The article in this issue of the GaBI Journal reminded me of The Rest of the Story radio programme originally hosted by Mr Paul Harvey that started each episode with, ‘And now for the rest of the story’. This is because these articles illustrate that sometimes what is not discussed in an article can be more interesting than what is.
In the first EditorialGaBI Journal’s Deputy Editor-in-Chief, Dr Robin Thorpe, responds to the Opinion article by Drs Sandeep N Athalye, Shivani Mittra, and Ankitkumar M Ranpur in which the authors present their arguments for why they think it is, ‘time for a paradigm shift’ in what the authors feel are excessively arduous regulatory requirements for marketing approval of biosimilars. Readers are encouraged to evaluate the points made in these two articles and to submit their comments as either articles or letters to the Editor. While I clearly have a conflict of interest since Dr Thorpe is my Deputy Editor-in-Chief, I felt that he presents a convincing ‘And now for the rest of the story’ rebuttal to the suggestions proposed in the Opinion piece. He points out that using the lack of problems with biosimilars that were approved using the ‘arduous’ system the authors propose to modify cannot be used to assume that products approved using a less arduous requirements are really biosimilars. In fact, there are multiple poor quality performance examples of follow-on biological products that were marketed in countries without having met arduous biosimilar requirements. Dr Thorpe also points out that biosimilar approval processes are already rapidly evolving and explains why some of the changes proposed either impractical or even impossible. Finally, he summarizes the dangers inherent in, ‘ill-advised, politically/financially driven pressures to inappropriately lower regulatory standards’ that, ‘could seriously damage the acceptability of biosimilars’. The acceptability of biosimilars is especially important since, as Dr Thorpe points out, ‘evidence suggests that reluctance to use/adopt biosimilars due to an unfounded suspicion of their quality, efficacy and safety by prescribers and patients and often too little difference between the price of the biosimilar and the originator products are more likely reasons’ for the inability of biosimilars to achieve their cost savings potential.
The two Original Research articles in this issue present results from two apparently straight-forward generic anti-diabetic product bioavailability studies. The first study compared a proposed biosimilar product Fortesia® tablets to the Merck Sharp & Dohm’s innovator Januvia® tablets (each containing 100 mg of sitagliptin). ‘And now for the rest of the story’. While only stated in the title, it appears that in this study both the follow-on proposed generic product and the reference Merck product contained sitagliptin monophosphate. The second study compared, ‘Fortreas® tablets containing 100 mg of sitagliptin as the hydrochloride to the originator Merck 100 mg sitagliptin as the monophosphate reference formulation. Neither manuscript mentions (‘the rest of the story’) is that sitagliptin has two possible (R and S) enantiomers The reference Merck product contains the monophosphate salt of the R enantiomer. It is assumed, but not stated by the authors, that the Fortesia® tablets used in the first study also contained the monophosphate salt of the R configuration. The second study also does not mention whether the proposed generic product contained the R enantiomer, but the authors make clear that it contained sitagliptin hydrochloride rather than sitagliptin monophosphate. The chemical composition of the sitagliptin used in a product is not a trivial legal/patent issue; as a recent court decision demonstrates [1]. While the products appeared to meet the regulatory requirements for declaring them to be bioequivalent, neither manuscript used a stereospecific assay. It is not possible to say whether the chiral or salt characteristics will affect the product’s performance. It is however important to avoid hidden differences that could be exploited by competitors to undermine confidence in a follow-on product. It is unfortunate that the authors did not disclose and discuss the issues of salt form and enantiomeric composition. It would be interesting to know whether these issues were raised by the regulators who have or will evaluate these studies. I personally would expect that regulators would require a stereospecific assay be used to evaluate the bioequivalence of chiral generic products unless there are data showing that the two enantiomers are pharmacologically equivalent. This is important because, as Dr Thorpe mentioned, anything that can be used to question the validity of the evaluation of follow-on products, generics or biosimilars, has the potential to limit confidence and acceptance of such products.
The issue of acceptance is a key component of the Meeting Report by Reilly et al. from the Alliance for Safe Biologic Medicines (ASBM) that focused on non-medical switching of biological products in Canada, Europe, and the US. This webinar was the latest in a series of meetings held in collaboration with the Generics and Biosimilars Initiative (GaBI). Of note, the majority of the ASBM’s funding comes from the pharmaceutical industry; including manufacturers of both innovator biological and biosimilar products. The report provides the content of the meeting and its conclusions in sufficient detail to give readers a sense of being present at this interesting meeting. However, (‘And now for the rest of the story’), while it is clearly important to examine stakeholder opinions and concerns, it is not clear whether these meetings or their reports result in increased or decreased acceptance of biosimilars on the part of the participants or readers of the report. It is hoped that the authors are correct when they conclude that, ‘continued regulatory reforms for biosimilars, more affordability with competition brought through biosimilars, and a fair healthcare system that passes the savings to the patients can make biosimilar development more sustainable in the future’ and that, ‘… apprehensions regarding biosimilars are already changing and in the future, a greater acceptance and faster adoption of biosimilars can be envisioned’.
I want to encourage all our readers and submitting authors to submit their ‘rest of the story’ comments, opposing viewpoints, or questions concerning any of these articles or my comments, as well as general comments about the acceptance of biosimilars in general.
Reference
1. Mylan failed to ‘immediately envisage’ the compounds in Merck’s patent covering Januvia. 14 October 2022. Available from: https://haugpartners.com/article/mylan-failed-to-immediately-envisage-the-compounds-in-mercks-patent-covering-januvia/
Professor Philip D Walson, MD Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Michael S Reilly, Esq; Gail Attara; Ralph D McKibbin, MD, FACP, FACG, AGAF; Professor Philip J Schneider, MS, FASHP, FASPEN, FFIP
Introduction: Biosimilars are now key players in the global drugs market offering potentially more affordable treatment options with similar safety and efficacy. However, there are concerns about non-medical switching practices of originator biologicals/biosimilars in different regions. A webinar was held to discuss non-medical switching practices and to explore the importance of safeguarding the physician–patient relationship. Methods: The webinar was held by the Alliance for Safe Biologic Medicines (ASBM) in collaboration with the Generics and Biosimilars Initiative (GaBI) on 20 July 2022. It consisted of various expert speaker presentations followed by a Q&A with the panel. The audience also had the opportunity to ask questions online throughout the webinar. Results: Presentations discussed key concerns about non-medical switching practices of originator biological/biosimilar medicines. There was particular emphasis on the practices in Canada, Europe and the US. Further details of the presentations were discussed during the Q&A and clarifications were made via the concurrent online Q&A. Conclusions: The webinar enabled in-depth discussion of non-medical switching practices in Canada, Europe and the US. There was specific emphasis on the forced-switching policies adopted in Canada and their shortcomings. There was also discussion about the US’s interchangeability designation. Overall, it was highlighted that safeguarding the physician–patient relationship is key in decisions about biologicals prescribing, dispensing and reimbursement. This can be achieved through robust policy and regulation and upholding transparent practices.
Submitted: 19 December 2022; Revised: 20 January 2023; Accepted: 21 January 2023; Published online first: 3 February 2023
Introduction
In joint effort with the Alliance for Safe Biologic Medicines (ASBM), the Generics and Biosimilars Initiative (GaBI) organized and hosted the second in a series of webinars on biosimilars entitled ‘Non-medical switching of biologicals/biosimilars: Canada, Europe and the US’. This webinar set out to give an overview of switching, substitution and interchangeability practices of originator biologicals/biosimilars in different regions and to explore the importance of safeguarding the physician–patient relationship.
Biologicals offer significant benefits and enhanced quality of life for patients with chronic diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and cancer. However, finding a working treatment regimen may take a long time and can involve trial and error for each individual. Biosimilars of originator biological drugs have been on the market for 16 years since their first launch in 2006 in Europe. At the time of the webinar, there were 84 approvals in the EU [1] and 34 in the US [2].
In many cases, biosimilar drugs can offer a more affordable treatment option with similar safety and efficacy. However, it is argued that government policies that force biosimilar switching for non-medical (non-medical switching refers to the switching of a patient’s medicine, often at the behest of a third party, for reasons other than the patient’s health and safety) and strictly economic reasons may have potential to ultimately affect patients’ treatment and their well-being, create mistrust in the healthcare system, undermine competition, increase total healthcare costs, and act as a barrier to innovation and future access to new biological drugs for patients.
Non-medical switching should consider two governing principles: 1) the physician–patient relationship must be protected to promote the best outcomes; and 2) patients stabilized on a biological therapy should not be forced to undergo a non-medical switch.
The webinar, and this follow-up article, discuss the non-medical switching practices in Canada, Europe and the US. The expert panelists provided a detailed overview of policies in the different regions and discussed the merits and concerns about non-medical switching practices. They also explored the importance of safeguarding the physician–patient relationship, through education and knowledge transfer.
Methods
In this online event, held on 20 July 2022 [3], the contributors discussed non-medical switching practices of biologicals, including biosimilars, in different regions and explored the importance of safeguarding the physician–patient relationship. The discussion highlighted that improved information and protecting the physician–patient relationship in medical switching will encourage smooth uptake of biosimilars.
The webinar was moderated by Dr Steven Stranne, JD, and partner at Foley Hoag LLP, who has a unique perspective as a physician and lawyer. Presentations were given by: Mr Michael S Reilly, Esq, Executive Director of the ASBM; Ms Gail Attara, President and CEO of the Gastrointestinal Society, Canada; Dr Ralph D McKibbin, Past President of the Pennsylvania Society of Gastroenterology and the Digestive Disease National Coalition; Dr Leah Christl, Executive Director, Global Biosimilars Regulatory Affairs and Regulatory and R&D Policy, Amgen; Dr Durhane Wong-Rieger, President and CEO of the Canadian Organization for Rare Disorders; and Professor Philip J Schneider, Professor of the Ohio State University College of Pharmacy. The presenters were also joined by two panelists, Ms Jaymee Maaghop, Outreach Coordinator at the Gastrointestinal Society, Canada, and Ms Urvashi Rathod, Project Officer at the International Federation on Ageing, Canada.
Overall, the panel was made up of academic clinicians patient advocates, industry specialist, policymakers and regulatory experts from Canada and the US. They shared their experience and knowledge of medical switching and principles and guidance on interchangeability of originator biologicals/biosimilars, highlighting specific concerns about, and the importance of a multi-stakeholder approach to protecting the physician–patient relationship in the practice of non-medical switching of originator biologicals/biosimilars.
Learning objectives The overall learning objectives of the webinar were outlined as follows:
To gain an insight on practice of switching originator biologicals/biosimilars in Europe and the US
To learn the current state of non-medical switching policies of originator biologicals/biosimilars in Canada
To hear the physicians’ concerns and experience of non-medical switching of originator biologicals/biosimilars
To understand the principles and guidance of interchangeability of originator biologicals/biosimilars in the US
To recognize patients’ concerns in non-medical switching of originator biologicals/biosimilars
To evaluate the role of healthcare providers (physicians, health policymakers, pharmacists, nurses) and patients in non-medical switching of originator biologicals/biosimilars
To identify the important elements and educational needs on non-medical switching of originator biologicals/biosimilars practices
To produce and publish a meeting report in GaBI Journal covering recommen dations and informational programmes on non-medical switching policies of originator biologicals/biosimilars.
Results
Expert speaker presentations
There were a variety of expert speaker presentations followed by Q&A and an in-depth panel discussion. The presentations are downloadable [3].
Overview of originator biologicals/biosimilars switching policy in Europe and the US Mr Michael Reilly noted that the first webinar in the series [4] examined several factors which led to the highly successful biosimilar programmes in Europe and the US. Europe is widely acknowledged as a global leader in biosimilars for successfully developing a robust and sustainable biosimilars programme. Many countries seek to emulate Europe’s success and ‘catch-up’.
White paper recommendations The white paper entitled ‘Policy Recommendations for a Sustainable Biosimilars Market: Lessons from Europe’ [5] identifies several ‘Must-Have’ principles, critical for countries to achieve biosimilar success:
Physicians should have the freedom to choose between off-patent originator biologicals and available biosimilars and to act in the best interest of their patients based on scientific evidence and clinical experience.
Tenders should be designed to include multiple value-based criteria beyond price, e.g. education, services, available dose strengths, and provide a sufficient broad choice (multi-winner tenders versus single-winner tenders) to ensure continuity of supply and healthy competition.
A level playing field between all participating manufacturers is the best way to foster competition; mandatory discounts which place artificial downward pressure on manufacturers do not engender a sustainable market environment.
Mr Reilly emphasized that Europe’s collaborative patient-based approach is key to the success of biosimilars. There are regular multi-stakeholder consultations held by the European Commission in Brussels and these consultations are transparent, open and inclusive. Education of patients to build trust in biosimilars has been a priority, as has establishing patient buy-in on biosimilar policy.
European physician survey and non-medical switching According to survey findings presented at the European Society of Medical Oncology 2019 Congress in Barcelona, Spain, 27 September to 1 October 2019 [6], European physicians oppose non-medical switching. The survey highlighted that those European physicians took great pride in their approach, which is very patient focused. Notably, despite having overwhelming confidence in biosimilars, they are strongly opposed (73%) to non-medical switching. In addition, in nearly every European country, physicians and patients choose freely among multiple approved products (originator and several biosimilars) and all are reimbursed. Many countries encourage physicians to prescribe the cheapest medicine, typically a biosimilar, to new (bio-naïve) patients. Even in Norway with a national tendering system, physicians retain prescription choice among all available products [7].
