Author byline as per print journal: Ralph D McKibbin, MD; Michael S Reilly, Esq
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Introduction: In the United States (US), a legal framework for approving biosimilars was established via the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). Now, 37 biosimilars have been approved. Some biosimilars in the US can be designated as ‘interchangeable,’ which means they can be automatically substituted at the pharmacy level. In 2021, the Alliance for Safe Biologic Medicines (ASBM) asked prescribing physicians in the US for their views on the prescribing, substitution and interchangeability of biosimilars. |
Submitted: 16 August 2022; Revised: 17 October 2022; Accepted: 27 October 2022; Published online first: 9 October 2022
In the US, a legal framework for approving biosimilars was established via the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The US Food and Drug Administration (FDA) approved its first biosimilar, Zarxio (filgrastim-sndz), in 2015 [1]. At the time of writing (September 2022), 38 biosimilars have since been approved by FDA [2].
FDA approval of a biosimilar is based on the ‘totality of the evidence’ from comparative analytical and functional assessments and comparative clinical (pharmacology, immunogenicity, safety and efficacy) assessments that support a conclusion of biosimilarity [3].
An approved biosimilar can also be designated as ‘interchangeable’ if it can be concluded that the biosimilar is expected to produce the ‘same clinical result as the reference product in any given patient’ and there is no increased risk in terms of safety or diminished efficacy associated with switching or alternating between the biosimilar and reference product [4]. With such designation, an interchangeable biosimilar can be substituted for its reference at the pharmacy level (where state law allows) without notification of, or permission from, the prescriber [5]. Under these circumstances, pharmacy-level substitution can be prevented if the prescriber affirms this on the prescription [6]. In most US states, it is necessary for the pharmacist to notify the patient and prescriber of the substitution having been made. FDA approved the first interchangeable biosimilar, Semglee (insulin glargine-yfgn), in July 2021 [6, 7]. As of September 2022, two additional interchangeable biosimilars have been approved [8, 9].
In 2021, the Alliance for Safe Biologic Medicines (ASBM) commissioned a web-based survey to be conducted by practitioners/physicians across the US. This was designed to document their perspectives on prescribing biosimilars, substitution and the interchangeable designation. In many ways this mirrored previous surveys carried out by the ASBM in Europe in 2013 and 2019 [10, 11]. These surveys revealed that, in Europe, awareness of biosimilars had increased between 2013 and 2019, with familiarity with biosimilars reaching 90.0% levels in 2019 compared to just 76.0% in 2013. In 2019, a strong majority of respondents (over 80.0%) felt that it is either ‘Very important’ or ‘Critical’ for them to decide which biological medicine is dispensed to their patients, representing a 10.0% increase over the results of the 2013 survey. Again, over 80.0% respondents considered authority to prevent a substitution either ‘Very important’ or ‘Critical’, another 10.0% increase over the 2013 findings. In 2019, physicians remained uncomfortable with switching a stable patient to a biosimilar for non-medical reasons. Between the two surveys there was also a sharp increase in physicians who were highly uncomfortable with a third party changing a patient’s medicine without consultation with the physician.
These ASBM surveys also draw on other previous surveys and workshops carried out across the world (Australia [12], Europe [10, 11, 13], South America [14] and the US [15, 16]) that asked for prescriber opinions on prescribing practices, naming and labelling of biologicals. In terms of naming, prescribers in Australia, Europe and the US, overall, agreed that there is a need for distinguishable non-proprietary names to be given to all medications. This current US ASBM survey makes it clear to physicians that biosimilars, as well as new originator biologicals, are distinguished from older reference originator products by means of a unique four-letter suffix representing the biosimilar manufacturer and asks for an opinion on whether these suffixes suggest or imply inferiority.
In September 2021, the ASBM conducted a web-based, quantitative survey with 401 participants practicing medicine in the US. Their therapeutic specialities were spread across: Allergy/Immunology, Dermatology, Endocrinology, Gastrointestinal, Infectious diseases, Internal medicine, Nephrology, Neurology, Oncology, Respiratory/Pulmonology, Rheumatology and Urology.
Survey respondents are from Industry Standard Research’s (ISR) contracted partner’s commercially available physician panel that covers more than 70 countries worldwide. They receive between US$25 and US$75 for survey participation, depending on specialty and geography.
