The development of biosimilar products is an area of growing interest in the
global medical community.This article will review current regulatory
recommendations,as well as discuss key considerations for the
early clinical phases of biosimilar development.
Considerations in the early
development of biosimilar products
Edward C.Li 1,*,Richat Abbas 2,Ira A.Jacobs 3and Donghua Yin 4
1Pharmacy Practice,University of New England College of Pharmacy,Portland,ME 04103,USA 2
Clinical Pharmacology,P?zer,Collegeville,PA 19426,USA 3
P?zer Emerging Markets/Established Products Medicines Development Group,P?zer,New York,NY 10017,USA 4
Biotechnology Clinical Development,P?zer,San Diego,CA 92121,USA
The widespread use and patent expiration of many biologics have led to global interest in development of biosimilar products.Because the manufacture of biologics,including biosimilars,is a complex process involving living systems,the development of a biosimilar is more rigorous than the development of a generic small molecule drug.Several regulatory agencies have established or are proposing guidelines that recommend a stepwise process to ensure the ef?cacy and safety of a biosimilar are highly similar to the reference product.This article also explores the early clinical phase of biosimilar development,which is particularly important to resolving any uncertainties that might remain following in vitro and in vivo evaluations and to enable a selective and targeted approach to Phase III clinical ef?cacy and safety investigation.
Introduction
The introduction of targeted biologics has been a major advance for the treatment of diseases and conditions such as cancer (active treatment and supportive care),rheumatoid arthritis,diabetes mellitus and other autoimmune disorders.The rapid emergence of biologics has led to widespread and global use.In 2012,?ve of the top ten global prescription products were biologics [1].Sales of biosimilars,accounting for 0.4%of the global biologics market,are increasing [2].In Europe,by volume,biosimilars make up 12%of the epoetin alfa market,7%of the growth hormone market and 18%of the ?lgrastim market [3].
The patents of some key biologics recently expired,and many more are going off-patent in the coming years.Coupled with current global socioeconomics,ongoing concern regarding patient access to biologics and further technologic innovations,a shift in pharmaceutical product development is occurring,giving rise to the development of biosimilars [1,4].Whereas the active ingredient of a generic drug product is chemically identical to a brand name drug,a biosimilar as a biological product cannot be identical to its reference product.The biosimilar product must be highly similar to an existing biologic branded product with no clinically meaningful differences.
R e v i e w s K E Y N O T E R E V I E W
Edward C.Li ,PharmD,BCOP,is Associate Professor in the Department of Pharmacy Practice at the University of New England (UNE)College of Pharmacy in Portland,Maine,USA.Dr Li maintains a clinical practice in ambulatory oncology at the New England Cancer Specialists in
Scarborough,USA.Dr Li earned his Doctor of Pharmacy degree from the Philadelphia
College
of Pharmacy.He completed a pharmacy practice
residency at the University of Wisconsin Hospital and Clinics in Madison and an oncology pharmacy practice residency at the
University of Maryland School of Pharmacy in Baltimore.Dr Li is a board-certi?ed oncology pharmacist and his research interests include the analysis of practice trends and outcomes research using large claims databases,such as SEER-Medicare data and the Maine All-Payer Claims Database.
Richat Abbas ,PhD,is Clinical
Pharmacology Lead/Director at P?zer,Inc.Dr.Abbas earned his PhD in Pharmaceutics,with focus on Pharmacokinetics (PK)and
Pharmacodynamics (PD),from the Ohio State University.He has more than 20years of pharmaceutical discovery,research and development experience,obtained at research laboratory,biotech,and medium to large international pharmaceutical companies.Dr.Abbas has contributed to the research and
development,and approval of a number of new oncology,CNS,
cardiovascular and metabolism,and biosimilar drugs.He has authored/co-authored over 100peer-reviewed publications,abstracts and
presentations,patents and book chapters.Dr.Abbas’sexpertisesinclude clinical pharmacology study design,implementation,data analysis,PK/PD modeling &simulation,quantitative pharmacology,QTc evaluation,biomarker,drug metabolism/interaction evaluation,biosimilar,
bioanalysis,and clinical studies in support of new drug development,formulation development/product enhancement/maintenance,and management.
Ira A.Jacobs is a fellowship trained surgical oncologist who started P?zer in November 2012as the oncology biosimilars global medical lead.Prior to P?zer,Doctor Jacobs worked as a medical director in oncology global development at Amgen for four years.He led clinical development programs in breast,lung,prostate,and bone
cancers.Prior to transitioning into industry,Dr.Jacobs was a staff surgical oncologist.He received his
BA,MD,and MBA degrees from the George Washington
University.He completed a general surgery residency at Morristown Memorial Hospital in Morristown,New Jersey and a surgical oncology fellowship at the University of Illinois in Chicago.He is the author of more than 25publications and has received numerous awards and honors.He is currently an active member of the American Society of Clinical Oncology,European Society of Medical Oncology,American Society of Hematology,International Association for the Study of Lung Cancer,American Association for Cancer Research,Society of Surgical Oncology,American Society of Breast Surgeons,and American College of Physician Executives.
Donghua Yin ,PhD,is currently a Senior Director of Clinical Pharmacology at Worldwide
Research and Development,P?zer Inc.His research in the
pharmaceutical industry focuses on pharmacokinetics and pharmaco-dynamics,and their applications in the discovery and development of therapeutic agents for oncology and in?ammatory diseases.At P?zer he has been Clinical Pharmacology Lead of multiple clinical development
programs for small molecules,therapeutic proteins,and
therapeutic vaccines.He obtained his Ph.D.in Pharmaceutics from the University of Tennessee Health Science Center in 2000,and conducted postdoctoral research at the Ohio State University.
*Corresponding author :Li,E.C.(eli@https://www.doczj.com/doc/ff1971240.html, )
1359-6446/?2015Published by Elsevier Ltd.https://www.doczj.com/doc/ff1971240.html,/10.1016/j.drudis.2014.12.017
https://www.doczj.com/doc/ff1971240.html,
1
Because the molecules are unlikely to be chemically identical,a biosimilar cannot be considered a generic form of an existing biological product.De?nitions of a biosimilar by regulatory agen-cies,as well as other related terms discussed in this article,are provided in the Glossary [5–7].