Mr Reilly explained that non-medical switching is permitted in some Eastern European countries although patients and physicians do retain some autonomy:
Estonia: Permitted, patient can refuse and pay price difference out-of-pocket.
Latvia: Non-bio-naïve patients can refuse and pay cost difference; the physician can prevent substitution. Others must use cheapest product.
Poland: Permitted, pharmacists are to discuss with patient.
Denmark’s unique approach Denmark has a unique approach to non-medical switching. The country has adopted a ‘winner takes all’ tendering process under which, following a transparent process, only the winning product will be reimbursed, and patients are not given a choice regarding a switch. Although the approach may seem radical, it is facilitated by the fact that Denmark has a small population (5 million versus 38 million in Canada, where forced switching policies have been adopted, see later section on ‘Current state of non-medical switching policies of originator biologicals/biosimilars in Canada’) that is ethnically homogenous (98% White), while Canada is more ethnically diverse. It is also the only country in Europe that has every patient covered by Digitized Medical Records, which Canada does not have.
Biosimilars in the US The US is now catching up with Europe in terms of the approval of biosimilars [8]. At the time of the webinar the US had approved two interchangeable biosimilars (meaning they can be automatically substituted at the pharmacy level subject to state laws [7]). In addition, there could soon be upwards of five biosimilars available for some originators in the US. This increased competition results in patients having access to more affordable alternative treatments.
Mr Reilly advised that in the US there is no government policy mandating non-medical switching. As in Europe, the thriving markets, high uptake rates (and savings) are due to many products competing for market share. In addition, all 50 States permit automatic substitution for ‘interchangeable’ biosimilars (those for which additional data, including switching studies have been gathered) [7].
Canada’s forced non-medical switch ing policy In contrast to Europe and the US, several jurisdictions in Canada have implemented non-medical forced switching policies.
Needlessly exclude physicians and patients from the treatment-decision process
Contribute to Canada lagging behind Europe and the US in terms of biosimilars use
Prioritize short-term savings over long-term growth and sustainability.
Canadian patient groups have been strongly opposed to these policies and vocal about them. In addition, the Canadian Association of Gastroenterologists issued statements opposing the forced-switching policies in place in Alberta and British Columbia. The Quebec heath technology assessment body, (Institut National d’excellence en Santé et en Services Sociaux, INESSS), published a report, Safety of switching biologics and their interchangeability, in May 2020 that says, ‘Non-medical switching in patients being treated with a reference biologic is generally not accepted by learned societies and the consulted clinicians’ [10].
Further presentations from patient organizations examine the Canadian patient experience of biosimilars. These organizations, the Canadian Organization for Rare Diseases and the Gastrointestinal Society, are part of a biosimilars working group, which includes ASBM, that is bringing the patient perspective to biosimilars policy discussions.
Current state of non-medical switching policies of originator biologicals/biosimilars in Canada This presentation was given by Ms Gail Attara, Gastrointestinal Society, Canada via a pre-recorded video.
Ms Attara gave a brief overview of the healthcare system in Canada, noting that there is universal medical healthcare for physician visits and hospital use but not for drugs, adding that there is tightly managed, variable by jurisdiction, limited publicly funded drug coverage. The downside to this is that, when a biological is changed, this usually leads to changes in the patient’s healthcare team.
Switching and substitution The Gastrointestinal Society in Canada has been active in the field of biosimilars since 2013 and has produced patient information pamphlets and a video [11]. These contain information defining:
Medical Switch: Medication is changed by a physician for reasons related to efficacy or tolerability.
Non-Medical Switch: Medication is chan ged, with or without physician consent, for reasons other than clinical necessity. May be driven by cost or convenience.
Regarding substitution, a pharmacist:
May substitute a biosimilar for its reference product.
Is subject to local (provincial) pharmacy laws and regulations.
Carries out ‘automatic’ or ‘involuntary’ substitution if performed without physician’s involvement.
2015 IBD patients Survey In 2015, the Gastrointestinal Society hosted a survey to help understand inflammatory bowel disease (IBD) patients’ opinions and outlooks regarding biosimilars (then called subsequent entry biologicals, or SEBs in Canada). There were 354 respondents. The results were presented at the European Crohn’s and Colitis Organization (ECCO) conference in Amsterdam in 2015 [12].
The IBD patients survey [n = 354] revealed that:
95% of respondents thought it was very (78%) or somewhat (17%) important that the physician has the sole authority to decide, together with the patient, the most suitable biological medicine to use to treat their disease.
94% of respondents thought it was very (75%) or somewhat (19%) important concerning if the pharmacist or government/private insurance plan made the determination which biological (innovator or biosimilar) to dispense to a patient on initiation of treatment.
96% of respondents thought it was very or somewhat concerning if the pharmacist, government drug plan, or private insurance plan made the determination of which biological (innovator or biosimilar) to dispense to a patient during treatment, including maintenance therapy (switch medicines without telling a patient).
Biosimilars Working Group Canada The Biosimilars Working Group was set up in Canada to ensure patient outcomes and considerations are at the centre of health policy discussions regarding decisions over biological treatment. The Working Group aims to create evidence-based educational materials for patients and healthcare professionals, which are hosted at www.biosimilaroptions.ca. Members of the working group include:
Alliance for Safe Biologic Medicines
Canadian Council of the Blind
Canadian Organization for Rare Disorders
Canadian Society of Intestinal Research
Crohn’s and Colitis Canada
Gastrointestinal Society
HS (hidradenitis suppurativa) Heroes
International Federation on Ageing
MedAccess BC
2017 Patient Organizations Focus Group In 2017, five patient organizations across therapeutic areas came together to conduct several cross-country focus groups [13]. This included:
Canadian Arthritis Patient Alliance
Canadian Psoriasis Network
Crohn’s and Colitis Canada
Gastrointestinal Society
The Arthritis Society (project lead)
The survey demographic is demonstrated in Table 1.
When discussing forced switching, the key findings with regards to patients were:
many patients experience a high degree of emotional impact from disease, treatment decision process, delays
this was the first time for biological switching in Canada and ‘trial-and-error’ approach to treatments amplified anxiety
overall, patients have a poor understanding of biosimilars, coupled with poor understanding of healthcare system in general
patients are opposed to forced non-medical switching
patients recognize role of biosimilars for new patients
patients are anxious for more clinical studies regarding impact of switching
patients are concerned that switching would reopen access and coverage questions.
The Canadian perspective Health Canada’s definitions related to interchangeability and switching of biological [14] are as follows:
Interchangeability: ‘Health Canada’s auth orization of a biosimilar is not a declaration of equivalence to the reference biologic drug. The authority to declare two products as interchangeable rests with each province and territory according to its own rules and regulations’.
Switching: ‘Patients and healthcare providers can have confidence that biosimilars are effective and safe for each of their authorized indications. No differences are expected in efficacy and safety following a change in routine use between a biosimilar and its reference biological drug in an authorized indication’.
There were also various statements released related to switching that were highlighted by national health technology bodies, including Heath Canada:
In 2016: ‘Health Canada recommends that a decision to switch a patient being treated with a reference biologic drug to a biosimilar should be made by the treating physician in consultation with the patient and taking into account available clinical evidence and any policies of the relevant jurisdiction’.
In 2019, Canada’s Drug and Health Technology Agency (CADTH): ‘Decisions about switching are generally made by individual patients and their practitioners based on the available clinical evidence,’ [15].
In 2020, INESSS, (Quebec only): ‘This report identifies certain populations or biologics for which very little or no data are available regarding the safety of biologics switch, and the significant concerns that clinicians have about non-medical switching’, [16].
The Canadian Association of Gastroenterology stated that it does not recommend non-medical switching from originator to biosimilar in patients with stable disease and are doing well on the originator and does not recommend automatic substitution [17].
The Canadian Rheumatology Association advised that there must be [17]:
‘respectful and informed conversation between the rheumatologist and patient prior to any transitioning/changing from an originator biological to a biosimilar’
‘no substitution without an informed consultation by the patient with the prescribing rheumatologist prior to any treatment change’.
Ms Attara stressed that these statements are all in contrast to the non-medical forced-switching policies.
Canada’s non-medical switching policies In Canada, non-medical switching policies had been adopted in a few provinces and one territory in Canada, see Table 2.
Forced to switch survey 2020 Canada Ms Attara then presented the results from the ‘Forced to Switch: Canadian Biosimilar Experience’ 2020 survey [18]. Figure 1 shows the demographic of respondents of the survey in terms of disease.
The survey gathered 145 responses bet ween 13 November 2019 and 6 February 2020. A number of issues were uncovered and 53 of these were classified as:
18 delays with biosimilar dose, required additional Remicade® dose
24 lack of communication from biosimilar patient support programme
9 had no biosimilar dose available at scheduled infusion date
2 lack of coverage issues for biosimilar.
Overall issues with the policies had implications for:
Mental health
66% of online survey respondents experience mental health related conditions, e.g. insomnia, anxiety disorders, mood disorders
majority of phone and email participants said they were stressed, anxious, depressed, and worried due to non-medical switch
beginning of COVID-19 pandemic.
Timing and consultation
delays in communications, accidental refills for originator biological, administrative backlog
lack of appropriate notice to switch.
It was also evident that there was a lack of biosimilar education regarding forced-switching and the reasoning behind this.
In addition, there were also issues related to:
Patient support programmes
exclusivity contracts (limited to 2019–2020)
accessibility (capacity and availability, geographic location).
Special authority
high request denial rates regarding physician requests for patients to remain on their treatment regimen: Alberta: 0.25% approved, British Columbia: 1% approved.
No exceptions for
British Columbia’s non-medical switch
some children with temporary special authority until November 2020
Alberta: non-medical switch excluded paediatrics and pregnant women.
In conclusion, most survey respondents were familiar with biological medications. Compared to other inflammatory conditions, inflammatory bowel disease sufferers (Crohn’s disease and ulcerative colitis) only have a few options with varied mechanisms of action. Here, efficacy, safety and doctor’s recommendation are the top three factors for selecting biosimilar treatment. Overall, patients maintain that they, along with their physician, should have the sole authority to decide the best biological medicine for their disease.
Biosimilars in Alberta and BC survey 2021 The 2021 ‘Biosimilars in Alberta and BC’ survey results were discussed [19]. Direct quotes from respondents included comments such as: ‘positive, so far, so good, and same as original’, ‘first injection didn’t sting like the originator biologic, which was a nice change’, and ‘the biosimilar injection hurts more than the biologic’. The side effects reported ranged from moderate to severe, and included diarrhoea, headache, nausea, fatigue, respiratory issues, and skin and pouch infections; and there were varied experiences from person to person.
Overall, it was too soon to tell regarding the non-medical switch policies related to Humira® adalimumab biosimilars at the time of the survey. The majority of respondents were not confident in their ongoing care and felt they were not given enough time to switch.
Alberta extended their switching deadline during the pandemic. In both provinces, most respondents had extra communications with their healthcare team to facilitate the switch, including telephone calls (57%), in-person appointments (31%), virtual appointments (20%), and email communications (20%). However, there were difficulties with scheduling appointments, requiring additional testing, and challenges with coordinating the biosimilar product in a different healthcare setting, e.g. from infusion clinic to in-hospital care. All in all, inadequate coordination was reported, and this was confounded by COVID-19.
Gastrointestinal Society Canada Ms Attara stressed the position of the Gastrointestinal Society Canada that a fair and equitable biosimilars policy is to set one price for reimbursement for all originator biologicals and their respective biosimilars. Originator companies could lower their prices to compete and thereby governments would not need to force patients to switch their medications. The Society believes that this is the most viable option and encourages all Canadian jurisdictions to implement such a policy so that patients do not have needless suffering. This ‘lowest cost alternative’ form of pricing policy is widespread in Canada for brand-name and generic drug products and gives governments the cost-savings they desire. Regrettably, Canadian jurisdictions will not adopt this. In view of this government hardline stance, the Gastrointestinal Society developed three documents that include minimal exception criteria that jurisdictions can adopt. These exceptions include a longer timeframe for switching children and elderly patients, those with severe disease and high-risk patients, and pregnant patients.
US physicians’ concerns/experience of non-medical switching of biologicals/biosimilars Dr Ralph D McKibbin, gastroenterologist, outlined the results of a 2021 ASBM survey of US physicians [20]. The survey examined:
Knowledge about biologicals and biosimilars/approval process
Confidence in biosimilars: their safety and efficacy
Substitution and switching: when and how? Who decides? What data should be required?
Product identification: how best to differentiate between a biological and its various biosimilars
Reimbursement policies: which products should be covered and why?
Overall, the survey highlighted that physician confidence in and comfort with biosimilars is high and the vast majority (~90%) of physicians have no concerns with prescribing biosimilars to new patients. However, they are less comfortable with non-medical switching.
US physicians are generally comfortable with non-medical switching if they are leading the switch, 80% of respondents are comfortable switching a patient to a biosimilar, see Figure 2.
Globally, physicians are divided on physician-led non-medical switching. While many physicians are comfortable switching a patient to a biosimilar themselves for non-medical reasons such as insurance coverage, a significant percentage are NOT comfortable doing this, see Figure 3.
Dr McKibbin noted that there are many different reasons for concern over non-medical switching. In many cases, a patient goes through several rounds of trial and error with their physician to find the right treatment that works for them. This process often takes several years and is the basis of the doctor–patient relationship.
Opposition to third-party non-medical switching The survey revealed that majority (about 60%) of US physicians are not comfortable with third-party non-medical switching for a patient who is stable on their current treatment. This was due to several concerns that are highlighted in Figure 4.