The physician panel provider uses their internal database of more than one million healthcare professionals worldwide for sampling. Also, when necessary, the physician panel provider partners with other market research companies to meet demands of healthcare clients in the industry. The market research companies go through very selective vetting process as well as training on ISO certification and market research industry standards to make sure all provide the best service to clients.
ISR’s physician panel provider uses the following channels for recruitment:
All survey respondents are managed online through the market research companies’ patented, internal, proprietary system, which is ISO 26362 certified since 2011.
The questionnaires were developed as a collaboration among ASBM management, ASBM membership, and ISR management. No ‘validation’ has been conducted as the instruments do not measure higher level ‘constructs’. They are purely direct measures of opinion and attitude.
The participants practiced medicine in states across the US, with the majority practicing in multi-specialty clinics (25.9%), academic medical centres (24.4%), and in the community setting (22.2%). The remainder practiced in private, family practice (17%) or hospitals (8.7%), see Figure 1. There was a fairly even spread of experience among the physicians, with 36.1% having a tenure period of over 20 years, 33.7% with tenure of between 11–20 years, and 30.2% with a tenure period under 10 years.
The spread of specialties practiced was fairly even, with each specialty being practiced by between 7.0%–9.2% of those that carried out the survey. As stated above, the specialties were Allergy/Immunology, Dermatology, Endocrinology, Gastrointestinal, Infectious diseases, Internal medicine, Nephrology, Neurology, Oncology, Respiratory/Pulmonology, Rheumatology, and Urology, see Figure 2.
All physicians that completed the survey said that they prescribed biologicals. Regarding the knowledge of biosimilars, the vast majority of them (97.8%) said they were either very familiar, with a complete understanding of them, or familiar with a basic understanding, however, 0.2% did say they had never heard of biosimilars.
Prescribers were asked to consider:
All data refer only to those who completed the survey. All data were analysed in MS Excel and checked manually.
Familiarity with biosimilars/confidence in their safety and efficacy
When carrying out the survey, participants were first given two explanatory texts to examine. These were:
Given immediately preceding Question 1:
Biological medicines are therapeutic proteins produced using living cells. The active substances of biological medicines are larger and more complex than those of non-biological medicines, i.e. ‘small molecule’ drugs. A biosimilar medicine is a biological medicine that is developed to be highly similar to an existing biological medicine (the ‘reference product’). To be approved by FDA, a biosimilar must demonstrate it has no clinically meaningful differences from an existing FDA-approved reference product in terms of safety, purity, and potency (safety and effectiveness).
Given immediately preceding Question 2:
FDA distinguishes biosimilars from older reference originator products by means of a unique four-letter suffix representing the biosimilar’s manufacturer. This suffix is appended to a non-proprietary name shared by the reference product and all its biosimilars, e.g. examplemab-xxxx, examplemab-yyyy. While older products have not been renamed, this is the same approach used for all newly approved biological products.
Question 1 considered the physicians’ confidence level regarding prescribing biosimilars and the majority (91.8%) said they were either highly or somewhat confident in doing this. The physicians that expressed most confidence (over 60.0% being highly confident) in prescribing biosimilars practiced in gastrointestinal, endocrinology and rheumatology.
Question 2 considered whether the use of an identifying suffix implies that a biosimilar is inferior to its reference product in terms of safety or efficacy, and most practitioners (72.8%) said that it did not. This was supported most by respiratory/pulmonology, endocrinology and infectious disease practitioners, with over 80.0% of each group stating that the suffix did not imply an inferior product. Note that FDA applies such suffixes not only to biosimilars but to all new biological products, while older reference products are not renamed with suffixes [17].
Prescribing and switching
The majority (89.0%) of physicians were either very or somewhat comfortable regarding prescribing a biosimilar to a ‘treatment-naïve’ (new) patient. Endocrinologists and gastrointestinal physicians were most comfortable, with over 60.0% of each group being very comfortable prescribing a biosimilar to a ‘treatment-naïve’ (new) patient.
Concerning how comfortable the physicians felt with switching a stable patient from an originator medicine to a biosimilar, 79.8% were either very or somewhat comfortable. Those that were most comfortable, with over 50.0% of practitioners in each group being very comfortable switching, were infectious disease, endocrinology oncology, and nephrology specialists.
