is unnecessarily burdensome and inefficient. It requires the accumulation of data from analytical, nonclinical (including in vivo studies in some jurisdictions), and clinical studies (including powered efficacy studies in most cases); this paradigm is known as ‘totality of evidence’ (ToE) and does not admit a conclusion of biosimilarity from analytical data alone. The record of biosimilar approvals in these jurisdictions shows that no biosimilar candidate that has been found highly similar to its reference in analytical and pharmacokinetic studies has failed to be approved. We propose a new paradigm (‘confirmation of sufficient likeness’, CSL) that emphasizes the demonstration of analytical resemblance between the biosimilar candidate and its reference, and permits the conclusion of biosimilarity upon this basis. CSL does not entail bridging studies between reference products, in vivo nonclinical studies, or powered efficacy studies and is, therefore, substantially more efficient than ToE while maintaining equivalent scientific rigor. Such efficiency will contribute to the attractiveness as well as the sustainability of biosimilars as a therapeutic modality. Show less

The status of insulins in the USA is about to change as a regulatory matter. After 23 Mar 2020 they, and other hormone products previously regulated as drugs by the US Food and Drug Administration (FDA), even though biologics in science, will become biologics as a regulatory matter too and will be licensed under the Public Health Service Act. This has a number of ramifications for sponsors, patients, and their physicians.

We clarify the misinterpretation of our earlier paper [Christopher J. Webster, Gillian R. Woollett (2017), “A ‘Global Reference’ Comparator for Biosimilar Development”. BioDrugs doi:10.1007/s40259-017-0227-4 http://link.springer.com/article/10.1007%2Fs40259-017-0227-4] and confirm that our approach assures the same quality of biosimilars approved in the highly regulated markets as would be the case if additional clinical studies are conducted.

Europe is way ahead of the U.S. in biosimilar approvals and establishing a sustainable competitive marketplace, and it is not clear that the U.S. can even catch up. But over-protecting the U.S. originator market may hurt the next generation of innovators. To prevent this, regulators including the FDA can take steps to advance the public perception of biosimilars and ease the path to creating them, and thereby help competition without prejudicing anyone.

A Refined Gold Standard
Perhaps the greatest turning point in the history of medicine occurred sometime in the 20th century when medical practice started doing more good than harm. While “First, do no harm” is always sound advice, it may not lead to optimal outcomes.

An FDA gold standard based on population health will deliver the same assurance of safety and efficacy for which the agency is justifiably proud. However, the refined gold standard can accommodate greater… Show more

A Refined Gold Standard
Perhaps the greatest turning point in the history of medicine occurred sometime in the 20th century when medical practice started doing more good than harm. While “First, do no harm” is always sound advice, it may not lead to optimal outcomes.

An FDA gold standard based on population health will deliver the same assurance of safety and efficacy for which the agency is justifiably proud. However, the refined gold standard can accommodate greater sensitivity to the patient who is waiting as well as recognize the vulnerabilities of the sponsor of a new medicine. There is immense value in new, population-based sources of evidence, including clinical experience in less than ideal populations or in less controlled study settings. “Good enough” real-world data is now far too valuable to ignore. It is far better to empower the FDA to make more flexible decisions while maintaining its critical oversight instead of sideline those who are most competent to judge risks and benefits. For this to happen, the FDA will need to lead.

Show less

To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars).
Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well… Show more

To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars).
Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases.
The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates.
While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity- related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.
Show less

It is important that systems are in place to ensure that appropriate and
comprehensive records are kept for use of all medications. It is fundamental
to an effective pharmacovigilance system that patient medical records
contain sufficient information to identify which medication has been prescribed,
when it was administered, and at what dose. The availability of
biologics from multiple sponsors has raised questions by some health care
providers about the ability of current… Show more