Survey data revealed that globally, it is very important, or critical, to physicians that they are able to prevent third-party substitution that they do not feel is medically appropriate. In addition, pharmacists want ‘more data’ before there is automatic substitution at the pharmacy level.
For example, a 2016 Australian survey [21], revealed that the majority (53%) of Australian physicians wanted clinical trials showing no loss of safety or efficacy switching between originator to biosimilar. In addition, 81% wanted switching studies before permitting automatic substitution between biosimilars. The 2017 Canadian survey [22] revealed that more than 80% of physicians wanted switching studies to be carried out before automatic substitution was permitted.
In both Australia and Canada, where forced switching policies have been adopted, there has been opposition from physician organizations.
US’s interchangeable designation In the US, a class of interchangeable biosimilars was created and is given this designation following the collection of additional data. This has been supported by US physician groups.
The US Food and Drug Administration (FDA) Interchangeability Guidance (drafted 2017, finalized 2019) states that ‘Interchangeable biosimilars’ may be substituted at the pharmacy without physician involvement [7]. The additional required data may include:
Identification and analysis of critical quality attributes
Identification of analytical differences and an analysis of the potential clinical impact of such differences
An analysis of the mechanism of action in each condition of use
An analysis of differences in ex pected pharmacokinetics (PK) and biodistribution in different patient populations
An analysis of differences in expected immunogenicity risk
An analysis of differences in expected toxicity
Information on factors that could affect safety or efficacy.
Following the introduction of the interchangeable designation, physicians have revealed that they are more comfortable with prescribing and substitution of these biosimilars, see Figure 5.
According to Dr McKibbin, it seems that the additional data requirements for an ‘interchangeable’ biosimilar show great promise in addressing physician concerns about switching and for building confidence in biosimilars.
Interchangeability of biologicals/biosimilars: US perspective Amgen’s Dr Leah Christl first outlined the definitions of pharmacy substitution, switching and interchangeability.
Pharmacy substitution: A practice where one drug is dispensed in place of another at the pharmacy level, without consulting the prescribers [23, 24].
Switching: Physician may elect to prescribe one medicine in place of another with the same therapeutic intent [24]. In Europe, in the context of biosimilars, the term ‘switching’ is used synonymously with the term ‘interchangeable’ [25].
Interchangeable: In the US this is defined by statute to mean that a biosimilar product is expected to behave the same in ‘any given patient’ and that there is no negative impact resulting from alternating or switching between the biosimilar product and the reference product [26]. US state pharmacy laws permit substitution at the pharmacy of only biosimilars that FDA has deemed ‘interchangeable’ [7].
The Biologics Price Competition and Innovation Act (BPCI Act) of 2009 created an abbreviated licensure pathway for biological products that are demonstrated to be biosimilar to (and in some cases also interchangeable with) an already FDA-approved biological product. FDA uses this definition of inter changeability when reviewing a request for an interchangeability designation.
Referring to the US interchangeability designation – an interchangeable biosimilar is a biosimilar that is expected to give the same clinical result in any given patient, and for a product that is administered more than once, the risk to safety or diminished efficacy as a result of switching is no greater than the risk of using the reference product without such switching.
It was also highlighted that a designation as an interchangeable biosimilar:
Requires additional data and information to scientifically support the statutory definition and pharmacy-level substitution.
Does not imply anything about the quality of the product: ºNon-interchangeable biosimilars are held to the same quality standards as interchangeable biosimilars.
Is not required for physicians to prescribe a biosimilar product in place of the reference product to treatment-naïve patients or patients currently in treatment: ºPhysicians should practice evidence-based medicine and consider the risks/benefits of switching patients between a reference product and its biosimilar.
Evidence to support interchangeability Dr Christl explained the evidence needed to support an interchangeable designation. Here, scientific justification to support the expectation of same clinical performance in all the reference product’s conditions of use is required. In addition, the presentation and device design differences must not adversely impact use or performance [7].
Figure 6 demonstrates how a study to support interchangeability may be designed. Integrated designs which serve to demonstrate biosimilarity and interchangeability are also acceptable.
Dr Christl shared the evidence required to support the interchangeability designation for Semglee® (insulin glargine-yfgn), see Table 3, and Cyltezo® (adalimumab-adbm), see Table 4.
Per the FDA Draft guidance for industry, Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products [31], insulin biosimilars generally do not need to have a switching study to support a demonstration of interchangeability. This is because ‘a comprehensive and robust comparative analytical assessment between a proposed interchangeable insulin product and the reference product demonstrating that the proposed interchangeable product is ‘highly similar’ to the reference product with very low residual uncertainty about immunogenicity generally would mean that an applicant would not need to conduct a comparative clinical immunogenicity study, e.g. a switching study, to support licensure under section 351(k)(4) of the PHS Act so long as the statutory criteria for licensure as an interchangeable are otherwise met’ [31].
Exclusivity for interchangeable biologicals The first interchangeable biosimilar approved is entitled to a period of exclusivity [32]:
Exclusivity is a period during which FDA must wait before granting a subsequent biosimilar to the same reference product an interchangeability designation
Multiple exclusivity triggers and considerations
The applicable trigger that would result in the shortest of any of the exclusivity periods is what would apply in a given situation.
FDA draft guidance on exclusivity for the first interchangeable biosimilar biological product is expected in 2022 [33] and that proposed legislation under discussion may impact first interchangeable exclusivity provisions.
The Purple Book In the US, the ‘Purple Book’ is a searchable, online database of biological products, including any biosimilar and interchangeable biological products, licensed by FDA under the Public Health Service Act (the PHS Act) [34].
The Purple Book searchable database includes:
The biological product licensing date
If the biological product has been determined to be biosimilar to or interchangeable with a reference biological product
The date of expiration of applicable regulatory exclusivity for a biological product if FDA has made an exclusivity eligibility determination.
Patent information for certain licensed biological products.
There are other categories as well that can be selected through the advanced search feature. This is not an exhaustive list of the categories of information Purple Book provides.
Pharmacy substitution of interchangeable biosimilars In practice, the interchangeability designation means that the interchangeable product may be substituted for the reference product by a pharmacist without the intervention of the prescriber, see Figure 7.
However, although FDA designates a biosimilar as interchangeable, US state pharmacy laws control substitution in the US [35]. Once an interchangeability designation is granted, a biosimilar may be substituted for the reference product by a pharmacist without the intervention of the prescriber in states that have approved legislation or regulations establishing state standards for biosimilar substitution [7, 35]. Dr Christl concluded by noting that as of June 2022, all 50 states, plus DC and Puerto Rico have enacted legislation establishing substitution laws for interchangeable biosimilars [35–37].
Patients’ perspective and expectations of non-medical switching of biologicals/biosimilars Dr Durhane Wong-Rieger, President and CEO of the Canadian Organization for Rare Disorders explained that critics of non-medical switching and forced substitution policies of biologicals/biosimilars are often, and inaccurately described as being ‘against’ biosimilars. Regarding patients, she notes that they are not anti-biosimilar, but pro-biosimilar. In addition, patients share the same goals as government payers who are implementing non-medical and forced switching, these are:
increased access to biological therapies
lower costs (that free funding to spend on other health benefits)
more treatment choices.
Despite having shared goals, there are disagreements with the method by which governments are pursuing these goals, they are:
limiting patients’ role in their treatment decision-making
restricting choice of patient/physician
ignoring variability in individual patient response
dismissing concerns of patient and physician organizations regarding forced switching
collecting insufficient data tracking Real-World Evidence about patient response that would address concerns about switching.
Dr Wong-Rieger highlighted that patients support biosimilars but have concerns over unnecessary switching. Patients on biological therapies generally have chronic diseases, thus, changes in treatment can have a significant impact on them. Many patients take years to find a medicine that works for them to help control disease and if a biological that is working for a patient, decisions related to switching therapies should be carefully considered. Changes in therapy could lead to an immune response and/or a loss of response to the new and old therapy, exposing patients to a scenario with no, or fewer, treatment options.
Biosimilar switching: an oncology scenario Dr Wong-Rieger gave the example of oncology patients leaders’ attitudes about biosimilar switching. She noted that cancer patients have only one chance to get the right drug and you cannot tell right away whether treatment is working or if there are side effects (may appear years later). Here, patients would prefer treatment with more safety and efficacy data rather than less. Regarding biologicals, these are highly specific to individual patients and you cannot extrapolate from one tumour type to another or from one stage to another. It is generally advised that, for cancer patients receiving adjuvant therapy, if patient is stable, they should not switch as there are unknowns related to individual impact. Oncology clinics lack long-term follow-up to assure pharmacovigilance needed for safe use of biosimilars. In this scenario, making healthcare savings is supported but prescribing should be based on ‘best for patient’ not ‘best for system’.
Biosimilar switching: an ophthalmology scenario Biosimilars are now available in the field of ophthalmology. They offer new, cost-saving alternatives to current treatments for retinal diseases which can cause blindness. However, it is important to guarantee that the biosimilar substitution policies for vision care are patient-centred: there is no coming back from a switch that was inappropriate for a particular patient – patients and physicians must determine this based on a patient’s needs, not third parties.
Advocare Network Patient Survey In mid-2016, a Consumer Advocare Network Patient Survey [38] of 200 patients with varied conditions from diabetes, inflammatory, blood disorders, immune-related, cancers, multisystemic, lysosomal storage, cardiovascular disease and cancer was undertaken.
Figure 8 shows that patients are highly supportive of biosimilars, very opposed to government switching and almost unanimously supportive of informed patient choice.
The Institute for Optimizing Health Outcomes – Europe The Institute for Optimizing Health Outcomes has a scorecard that rates the biosimilar policy frameworks of European countries across success factors for biosimilar sustainability:
Improving patient access and physician prescription choice of safe, high-quality biological medicines
A framework that considers the needs of all stakeholders
Providing a means to manage existing healthcare budgets
Safeguarding a healthy level of competition and supply.
Dr Wong-Rieger highlighted that Canada’s public drug plans would have scored at the bottom. By taking away physician pre scription choice and mandating non-medical biosimilar switching, the government has set up a non-sustainable situation. This has led to patient backlash over the disregard for their biologicals management challenges and anxieties about switching.
Patient/physician choice does not need to be sacrificed to achieve biosimilar savings. The experience of European countries has shown that it is possible to build strong, successful and sustainable biosimilar markets that achieve a high number of approvals, high uptake rates, and high savings. These can come without:
Automatic substitution of biologicals and biosimilars
Switching current/stable patients
Limiting which approved products can be prescribed/will be reimbursed.
It is important that Canadian patients should have the same options as their counterparts in Europe.
In conclusion, Dr Wong-Rieger noted that patients understand and share the goals of regulators who want to encourage use of biosimilars. However, they disagree with regulators’ methods, i.e. going around patients and physicians to accomplish this without their involvement. She stressed that these goals can be achieved without sacrificing patient/physician control of treatment decisions. Biosimilar policies need to factor in the concerns of patients and physicians and that these policies need to work for the patient community. In addition, patients, via patient organizations, should be included as partners in every step of the biosimilar policymaking process. Patients themselves must remain partners in their own treatment decision-making process. It is key that the government also works to address, not ignore, patient and physician concerns, e.g. track outcomes of biological switching and collect and analyse real-world evidence.
Canadian non-medical switching policies on biologicals/biosimilars – implications for physicians and patients This presentation was given by Professor Philip J Schneider (Pharmacist, Ohio State University).
Professor Philip J Schneider, pharmacist, and Professor of Pharmacy at the Ohio State University, outlined that there are several issues to consider when assessing Canada’s non-medical and forced switching policies:
Does it effectively achieve savings?
Does it prioritize the patient?
Does it adequately consider physician concerns/objections?
Does it reflect the principles upon which it was enacted, i.e. as a means of ‘catching up to Europe’?
Does it promote sustainable biosimilar market?
Does it build confidence in biosimilars?
In Canada’s forced switching policies, there is relatively little transparency relative to those of Denmark and Norway, the only European countries to use a national tender system, Of these, only Denmark, following a transparent bidding process process, will solely reimburse the winning product except in rare substantiated circumstances. Many of the savings biosimilars bring come from innovator products and additional biosimilars cutting prices to compete. As such, forced-switching artificially achieves high market share but loses any savings which would occur from competition. Professor Schneider asks, ‘Are we sub stituting one monopoly for another?’.
In addition, patient objections to forced switching policies have been well-documented for many years. While creating numerous exceptions to these policies can mitigate some of their worst effects, this highlights the problem that the policy itself is wrong at its core because it makes the patient–physician relationship secondary or tertiary, rather than central to patient care.
Regarding physicians, it was noted that a key role for them is to function as learned intermediaries that can balance patient-specific factors against policies made by governments (and other payers) based on population-derived factors. However, we have seen that Canadian non-medical switching policies are typically enacted despite a lack of acceptance (and often strong objections) among physicians. It was also noted that in 2020, the INESSS report stated ‘Non-medical switching in patients being treated with a reference biologic is generally not accepted by learned societies and the consulted clinicians’ [10].
Canada’s policies have little similarity to the successful switching policies in Europe. However, the proponents of the forced-switching policy in Canada frequently cite European biosimilar policies as a basis for policy in Canada. These European governments achieved their success by:
avoiding automatic substitution
preserving and expanding rather than restricting patient/physician choice
achieving savings through competition between many reimbursed products.
This is the direct opposite of what is happening in forced-switching provinces of Canada.