Interchangeability
Prior to being asked about interchangeability, the participants were given the following text to examine:
The FDA recently granted the first ‘interchangeable’ designation to an insulin glargine biosimilar. This means the biosimilar’s manufacturer has provided additional data to FDA demonstrating that a patient repeatedly switched between the biosimilar and the originator can expect the same clinical results, without additional risks, as a patient who remained on the originator. Thus, it can be substituted at the pharmacy level without prior approval from the prescribing physician, unless he/she expressly prevents substitution when prescribing.
Then, when asked if they were more or less likely to prescribe a biosimilar carrying interchangeable status, 56.8% said they were much or somewhat more likely to prescribe it, whereas 36.4% said that the interchangeable designation would not affect their prescribing behaviour. Over 60.0% of those practicing infectious diseases, gastrointestinal, allergy/immunology, oncology and rheumatology were more or somewhat more likely to prescribe a biosimilar with interchangeable status. However, those practicing endocrinology, internal medicine, and urology were less likely to be affected by the interchangeable status, with over 40.0% of practitioners in each therapeutic specialty stating so, see Table 3.
When asked about comfort levels with pharmacy substitution of a biosimilar with the interchangeable designation, 59.1% were somewhat or much more comfortable with this, whereas 33.2% said that the interchangeable designation would not affect how comfortable they felt about pharmacy substitution. 60.0% or more of those practicing allergy/immunology, gastrointestinal, internal medicine, infectious diseases, and oncology were much or somewhat more comfortable with pharmacy-level substitution of biosimilars with interchangeable status. The comfort level of those practicing endocrinology and rheumatology was less likely to be affected by the interchangeable status, with over 40.0% of practitioners in each therapeutic specialty stating so, see Table 4.
When asked if, knowing that an interchangeable biosimilar may be automatically substituted, would the physicians be more or less likely to prescribe its reference product, 37.7% were somewhat or much more likely to prescribe it, whereas 50.9% said that the status would not affect the likelihood of them prescribing the reference product, see Figure 5, and 11.5% were somewhat or much less likely to prescribe the reference product. More physicians practicing gastrointestinal, internal medicine, nephrology, oncology, and rheumatology were much or somewhat more likely to prescribe the reference product, with over 40.0% of practitioners in each therapeutic specialty stating this. However, over 50.0% of those practicing dermatology, neurology and respiratory/pulmonology medicine stated that the interchangeable status would not affect the likelihood of them prescribing a reference product. And over 17.0% of those practicing infectious diseases and endocrinology were somewhat or much less likely to prescribe the reference of a biosimilar with interchangeable status.
With regard to automatic substitution, 43.6% of practitioners thought that, if a biosimilar is approved as interchangeable for one indication of its reference product, see Figure 5, it should automatically be approved (through extrapolation) as interchangeable for all indications of the reference product. The practitioners in the fields of endocrinology, gastrointestinal, and oncology, were most in favour of this, with 50.0% or more of practitioners in each field, believing that automatic substitution was appropriate.
Substitution and switching
When faced with a situation where substitution by a pharmacist is an option, 67.1% of practitioners thought it was critically or very important for them to have the authority to designate a biological medicine as ‘DISPENSE AS WRITTEN’ or ‘DO NOT SUBSTITUTE’, see Figure 6. The practitioners in the fields of dermatology, internal medicine and respiratory/pulmonology were most behind this, with over 70.0% of practitioners in these groups stating this authority was critically or very important.
When faced with a situation where it is permissible for payer (public or private) to require a patient who is stable on their current biological to switch to a biosimilar, 64.4% of practitioners thought it was critically or very important to have the authority to designate a biological medicine as ‘DISPENSE AS WRITTEN’ or ‘DO NOT SUBSTITUTE’, see Figure 6. The practitioners in the fields of dermatology and internal medicine were most behind this, with over 70.0% of practitioners stating this authority was critically or very important.
When asked about how important it would be for practitioners to be notified by the pharmacist that a patient has received a biological other than the one prescribed, if the patient was receiving chronic (repeated) treatment, see Figure 7, 71.0% said it was critically or very important. Dermatology practitioners were most concerned about this, with almost 85.0% stating it was critically or very important. On the other hand, infectious disease and endocrinology practitioners were least concerned about this, with a relatively large proportion (more than 20.0% of each group) stating it was only slightly important or not important.
