Hazel Gorham, PhD

A number of top-selling biological products in key therapeutic areas such as cancer, diabetes, and rheumatoid arthritis have recently lost, or will soon lose, patent protection. IMS Health estimates that $92 billion in global sales of branded drugs and biological products will have lost patent protection between 2011 and 2015.

 This “patent cliff,” together with public healthcare budget cuts, advances in technology for the manufacturing of biologics, and the identification of specific legal and regulatory pathways in many countries for the approval of biosimilars, has fueled the race for the manufacturers of biosimilar products to obtain marketing approval for their products as quickly as possible. 

	Due to their complex structure and manufacturing processes, a biosimilar product is not an identical copy of the original reference product and its similarity to the reference must be demonstrated. The development of a biosimilar shares most of the operational challenges facing that of new chemical entity. However, due to the specific regulatory requirements for demonstrating similarity across all phases, and the lack of understanding of the concept of biosimilarity among stakeholders including physicians and patients, there are a number of unique operational challenges specific for biosimilar development. This article explores some of these challenges and how they can be addressed from the outset with strategic planning.

	As is required of manufacturers of originator or reference products, manufacturers of biosimilars must demonstrate the quality, efficacy, and safety of their product. However, regulatory approval of a biosimilar product is based on a demonstration of its similarity to the previously approved reference product, and not on an independent demonstration of its efficacy, safety, and other characteristics (see Figure 1).

	Demonstration of similarity to the reference product starts at the beginning of development, when the characteristics of the biosimilar product are first established. A key aspect of a direct comparative analysis of the biosimilar to the reference drug is to determine the inherent variability of the reference product’s critical quality attributes (see Figure 2 below),

 including changes in these attributes due to modifications of manufacturing processes (see Figure 3 below).

 The European Medicines Agency (EMA) guideline refers to this as determining the quality target product profile, or QTPP.

	The ranges for each critical quality attribute need to be established when determining the target profile for the biosimilar product. To do this, the manufacturer of the biosimilar must procure multiple batches of the reference product with differing expiry dates. This can be problematic, as originator companies release only a limited number of batches of commercial stock with different expiry dates over a given period of time. Therefore, it is critical that manufacturers of biosimilars take into account the need to acquire these multiple batches over a significant time period, including prior to the start of development and manufacturing activities, and throughout the development process.

	Comparative Phase I pharmacokinetics/pharmacodynamics (PK/PD) studies are an essential part of the biosimilar development program. Bioequivalence studies for biosimilar products are generally large in size due to large intra- and inter-subject variability, and can involve up to hundreds of subjects, depending on the molecule. Obtaining a sufficient quantity of a single batch of the reference product to conduct a large Phase I study can be challenging. Some variability between different batches of the reference drug can be expected (e.g., biological activity, Figure 2); however, such variability could compromise the comparability exercise and as such it is optimal to use only one batch in the PK/PD study.

	If regulatory approval of the biosimilar product requires the conduct of comparative efficacy and safety studies, an even larger quantity of the reference treatment will need to be purchased. Although the use of multiple batches of reference product for these types of studies is acceptable, and even preferable, ensuring a continued supply of the drug is challenging as manufacturers of originator products carefully control the release of commercial supplies. Furthermore, the total cost for purchasing the reference product should also be taken into account, as it can be a significant part of the overall study budget.

	Both the reference drug and the agent under investigation are considered to be investigational medical products (IMPs) in comparative efficacy and safety studies. The release of an IMP by a qualified person and importation of the IMP into many countries may require a certificate of analysis (CoA). Obtaining a CoA for commercial supplies of reference product can prove difficult. In fact, supportive documentation for reference drug purchased from the US will not include a CoA. If a CoA is not available, the biosimilar manufacturer will have to conduct its own analysis of the reference product to produce a CoA, which could have significant impact on timelines and cost.

Phase I pharmacokinetic/pharmacodynamic challenges

	Comparative PK studies are designed to demonstrate similar PK profile of the biosimilar and the reference medicinal product with regard to key PK parameters. The criterion used to compare two treatments with the purpose of evaluating if the 90% confidence interval of the geometric mean ratio of AUC and Cmax between the test and reference fall within 80%-125%.

 The ideal study design to evaluate bioequivalence of two products is a crossover design (two-period, two-treatment crossover design), where the two phases of treatment are separated by a washout period. The washout period should be sufficient to ensure that drug concentrations are below the 

lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally, at least five elimination half-lives are necessary to achieve this.

	The primary advantage of the crossover design is that since the treatments are compared on the same subject, the inter-subject variability does not contribute to the error variability of the study. However, concerning a product with a long half-life-a common characteristic of biosimilar products-a crossover study design would lead to protracted clinical studies. Such lengthy studies are susceptible to high subject dropout rates and increased subject variability, thereby potentially putting the successful outcome of the study at risk. Under such circumstances, regulatory guidance, from both the FDA and the EMA, allow for a parallel study design.