In 2005,the European Medicines Agency (EMA)became the ?rst drug regulatory body to develop,approve and publish guidelines for the development of biosimilars [8].The EMA approved the ?rst biosimilar product (somatropin)in April 2006.In 2009,WHO released its own guidelines for biosimilar development,which were based on the EMA principles [9].The FDA released a series of draft guidances from 2012to 2013following authorization under the Biologics Price Competition and Innovation Act subsection of the Patient Protection and Affordable Care Act of 2009[10].Several countries (e.g.Australia,Canada,China,India,Japan,Korea,Mexico,among others)have developed or are developing their own pathways for biosimilar approval based in part on the regula-tory paradigm for biosimilar products outlined by the EMA.As of December 2014,the EMA has approved more than 20biosimilar products,including the ?rst biosimilar monoclonal antibody [11].Although in draft form,the FDA guidances provide comprehen-sive recommendations to sponsors.Until the FDA validates this guidance by approving the ?rst biosimilar via the 351(k)pathway,uncertainties regarding the standards required for biosimilarity could remain.Unlike the EMA,the FDA has the statutory authority to approve biosimilar products as interchangeable.The higher standards required to qualify as interchangeable have not yet been issued by the FDA.In general,the EMA and FDA biosimilar guide-lines are aligned,considering the differing level of maturity of the biosimilar pathways put into place by different legislative bodies worldwide.In general,regulatory guidelines make it evident that development of a biosimilar requires extensive investigation to demonstrate that the proposed biosimilar is highly similar to the reference biological product.
The stepwise development of a biosimilar involves an extensive side-by-side comparison of quality data between the biosimilar and its reference biological product followed by a transition from nonclinical laboratory and animal testing to early clinical devel-opment (Phase I)and ?nally Phase III development in humans to resolve any remaining uncertainty that the biosimilar might not be similar to the reference product.(While there are variations in how they are de?ned,for the purposes of this article,preclinical studies refer to studies conducted in animals,whereas nonclinical studies include all studies not conducted in humans.Therefore,nonclinical studies include preclinical studies,as well as physico-chemical and biological studies.)This article explores the regula-tory guidelines for early clinical development of a biosimilar product,because these guidelines shape the clinical development program,and de?nes key considerations in the early clinical development program.Additional considerations in the early clinical development of a biosimilar also are explored,with sug-gestions to resolve decisions commonly encountered in the early clinical development of a biosimilar.
Overarching goal of the early clinical development program of a biosimilar product
An overarching goal of the biosimilar development program for its sponsor is to receive the same approved labeling as the reference product without having to repeat clinical studies in every licensed indication.This requires evidence gained through the compre-hensive development process of a biosimilar.Although there is no one path to develop a given biosimilar product,regulatory agen-cies have put guidelines in place that recommend an extensive comparability exercise consisting of a rigorous,scienti?c-focused,stepwise development process,with each step building on previ-ous ones (Fig.1)[6,7].Clinical development consists of an early phase (typically considered Phase I)and a late phase (Phase III).Early clinical development includes evaluations of pharmacoki-netics (PK),pharmacodynamics (PD)and safety/immunogenicity in humans.
Regulatory guidelines regarding biosimilars:European Union and USA
The legal pathway for the regulatory approval of biosimilars was ?rst adopted in European Union (EU)legislation in 2004and came into effect in 2005.Based on this,the EMA established the regula-tory pathway in 2005with the release of guideline CHMP/437/04[8].This guideline provided the regulatory framework as a resource for sponsors that ‘may choose to develop a new biological medici-nal product claimed to be ‘similar’to a reference medicinal prod-uct,which has been granted a marketing authorization in the [European]Community’[8].In addition to the 2005guideline,which is undergoing revision,the EMA has released several prod-uct-class-speci?c guidelines (e.g.for low-molecular-weight hepar-ins and monoclonal antibodies).
EMA and FDA biosimilar guidelines
Despite sharing many fundamental points,there are differences between the EMA and FDA biosimilar guidelines that could be important considerations when undertaking the biosimilar development process (Table 1).The FDA can approve both a biosimilar and an interchangeable biosimilar [7].Individual
GLOSSARY
Biosimilar from the European Medicines Agency (EMA)–biological medicinal product that contains a version of the active substance of an already authorized original biological medicine product (reference medicinal product).A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics,biological activity,safety and ef?cacy based on a comprehensive comparability exercise [6].From the US Food and Drug Administration (US FDA)–the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful
differences between the biological product and the reference product in terms of safety,purity and potency of the product [7].Pharmacodynamics the effects of a drug on the body [7].Pharmacokinetics how the body acts on the drug [7].Residual uncertainty properties,information or some other characteristic that remains unclear from previous investigations.
Stepwise approach an iterative process for comparing a biosimilar with a reference biological product.
Totality of evidence an assessment that considers the quantity and quality of evidence to support biosimilarity [7,33].
2
https://www.doczj.com/doc/ff1971240.html,
Reviews KEYNOTE REVIEW
states,however,can pass legislation to regulate interchangeability.Although biosimilars are approved by the EMA,which issues a Pan EU Marketing Authorisation,the EMA is silent on interchange-ability status for this reason and each individual national member state must determine their policy with respect to interchangeabil-ity.For the FDA to approve a biosimilar as interchangeable with the reference product,the sponsor must demonstrate that ‘the risk in terms of safety or diminished ef?cacy of alternating or switching between use of the biological product [biosimilar]and the refer-ence product is not greater than the risk of using the reference product without such alternation or switch’[12,13].
Another,more-data-driven difference is that EMA guidelines emphasize in vitro nonclinical assessment rather than in vivo toxicology studies,which is in keeping with EU Directive 2010/63/EU regarding the protection of animals used for scienti?c purposes [14].The FDA has the ability to waive requirements for in vivo toxicology assessment,but typically does not do so in the absence of suf?cient clinical data.