The majority (67.8 %) of practitioners thought it was either totally acceptable or acceptable, if agreed in advance, for a pharmacist to determine which biological (innovator or biosimilar) to dispense to a patient on initiation of treatment. However, dermatologists were least in support of this, with 68.4 % of them stating this was not acceptable, see Table 8.
The majority (68.5%) of practitioners stated that it was critically or very important for them to have the sole authority to decide, together with patients, the most suitable biological medicine for their disease. Dermatology, gastrointestinal and allergy/immunology practitioners were most behind this, with over 75.0% of each group stating it was critically or very important, see Figure 9.
Regarding switching patients to a biosimilar for non-medical reasons, i.e. cost or coverage, 77.8% of practitioners were very or somewhat comfortable with this idea, see Figure 9. Endocrinology, oncology, and rheumatology practitioners were most behind this, with over 80.0% of each group stating they were very or somewhat comfortable with switching for non-medical reasons. Dermatologists were most uncomfortable with this, with over 30.0% of the practitioners stating they were somewhat or very uncomfortable with switching for non-medical reasons.
Concerning third-party switching of a patient to a biosimilar for non-medical reasons, i.e. cost or coverage, 40.4% of practitioners stated they were very or somewhat comfortable with this idea. Endocrinologists were most comfortable with this, with over 25.0% of them being very comfortable with third party switching. Dermatologists were again least comfortable with this, with almost 85.0% of them being somewhat or very uncomfortable.
Of the physicians who were unsure about or uncomfortable with third-party switching of a patient to a biosimilar for non-medical reasons, they cited unknown immunogenicity reactions, potential symptoms return and legal liability as a physician, as their top three greatest concerns about non-medical switching to a biosimilar.
Over 70.0% of physicians thought it was critically or very important that payers, such as health insurers and government agencies, have the formulary flexibility to reimburse multiple products in a particular class, including originator products and biosimilars. Over 25.0% of gastrointestinal and allergy/immunology practitioners stated this was of critical importance.
Almost 75.0% of physicians thought it was critically or very important that payers, such as health insurers and government agencies, consider factors other than cost when determining coverage. Over 35.0% of gastrointestinal and neurology practitioners stated this was of critical importance.
The split was more even regarding comfort levels regarding situations where a payer requires a switch to be made for a patient who is stable on their current biological onto their preferred biological or biosimilar product, 45.9% were very or somewhat comfortable with this whereas 52.9% were somewhat or very uncomfortable with this. Those that were most comfortable with this were the endocrinologists and oncologists, with 60.0% and over being very or somewhat comfortable. Dermatologists were least comfortable with this, with over 80.0% being somewhat or very uncomfortable with a payer requiring a switch to be made for a patient who is stable on their current biological onto their preferred biological or biosimilar product.
The majority of physicians, over 80.0%, stated that a scenario where multiple products, including innovator and biosimilars are reimbursed, and biosimilars may be encouraged for new patients with no automatic substitution permitted, would be better for patients over a scenario where only government chosen biosimilars are reimbursed and new patients must be prescribed a biosimilar and current patients forced to switch.
The survey reveals information about these US physicians’ familiarity with biosimilars, how they feel about the interchangeable designation, and biological medicines switching choices made by them, pharmacists and payers.
The survey study was funded by the Alliance for Safe Biologic Medicines (ASBM) and administered by Industry Standard Research, LLC.
The ASBM is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion.
The activities of the ASBM are funded by its member partners who contribute to ASBM’s activities. Visit www.SafeBiologics.org for more information.
Ralph D McKibbin, MD
810 Valley View Boulevard, Altoona, PA 1660, USA
Michael S Reilly, Esq
Competing interests: Dr Ralph D McKibbin is a gastroenterologist in active practice. He serves as chair of the executive committee for the Alliance for Safe Biologic Medicines for which he receives fair market compensation. He also serves pro bono in an advisory role for other organizations including the Pennsylvania Society of Gastroenterology, the American College of Gastroenterology, the Digestive Disease National Coalition, and the Dean’s Development Council of the Penn State Ross and Carol Nese College of Nursing. He provides disease state lectures for AbbVie and Bristol Meyer Squibb for fair market compensation.
Mr Michael S Reilly, Esq is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002 to 2008.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA |
Disclosure of Conflict of Interest Statement is available upon request.
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