 In a parallel design, although there are no concerns with regard to sequence, period, or carryover effect or dropouts during the study, the inter-subject variability is very high and, hence, the sensitivity of the test considerably reduced. A larger number of subjects compared to a crossover design is, therefore, required to attain the same sensitivity.

	The need for a large number of subjects, within a Phase I study setting, can be a point of concern for an ethics committee (EC). Careful explanation of the concept of biosimilarity, regulatory guidance for biosimilar product development, and justification for the proposed study design should be provided up front to the institutional review board (IRB)/EC to minimize the risk of a rejection of the clinical trial application.

	The recruitment of large number of subjects for a Phase I biosimilar study is particularly challenging. Recruitment of patients from multiple sites can significantly add to the variability of the patient data. Patients, therefore, should be recruited from a single site. 

Phase III safety and efficacy study challenges 

	Efficacy trials of biosimilar medicinal products do not aim at demonstrating efficacy, 

, since this has already been established with the reference product. The aim of the clinical data is to determine that there are no clinically significant differences between the biosimilar and its reference product.

	As for all clinical comparability trial designs, assay sensitivity defined as a “the ability to distinguish an effective treatment form a less effective or ineffective treatment” has to be ensured.

 Assay sensitivity in a non-inferiority or equivalence trial is deduced from two determinations 1) historical evidence of sensitivity to drug effect 2) appropriate trial conduct i.e. trial conduct should also adhere closely to that of the historical trials and should be of high quality. Determining the drug effect size from historical reports and adhering to historical trial design can be problematic.

 Patient treatment is continually evolving and with time, new treatments and regimens are accepted as the standard of care.

	Different regimens are also often used in different countries for the same drug product, a particular challenge for the development of an acceptable global clinical study design. For example, the originator product Neulasta

 (pegfilgrastim) clinical efficacy studies examined the duration of severe neutropenia in breast cancer patients undergoing chemotherapy treatment consisting of doxorubicin and docetaxel (AT).

 However, the standard of care has changed over time with other chemotherapy regimens, and this could lead to issues with ECs and investigators. Defining the effect size can also be challenging without historical data, which, in turn, could result in the study not being powered appropriately unless a placebo arm is included. Additionally, the choice of clinical endpoints, selected on the basis of the sensitivity to detect clinically meaningful differences, may differ from those standardly used on new active substance. This, too, can result  in questions being raised by the EC and later, following marketing approval, the acceptability of the clinical data by prescribing physicians.

	Patient recruitment is the most challenging aspect of the clinical trial process, consuming approximately 30% of the clinical timeline and often leading to trial delays.

 In addition to the usual recruitment demands, biosimilar trials face additional challenges. These include a lack of awareness by investigative sites and patients as to what a biosimilar product is; competition for patients among clinical trials investigating new biological molecules; changes in the standard of care; protocol adherence; and lack of incentives for investigators and patients.

	Education of clinical trial site staff, physicians, and patients is critical to the recruitment of subjects into biosimilar trials. An Industry Standard Research report

 examining ways to improve recruitment into biosimilar studies, addresses a number of recommendations on how to interact and communicate with prospective participants. It also describes potential strategies for enhancing patient recruitment. The report emphasizes the importance of patient education regarding the potential value of biosimilars, including evidence that biosimilars can provide affordable alternatives to more costly, branded therapies, thereby increasing access to treatments that would otherwise be beyond the financial means of many patients.

Competition against new biological molecules

	Competition for patient populations is fierce. As of Jan. 11, 2016, there are 55 Phase III studies listed on 

 actively recruiting for adult patients with rheumatoid arthritis. Of those, one is investigating biosimilar products. Although not all of the remaining 54 studies are investigating new biological molecules, these numbers help illustrate the level of competition for patients within a single indication. 

	Familiarity with the reference product and/or product treatment and local practices can lead to intersite variation of study procedures and possible protocol deviations. Site support with regard to protocol training and supportive protocol study aids is key to obtaining quality data in biosimilar studies.

Incentives for investigators and patients

	There can be a lack of incentive for investigators regarding participation in clinical trials for biosimilar products, when compared to studies involving new biological molecules. Comparative efficacy and safety studies for biosimilars are often perceived by investigators as having little scientific interest or as lacking novel or interesting study designs. Patients may also not see any advantage to participating in a biosimilar study as they may have access to the reference product as part of their standard of care.

	As described earlier, key to overcoming this issue is the education of the site staff, physicians, and patients about the potential value of biosimilars. In some cases, patient recruitment can be accelerated by conducting the studies in countries and markets with the greatest unmet clinical need. Although the quality of research can be very high in these countries, experience in the use of the reference product may be limited. Site support, therefore, remains critical to the success of the clinical study.