It is important that systems are in place to ensure that appropriate and
comprehensive records are kept for use of all medications. It is fundamental
to an effective pharmacovigilance system that patient medical records
contain sufficient information to identify which medication has been prescribed,
when it was administered, and at what dose. The availability of
biologics from multiple sponsors has raised questions by some health care
providers about the ability of current pharmacovigilance systems to trace
specific biologics.
In this article, periodic safety update reports were used to assess
current postapproval safety monitoring for 3 biosimilars (epoetin alfa,
somatropin, and filgrastim) that collectively represented nearly 350 million
patient days of treatment worldwide. Collectively, the data show that spontaneous
adverse drug reactions are reported by brand name in the majority of
cases and are attributable to a specific medicine. Also discussed are the
informational elements critical to monitoring biologics, or indeed any medicine,
to ensure the availability of complete information so medicines that
a patient has received can be quickly identified should a safety event occur.
We support the addition of a single data element, the batch/lot number,
to enhance the value of current pharmacovigilance systems. Adoption of
2-D barcodes in the European Union (EU) and standardized numerical identifiers
in the United States addresses this need, since they include batch/
lot numbers. These identifiers are already being implemented in the United
States and the EU to improve patient safety, reduce medication errors,
facilitate anticounterfeiting, and enable effective product recalls and
adverse event reporting. Importantly, electronic identifiers will ameliorate
safety reporting concerns with respect to biosimilars, while concurrently
achieving these much broader public health objectives through more complete
pharmacovigilance data.
Show less

21st century change has yet to really reach health care. Amazon can predict our next purchases, but medical specialists have trouble coordinating our prescriptions. Most people haven’t sent or received a fax in years, but doctors and hospitals still depend on them. So many aspects of our lives and economy are being customized, dematerialized, accelerated.

How will health care catch up? We believe a vanguard of tech-savvy patients will lead the way.

We believe that change is… Show more

21st century change has yet to really reach health care. Amazon can predict our next purchases, but medical specialists have trouble coordinating our prescriptions. Most people haven’t sent or received a fax in years, but doctors and hospitals still depend on them. So many aspects of our lives and economy are being customized, dematerialized, accelerated.

How will health care catch up? We believe a vanguard of tech-savvy patients will lead the way.

We believe that change is inevitable but will be slowed by inertia and regulatory or monopolistic barriers. Some providers will resent less obedient patients, but others will enthusiastically support more individually appropriate solutions and take risks with their patients. It’s likely that the early adopters (most likely the more affluent and educated) will soon become a noticeable minority in some physicians’ offices. Some health care providers and insurers will see the opportunity and evolve to support these individuals. The rest of us should cheer them on, however disruptive they may at first appear—or we will die waiting too. Show less

Biosimilars have the opportunity to foster competition, but there are policy and market barriers that limit the growth of a functioning market

Abstract: Major drug regulators have indicated in guidance their flexibility to accept some development data for biosimilars generated with reference product versions licensed outside their own jurisdictions, but most authorities require new bridging studies between these versions and the versions of them licensed locally. The costs of these studies are not trivial in absolute terms and, due to the multiplier effect of required repetition by each biosimilars sponsor, their collective costs are… Show more

Abstract: Major drug regulators have indicated in guidance their flexibility to accept some development data for biosimilars generated with reference product versions licensed outside their own jurisdictions, but most authorities require new bridging studies between these versions and the versions of them licensed locally. The costs of these studies are not trivial in absolute terms and, due to the multiplier effect of required repetition by each biosimilars sponsor, their collective costs are substantial. Yet versions of biologics licensed in different jurisdictions usually share the same development data, and any manufacturing changes between versions have been justified by a rigorous comparability process. The fact that a biosimilar is usually expected to be licensed in multiple jurisdictions, in each case as similar to the local reference product, confirms that minor analytical differences between versions of reference biologics are typically inconsequential for clinical outcomes and licensing. A greatly simplified basis for selecting a reference comparator, that does not require conducting new bridging studies, is proposed and justified based on the shared data of the reference product versions as well as the proof offered where biosimilars have already been approved. The relevance of this proposal to the interchangeability designation available in the US is discussed. Show less

Biosimilars have the opportunity to foster competition, but there are policy and market barriers that limit the growth of a functioning market

While attention on drug prices continues, discussions regarding competition often focus on generic drugs, which have long played a role in spurring competition and cost reduction within the pharmaceutical industry. However, biologics have become an increasingly important part of care delivery in the United States.