Among the commonalities of the EMA and FDA guidelines for biosimilar development is to approve biological products for marketing that have established similarity between the proposed biosimilar and reference biological product through extensive comparative assessments.This goal differs from that of generic small molecules,where establishing bioequivalence to the refer-ence product through an exercise comparing bioavailability is suf?cient [6].In establishing similarity between the proposed biosimilar and the reference biological product,it is important to show that the previously demonstrated safety and ef?cacy of the reference biological product also applies to the proposed biosimi-lar [6,7].In general,at least one Phase III clinical ef?cacy and safety trial is required to demonstrate similarity relative to the reference product.However,establishing ef?cacy and safety of the proposed biosimilar are not objectives of the biosimilar development pro-cess [6,7].In limited circumstances,such as for structurally
more simple biological medicinal products,a clinical ef?cacy study might not be necessary if similarity of physicochemical characteristics and biological activity or potency of the proposed biosimilar and the reference product can be convincingly shown and similar ef?cacy and safety can clearly be deduced from these data and comparative PK data.In vitro and/or clinical PD data might be needed for support [6].Although not described by the EMA or FDA,examples of structurally less complex biosimilars might be insulin and heparin.
To establish similarity between the proposed biosimilar and reference biological product,the EMA and FDA require that the stepwise comparability assessment be scienti?cally rigorous.The type and amount of analyses and testing that will be suf?cient to demonstrate biosimilarity will be determined on a product-speci?c basis [7].Each step of the comparability assessment is intended to build on the preceding steps,with each step serving to resolve as much remaining uncertainty as possible regarding similarity be-tween the proposed biosimilar and reference biological product.Consequently,physicochemical and biological characterizations serve as the beginning and foundation of the stepwise approach.Together with the subsequent preclinical studies (in vitro and,if needed,in vivo ),these preceding steps collectively serve to inform the nature and extent of the clinical development program [6,7].Thus,more comprehensive and robust physicochemical,biologi-cal and preclinical investigations provide scienti?c justi?cation for a selective and targeted approach to clinical testing [7].A targeted approach is further supported by resolving the clinical importance of any differences found between the proposed biosimilar and reference biological product early in the stepwise development process.
In the EU and the USA,the reference product is legally de?ned as having been approved or licensed in the respective region using a full complement of safety,quality and ef?cacy data;thus,a biosimilar product cannot serve as a reference product for another
Pharmaco-vigilance
Preclinical studies
Biological characterization
Physicochemical characterization
Phase II/III
Phase I
Effectiveness
Safety
Immuno-genicity
PK, PD
Safety
Immuno-genicity
Clinical studies
Drug Discovery Today
FIGURE 1
Stepwise development of a biosimilar.The stepwise development of a biosimilar involves the ?ve major steps shown:physicochemical characterization,biological characterization,nonclinical studies in animals,clinical studies in humans and postmarketing pharmacovigilance.Early clinical development in humans involves pharmacokinetic (PK)and pharmacodynamic (PD)investigation,as well as safety investigations focusing on immunogenicity.Phase III clinical development involves one or more studies to assess effectiveness and safety in humans relative to the reference biological product.
https://www.doczj.com/doc/ff1971240.html,
3
R e v i e w s K E Y N O T E R E V I E W
proposed biosimilar.To facilitate global development,however,the EU and the USA allow bridging to the respective EU or USA reference product (or a reference product approved or licensed in another region with standards compatible with the International Conference on Harmonization)via comparative analytical and PK data to allow selection of a single comparator to be used in the single global Phase III study and any preceding in vivo toxicology studies [6,7].Comparison to a reference biological product ap-proved or licensed by another regulatory agency with similar scienti?c and regulatory standards (i.e.one that adheres to stan-dards adopted by the International Conference on Harmoniza-tion)is required.Justi?cation for the use of a product approved by
another regulatory agency must be made and supported by data from analytical and/or comparative PK studies [6].Prior to using a product approved by another regulatory agency as a comparator,it might be advisable for the sponsor to consult with the regulatory agency and provide the scienti?c justi?cation for using the select-ed product.
General considerations for clinical development of a biosimilar
Comparative assessments of PK and PD occur in early clinical development,whereas evaluations related to unresolved ef?cacy,safety and immunogenicity issues mainly occur in Phase III
TABLE 1
General guidelines for biosimilar development a
Guideline
Effective date
Purpose or focus
European Medicines Agency
Guidelines on Similar Biological Medicinal Products
October 2005(under revision)
To introduce the concept of similar biological medicinal products;to outline the basic principles to be applied;and to provide applicants with a ‘user guide’,showing where to ?nd relevant scienti?c information in the various Committee for Medicinal Products for Human Use (CHMP)guidelines,to substantiate the claim of similarity [8]
Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance:Non-Clinical and Clinical Issues
June 2006
(under revision)
To outline the nonclinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed.The nonclinical section addresses the pharmaco-toxicological assessment.The clinical section addresses the requirements for pharmacokinetics (PK),pharmacodynamics (PD),ef?cacy studies.The section on clinical safety and pharmacovigilance addresses clinical safety studies as well as the risk
management plan with special emphasis on studying the immunogenicity of the similar biological medicinal product [34]
Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substances:Quality Issues
June 2006
(under revision)
To outline the quality requirements for a biological medicinal product claiming to be similar to another one already marketed.The guideline addresses the requirements regarding manufacturing processes,the comparability exercise for quality,considering the choice of reference product,analytical methods,physicochemical characterization,biological activity,purity and speci?cations of the similar biological medicinal product [35]
Questions and Answers on Biosimilar Medicines (Similar Biological Medicinal Products)
September 2012
Not stated
FDA
Guidance for Industry:Scienti?c Considerations in Demonstrating Biosimilarity to a Reference Product
Draft
To assist sponsors in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for purposes of the submission of a marketing application under section 351(k)of the Public Health Service (PHS)Act [7]
Guidance for Industry:Quality Considerations in Demonstrating Biosimilarity to a Reference Product
Draft
To provide recommendations to applicants on the scienti?c and technical information of the chemistry,manufacturing and controls (CMC)section of a marketing application for a proposed biosimilar product submitted under section 351(k)of the PHS Act [10]
Guidance for Industry:Formal Meetings Between the FDA and Biosimilar Biological Products Sponsors Draft for Applicants
Draft
To provide recommendations to industry on formal meetings between the FDA and biosimilar biological product sponsors or applicants [36]
Guidance for Industry:Biosimilars:Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
Draft
To provide answers to common questions from sponsors interested in developing proposed biosimilar products,biologics license application holders and other interested parties regarding the FDA interpretation of the Biological Price Competition and Innovation Act of 2009[37]
Guidance for Industry:Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
Draft
To assist sponsors with the design and use of clinical pharmacology studies to support a decision that a proposed therapeutic biological product is biosimilar to its reference product [38]
WHO
Guidelines for Evaluation of Similar Biotherapeutic Products (SBPs)
October 2009
To provide globally acceptable principles for licensing biotherapeutic
products that are claimed to be similar to biotherapeutic products of assured quality,safety and ef?cacy that have been licensed based on a full licensing dossier [9]
a
Product-speci?c and other relevant biosimilar guidelines developed by the European Medicines Agency,available at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c .