In addition, several of the questions highlighted above are considered in the white paper: ‘A critical review of substitution policy for biosimilars in Canada’ [9]. This white paper also identified three ‘must-haves’ for any biosimilars policy:
Physicians should have the freedom to choose between off-patent originator biologicals and available biosimilars and to act in the best interest of their patients based on scientific evidence and clinical experience.
Tenders should be designed to include multiple value-based criteria beyond price, e.g. education, services, available dose strengths, and provide a sufficient broad choice (multi-winner tenders versus single-winner tenders) to ensure continuity of supply and healthy competition.
A level playing field between all participating manufacturers is the best way to foster competition; mandatory discounts which place artificial downward pressure on manufacturers do not engender a sustainable market environment.
Professor Schneider added that physician confidence in biosimilars is high, in Canada and elsewhere. However, they want more data showing safety of switching and they still want to be involved in substitution decisions. Data show these attitudes are consistent among physicians worldwide. He also noted that ignoring and dismissing these concerns does not build confidence. For example, and in contrast to Canada, the US is achieving uptake rates comparable to those of Europe (40%–80%) by addressing these concerns, e.g. interchangeability, state substitution laws.
The key reasons contributing to the failure of forced-switching policies include that:
They ignore physician concerns and objections, fail to let confidence grow through data, prioritize short-term savings over long-term savings that result from competition, and undermine growth and sustainability of biosimilar markets.
In effect, they fail by seeking a shortcut to uptake/savings rather than creating conditions for the desired behaviours to occur naturally, e.g. European and US markets.
Professor Schneider concluded that Health policies should always begin and end with the patient and the patient/physician relationship is central to making treatment decisions – a policy which removes this from the equation must meet a very high burden of proof.
Summary of panel discussions/Q&A
Following the speaker’s presentations, there was a panel discussion moderated by Dr Steven Stranne and five questions were discussed.
Question 1: Could you tell us more about the costs for the patient associated with non-medical switching?
Ms Maaghop from Canada’s Gastrointestinal Society noted that, in the context of Canada, the patient support programmes, which administer the originator biologicals and biosimilars are funded by pharmaceutical companies and the government does not have to bear the cost burden of these. Despite these programmes existing, a lot of coordination is still required. Throughout the forced switching processes there were delays in communication between the patients and the healthcare providers, which caused issues as outlined by Ms Attara.
Ms Maaghop gave the example of a study carried out by gastroenterologists in Alberta where they calculated that for 2,000 patients, it was estimated that a minimum of 650 clinic hours [39] were required for the administration of a non-medical switch for patients in addition to their usual, very-heavy work schedules. These increased hours were not even possible when the assessment was done during 2019 and the pandemic confounded the situation, making it very difficult for gastroenterologists to meet the demands. The doctors also calculated that this would lead to more than 60 avoidable surgeries in Alberta.
Ms Rathod of the International Federation of Ageing noted that there is a risk of loss of stability for the patients that are switched, i.e. increased risk of disease worsening [39]. This is significant as it often takes several years for a patient to find a drug that works well for them. There are also geographical and logistical issues that come with accessing biosimilars, especially when clinics for biologicals are separated from those where the biosimilars are located.
Professor Schneider noted that usually, switching therapies is done for cost-based reasons and so switching is likely to improve affordability for patients. However, this may also undermine confidence due to the perception that they are receiving a less expensive and therefore inferior drug. This creates a nocebo effect. Therefore, for patients to have confidence in a biosimilar, clinicians need to spend time with the patient, explaining the benefits of biosimilars in terms of cost, safety and efficacy and such conversations can be time consuming.
Dr McKibbin noted that, from a physician’s perspective and as lead author on a white paper of the Digestive Disease National Coalition [40] that looked at non-medical switching and authorization tactics. This showed that every type of pharmacy manipulation and control has a hidden cost to the system, such as lack of adherence. The idea that you are just switching one bottle of medication for another, cheaper one, in the pharmacy is not entirely straightforward and the hidden costs need to be considered. Patients have complex chronic diseases and need to be looked at individually. The one-dimensional perspective can be given, but each case is far more multifaceted.
Question 2: How can a patient organization keep track of developments like the interchangeable status?
Dr Christl noted that the best way to keep up to date on the status of biological products is with FDA’s Purple Book [34]. The Purple Book provides information on all FDA-approved biological products, including information regarding biosimilars and interchangeable biosimilars. The database is also set up so that if a brand name or active ingredient is searched for, then all available related products will come up. Here, prescribers and patients can see what products are approved, although not all those approved are available. FDA also shares information when they approve new products.
Ms Rathod added that this reiterates the importance of having information publicly available and for this to be regularly updated. This helps patient organizations ensure that the correct information is passed on to patients in a timely manner for decisions on treatment options to be made.
Dr Christl added that there is no all-encompassing resource for products that are undergoing clinical trials. There is also the registry site for clinical trials at www.clinicaltrials.gov. Getting information on this comes from, e.g. individual companies, trade press, market analyst positions. However, this type of information is not always publicly available. Patient organizations can potentially keep track of this and provide it as a resource, but this requires manual data mining.
Ms Maaghop noted that in Canada, the federal regulator, Health Canada, has deferred the authority over interchangeability status to provinces and territories. There is, therefore, variability in what the policies look like across the country. Patient organizations have a role to play here.
Question 3: Can we compare transparency in Canada to some of the experiences in Norway, Denmark, and the EU?
Professor Schneider noted that, in Europe, and specifically in Norway and Denmark, where they have adopted single tendering systems, patients and physicians are involved in decisions at the front end. This is not just a regulatory decision, but prescriber input is valued. In addition, alternative treatment options are available for selection by physicians. Norway moved from a single tendering system to a multi-tender system due to supply chain issues and to ensure reliability of supply. In addition, in these nations, culturally, it has been agreed by physicians and regulators that the issue of rising cost of healthcare needs to be addressed. However, this needs to be achieved in a way that addresses individual needs of patients, effectiveness and safety of therapy is paramount. These countries have adopted transparent policies, which are lacking in Canada.
Mr Reilly noted that in a meeting he attended with the British Columbia regulator, a representative from Norway’s health system presented but cautioned that their system would likely not work in Canada. He also noted that when he attends European biosimilars meetings, including periodic meetings at the European Commission, he does not see Canadian representatives. He remarked that this absence is unusual for a country supposedly modelling their biosimilar practices on those of Europe. The meetings are reflective and forward looking and a recent meeting highlighted that single tender systems are ineffectual. In Canada, it was suggested that adverse event tracking would be done through monitoring increased hospitalizations, yet this was not a realistic measure. He also highlighted the success of the US model and voiced the opinion that the Canadians are not adopting the correct approach which is not interactive and is not a long-term way to buy and build.
Question 4: What is the most important thing that policymakers should consider when contemplating a long-term sustainable biosimilars programme?
Dr Christl noted that, from a regulatory standpoint, global regulatory authorities like FDA and the European Medicines Agency (EMA) look at scientific alignment and leveraging global development programmes, recognizing that biosimilars are being developed globally. From a development standpoint, work needs to be done to ensure manufacturers are not conducting studies that are not scientifically warranted or recommended by regulatory authorities where authorization is sought. There are also aspects related to ensuring that data from clinical studies is not duplicated and here bridging data can be used to support the use of what is known as a non-regionally approved comparator data. It is key to look at ways to streamline development and make sure it is efficient. In addition, processes and approvals need to be done in a timely fashion. Maintaining robust, scientifically appropriate regulatory standards is essential to ensuring stakeholder confidence in biosimilars globally. There is confidence in what the stringent regulatory authorities are doing to approve the products and prescribers know that when a biosimilar is approved to be as safe and efficacious as a reference product, they can trust this. It is important to maintain the regulatory standards and confidence in them. This will ensure that the acceptance and uptake of biosimilars globally is maintained. Regulators are focused on this but are also looking at efficiencies in terms of global development to bring biosimilars to the market in a timely fashion.
Mr Reilly noted that streamlining of regulatory standards is important in terms of delivering a high standard in an efficient way. There are conversations going on about reducing regulatory standards and making them less stringent, particularly in countries that find it harder to meet the standards. He stressed that the ASBM has been involved in these conversations with European regulators and has discussed the morality of reducing the stringency of regulations in some regions. At the ASBM, it is believed that the confidence we have in biosimilars is due to the position of the standards and these should not be lowered, no matter where you are. The surveys that have been carried out in recent years across Latin America [41], Canada [22], and the EU [6], have all shown really high levels of physician confidence in biosimilars due to where the standards are.
Mr Reilly said that the Canadian regulators say that their policy is based on catching up with Europe, however, it is not possible to do this unless the foundational understanding of the European approach is there. The US is in a good position today in terms of competition and pricing of biosimilars. The Canadian approach is not good for patients or physicians and does not increase confidence. It is important to maintain high standards and foster competition in the marketplace and build confidence with the patient and physician community.
Dr McKibbin noted that from the advocacy patient-physician relationship, transparency is key. Adding that, if you look at drug studies and approvals, the definitions of endpoints change with time and what used to be considered a success is now much more stringent. Transparency in data that we continue to collect to monitor safety, immunogenicity and effectiveness of biosimilars, is the key to improving the future. The next step to improving the whole system is interchangeability. The 360 concept of continuous improvement gives us the confidence in the system to move forward. Interchangeability will cut costs and we will be able to substitute at the pharmacy, there will be less hassle and cost at the physician’s office. Transparency and discussion are the key to moving forward.
Question 5: As policymakers and other stakeholders, how fast can we forestall shortages of biological products (originators and/or biosimilars)?
Professor Schneider advised that as a pharmacist, drug shortages are constantly managed. These have been a problem for a long time, but they have been made much worse due to COVID and global supply chain issues. The recent infant formula shortage in the US is a sharp example; this happened because there was a concentrated source of formula, with 70% coming from one manufacturer and they had problems with the manufacturing facility. The US then had to import formula. Squeezing the market so that there are fewer sources of product is available and makes us vulnerable to supply chain issues.
Mr Reilly added that, in 2004 there was an influenza vaccine shortage, 1.5 million doses of flu vaccine or half of the US supply, was missing. This was due to a regulatory issue in the EU that prevented doses from a supplier reaching the US. This strengthens Professor Schneider’s point about having multiple suppliers. In the EU they discuss tenders and multi-winners as in single tender systems you can end up with shortages. It is important to have multiple competitors in the arena.
Concurrent online Q&A Due to the nature of the webinar, the audience had the opportunity to ask questions throughout the meeting, by submitting them online during the presentations and Q&A session.
Question 1:Would you be able to provide some context to Health Canada’s website that states, ‘No differences are expected in efficacy and safety following a change in routine use between a biosimilar and its reference biologic drug in an authorized indication’. Is this statement misleading?
Ms Jaymee Maaghop of the Gastrointestinal Society, Canada replied that, ‘We asked for clarification on this sentence during a recent consultation with Health Canada, especially since they had a different definition in 2016: ‘Health Canada recommends that a decision to switch a patient being treated with a reference biologic drug to a biosimilar should be made by the treating physician in consultation with the patient and taking into account available clinical evidence and any policies of the relevant jurisdiction.’ Unfortunately, to date this is still not clear.
Question 2:How can patient organizations track other biologicals in line for gaining interchangeable status, like Cyltezo/Humira? The work we do to help patients through the transition will largely rely on access to which are approved as interchangeable, and which are not.
Dr Leah Christl advised that FDA’s Purple Book can be a good resource.
Conclusions
This webinar provided the opportunity to gain insight on ‘switching and substitution practices’ in Canada and Europe and the interchangeable designation in the US. The speakers shared their experience and knowledge on switching and substitution practices globally and principles on interchangeability of biosimilars in the US. There was specific emphasis on the forced-switching policies adopted in Canada and their shortcomings. The speakers also highlighted that improved information and protecting the physician–patient relationship in medical switching of biologicals/biosimilars will encourage smooth uptake of biosimilars. The regulatory and scientific standards for interchangeable biosimilars in the US were generally supported. In addition, the importance of a multi-stakeholder approach protecting the physician–patient relationship in the practice of switching of biologicals, including biosimilars, was emphasized. Overall, it was highlighted that maintaining trust in biosimilars is key to safeguarding the physician–patient relationship. This can be achieved through robust policy and regulation and upholding transparent practices.
Acknowledgement
The Generics and Biosimilars Initiative (GaBI) wishes to thank all speakers and moderator in delivering the presentations, implementing the panel discussion and clarifying information when finalizing the meeting report, as well as Mr Michael S Reilly for his strong support through the offering of advice and information during the preparation of the webinar.
The authors would like to acknowledge the help of the webinar speaker faculty and all participants, each of whom contributed to the success of the webinar and the content of this report, as well as the support of the moderator in facilitating meaningful discussion during the panel discussions, and contributing to the finalization of this meeting report.
Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing and finalizing this meeting report manuscript.
Speaker Faculty, Panelists and Moderator
Speakers Gail Attara Leah Christl, PhD Ralph D McKibbin, MD, FACP, FACG, AGAF Michael S Reilly, Esq Professor Philip J Schneider, MS, FASHP, FASPEN, FFIP Durhane Wong-Rieger, PhD
Panelists Jaymee Maaghop Urvashi Rathod
Moderator Steven Stranne, MD, JD
Editor’s comment
Speakers and moderator had provided feedback on the article content and panel discussion, read and commented the revised content of the manuscript, and approved the final report for publication.
Competing interests: The webinar was funded by ASBM.
Provenance and peer review: Not comm ission ed; externally peer reviewed.