In 2010, a biosimilar… Show more

Biosimilars have the opportunity to foster competition, but there are policy and market barriers that limit the growth of a functioning market

While attention on drug prices continues, discussions regarding competition often focus on generic drugs, which have long played a role in spurring competition and cost reduction within the pharmaceutical industry. However, biologics have become an increasingly important part of care delivery in the United States.

In 2010, a biosimilar approval pathway was created with an expectation that a multi-source competitive market could offer potential savings for the U.S. health system.1 As of February 2017, the pipeline of biosimilars in development includes 64 biosimilars, referencing 23 different originator products, enrolled in the Biosimilar Product Development Program at the U.S. Food and Drug Administration (FDA). Biologics have grown to represent 79% ($11.5B) of Medicare Part B and 21% ($8.7 B) of Medicare Part D spending for the top 20 drugs in each program.2 The timing of available biosimilars is notable for the healthcare system. Six of the 12 biologics covered by Medicare Part B no longer have outstanding exclusivity as of 2017, representing a total of $5.28 billion in Medicare Part B spending in 2015.
Show less

Much has been made of biosimilars as a new regulatory concept, yet it is clear that misunderstandings are widespread, including the scientific justification for use in all indications of the
reference product or “extrapolation.” However, as this article shows, biosimilarity and extrapolation are not new concepts and most patients being treated with a branded biologic have already
received a similar version of the original reference biologic based on changes in the manufacturing process.

Review of international clinical trial requirements for biosimilar development and strategies for minimizing trial expense and time.

This paper discusses biosimilars and interchangeable biologics. It explains how the latter will be exactly the same product as the former, but represent those on which additional studies have been conducted in the expectation of a commercial return (likely clinical switching studies). A formal regulatory designation of interchangeability for a biologic is only possible in the US.

Experts debate the clinical evidence standards needed to approve major manufacturing changes for biologics, biosimilars, and interchangeable biosimilars. As sponsors consider their development plans, the resource investment required to develop an analytically highly similar candidate must be balanced by regulatory relief for the clinical studies required to achieve the necessary indications for the marketed product. This article discusses biosimilarity and comparability as related scientific… Show more

Experts debate the clinical evidence standards needed to approve major manufacturing changes for biologics, biosimilars, and interchangeable biosimilars. As sponsors consider their development plans, the resource investment required to develop an analytically highly similar candidate must be balanced by regulatory relief for the clinical studies required to achieve the necessary indications for the marketed product. This article discusses biosimilarity and comparability as related scientific and regulatory concepts and the usefulness of clinical data for both Show less

Abstract
The development of biologic therapeutics using advanced technology to copy and improve on nature's design of complex peptides, proteins, and glycoproteins has enabled the treatment of diseases in entirely new ways and brought unique and lifesaving treatments to many people. However, at least in part because of cost pressures, access to these truly amazing products has not been uniformly available; many patients do not qualify for these treatments, or the treatment is postponed until… Show more

Abstract
The development of biologic therapeutics using advanced technology to copy and improve on nature's design of complex peptides, proteins, and glycoproteins has enabled the treatment of diseases in entirely new ways and brought unique and lifesaving treatments to many people. However, at least in part because of cost pressures, access to these truly amazing products has not been uniformly available; many patients do not qualify for these treatments, or the treatment is postponed until disabilities accumulate. The development of biosimilars—essentially copies of the original biologic drugs after patent expiration—allows for wider and, as important, earlier access to these agents because of their lower cost and consequently greater affordability. The development and commercialization of biosimilars can help address unmet medical needs by improving access to well-established therapeutic interventions while improving health-care affordability. Show less

This paper describes the scientific basis of the QbD and "goalposts" approach taken by Sandoz to their successful development of biosimilars.
The paper is available as a free download at:
http://www.landesbioscience.com/journals/mabs/article/15005/

Let us know what you think.