4
https://www.doczj.com/doc/ff1971240.html,
Reviews KEYNOTE REVIEW
clinical development of a biosimilar(Fig.1)[7,15].Following regulatory approval of a biosimilar(and biologics in general), postmarketing surveillance,particularly to identify rare adverse events,is an important step[7,15].Clinical development must include studies(including PK,PD and assessment of immuno-genicity)suf?cient to demonstrate safety,purity and potency of the proposed biosimilar in appropriate conditions for which the reference product is licensed and for which licensure is sought for the biosimilar[7].In conducting clinical studies,endpoints and study populations are selected that will be clinically relevant and sensitive in detecting clinically meaningful differences[7].
Strategic design of early clinical development of a proposed biosimilar
A strategically designed early clinical development program could allow a selective and targeted approach to the Phase III clinical trial(s)of ef?cacy,safety and immunogenicity.Establishing the PK similarity to a licensed or approved reference product in a sensitive and homogeneous population is the?rst step of the clinical program of a proposed biosimilar.When clinically relevant PD markers are available,comparative assessment of the PD effects between the proposed biosimilar and a reference product can add information for the biosimilarity determination and lead to a more targeted approach to the Phase III clinical program.Evaluation of immune response in the early clinical stage can provide initial immunogenicity data for the proposed biosimilar.It also can facilitate the use of appropriate assays and an optimal study design for the comparative immunogenicity assessment in the Phase III trial.
Approach to resolving remaining uncertainties
Another strategic decision relates to the extent of the uncertain-ties regarding similarity that remain following the nonclinical phase of development.In considering which of these remaining uncertainties to address,the key question for the sponsor of the biosimilar,as well as the regulatory agency,is:how similar is similar enough[16]?If no or minimal differences between the proposed biosimilar and reference product are observed during the physicochemical and in vivo nonclinical investigations,the clinical investigations can follow a targeted approach to address residual uncertainties related to PK,ef?cacy,safety and immuno-genicity.Owing to the species difference,investigation in animals will not adequately address the residual uncertainties related to PK and PD,but it might identify any substantial differences between the proposed biosimilar and the reference product. Regardless of whether differences are observed,the value of ani-mal PK and PD investigations is limited and does not negate the need for the quantitative data derived from PK and PD studies in humans[7].
Similarly,immunogenic assessment in animals is not necessari-ly predictive of immunogenic responses to protein products in humans,because animals can be overly reactive to human protein [7].In addition,animal studies typically involve a small number of animals,thus making it dif?cult to draw conclusions on the comparison of immunogenicity between the proposed biosimilar and a reference product.Despite these limitations,immunogenic-ity assessment in animals adds value during the development of a biosimilar agent.For example,signi?cant differences in the immune response pro?le in inbred strains of mice can indicate
the proposed biosimilar and reference product differ in one or more product attributes not previously identi?ed.If identi?ed,
this information could inform the design of the immunogenicity assessment in humans[7].
The question of‘how similar is similar enough’must be considered in the context of the time and resources needed
to resolve uncertainties.As a general principle,uncertainties remaining after completing early clinical development should
be those that can be resolved only with a Phase III clinical trial
of ef?cacy,safety and immunogenicity.Statistical approaches should be considered when determining the similarity of the proposed biosimilar to the reference product.For example,the biosimilarity index assesses the probability that the observed
signi?cant result from a clinical trial is reproducible[17].It uses
a stepwise process that is robust to the study endpoints, criteria and study designs[18].Scienti?c-and risk-based approaches to resolving uncertainties to an acceptable level
in any given clinical setting are a key principle of the FDA guidances[16].
Targeting the pro?le of the proposed biosimilar product
The pro?le of the reference product and others within the same class,if any,is another consideration in designing early clinical studies.For example,if the PK of the reference product is known to
be different among different subpopulations,conducting the PK similarity study of the proposed biosimilar in a representative but sensitive and homogenous subpopulation will provide a clearer comparison of the intrinsic PK properties for the proposed biosi-
milar and the reference https://www.doczj.com/doc/ff1971240.html,parisons of the interactions
with various factors affecting the PK between the proposed biosi-
milar and the reference product can be further assessed in a larger Phase III trial in the target patient population using a population
PK approach.
Stakeholder perspectives and needs
Increased patient access is a factor stimulating biosimilar devel-opment.A survey conducted by the National Comprehensive Cancer Network(NCCN)found that stakeholders,including physicians,nurses and pharmacists,had a high interest in pre-scribing,dispensing and administering biosimilars[19].This and other surveys have found that stakeholders want to understand
the concepts related to biosimilar development and the regulato-
ry process involved.Currently,this knowledge often is limited [19,20].