Authors
Michael S Reilly, Esq Gail Attara Ralph D McKibbin, MD, FACP, FACG, AGAF Professor Philip J Schneider, MS, FASHP, FASPEN, FFIP
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Blevins TC, Barve A, Raiter Y, Aubonnet P, Athalye S, Sun B, et al. Efficacy and safety of MYL-1501D versus insulin glargine in people with type 1 diabetes mellitus: results of the INSTRIDE 3 phase 3 switch study. Diabetes Obes Metab. 2020;22(3):365-72. 28. U.S. Food and Drug Administration. BLA 761201. BLA Approval [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761201Orig1s000ltr.pdf 29. Boehringer-Ingelheim. VOLTAIRE-X phase III data in patients with moderate-to-severe chronic plaque psoriasis support interchangeability application [home page on the Internet]. [cited 2023 Jan 20]. Available from: https://www.biospace.com/article/releases/voltaire-x-phase-iii-data-in-patients-with-moderate-to-severe-chronic-plaque-psoriasis-support-interchangeability-application/ 30. U.S. Food and Drug Administration. BLA761058/S008. Supplemental approval fulfillment of post marketing requirement [homepage on the Internet]. [cited 2023 Jan 20]. Available here: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761058Orig1s008ltr.pdf 31. U.S. Food and Drug Administration. Clinical immunogenicity considerations for biosimilar and interchangeable insulin products. Guidance For Industry. Draft Guidance. November 2019 [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://www.fda.gov/media/133014/download 32. U.S. Food and Drug Administration. Biologics Price Competition and Innovation (BPCI) Act [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://www.fda.gov/media/78946/download 33. U.S. Food and Drug Administration. CDER guidance agenda new & revised draft guidance documents planned for publication in calendar year 2022 (July 2022) [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://www.fda.gov/media/134778/download 34. U.S. Food and Drug Administration. Purple book database of licensed biological products [home page on the Internet]. [cited 2023 Jan 20]. Available from: https://purplebooksearch.fda.gov/about 35. National Conference of State Legislatures. State laws and legislation related to biologic medications and substitution of biosimilars. 22 October 2018 [homepage on the Internet]. [cited 2023 Jan 20]. Available from: www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx 36. Safe Biologics. Oklahoma becomes final state to permit biosimilar substitution. 2021 [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://safebiologics.org/2021/05/oklahoma-becomes-final-state-to-permit-biosimilar-substitution/ 37. Council of the District of Columbia. D.C. Law 23-133. Access to Biosimilars Amendment Act of 2020 [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://code.dccouncil.us/us/dc/council/laws/23-133 38. Consumer Advocare Network. Patient survey [homepage on the Internet]. [cited 2023 Jan 20]. Available from: https://safebiologics.org/wp-con tent/uploads/2022/12/Advocare-Biosimilars-Pati ent-Perspective-Update-Nov-2018.pdf 39. Kaplan GG, Ma C, Seow CH, Kroeker KI, Panaccione R. The argument against a biosimilar switch policy for infliximab in patients with inflammatory bowel disease living in Alberta. J Canadian Assoc Gastroenterol. 2020;3(5):234-42. 40. McKibbin RD. Patient access to care and treatments in the cost-shifting era: preserving the patient-provider decision-making relationship. Available from: https://www.ostomy.org/wp-content/uploads/2020/11/HMC_2_DDNC_Whitepaper_2020.pdf 41. Reilly MS, Gewanter HL. Prescribing practices for biosimilars: questionnaire survey findings from physicians in Argentina, Brazil, Colombia and Mexico. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):161-6. doi:10.5639/gabij.2015.0404.036
Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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Abstract: The Opinion published in this issue of GaBI Journal titled ‘Biosimilars drug development: time for a paradigm shift?’ by Sandeep N Athalye, Shivani Mittra and Ankitkumar M Ranpur proposes a number of changes to the regulatory processes currently in place for biosimilars. This response letter considers the implications and consequences of these.
Submitted: 8 December 2022; Revised: 8 December 2022; Accepted: 18 December 2022; Published online first: 8 December 2022
In the Opinion entitled Biosimilars drug development: time for a paradigm shift? in this issue of GaBI Journal, the authors question the need for what they consider to be the arduous regulatory requirements for approval of biosimilars [1]. The Opinion repeats already proposed and often published possibilities for changing and particularly abbreviating the established biosimilar approval process. These are the personal opinions of the authors and others will agree or disagree largely depending on their view of the current regulatory systems for assessing biosimilars and how these affect biosimilar development.
A significant factor which the authors claim supports their proposals is that, to date approved biosimilars have been shown to have noefficacy or safety concerns. This is certainly largely true for real biosimilars approved by experienced regulatory authorities (mainly in developed nations). But all of these have been approved using the current regulatory guidelines! Most of the approved biosimilars have been produced by ‘Big Pharma’ or subsidiaries of Big Pharma who have much experience with producing biological products andsignificant resources for this. Where this has not been the case, e.g. for copy products marketed in developing nations problems have arisen and quality, efficacy and safety of some of these products is suspect if not clearly compromised. It is therefore a possibility thatloosening the requirements for approval of biosimilars would result in unsatisfactory products.
Biosimilar approval requirements as detailed in the various guidelines produced by the relevant regulatory agencies are constantlyevolving, and are continuously updated to take account of experience gained and scientific, technical and clinical advances. The guidelines are thus living documents and not inflexible ‘tablets set in stone’. An example of this flexibility is the most recent draft of thebiosimilar guideline adopted by the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, which includes clearindications where clin ical efficacy trials are not needed. This type of trend is reflected in guidance from other regulatory jurisdictions. The general move towards more reliance on quality (chemistry, manufacturing, and controls, CMC) assessment (including the quality comparability assessment) and on clinical pharmacokinetics/pharmacodynamics (PK/PD) and less need for clinical efficacy andsometimes immunogenicity assessments is clearly ongoing, but the authors seem unaware of it. The authors’ opinion gives theincorrect impression that inflexible, unjustified regulations are hindering production of biosimilars; this does not seem to be the case at least in the developed world.
The desirability of ‘One global reference product’ is mentioned in the letter. There are two possible alternatives for this. Firstly, a ‘physical’ global reference product could be provided by some suitable organization, which could be used for biosimilar development by those who require it. Although this may seem rea- sonable (it has been proposed several times previously) there are serious problemswith it, such as who provides the product, who characterizes it, who dis- tributes it and how its stability and sustainability is guaranteed.Also, how does it relate to products used in the country in which the biosimilar is being developed and how are users and regulators to be convinced that it is an appropriate reference product for use in their jurisdiction?
A second approach would not provide the reference product as such, but nominate a commercially available reference product from one source which could be globally’ adopted by those who want to use this approach. This suffers from similar problems to the first approach mentioned above. In addition there are possible issues with continued availability of this as a reference product and ensuring consistent prod uct characteristics, as commercial products undergo development and change unpredictably over time. These are just some of the problems with this ‘global reference product’ concept.
The authors blame over arduous, unnecessary regulatory requirements for apparently poor uptake of biosimilars. However, evidence suggests that reluctance to use/ adopt biosimilars due to an unfounded suspicion of their quality, efficacy and safety by prescribers andpatients and often too little difference between the price of the biosimilar and the originator products are more likely reasons for this.
Biosimilars are now firmly established in most developed nations as copy biologicals with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biosimilar products. Although the regulatory requirements must (and do) evolve as experience and science progresses, this must be carefully evaluated to ensure that efficacy and safety are not compromised. If biosimilars are to increase in uptake as acceptable biological products it is important that they are perceived as being as accept- able as stand-aloneproducts by all involved in their production and use. Any perception that ill-advised, politically/financially driven pressures to inappropriately lower regulatory standards for their approval could seriously damage the acceptability of biosimilars.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Reference 1. Athalye SN, Mittra S. Biosimilars drug development: time for a paradigm shift? Generics and Biosimilars Initiative Journal (GaBI Journal). 2023;12(1):17-22. doi:10.5639/gabij.2023.1201.005
Author: Robin Thorpe, PhD, FRCPath, Deputy Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Sandeep N Athalye, MBBS, MD; Shivani Mittra, MPharm, PhD; Ankitkumar M Ranpura, MD
Abstract:
The sky-rocketing cost of developing biosimilars is becoming a shared deterrent for biosimilar developers. The regulatory requirements for biosimilars must see a natural evolution and a paradigm shift towards removing inefficiencies in clinical designs to make way for cost-effective, sustainable development models. In this article, the authors provide a few suggestions that can lead to leaner and faster clinical development of biosimilars in the regulated market, and further across the globe, while not compromising the scientific validity of their development.
Submitted: 2 November 2022; Revised: 21 December 2022; Accepted: 21 December 2022; Published online first: 30 December 2022
In the US healthcare system, of the 126 billion US dollar spent on biologicals in 2018, only 2% was spent on biosimilars [1]. Biosimilars with a faster entry, higher volume share, and more robust price competition, can lead to substantially more savings (US$124.2 billion) between 2021 and 2025 [2]. An analysis of more than one million patient-treatment years with biosimilars has raised no efficacy or safety concerns and this, in turn, should build confidence in the regulators, payers, physicians, and patients based on the substantial repertoire of the real-world data [3].
Biosimilar approvals require data from comprehensive analytical and clinical studies in ‘highly regulated’ jurisdictions such as the European Union, Japan and the US. These include non-clinical in-vitro studies of the molecular function; human pharmacokinetic (PK) and pharmacodynamic (PD) studies; a powered clinical efficacy study in the most sensitive indication of the reference product; and human immunogenicity studies, including ‘switch’ studies between the reference product and the proposed biosimilar for the US [4].
With the optimally regulated development of insulin biosimilars in place, the focus is now on the newer immuno-oncology biosimilars. Development for these is laden with challenges pertaining to the requirement of large efficacy equivalence trials, high costs of the reference products, and additional cost of concurrent chemotherapy drugs, amongst other challenges. The importance of harmonizing policies for biosimilar development, globally, cannot be emphasized more keeping in mind the inflection point where biosimilar developers are finding themselves to be.
The following suggestions can lead to leaner and faster development along with faster uptake of biosimilars in the regulated markets and, further, across the globe:
(1) Policies that encourage ‘totality of evidence’ but with an optimally customized trial design for each molecule, are required. For example, for denosumab biosimilar development, where the dosing is every 6 months, any additional switch requirement beyond one year increases the trial duration by 6 months, leading to a time and cost increase in the development. Single switch studies assess the effect of ‘switching’ to a biosimilar with regard to immunogenicity and related safety. Molecules such as denosumab, secukinumab and daratumumab have very low immunogenicity, <1%, <1% and <0.35%, respectively, and have not reported any efficacy or safety concerns even on long terms [5–7].
Previous studies have reported the anti-drug antibody incidence rate to be <1% with 8-year treatment with denosumab, and there is no evidence of PK differences, toxicity, or difference in the clinical response. This has been validated in several studies with denosumab and its biosimilars, see Table 1. In the case of secukinumab, of the <0.1% subjects that developed anti-drug antibodies, approximately one-half had neutralizing antibodies which were not observed to be associated with any loss of efficacy [7]. Hence, single-switch studies for such molecules would not offer any additional information and should not apply to the development of their biosimilars.
Biosimilars approved to date by the US Food and Drug Administration (FDA) have not shown any major safety or immunogenicity concerns after single or multiple switches (if done), underscoring the importance of either completely waiving off the single-switch studies or only considering these for highly immunogenic drugs. Two systematic reviews by Cohen et al. (2018) and Barbier et al. (2020) consisting of 90 and 178 switch studies involving 14,225 and ~21,000 subjects, respectively, have shown no difference in the safety, efficacy and immunogenicity outcomes related to switching from the reference biological to the corresponding biosimilar [8, 9]. These results should assure regulators, prescribers, payors and patients that the risk of immunogenicity-related safety concerns or diminished efficacy remains unchanged after switching. Granting interchangeability claims for such low immunogenic molecules should be allowed based on the safety and efficacy trial data.
(2) The use of ‘one global reference product’ for biosimilar development trials can bring down the costs in a big way. The huge cost involved for reference drugs requirement is another deterrent to multiple players interested in developing biosimilars. The high cost of reference listed drugs (RLDs) for biologicals (Pembrolizumab, US$10,474 per vial: Daratumumab, US$6,500 per infusion; Nivolumab, US$7,436 per vial and Pertuzumab, US$6,216 per vial) makes one think why a single, most cost-effective amongst all available RLD’s cannot suffice for all developed regulatory markets [10–14]. PK bridging studies between the reference drugs (such as US-licensed and EU-approved reference products) are required considering the possibility of a drift in the quality attributes in the originator molecule across regions. This adds to the trial complexity and timelines, in addition to the cost, especially in the integrated patient trials in the oncology space. Based on past data on approved biosimilars, there is no evidence that such differences are observed. The two-arm clinical PK study instead of three arms, with either of the RLD, can substantially reduce the trial complexity, duration, and cost.
A World Health Organization survey in 2019‒2020 in 20 countries has recognized the challenges related to the RLDs, which include limited access to information on the RLDs, financial constraints due to their price, and difficulty in obtaining RLD samples to assess comparability [15]. While some countries accept RLDs that are foreign-licensed and -sourced, especially from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use countries [16], many others require a domestically licensed/marketed reference product or else require bridge studies for a foreign-sourced reference product that end up being costly and often unnecessary, see Table 2. To address these challenges and to bring about harmonization to have a single global reference product, exchanging information with other national regulatory authorities builds confidence in accepting foreign-sourced reference products, thus avoiding unnecessary bridge studies.