	Biosimilar development programs face a number of unique operational challenges associated with the guiding principle of establishing similarity between the biosimilar and the reference product. As more and more branded biologics lose patent protection, the race to launch biosimilar products will intensify as manufacturers compete to be among the first to establish their position in a rapidly evolving marketplace. Careful strategic planning and understanding of the operational challenges are crucial to minimize the impact of these issues and to assure the successful development and approval of a biosimilar product.

PhD, is Director, Biosimilars Development, Scientific Affairs, at PRA Health Sciences, email: 

, is Executive Director, Biosimilars Development, Scientific Affairs, at PRA Health Sciences, email: 

	1. IMS Institute for Healthcare Informatics Report. (2011) “The Use of Medicines in the United States: Review of 2010.” 

https://www.imshealth.com/files/web/IMSH%20Institute/Reports/	The%20Use%20of%20Medicines%20in%20the%20United%20States%202010/	Use_of_Meds_in_the_U.S._Review_of_2010.pdf

	2. Brockmeyer C. and Binocrit A.S. (2009) “Assessment of Quality, Safety and Efficacy of Biopharmaceuticals.” 

	3. Schneider C.K. (2013) “Biosimilars in Rheumatology: The Wind of Change.” Annals of the Rheumatic Diseases, 272(3), pp. 315-317.

	4. Schiestl M., Stangler T., Torella C., et al. (2011) “Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals.” 

	5. European Medicines Agency. (October 2014). Guideline on Similar Biological Medicinal Products. (CHMP/437/04 Rev 1), 

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/	2014/10/WC500176768.pdf

	6. European Medicines Agency. (May 2014) Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues (Revision 1). (EMA/CHMP/BWP/247713/2012), 

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline	/2014/06/WC500167838.pdf

	7. European Medicines Agency. (January 2010) Guideline on the Investigation of Bioequivalence. (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) 

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/	2010/01/WC500070039.pdf

	8. Food and Drug Administration. (May 2014) draft 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

	9. European Medicines Agency. (20 January 2010) Guideline on the Investigation of Bioequivalence. (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) 

	10. International Conference on Harmonisation (ICH) topic E10. (January 2001) Note for guidance on choice of control group in clinical trials (CPMP/ICH/364/96) 

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/	2009/09/WC500002925.pdf

	11. Neulasta: EPAR-Scientific Discussion (June 19 2009 

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000420/WC500025941.pdf

	12. Industry Standard Research (ISR) Report. (2012)  Improving Patient Recruitment in Biosimilar Trials,

http://www.isrreports.com/product/improving-patient-recruitment-in-biosimilar-trials

Articles

Using strategic planning to address hurdles in biosimilar development programs from the outset.

Operational Challenges for Biosimilar Studies

. The EMA development and approval pathway for biosimilars: A stepwise approach to demonstration of biosimilarity between a biosimilar and the originator reference product.

An example of batch-to-batch variability in biological activity for a biologic drug substance: In-vivo biological activity of 20 consecutive batches of Binocrit.

 Comparison of a different pre- and post-change batches of rituxan/mabthera.

 The ideal study design to evaluate bioequivalence of two products is a crossover design (two-period, two-treatment crossover design), where the two phases of treatment are separated by a washout period. The washout period should be sufficient to ensure that drug concentrations are below the lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally, at least five elimination half-lives are necessary to achieve this.

	The primary advantage of the crossover design is that since the treatments are compared on the same subject, the inter-subject variability does not contribute to the error variability of the study. However, concerning a product with a long half-life-a common characteristic of biosimilar products-a crossover study design would lead to protracted clinical studies. Such lengthy studies are susceptible to high subject dropout rates and increased subject variability, thereby potentially putting the successful outcome of the study at risk. Under such circumstances, regulatory guidance, from both the FDA and the European Medicines Agency (EMA), allow for a parallel study design.

 However, the standard of care has changed over time with other chemotherapy regimens, and this could lead to issues with ECs and investigators. Defining the effect size can also be challenging without historical data, which, in turn, could result in the study not being powered appropriately unless a placebo arm is included. Additionally, the choice of clinical endpoints, selected on the basis of the sensitivity to detect clinically meaningful differences, may differ from those standardly used on new active substance-again resulting in questions being raised by the EC and later, following marketing approval, the acceptability of the clinical data by prescribing physicians.

 In addition to the usual recruitment demands, biosimilar trials face additional challenges. These include a lack of awareness by investigative sites and patients as to what a biosimilar product is; competition for patients among clinical trials investigating new biological molecules; changes in the standard of care; protocol adherence; and lack of incentives for investigators and patients.

	3. Schneider C.K. (2013) “Biosimilars in Rheumatology: The Wind of Change.” 

A number of top-selling biological products in key therapeutic areas such as cancer, diabetes, and rheumatoid arthritis have recently lost, or will soon lose, patent protection.