Unlike generic small molecules,where adoption by hospitals
is often without formal review by the Pharmacy&Therapeutics Committee,the NCCN survey,which included277participants
in the16th annual NCCN congress(physicians,nurses,phar-macists and other clinicians and nonclinicians from the USA
and around the world),found the majority of respondents would require a review and discussion before using a biosimilar [19].Moreover,two-thirds of respondents indicated informa-
tion about PK was very important and three-quarters indicated Phase III clinical studies directly comparing the safety and
ef?cacy of the biosimilar with the reference product were very important[19].
https://www.doczj.com/doc/ff1971240.html,5
R
e
v
i
e
w
s
K
E
Y
N
O
T
E
R
E
V
I
E
W
Stakeholders are looking for clinical results showing a biosimilar product is highly similar to the reference product without unex-pected side-effects or other complications [19–23].Speci?cally,the need for safety data was shown in the results of a recent European Crohn’s and Colitis Organisation survey of nearly 275members [24].The majority of respondents were aware that biosimilar monoclonal antibodies are not the same molecules as the refer-ence product,with nearly seven of ten citing immunogenicity as their main concern.These considerations must be balanced by the fact that unwanted immunogenicity is a risk with any new biolog-ical product and is not speci?c to biosimilars.In addition,advances in science could mean the methods used to assess immunogenicity by biosimilar sponsors could be more sensitive than those used for the reference product at the time of approval.Early clinical studies provide a means to evaluate not only com-parative PK and PD but also initial assessment of immunogenicity.Interchangeability and automatic substitution also are important considerations to healthcare providers [22],and there is a diversity of opinion regarding how these issues should be addressed.
PK and PD
A study to demonstrate the PK similarity between the proposed biosimilar and the relevant reference product is a key component of the early clinical development of a biosimilar program.The primary objective of this study is to compare the intrinsic PK properties of a proposed biosimilar with the reference product.In the cases when PD markers are available,comparative PD assessment can be added as a study objective.
A key question in designing the PK similarity study is whether to conduct the study in healthy volunteers or patients with the disease that is relevant to the target indication.The choice of the PK study population should take into account factors includ-ing prior clinical experience of the reference product,sensitivity to detect intrinsic differences in PK and variability of PK among the candidate populations.If safety differences compared to the refer-ence biologic are not a concern,healthy subjects generally are preferred for the PK comparability study because this population can be associated with fewer complicating factors that affect PK (e.g.disease status,concomitant medications)than patient popu-lations,thereby representing a relatively homogeneous popula-tion to compare intrinsic PK properties sensitively.The healthy subject population could have a different immune response to the treatment than disease populations,because patients can have altered immune status owing to their disease or the need to receive concomitant immune-modulating medications.In cases where the development of antidrug antibodies can substantially alter the PK and thus affect the PK assessment,conducting the PK comparability study in a less immunogenic population might be desirable.In cases where the safety pro?le of the product does not allow a study in healthy subjects,the PK similarity will need to be assessed in an appropriate patient population in which the disease state is consistent with the indication for which the proposed biosimilar is being developed [25,26].
For the PK comparability study,a parallel design generally is needed when the elimination half-life of the proposed biosimilar is long.A crossover design can be used when the elimination half-life of the biosimilar is short (e.g.fewer than ?ve days),the incidence of immunogenicity is expected to be low or there is
known inter-subject variability in PK with the reference product [7].In a crossover design,subjects are randomized to receive the biosimilar or reference product sequentially during the ?rst treat-ment period followed by the alternative treatment during the second treatment period,with a washout between the two treat-ment periods [27].
The dose and route of administration used in the PK investiga-tion should be those determined to be the most sensitive to detect differences in PK between the proposed biosimilar and the refer-ence product [7].When multiple therapeutic dose levels are used for the reference product,a low dose might be more sensitive than a high dose for detecting differences in the target-mediated dispo-sition involved in the distribution and elimination mechanisms for some biologics [28].If the biosimilar can be administered intravenously and subcutaneously,PK studies using the subcuta-neous route generally are suf?cient because absorption and elimi-nation characteristics can be evaluated [15].
For a single-dose study,key parameters for the PK similarity assessment will include the maximum drug concentration (C max ),area under the concentration–time curve (AUC)from zero to the last time point with measurable concentration (AUC 0–t )and AUC from time zero extrapolated to in?nite time (AUC 0–1).For a multiple-dose study,the key PK parameters will include C max ,AUC within one dose interval (AUC tau )and the trough concentra-tion (C trough )under steady-state conditions [7,15].PK similarity of the proposed biosimilar to the reference product will be estab-lished through bioequivalence testing of the key PK parameters,using prede?ned acceptance criteria [29].When the acceptance criteria of PK similarity are not met,investigations will be needed to determine whether the observed difference is due to study design limitations or to differences in intrinsic PK properties.Additional assessment will be needed to address the residual uncertainty in PK and determine the clinical meaningfulness of the observed difference.
Whenever a clinically relevant PD marker is available in the population selected for the PK comparability study,comparative assessment of the PD effect also can be considered as part of the objectives for the PK similarity study.Investigation of the PD pro?le of a biosimilar can add value to the totality of evidence for demonstrating biosimilarity and reduce the residual uncertain-ties after the early clinical development.When the PD marker is involved in the mechanisms-of-action shared by multiple indica-tions,the PD data could also be used as strong evidence to support the extrapolation across approved indications of the innovator product beyond those selected for the Phase III testing for the proposed biosimilar.Furthermore,the comparative PD data are especially valuable when the PD endpoints are more sensitive than the ef?cacy or safety endpoints of the Phase III trial in detecting small differences between the proposed biosimilar and the refer-ence product.In speci?c cases (e.g.for structurally less complex biosimilars)the EMA and FDA note that addition of comprehen-sive PD data to PK and other investigations that convincingly demonstrate high similarity between the biosimilar and reference product could obviate the need for a comparative Phase III clinical ef?cacy and safety study [6,7].