(3) There is also a strong need to have common statistical methods (currently, it is Risk Ratio for FDA versus Risk Difference for EMA) to assess biosimilarity and hence to calculate the sample size for the equivalence and efficacy trials [17]. The difference between two-population means, for efficacy measures, is a widely used method as specified by European Medicines Agency (EMA) [18] for establishing margins for the calculation of the sample size. Differences in the statistical methods for assessing biosimilarity and sample-size estimation lead to huge differences in the sample-size requirement for confirmatory trials between FDA and EMA [18, 19]. The opportunity to use asymmetric margins is also a relevant consideration for future biosimilar development based on scientific reasoning. The large sample size and cost of reference products for such trials can become a barrier for companies developing biosimilars globally. Hence, having a uniform method to arrive at a trial size, with an intent to keep the totality of evidence approach, can be helpful in simplifying biosimilar development.
(4) Conducting a clinical trial for an orphan drug becomes costly due to recruitment challenges, and operational costs escalate due to the longer duration of the trial and the reference product cost. Procurement of reference products through tightly managed channels and access to patients is a challenge. No guidance exists for developing orphan drug biosimilars. Waiving off the clinical efficacy similarity trial for such orphan drugs can significantly reduce the cost of development with the burden of proof shifting to CMC (Chemistry, Manufacturing and Controls) similarity, sensitive functional assays, PK data. Innovative trial designs and statistics for smaller trials should be accepted if a waiver is not possible because of the non-availability of PD markers.
In conclusion, continued regulatory reforms for biosimilars, more affordability with competition brought through biosimilars, and a fair healthcare system that passes the savings to the patients can make biosimilar development more sustainable in the future. Greater savings may be feasible if managed care in the US and similar organizations across the globe increase biosimilar utilization and promote competition. The cost of developing biosimilars should be an important factor in the continued future growth of this sector. Initial apprehensions regarding biosimilars are already changing and in the future, a greater acceptance and faster adoption of biosimilars can be envisioned. A simple yet effective analogy that can make everyone realize the importance of biosimilars is that, just for a moment, we all close our eyes and think of a healthcare world without generics.
Funding sources
Biocon Biologics Ltd funded the Article Processing Charges.
Disclaimer
The opinions expressed in this article are personal views of the authors and should not be understood as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated.
Competing interests: SNA, SM and AMR are employees of Biocon Biologics Ltd. SNA and SM hold stocks in Biocon. AMR declares no conflict of interest.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Sandeep N Athalye, MBBS, MD Shivani Mittra, MPharm, PhD Ankitkumar M Ranpura, MD
Clinical Development and Medical Affairs
Biocon Biologics Ltd, Biocon House, Tower 3, Semicon Park, Plot No 29-P1 & 31-P, KIADB Industrial Area, Electronic City Phase – 2, Hosur Road, Bengaluru 560100, Karnataka, India
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Author for correspondence: Sandeep N Athalye, MBBS, MD, Chief Medical Offi cer, Biocon Biologics Ltd, Biocon House, Tower 3, Semicon Park, Plot No 29-P1 & 31-P, KIADB Industrial Area, Electronic City Phase – 2, Hosur Road, Bengaluru 560100, Karnataka, India
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Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Chuei Wuei Leong1, PhD; Elton Sagim1, BBiomedSc, Kar Ming Yee1, BPharm; Muhammad Shalhadi Saharuddin1, BSc; Sharifah Radziah Syed Abd Rahim1, MSc; Khairil Sabri1, BSc; Mohd Zulhairi Jamaluddin1, BSc; Shahnun Ahmad1, MBBS; Atiqah Amran1, BSc; Rabab F Tayyem2, PhD
Introduction/Study Objectives: The present study aimed to evaluate the comparative bioavailability of a new generic sitagliptin formulation. Methods: This was an open label, randomized, balanced, two-sequence, two-treatment, two-period, single oral dose, crossover, bioequivalence (BE) study in 30 healthy male volunteers under fasting conditions. A 100 mg single dose of sitagliptin in the form of sitagliptin hydrochloride monohydrate (test) and sitagliptin phosphate monohydrate (reference) tablets were administered to each volunteer, separated by one week washout period. Twenty-two blood samples were collected at pre-dose and up until 48 hours post-dose. Sitagliptin concentrations were determined via a validated LC-MS/MS method following a protein precipitation step. Pharmacokinetic (PK) parameters were estimated via non-compartmental analysis and then compared between the reference and test formulations by performing a multivariate analysis of variance. Results and Discussion: No statistically significant difference was found between the test and reference formulations in terms of the maximum concentration (Cmax), area under the curve (AUC), AUC0-inf, and AUC0-48. The 90% confidence intervals of sitagliptin Ln-transformed Cmax, AUC0-inf, and AUC0-48 were within the regulatory BE acceptance range of 80%–125%. Conclusion: The test formulation met regulatory definition of BE to the reference formulation under fasting condition in these healthy male volunteers.
Submitted: 15 September 2022; Revised: 29 November 2022;Accepted: 30 November 2022; Published online first: 20 December 2022
Introduction/Study Objectives
Diabetes mellitus is a highly prevalent disease affecting over half a billion people, accounting for over 10% of the world’s adult population, with an anticipated 46% increase by 2045 and a drastic economic and health burden [1]. Most diabetic patients present with type 2 diabetes mellitus (T2DM) [2], characterized by impaired insulin sensitivity resulting in hyperglycaemia [3]. Furthermore, T2DM is associated with both microvascular and macrovascular complications that are the major causes of its morbidity and mortality [4, 5]. As T2DM progresses, pancreatic β cells progressively deteriorate, requiring effective glycaemic control that can be achieved by lifestyle modifications and treatment with any of a number of hypoglycaemic agents [3].
Sitagliptin is an oral hypoglycaemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme [6] responsible for the inactivation of the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (DPP-4). DPP-4 inhibition results in an incremental prolongation of incretin activity leading to a glucose-dependent boost of insulin secretion and a decrease in glucagon secretion [7]. Sitagliptin’s glycaemic control effect is characterized by lowering of both fasting and postprandial glucose concentrations [8]. DDP-4 inhibitors (DPP-4i) are well tolerated when given either alone or in combination with other hypoglycaemic agents and its use is associated with a clinically insignificant risk of hypoglycaemia or weight gain [9]
The absorption of sitagliptin is rapid, with a median time to the maximum concentration (Tmax) of 1–4 hours and an apparent half-life (T1/2) of 8–14 hours [10, 11]. Sitagliptin is metabolized via oxidation catalyzed mainly by cytochrome P450 (CYP) 3A4 isoenzymes in the liver, with a small contribution from CYP2C8 [12]. Sitagliptin area under the curve (AUC) is increased in a relatively dose-dependent fashion in healthy volunteers [11] and its absolute bioavailability was found to be 87%. The majority of a sitagliptin dose is excreted unchanged in urine (87%) and feces (13%) [12, 13]. The renal elimination of sitagliptin is by active tubular secretion. Its renal clearance has been reported to be 388 mL/min [11]. Therefore, renal function is expected to be a significant factor affecting the pharmacokinetics (PK) of sitagliptin [14]. However, no dose adjustment is required in patients with only mild renal impairment; that is patients with a creatinine clearance of equal to or more than 50 mL/min but less than 80 mL/min. Minor decreases in renal function were found to have a clinically insignificant impact on sitagliptin PK. [14].
Different sitagliptin salts, e.g. hydrochloride, malate, and tartrate, have judged to have similar bioavailabilities compare to the reference sitagliptin phosphate product (Januvia®) with similar safety and efficacy profiles when they were given market authorization [15]. In a recent study comparing the tablet formulations of sitagliptin hydrochloride with sitagliptin phosphate, the uniformity of dosage form as measured by weight variability was found to be superior in sitagliptin hydrochloride tablets. Furthermore, sitagliptin hydrochloride tablets were shown to have superior chemical stability compared to sitagliptin phosphate and were therefore considered a better option [16]. Similar dissolution profiles were also demonstrated for both sitagliptin phosphate and hydrochloride salts, with an acceptable similarity factor, indicating that both salts have similar in vivo behaviour [17]. This was explained by sitagliptin’s high bioavailability and solubility [18]. This study aimed to evaluate the relative bioavailability of a test formulation (containing 100 mg of sitagliptin in the form of sitagliptin hydrochloride) with a reference tablet formulation (containing 100 mg of sitagliptin in the form of sitagliptin phosphate).
Methods
Study design
The relative bioavailability of a single dose of a test formulation with a reference formulation, both containing 100 mg sitagliptin, was evaluated in an open-label, randomized, balanced, two-period, two-way, two-sequence crossover study design in healthy, fasting adult volunteers. The washout period was one week between the two study periods.
The study was carried out in the ACDIMA BioCentre in Amman, Jordan in accordance with the International Conference on Harmonization–Good Clinical Practice, the Declaration of Helsinki, and the ASEAN (Association of Southeast Asian Nations) guideline for the conduct of bioequivalence (BE) studies. Approval was obtained from the ACDIMA BioCenter’s Institutional Review Board (IRB) (Research ID: 940-2019) on 15 September 2020 and the Jordan Food and Drug Administration (JFDA) (Research ID: 6/BIO/20) on 5 February 2020. Informed consents were obtained from all participants prior to enrolment. The study was also registered in the Thai Clinical Trials Registry (TCTR20220628001) on 28 June 2022.
Study population
Participants were recruited based on the fulfilment of the inclusion criteria of: 1) healthy as confirmed by the medical evaluation [basic medical check-up, medical history, electrocardiogram (ECG), and laboratory findings (complete blood count, biochemical tests, serological tests, and urine analysis] performed on admission; 2) body mass index (BMI) of 18.5 to 30 kg/m2 (weight more than 59 kg); 3) adults aged between 18 and 50 years; 4) not receiving any medications for the last two weeks prior to the commencement of the study; 5) non-pregnant women; 6) with fasting blood glucose concentration of more than 70 mg/dL prior to dosing at the start of each period. Exclusion criteria included: 1) heavy smokers (more than 10 cigarettes per day); 2) presence of any contraindications or allergies to sitagliptin; 3) consumption of grapefruits products in the prior week or caffeinated beverages within two days of the study date; and 4) abuse of alcohol or illicit drugs which was confirmed by laboratory testing (alcohol saliva test and urine test for benzodiazepines, amphetamine, marijuana, cocaine and opiates).
Based on sample-size calculation to achieve a power of 80%, considering an intra-subject and inter-subject coefficient of variation (ISCV) for sitagliptin AUC following a 100 mg single dose found in the literature to be around 5.8% and 15.1%, respectively [19], a minimum of 12 subjects was required to be recruited; therefore, thirty subjects from the Jordan population were enrolled for this study.
Study products and administration
The BE of Fortreas® tablets (containing 100 mg of sitagliptin in the form of sitagliptin hydrochloride) manufactured by Duopharma, Malaysia (test formulation) was compared with Januvia® tablets (containing 100 mg of sitagliptin in the form of sitagliptin phosphate) manufactured by Merck Sharp & Dohme Ltd, England (reference formulation) in the present study. Volunteers were assigned randomly to ingest the reference or test tablet with 240 ± 2 mL of water after overnight fasting of 10–12 hours. Subjects were instructed to stay in an upright position for four hours after dosing. Standardized meals were served to all volunteers at a fixed schedule throughout the study where on Day 1, standardized dinner (chicken scallop sandwich) was served 12 hours before dosing and on Day 2, standardized lunch (chicken rice and bread) was served 4 hours after dosing, a snack 8 hours after dosing, and a standardized dinner (chicken scallop sandwich) 12 hours after dosing. Fluid restrictions were placed only on Day 2 of the study. Subjects were not allowed to drink water 1 hour before dosing and 4 hours after, except for: 120 ± 2 mL of water was served 1 hour before dosing, 240 ± 2 mL of water with the dose and 120 ± 2 mL of water 2 and 3 hours after dosing.
Sampling
A total of 22 blood samples (7 mL each) were taken from each volunteer at pre-dose and 0.3, 0.7, 1, 1.3, 1.7, 2, 2.3, 2.7, 3, 3.3, 3.7, 4, 4.3, 4.7, 5, 6, 8, 10, 12, 23, and 48 hours post-dose. Lithium heparin tubes were used for blood samples collection; then, centrifugation at 4,000 RPM for 5 min at 10°C was carried out. Plasma was separated and stored in the freezer (-70°C), then transferred to the bioanalytical laboratory site of the on-site ACDIMA BioCentre–Bioanalytical Unit and stored in a freezer (-70°C) until the bioanalytical analyses were performed.
Subject monitoring
Throughout the study, clinical assessments and laboratory investigations were performed in an attempt to evaluate both protect the safety of all participants and report and assess any adverse events observed during the study.
Determination of sitagliptin plasma concentrations
An analytical method for the estimation of sitagliptin in human plasma was developed and validated using reversed-phase liquid chromatography and tandem mass spectrometry (LC-MS/MS) with positive ion electrospray ionization (Agilent, USA). Plasma was extracted through protein precipitation where 200 μL of each plasma sample was spiked with 25 μL Sitagliptin D4 as an internal standard; then 1 mL of the precipitation solvent, acetonitrile, was added, and the mixture was vortexed and centrifuged for 5 min at 6,000 RPM at 5°C. Afterward, 10 μL was injected via the autosampler, and separation was performed using an Agilent Eclipse XDB CN (150 × 4.6 mm, i.d.: 5 μm) at 35°C and a flow rate of 1 mL/min of the mobile phase, which was composed of acetonitrile and 50 mM ammonium formate (50:50, v/v) with 0.5 mL formic acid. Quantitation of the analyte was done on a triple-stage quadrable mass spectrometer. Sitagliptin and internal standard were monitored at the molecular ion 408.2–412.1 m/z and MS/MS (daughter) 235.0–239.0 m/z, respectively. Validation of the method was carried out in the range of concentrations between 1 ng/mL to 750 ng/mL with good linearity of r2 equals 0.999. The method achieved intra-and inter-day precision of less than 5% and accuracy of 98.8%–103.5%. The analyte and the internal standard recoveries were 82%–88%. The limit of quantification was found to be 1 ng/mL. Between-and within-day CV% were below 3.3% and 4.5%, respectively.
Pharmacokinetic and statistical analysis
The randomization schedule was carried out using SAS software. The data analysts were blinded for the randomization, and the bioanalytical laboratory conducting the PK analysis was blinded for the identity of the test and reference product ingested to avoid any bias arising from the open-label study design. Pharmacokinetic parameters were estimated by performing non-compartmental PK analysis using the Phoenix WinNonlin version 8.1 (Pharsight Corporation, USA) in terms of maximum concentration (Cmax), AUC, 0 to infinity (AUC0–inf), AUC, 0 to 48 hours (AUC0–48), elimination constant (Ke), Tmax, and T1/2 of the drug. Statistical analysis was carried out using SAS software version 9.4 (SAS Institute Inc, Cary, North Carolina) by performing multivariate analysis of variance (ANOVA) on the Ln-transformed and untransformed PK parameters Cmax, AUC0–48, and AUC0–inf using the linear mixed effects model with sequence and period X treatment were included as the fixed effects and subjects as the random effect. The test formulation BE with the reference product was established based on an alpha value of 0.05 (within a 90% confidence interval (CI)).
Results and discussion
The relative bioavialability of a test formulation with a reference formulation in 30 healthy male volunteers under fasting conditions was investigated in the current study in an attempt to meet regulatory requirements for declaring the test formulation to be bioequivalent to the reference product. The participation of four volunteers was terminated due to the violation of the study protocol during the second period (positive results of illicit drugs). One volunteer withdrew during the second period due to personal reasons. While women meeting the inclusion and exclusion criteria were eligible to be enrolled, only male volunteers were successfully recruited. Data obtained from 25 male volunteers who completed the study were included in the analysis with a mean ± standard deviation BMI of 25.0 ± 2.7 kg/m2 and age of 27.6 ± 9.5 years, as summarized in Table 1. Mild headache was reported in one subject, while the white blood cells count (WBC) was above the normal range for two (13.5 and 15.3 × 109 cells/L) for two participants 48 hours after the dose. However, these changes were not considered to be clinically significant.
A one week washout period, sufficient to cover at least ten elimination half-lives of sitagliptin, was included in the crossover study design between the two phases to avoid any possible carryover phenomenon. The PK parameters of the reference and test formulations, i.e. AUC0-inf, AUC0-48, Cmax, Tmax, and T1/2, are presented in Table 2. Cmax, AUC0-inf, and AUC0-48 values were comparable between the test and reference formulations. Furthermore, intrasubject variabilities in Cmax were found to be 20.3% and 23.6%, AUC0-48, 14.3% and 15.6%, and AUC0-inf, 14.4% and 15.4% for the test and reference formulation, respectively. Tmax achieved comparable results with those reported in previous BE studies of a single dose of sitagliptin 100 mg [20] or 50 mg [21] tablet in American Hispanic/Latino and non-Hispanic/Latino volunteers. All PK parameters were identical to those recently reported in a Malaysian population following a 100 mg single dose of sitagliptin tablet [22]. Cmax, Tmax, and T1/2 were comparable in an Asian population receiving a single dose of sitagliptin 100 mg or 500 mg tablets alone or in combination with metformin [23–26]. Sitagliptin safety profile, tolerability, PK, and pharmacodynamics (PD) were evaluated in single doses ranging from 1.5 mg to 600 mg. The PK parameters found in these studies were in line with current results [11].
A comparison of the mean plasma concentration/time profiles of sitagliptin test and reference formulations in these 25 healthy male volunteers is represented in Figure 1 (all data points below the limit of quantification were entered in as zero and were included as zero in the calculation of means). The current results showed that the median Tmax was comparable for both formulations. Sitagliptin elimination occurred gradually over the sampling interval of 48-hours. No significant difference was found in Cmax, AUC0–inf, or AUC0–48 between the test and reference formulations based on the multivariate ANOVA statistical analysis. The 90% CIs of the Ln-transformed Cmax, AUC0–inf, and AUC0–48, were 89.2%–06.0%, 100.4%–103.5%, and 100.8%–104.0%, respectively. The two-sided 90% CIs of Ln-transformed Cmax, AUC0-inf, and AUC0–48 of sitagliptin were within the BE acceptance range of 80%–125%, as defined by the ASEAN Guideline for the Conduct of Bioequivalence Studies [27]. Therefore, the test formulation successfully met the acceptance criteria for a BE study.
The current study involved only Caucasian participants. This might influence the generalizability of the study findings in other populations. Furthermore, only male volunteers were recruited, limiting the ability to extrapolate the PK parameters to the female population. Inter-individual variability was accounted for in the randomized crossover study design, therefy limiting its potential impact on the BE of the study products. With these potential limitations, it was concluded that the PK profiles of study products in terms of absorption, distribution, metabolism, and elimination were comparable. However, no investigation of drug PD was carried out in the current study. This would be a potential topic for future studies involving racially and sexually diverse actual diabetic patient populations.
Conclusions
The present study found that single doses of the test and reference formulations, each containing 100 mg sitagliptin in the form of sitagliptin hydrochloride monohydrate and sitagliptin phosphate monohydrate, respectively produced drug concentration/time curves under fasting conditions that met regulatory requirements for declaring the products to be bioequivalent.
Funding sources
This work was financially supported by the Duopharma Biotech Berhad.
Competing interests: CWL, ES, KMY, MSS, SRSAR, KS, MZJ, SA, and AA are employees of Duopharma, RFT is an employee of ACDIMA BioCenter that was paid to perform the study for Duopharma.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Chuei Wuei Leong1, PhD Elton Sagim1,BBiomedSc Kar Ming Yee1, BPharm Muhammad Shalhadi Saharuddin1, BSc Sharifah Radziah Syed Abd Rahim1, MSc Khairil Sabri1, BSc Mohd Zulhairi Jamaluddin1, BSc Shahnun Ahmad1, MBBS Atiqah Amran1, BSc Rabab F Tayyem2, PhD
1Duopharma Innovation Sdn Bhd, Selangor,
No. 2, Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, Shah Alam 40150, Darul Ehsan, Malaysia 2ACDIMA BioCenter, Amman 11190, Jordan
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Predictors of recurrent ischemic stroke in obese patients with type 2 diabetes mellitus: a population-based study. J Stroke Cerebrovasc Dis. 2020;29(10):105173. 6. Dhillon S. Sitagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs. 2010;70(4):489-512. 7. Scott LJ. Sitagliptin: a review in type 2 diabetes. Drugs. 2017;77(2):209-24. 8. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP.Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008;24(2):489-96. 9. Pfeiffer AF, Klein HH. The treatment of type 2 diabetes. Dtsch Arztebl Int. 2014;111(5):69-82. 10. Bergman AJ, Stevens C, Zhou YY, Yi B, Laethem M, De Smet M, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28(1):55-72. 11. 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Charoo NA, Abdallah DB, Bakheit AA, Haque KU, Hassan HA, Abrahamsson B, et al. Biowaiver monograph for immediate-release solid oral dosage forms: sitagliptin phosphate monohydrate. J Pharm Sci. 2022;111(1):2-13. 16. Zakowiecki D, Edinger P, Papaioannou M, Hess T, Kubiak B, Terlecka A. Exploiting synergistic effects of brittle and plastic excipients in directly compressible formulations of sitagliptin phosphate and sitagliptin hydrochloride. Pharm Dev Technol.2022;27(6):702-13. 17. Boddu R, Vadla HC, Prathap VR, Kothamasu U, Rallabandi BC, Gannu R, et al. Development of an in vitro-in vivo correlation for sitagliptin and metformin prolonged-release tablet formulations. Turk J Pharm Sci. 2021;18(2):233-41. 18. Tsume Y, Mudie DM, Langguth P, Amidon GE, Amidon GL. The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur J Pharm Sci. 2014;57:152-63. 19. Drugs.com. Januvia [homepage on the Internet]. [cited 2022 Nov 29]. Available from: https://www.drugs.com/pro/januvia.html#s-34089-3 20. Fediuk DJ, Matschke K, Liang Y, Pelletier KB, Wei H, Shi H, et al. Bioequivalence of ertugliflozin/sitagliptin fixed-dose combination tablets and coadministration of respective strengths of individual components. Clin Pharmacol Drug Dev. 2019;8:884-94. 21. Migoya EM, Miller JL, Gutierrez M, Zheng W, Johnson-Levonas AO, Liu Q, et al. Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study. Clin Drug Investig. 2010;30(12):855-66. 22. Loh GOK, Wong EYL, Tan YTF, Lee YL, Pang LH, Chin MC, et al. Simple and rapid LC-MS/MS method for determination of sitagliptin in human plasma and application to bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 2020;1159:122337. 23. Reddy S, Ahmed I, Ahmad I, Mukhopadhyay A, Thangam S. 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Author for correspondence: Chuei Wuei Leong, PhD, Formulation and R & D Technologies, Duopharma Innovation Sdn Bhd, No. 2, Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, Shah Alam 40150, Selangor, Daryl Ehsan, Malaysia
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Author byline as per print journal: Chuei Wuei Leong1, PhD; Elton Sagim1, BBiomedSc; Kar Ming Yee1, BPharm; Muhammad Shalhadi Saharuddin1, BSc; Nik Mohd Zulhakimi Nik Abdullah1, BSc; Noramirah Farhanah Saberi1, BSc; Rajavikraman Boopathy1, DipSc; Shahnun Ahmad1, MBBS; Atiqah Amran1, BSc; Raman Batheja2, PhD; Rajan Sharma2>, MBBS; Kiran Kumar Vuppalavanchu2, MPharm
Introduction/Study Objectives: The aim of the current study is to assess the rate and extent of absorption of a test and reference formulation containing sitagliptin. Methods: An open-label, balanced, randomized, two-treatment, two-period, two-sequence crossover study was implemented to investigate the pharmacokinetic bioequivalence of a test and reference tablet products both containing a single dose of sitagliptin 100 mg in 28 healthy volunteers under fasting conditions. A total of twenty blood samples were obtained at pre-dose and multiple time intervals post-dose throughout the 48 hours sampling period. Sitagliptin concentrations were analysed using an LC-MS/MS validated method following a solid phase plasma extraction step. Sitagliptin pharmacokinetic parameters estimated with non-compartmental pharmacokinetic analysis were compared between the test and reference formulations with a multivariate analysis of variance. Results and Discussion: The differences between the reference and test formulations in terms of area under the curve, 0 to infinity (AUC0-inf), AUC0-48, and the maximum concentration (Cmax) were found to be not significant. The 90% confidence intervals of sitagliptin Ln-transformed AUC0-inf, AUC0-48, and Cmax, were within the pharmacokinetic bioequivalence acceptance range of 80%–125%. Conclusion: The test formulation of sitagliptin was bioequivalent in terms of exposure to the reference formulation in healthy volunteers under fasting conditions.
Submitted: 15 September 2022; Revised: 7 November 2022; Accepted: 21 November 2022; Published online first: 5 December 2022
Introduction/Study Objectives
Diabetes mellitus is a multifactorial disease impacting different organ systems [1]. Until 2021, diabetes mellitus has affected 536.6 million people (10.5% of the world’s population between 20–79 years old). These numbers are expected to rise to 783.2 million people (12.1% of the world’s population), leading to severe health and economic burden [2]. Type 2 diabetes mellitus (T2DM) accounted for more than 95% of diabetes mellitus incidents [3]. T2DM is characterized by cells’ resistance to insulin resulting in elevated blood glucose levels [1] and is associated with high morbidity and mortality mainly due to its microvascular and macrovascular complications [4, 5]. T2DM requires effective glycaemic control generally achieved by lifestyle modifications and oral hypoglycaemic agents, which are considered to be the first line, especially when the β cells further deteriorate as the disease progresses with time [1].
Sitagliptin is a potent and selective dipeptidyl-peptidase (DPP-4) inhibitor, listed in 2017 among the top 20 drugs for T2DM treatment [6]. Like other DPP-4 inhibitors, sitagliptin deactivates the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide, which increases and extends the activity of incretin resulting in a glucose-dependent secretion of insulin and inhibition in glucagon [7]. Sitagliptin decreases not only the HbA1c but also the fasting and postprandial glucose [8]. Furthermore, it is safe to be used in combination with other oral hypoglycaemic agents with no additional risk of hypoglycaemia or weight gain [9].