Key criteria for selection of PD measures include the following:(i)relevance to clinical outcomes;(ii)ability to be assessed after a suf?cient period following dosing with appropriate precision;and
6
https://www.doczj.com/doc/ff1971240.html,
Reviews KEYNOTE REVIEW
(iii)availability of assays with appropriate sensitivity to detect clinically meaningful differences between the proposed biosi-milar and reference product[7,15].Examples might be the hemoglobin level with epoetin alfa or the American College of Rheumatology20%response rate with in?iximab.Although uncommon,the inclusion of PD data where there is an estab-lished association between the PD endpoint and clinical ef?cacy can add support to the determination of similarity and provide added support for a selective and targeted approach to later clinical Phase III safety and ef?cacy studies[7,15].In some cases, sensitive and clinically important PD endpoints or assays are not available.If this occurs,discussion with regulatory agencies might be appropriate.In addition,a combination of markers that assess different domains of activities and are based on sound pharmacologic principles,including dose–concentration sensitivity,can provide suf?cient evidence to assess clinical comparability[7,15].
Clinical safety and immunogenicity
PK and PD studies conducted at the early clinical development stage are not designed to compare the safety and immunogenicity of the proposed biosimilar with the reference product,especially when these studies are not conducted in the therapeutic setting. Nevertheless,the safety and immunogenicity data gathered from these studies are valuable in the context of biosimilarity determi-nation.Observation of a substantial difference in the safety or immunogenicity pro?les could help identify potential product differences,providing information to guide the design and con-duct of the Phase III trials.
The scope of investigations related to clinical safety is depen-dent on residual uncertainty regarding the proposed biosimilar,as well as safety concerns,if any,related to the reference product and its class[7,15].To assess safety,the type,severity and frequency of adverse reactions observed with the proposed biosimilar are com-pared with those observed during the clinical use of the reference product.Safety related to infusion-related reactions and immuno-genicity is an important consideration because of the immuno-genic potential of all biologics and the potential impact of immune responses on safety and ef?cacy[7,15].
For the PK and PD studies conducted in early development,the goals of immunogenicity testing are severalfold.The?rst is to monitor the incidence and severity of human immune response to the treatment,especially if these are the?rst studies of the pro-posed biosimilar being given to humans.Although the sample size of these studies might be limited,they could identify the substan-tial differences,if any,in immunogenicity properties between the products so as to inform the nature and extent of immunogenicity investigation during Phase III clinical development[7,30,31]. Second,information about the presence and magnitude of anti-drug antibodies and neutralizing antibodies will help evaluate if the PK or PD assessment is affected by the development of immune response.It is known that the formation of antidrug antibodies can alter the PK behavior of the drug molecule.Third,the immu-nogenicity assessment in early trials can help evaluate perfor-mance of the immunogenicity assays for analyzing clinical samples,providing valuable data to support the use of adequate assays for testing samples from the comparative immunogenicity assessment in Phase III trials.
The assessment of immunogenicity in early clinical studies can
be conducted using the same assay format and sampling schedule
for the proposed biosimilar and reference product.Assays capable
of sensitively detecting immune responses,even in the presence of circulating drug product,might need to be developed[7].The assay strategy follows a tiered approach of screening,con?rmation
and titer determination.The samples con?rmed as positive for antidrug antibodies are further tested for the neutralizing capacity
of the antibodies[31,32].The immunogenicity assessment end-points in the early clinical trials include antibody titer,time course
of development,persistence,disappearance and association with clinical sequelae[7].
Assessment of the early clinical development program
A?nal task in the early clinical development of a biosimilar product is to determine whether the objectives of the early clinical development program have been achieved and the extent to which uncertainties remain regarding similarity with
the reference product[7].Remaining uncertainties that do
not require a Phase III clinical trial for resolution could be addressed using a targeted approach in further early clinical development.
Summary and concluding remarks
Clinical development of a biosimilar is a stepwise process that includes early clinical investigations in humans.Clinical investi-gation standards needed to demonstrate that a proposed biosimi-
lar is highly similar to the reference biological product are based on guidelines from the EMA and FDA.Although these guidelines share some similarities,there are important differences between them,for example,the statutory ability of the regulatory agency to
de?ne an interchangeable biosimilar,as well as differences in the approach to in vivo clinical data requirements.Furthermore,these guidelines continue to evolve as more biosimilar products are submitted for regulatory approval and considerations associated
with clinical development(such as appropriate compound no-menclature and labeling of biosimilars)are identi?ed.
Strategically designed early clinical studies can address the resid-
ual uncertainty following nonclinical investigations and guide a selective and targeted approach to Phase III clinical trials.For biosimilars,the uncertainties addressed by early clinical studies
are related to PK,PD and,to a lesser degree,safety and immunoge-nicity in humans.The PK comparability assessment should be conducted in a relatively homogeneous population and under sensitive https://www.doczj.com/doc/ff1971240.html,parative PD assessment can add value
to the biosimilarity determination,leading to a targeted approach
in Phase III investigations.Evaluation of safety and immunogenici-
ty as secondary objectives in PK and PD studies can identify sub-stantial differences in the proposed biosimilar and the reference product.The immunogenicity assessment in early-stage studies can
help evaluate adequacy of the immunogenicity assays to be used for sample analysis in Phase III trials.These extensive clinical evalua-
tions in early-phase studies can allow a more targeted Phase III clinical program and approval process for a given biosimilar.
https://www.doczj.com/doc/ff1971240.html,7
R
e
v
i
e
w
s
K
E
Y
N
O
T
E
R
E
V
I
E
W
Con?icts of interest
This supplement was funded by P?zer Inc.Edward C.Li,PharmD,BCOP,was a paid consultant to P?zer for the research and author-ship of this supplement.Richat Abbas,PhD,Ira A.Jacobs,MD,MBA,FACS,and Donghua Yin,PhD,are employees of P?zer.
Medical writing and editorial support to prepare this supplement was provided by Clint Earnheart,PhD,and Jacqueline Egan of QD Healthcare Group.This support was also funded by P?zer.Edward C.Li has the following additional con?icts of interest to disclose:Advisor for Amgen and Hospira.