Sitagliptin is absorbed rapidly with a median time to the maximum concentration (Tmax) of 1–4 hours and an elimination half-life (T1/2) of 8–14 hours [10, 11]. The area under the curve (AUC) of sitagliptin was found to increase in a dose-dependent manner in healthy volunteers [11], and its absolute bioavailability was 87% [12, 13]. The metabolism pathways of sitagliptin are mainly through oxidation in the liver via cytochrome P450 (CYP) 3A4 isoenzymes, with a secondary role from CYP2C8 [12]. Sitagliptin is excreted unchanged in urine (87%) and feces (13%) [12, 13]. Furthermore, it undergoes active tubular secretion in the kidney with a renal clearance recorded as 388 mL/min [11], which is why it can be foreseen that the pharmacokinetics of sitagliptin are largely affected by renal function [14]. On the other hand, in the presence of a creatinine clearance between 50 mL/min and 80 mL/min, classified as a mild renal impairment, no dose adjustment is needed because it was not found to have any clinically significant impact on sitagliptin pharmacokinetics [14].
Phase I clinical studies failed to demonstrate the pharmacokinetic interactions between sitagliptin and simvastatin, metformin, oral contraceptives, warfarin, glyburide, or rosiglitazone likely due to the sitagliptin’s lower affinity for CYP3A4, CYP2C8, and CYP2C9 [15–20]. Digoxin AUC(0–24) was found to be increased by 11% and 18% with the administration of 100 mg and 200 mg sitagliptin, respectively [21]. However, it was not likely to be clinically significant [21]. The absence of interactions between 83 concurrently administered medications and sitagliptin was also demonstrated in a population pharmacokinetic model of phase I and phase IIb studies [22].
From a pharmaceutical perspective, the generic formulation can produce equally effective treatments potentially at lower cost, provided that it has identical active pharmaceutical ingredients and a comparable pharmacokinetic profile [23]. This study aimed to evaluate the bioequivalence in terms of exposure of a test formulation with a reference formulation each containing sitagliptin phosphate monohydrate equivalent to 100 mg sitagliptin. The study was conducted in fulfillment of the requirements by the regulatory authorities to market the test formulation.
Methods
Study design
A study design of an open-label, balanced, randomized, two-treatment, two-period, two-sequence crossover in healthy adult human volunteers was employed to evaluate the pharmacokinetic bioequivalence of a two formulation of sitagliptin 100 mg. The two periods were separated by a washout period of five days.
The study was conducted at VerGo Pharma Research Pvt Ltd (Division VerGo Clinicals), Goa, India, in accordance with the Declaration of Helsinki, the International Conference on Harmonization–Good Clinical Practice, and the ASEAN Guideline for the Conduct of Bioequivalence Studies. This study was approved by Aavishkar Ethics Committee (Research ID: 789-18) on 22 June 2020. The study was also registered in the Thai Clinical Trial Registry (TCTR20220621004) on 20 June 2022. Prior to their enrolment in the study, informed consents were obtained from the subjects.
Study population
Recruitment of volunteers was carried out based on the fulfillment of the inclusion criteria of: 1) healthy, assessed by the medical check-up (medical history, basic medical check-up, electrocardiogram (ECG), and laboratory findings (complete blood count, serological tests, biochemical tests, and urine analysis) performed prior to participation; 2) adults aged between 18 yrs and 55 yrs; 3) body mass index (BMI) of 18.5 kg/m2 to 30 kg/m2 with weight not less than 50 kg for males and 45 kg for females; 4) non-pregnant women; 5) non-smokers or smokers with less than ten cigarettes per day; 6) non-alcoholic individuals. Participants taking any prescription medications for the last 14 days or any over-the-counter medication for the last seven days before the initiation of the study; having any allergies or hypersensitivity to sitagliptin, those who consumed grapefruit juice in the 48 hours or caffeinated drinks 24 hours before the initiation of the study, and participants with drug abuse were excluded.
Based on the literature, the maximum intra-subject coefficient of variation (ISCV) in Cmax was found to be 19% [24] and considering a power of at least 80% and a significance level of 5%, the sample size of 28 subjects was considered to be sufficient to establish pharmacokinetic bioequivalence between the formulations considering possible withdrawal and dropouts.
Study products and administration
In the present study, the pharmacokinetic bioequivalence of Fortesia® tablets (containing 100 mg of sitagliptin) manufactured by Duopharma, Malaysia (test formulation) was compared with Januvia® tablets (containing 100 mg of sitagliptin) manufactured by Merck Sharp & Dohme Ltd, England (reference formulation). After overnight fasting of at least 10 hours, volunteers were randomly allocated to take the test or reference products with 240 mL of water. Participants were instructed to remain seated for two hours after receiving the dose of the test or reference products. All participants received standard meals at a fixed schedule during the course of the study.
Sampling
A total of 20 blood samples (4 mL each) were collected from each volunteer at pre-dose and 0.5, 1, 1.3, 1.7, 2, 2.3, 2.7, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 16, 24, 34, and 48 hours post-dose into K2-ethylenediaminetetraacetic acid vacutainers. Centrifugation was then performed at 4,000 revolutions per minute (RPM) for 10 minutes at 10°C. After its separation, plasma was stored in the freezer (-30°C ± 10°C), then transferred to the bioanalytical department of VerGo clinicals, where it was stored in a freezer (-70°C ± 15°C) until the analytical analysis was carried out.
Subject monitoring
Clinical and laboratory investigations were carried out to assess the safety and report any adverse events observed during the study. Vital were monitored at time of check in, before drug administration and at 2 hours, 6 hours, and 11 hours before check out and before each ambulatory sample collection in each period. In each period subject’s blood glucose monitoring was performed before dosing and at 1 hours, 3 hours, and 7 hours (± 30 minutes) after dosing.
Determination of sitagliptin plasma concentrations
Analytical method for estimation of sitagliptin in human plasma was developed and validated using liquid chromatography and tandem mass spectrometry (LC-MS/MS) with positive ion electrospray ionization using selected reactions monitoring (SRM) mode (Shimadzu, Japan). Plasma extraction was performed through the solid-phase extraction method using Strata™-X 33µm polymeric sorbent cartridges. 10 µL of the sample was injected via the autosampler, and separation was done using a HyPURITY C8 column (100 mm × 4.6 mm, i.d.: 5µm) at a temperature of 40°C and a 0.8 mL/min flow rate of the mobile phase consisting of acetonitrile and 0.1% formic acid (70:30, v/v). Sitagliptin and internal standard were monitored at the molecular ion 408.2–412.2 m/z and MS/MS (daughter) 235.1–239.1 m/z. Sitagliptin D4 was used as an internal standard. Analyte quantitation was performed on a triple quadrupole mass spectrometer using atmospheric pressure ionization (API), operated in multiple reaction monitoring (MRM) and positive ion mode. The method was validated in the concentration range of 2.024–800.714 ng/mL with good linearity of r2 equals 0.999. The method achieved a within- and between-day CV% of less than 5.3% and 4.3%, respectively, and an accuracy of 93%–110%. Recovery was 78.2%–83.1% for both the internal standard and the analyte. The lower and upper limits of quantification (LLOQ and ULOQ) were found to be 2.0 ng/mL, and 800.7 ng/mL, respectively.
Pharmacokinetic and statistical analysis
Treatments were allocated to subjects by carrying out randomization using SAS software. To eliminate any bias resulting from the open-label study design, the bioanalytical department performing the bio-analysis was blinded for the identity of reference and test, and the sample analysts were blinded for the randomization schedule. Non-compartmental pharmacokinetic analysis was performed through the Phoenix WinNonlin version 6.3 (Pharsight Corporation, USA) to estimate pharmacokinetic parameters such as the AUC, 0 to infinity (AUC0-inf), AUC, 0 hours to 48 hours (AUC0-48), maximum concentration (Cmax), elimination constant (Ke), Tmax, and T1/2 of the drug. Statistical analysis was performed via SAS software version 9.4 (SAS® Institute Inc., USA, Version 9.4), where multivariate analysis of variance (ANOVA) was carried out on the Ln-transformed pharmacokinetic parameters Cmax, AUC0-48, and AUC0-inf with treatment, period, sequence and subjects nested within the sequence as a fixed effect. The BE of the test formulation with the reference product was assessed based on an alpha value of 0.05, i.e. within a 90% confidence interval (CI).
Results and discussion
The present work investigated the pharmacokinetic bioequivalence of a test product formulation with a reference formulation both containing 100 mg of sitagliptin in 28 healthy volunteers under fasting conditions. One volunteer withdrew before receiving the dose in the first period due to a medical event (nausea followed by one episode of vomiting). Twenty-seven volunteers had completed the study, and their data were included in the analysis. Table 1 summarizes the demographic characteristics of the healthy volunteers with a mean ± standard deviation age of 27.0 ± 5.9 years and BMI of 23.1 ± 2.8 kg/m2. Regarding safety, no serious adverse events were reported during the study. Two volunteers had red blood cells count below the normal range, one of them had elevated aspartate transaminase levels (AST), and another volunteer had increased eosinophils count. The reported adverse events were mild, and they resolved without any sequelae. The adverse events were unlikely due to the investigational product. The elevated AST was rarely reported with sitagliptin use only in a single case in the literature provoked by a possible interaction with the hepatitis B virus [25]. However, multiple reports of the increased eosinophils count were available and were possibly related to the sitagliptin pharmacological effect of DPP-4 inhibition [26, 27].
The crossover study design involved five days washout step between the two periods adequate to account for at least 10 half-lives of sitagliptin to avoid the carryover phenomenon. The pharmacokinetic parameters of the test and reference formulations, i.e. AUC0-48, AUC0-inf, Tmax, Cmax, and T1/2, are summarized in Table 2. Cmax, AUC0-inf, and AUC0-48 values were comparable between the test and reference formulation. Additionally, intrasubject variabilities in AUC0-48 were found to be 16.5% and 19.1%, and AUC0-inf, 16.7% and 19.2%, and Cmax, 24.1% and 27.6%, for the test and reference formulation, respectively. The pharmacokinetic profile found in other pharmacokinetic bioequivalence studies of a single dose of sitagliptin 100 mg or 500 mg tablets alone or in combination with metformin performed in the Asian population in terms of AUC0-inf [28, 29], T1/2 [29-31], and Tmax [32] was comparable with the present results. Similar results in terms of Tmax [33] and Cmax [22] have also been reported in previous pharmacokinetic bioequivalence studies of a single dose of sitagliptin 50 mg [33] and 100 mg [22] tablet in American Hispanic/Latino and non-Hispanic/Latino volunteers. The current results were also in line with ones reported in European volunteers in the original study investigating the pharmacokinetics, pharmacodynamics, safety, and tolerability of single doses of sitagliptin ranging between 1.5 mg and 600 mg [11]].
Figure 1 represents the mean plasma concentration of sitagliptin in the plasma for the test and reference formulations versus the time profiles in 27 healthy volunteers (all below the limit of quantification data points were inserted as zero and were involved in the calculation of means). The median Tmax was comparable between the two formulations based on the current results. The elimination of sitagliptin occurred gradually during the sampling interval of 48-hour. The differences in Cmax, AUC0-inf, or AUC0-48 between the reference and test formulation were found to be not significant based on the multivariate ANOVA statistical analysis. The 90% CIs of the Ln-transformed AUC0-48, AUC0-inf, and Cmax, were 99.2%–103.3%, 99.2%–103.2%, and 95.6%–108.7%, respectively. The two-sided 90% CIs of Ln-transformed AUC0-48, AUC0-inf, and Cmax of sitagliptin were within the pharmacokinetic bioequivalence acceptance range of 80%–125%, according to the ASEAN Guideline for the Conduct of Bioequivalence Studies [34].
The pharmacokinetic profile of sitagliptin found in the current study may represent the Asian population as only Asian participants were included affecting the generalizability of the results in different populations. However, the inter-individual variability was addressed in the randomized crossover study design eliminating its effect on the pharmacokinetic bioequivalence of the study products, i.e. it can be concluded that the pharmacokinetic profiles of test and reference products were similar in terms of absorption, distribution, metabolism, and elimination. The pharmacodynamic bioequivalence was not investigated in the current study and could be a potential topic for future studies in patients as complementary to the exposure term.
Conclusion
The pharmacokinetic bioequivalence of a single dose test product with a reference product, each containing 100 mg sitagliptin under fasting conditions, was confirmed in the present study in terms of AUC0-inf, AUC0-48, and Cmax. The 90% confidence intervals of sitagliptin Ln-transformed AUC0-inf, AUC0-48, and Cmax, were within the pharmacokinetic bioequivalence acceptance range of 80%–125%. The study was in fulfillment of the requirements by the regulatory authorities to market the test formulation.
Funding sources
This work was financially supported by Duopharma Biotech Berhad.
Competing interests: CWL, ES, KMY, MSS, NMZNA, NFS, RB, SA, and AA are employees of Duopharma. RB, RS, and KKV are employees of VerGo Pharma Research.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Chuei Wuei Leong1, PhD Elton Sagim1, BBiomedSc Kar Ming Yee1, BPharm Muhammad Shalhadi Saharuddin1, BSc Nik Mohd Zulhakimi Nik Abdullah1, BSc Noramirah Farhanah Saberi1, BSc Rajavikraman Boopathy1, DipSc Shahnun Ahmad1, MBBS Atiqah Amran1, BSc Raman Batheja2, PhD Rajan Sharma2, MBBS Kiran Kumar Vuppalavanchu2, MPharm
1Duopharma Innovation Sdn Bhd, No. 2, Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, Shah Alam, 40150, Selangor, Darul Ehsan, Malaysia 2VerGo Pharma Research Pvt Ltd (Division VerGo Clinicals), Goa 403110, India
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Author for correspondence: Chuei Wuei Leong, PhD, Formulation and R & D Technologies, Duopharma Innovation Sdn Bhd, No. 2, Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, Shah Alam 40150, Selangor, Darul Ehsan, Malaysia
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