References
1Lindsley,C.W.(2010)The top prescription drugs of 2012globally:biologics
dominate,but small molecule CNS drugs hold on to top spots.ACS Chem.Neurosci.4,905–907
2Rickwood,S.and Di Biase,S.(2013)IMS Health.Searching for terra ?rma in the biosimilars and non-original biologics market.Insights for the coming decade of change.(https://www.doczj.com/doc/ff1971240.html,/cds/imshealth/Global/Content/Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf ;accessed 23.04.14)
3Biosimilar accessible market:size and biosimilar penetration.IMS Health (http://ec.europa.eu/enterprise/sectors/healthcare/?les/docs/biosimilars_imsstudy_en.pdf ;accessed 23.04.14)
4Calo-Fernandez,B.and Martinez-Hurtado,J.L.(2012)Biosimilars:company strategies to capture value from the biologics market.Pharmaceuticals (Basel)5,1393–14085US Food and Drug Administration (2013)Generic drugs:questions and answers.(https://www.doczj.com/doc/ff1971240.html,/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm100100.htm ;accessed 23.04.14)
Most recent FDA draft guidance for industry:clinical pharmacology data to support a demonstration of biosimilarity to a reference product
The Guidance for Industry:Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product,issued by the FDA in May 2014,is the fifth and latest in a series of draft guidances to industry that the FDA is developing to implement the Biologics Price Competition and Innovation Act of 2009[38].This draft guidance provides additional detail on the use of clinical pharmacology studies to support biosimilarity and focuses on three key concepts [38]:
Exposure and response assessment Evaluation of residual uncertainty
Four tiers relating to analytical quality and similarity (not similar,similar,highly similar and similar with ?ngerprint-like similarity)
The draft guidance describes the value of exposure–response data for pharmacokinetic (PK)assessments or pharmacodynamic (PD)markers in demonstrating no clinically meaningful differences between a proposed biosimilar and a reference biologic [38].As described in previous guidances,biosimilar development uses a stepwise,risk-based comparability exercise to resolve residual uncertainty regarding the similarity between the proposed biosimilar and the reference biologic.In its review of the biosimilar data package,the FDA uses a ‘totality of the evidence analysis’[38].
Although not part of clinical development,the key role of comparative structural and functional studies to inform clinical development is detailed [38].The FDA introduced the concept of four assessments that could result from the comparative analytical characterization:‘not similar’,‘similar’,‘highly similar’and ‘highly similar with fingerprint-like similarity’[38].These tiers relate to analytical similarity.The ultimate goal is to achieve the statutory standard for analytical similarity (highly similar)that allows approval of the product as a biosimilar as per the 351(k)pathway when supported by other appropriate data [38].The greater the level of analytical similarity achieved the more targeted the clinical data package can be [38].The tiers are intended to form a point in time assessment that can change when more data are generated to compensate for residual uncertainty [38].The importance of comparative PK/PD assessments to resolve any residual uncertainty in the analytical similarity is highlighted [38].
Regarding the use of clinical pharmacology studies to support biosimilarity,the importance of using appropriate bioanalytical methods to evaluate the PK and PD properties is emphasized,with considerations given to general assay selection [38].The benefits and limitations of specific assays (i.e.ligand binding,concentration and activity)and considerations for PD assay selection are described [38].
The clinical pharmacology studies should also collect safety and immunogenicity data [38].The assessment of safety and immunogenicity should consider published data regarding the reference biologic including those related to the time-course of the safety signals or immune responses [38].Several other considerations are noted,including the selection between crossover and parallel study designs used to evaluate clinical PK and PD similarity,the requirement to use the US-licensed reference product or establish bridging to the US-licensed reference product and the relevance of specific characteristics of the proposed biosimilar in selecting the study design (study population,dose selection,route of administration)[38].The PK endpoints for the different study design (single-vs multiple-dosing)and different routes of administration (intravenous and subcutaneous routes)also are discussed [38].Extensive information is provided regarding how human PD data can be used to assess the clinically meaningful differences and address the residual uncertainty and the design considerations for the PD assessment (e.g.sampling time points and duration,PD endpoint for comparison)[38].Statistical evaluation of PK and PD results is based on:(i)a criterion to allow the comparison;(ii)a confidence interval for the criterion;and (iii)an acceptable limit [38].
The current draft FDA guidance addresses the use of modeling and simulation tools when designing a PK and/or PD study [38].These tools can be used to analyze publicly available data for the dose–response or exposure–response relationship of the reference biologic,or
information generated by the sponsor using a small PK/PD study,to justify the biosimilar dose used in the study [38].A similarity study with multiple dose levels to compare PK/PD between the proposed biosimilar and the reference product could also be considered when clinical pharmacology evaluation is likely to be the major source of information to assess clinically meaningful differences [38].In addition,modeling and simulation can also be used to define the acceptable limits for PD similarity using publicly available information on biomarker–clinical-endpoint relationships [38].
8
https://www.doczj.com/doc/ff1971240.html,
Reviews KEYNOTE REVIEW
6European Medicines Agency(2013)Guideline on similar biological medicinal products.
(http://www.ema.europa.eu/docs/en_GB/document_library/Scienti?c_guideline/ 2013/05/WC500142978.pdf;accessed23.04.14)
7US Food and Drug Administration(2012)Guidance for industry:scienti?c
considerations in demonstrating biosimilarity to a reference product.(http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM291128.pdf;accessed23.04.14)
8European Medicines Agency(2005)Guideline on similar biological medicinal products.
(http://www.ema.europa.eu/docs/en_GB/document_library/Scienti?c_guideline/ 2009/09/WC500003517.pdf;accessed23.04.14)
9World Health Organization(2009)Guidelines on evaluation of similar biotherapeutic products(SBPs).(http://www.who.int/biologicals/areas/biological_therapeutics/ BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf;accessed23.04.14)
10US Food and Drug Administration(2012)Guidance for industry:quality considerations in demonstrating biosimilarity to a reference protein product.(https://www.doczj.com/doc/ff1971240.html,/ downloads/Drugs/GuidanceComplianceRegulatoryInformatin/Guidances/
UCM291134.pdf;accessed23.04.14)
11European Medicines Agency(2013)European public assessment reports–biosimilars.
(http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_ search.jsp&mid=WC0b01ac058001d124&searchTab=searchByAuthType&keyword =Enter keywords&searchType=name&alreadyLoaded=true&status=Authorised& status=Withdrawn&status=Suspended&status=Refused&jsenabled=false&search GenericType=biosimilars&orderBy=authDate&pageNo=1;accessed12.12.14)
12Patient Protection and Affordable Care Act,42U.S.C.§18001.(https://www.doczj.com/doc/ff1971240.html,/ fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf;accessed08.05.14)
13US Food and Drug Administration(2012)Biosimilars:questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of2009.(http:// https://www.doczj.com/doc/ff1971240.html,/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM273001.pdf;accessed23.04.14)
14European Commission(2010)Directive2010/63/EU of the European Parliament and of the Council of22September2010on the protection of animals used for scienti?c purposes.
(http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/
?uri=CELEX:32010L0063&from=EN;accessed08.05.14)
15European Medicines Agency(2013)Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical issues.(http://www.ema.europa.eu/docs/en_GB/document_library/
Scienti?c_guideline/2013/06/WC500144124.pdf;accessed23.04.14)
16Kozlowski,S.et al.(2011)Developing the nation’s biosimilars program.N.Engl.J.
Med.365,385–388
17Chow,S.C.et al.(2011)Scienti?c factors for assessing biosimilarity and drug interchangeability of follow-on biologics.Biosimilars1,13–26
18Zhang,A.et al.(2013)Statistical considerations in biosimilar assessment using biosimilarity index.J.Bioequiv.Availab.5,209–214
19Zelenetz,A.D.et al.(2011)NCCN Biosimilars White Paper:regulatory,scienti?c, and patient safety https://www.doczj.com/doc/ff1971240.html,w.9(Suppl.4),S1–S22 20Clarkston Consulting(2013)Biosimilars are coming.Are you ready?(http://www.
https://www.doczj.com/doc/ff1971240.html,/wp-content/uploads/2013/06/
Insights_Biosimilars_US20133.pdf;accessed23.04.14)
21Carroll,J.(2013)Europe offers example for approving biosimilars.Manag.Care22,4–5 22Alliance for Safe Biologic Medicine(2012)ASBM biosimilars survey.(http://safebiologics.
org/resources/wp-content/uploads/2012/09/ASBM-Survey-1.pdf;accessed23.04.14) 23BioTrends Research Group(2012)Biosimilars:market access and pricing issues according to surveyed and interviewed payers.(https://www.doczj.com/doc/ff1971240.html,/Articles/
Biosimilars-Payer-Nov-2012;accessed23.04.14)24Danese,S.et al.(2014)Are IBD specialists aware of biosimilar monoclonal antibodies?Results from a survey among ECCO members.9th Congress of
European Crohn’s and Colitis Organization,Copenhagen,Denmark(Abstract
DOP078)
25Fasanmade,A.A.et al.(2009)Population pharmacokinetic analysis of in?iximab in patients with ulcerative colitis.Eur.J.Clin.Pharmacol.65,1211–1228
26Klotz,U.et al.(2007)Clinical pharmacokinetics and use of in?iximab.Clin.
Pharmacokinet.46,645–660
27US Food and Drug Administration(1998)Guidance for industry.E9statistical principles for clinical trials.(https://www.doczj.com/doc/ff1971240.html,/downloads/drugs/
guidancecomplianceregulatoryinformation/guidances/ucm073137.pdf;accessed
23.04.14)
28European Medicines Agency(2012)Guideline on similar biological medicinal products containing monoclonal antibodies–non-clinical and clinical issues.(http://www.ema.
europa.eu/docs/en_GB/document_library/Scienti?c_guideline/2012/06/
WC500128686.pdf;accessed05.12.13)
29McKeage,K.(2014)A review of CT-P13:an in?iximab biosimilar.BioDrugs http:// https://www.doczj.com/doc/ff1971240.html,/10.1007/s40259-014-0094-1
30US Food and Drug Administration(2013)Guidance for industry.Immunogenicity assessment for therapeutic protein products.(https://www.doczj.com/doc/ff1971240.html,/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf;
accessed23.04.14)
31European Medicines Agency(2007)Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins.(http://www.ema.europa.eu/docs/en_GB/
document_library/Scienti?c_guideline/2009/09/WC500003946.pdf;accessed
23.04.14)
32US Food and Drug Administration(2009)Guidance for industry.Assay development for immunogenicity testing of therapeutic proteins.(https://www.doczj.com/doc/ff1971240.html,/downloads/
Drugs/.../Guidances/UCM192750.pdf;accessed23.04.14)
33US Food and Drug Administration(1998)Guidance for industry.
Providing clinical evidence of effectiveness for human drug and biological products.
(https://www.doczj.com/doc/ff1971240.html,/downloads/Drugs/.../Guidances/ucm078749.pdf;accessed
23.04.14)
34European Medicines Agency(2006)Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:non-clinical and clinical
issues.(http://www.ema.europa.eu/docs/en_GB/document_library/
Scienti?c_guideline/2009/09/WC500003920.pdf;accessed23.04.14)
35European Medicines Agency(2006)Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:quality issues.(http://
www.ema.europa.eu/docs/en_GB/document_library/Scienti?c_guideline/2009/09/
WC500003953.pdf;accessed23.04.14)
36US Food and Drug Administration(2013)Guidance for industry.Formal meetings between the FDA and biosimilar biological product sponsors or applicants.(http://www.
https://www.doczj.com/doc/ff1971240.html,/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM345649.pdf;accessed23.04.14)
37US Food and Drug Administration(2012)Guidance for industry.Biosimilars:questions and answers regarding implementation of the Biological Price Competition and Innovation
Act of2009.(https://www.doczj.com/doc/ff1971240.html,/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm259797.htm;accessed23.04.14)
38US Food and Drug Administration(2014)Guidance for industry.Clinical pharmacology data to support a demonstration of biosimilarity to a reference product.(http://www.fda.
gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm397017.pdf;accessed30.05.14)
https://www.doczj.com/doc/ff1971240.html,9
R
e
v
i
e
w
s
K
E
Y
N
O
T
E
R
E
V
I
E
W