Definition of Biosimilar

Biosimilars can be thought of as generic versions of biologics. Unlike generic versions of traditional medicines, which can be shown to be chemically identical to brand versions in chemical structure, generic versions of biologics can never be shown to be as identical to brand versions of the same biologic. This is due to the complexity of biologics‟ molecular structures, proprietary manufacturing processes including originating cell cultures, and uncertain responses in real life use. Regulatory agencies developed terms to describe these generic versions of biologics as being very similar, but not exactly the same as the brand version.

The US Food and Drug Administration (FDA) define biosimilarity as: “a biological product highly similar to the reference product notwithstanding minor differences in clinically inactive components;” and with “no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product.”¹⁶ Other regulatory agencies use the terms

“follow-on biologics” or “subsequent entry biologics” to generally refer to the same

“biosimilar” products, emphasizing the common characteristic of these products as imitators of the originator product.

For the remainder of this paper, the terms biosimilar(s), biosimilar drug(s), biosimilar product(s) will be used interchangeably to refer to imitator versions of originator biologic products.

9 2.4 Literature Review

This study is motivated by other comparative studies that analyze biosimilar regulations across the globe.^1,2,3 Ricardo Ibarra-Cabrera et. al., 2013 conducts a world-wide comparison on biosimilar regulations highlighting European Medicines Agency (EMA) product-specific guidelines and special focus on laws in Mexico forming the basis of the country‟s “biocomparables‟ regulations.¹ While Abreu et. al., 2014 also describe global biosimilar regulations, special focus in their study is on the information requirements of regulators to address uncertainty in outcomes from biosimilars in comparison to the originator biologic.² Knezevic and Griffiths, 2011 highlight WHO‟s role in developing recommendations for biosimilar regulations and the opportunity for global and regional cooperation in setting standards for licensing biosimilars.³

Other studies were found to be helpful in comparing national drug

reimbursement agencies and policies across major developed economies.^4,5,6 Cohen, Malins, and Shahpurwala, 2013 describe how national health insurer‟s reviews of comparative-effectiveness and cost-effectiveness evidence can lead to lower drug prices in comparison to the US which does not conduct such reviews at a national level.⁴ O‟Donnell et. al., 2009 also describes in detail national bodies conducting health technology assessments (HTA) and some challenges they face such as arguments on rationing health care.⁵ Barnieh et. al., 2014 similarly describes national bodies (in OECD countries) that administer restrictive formularies as an approach to manage drug expenditures.⁶ This thesis applies many of results from these three studies to the

biologics or biosimilars drug classes. A similar approach was taken by Rovira et. al., 2011 and Declerck and Simoens, 2012 which were identified for linking biosimilar regulations and reimbursement policies in comparisons of European Union member states.^7,8

10

In the analysis of corporate strategies of pharmaceutical companies, Wilkie, Johnson, and White, 2012 was cited for empirically testing relationships between brand name defense strategies against generic competition in traditional, small-molecule pharmaceuticals.¹⁷ Rothaermel, 2001 describes strategic alliances between large pharmaceutical companies and smaller biotech companies in the early development of biologics.¹⁸

In developing hypothesis for incumbent biologic manufacturer‟s corporate strategy, in response to potential biosimilar competition, Porter, 1979 motivates the view that corporate strategy can be viewed in part as a response to competitive forces in the market.¹⁹ An important addition to this view of competition comes from Ellison and Snyder, 2010 who propose a theory of countervailing power where the effectiveness of reimbursement policy in obtaining pricing concessions from suppliers depends on the size and market power of payers, as well as the degree of competition between

suppliers.²⁰ Lastly, the time dimension of corporate strategy is viewed by Ramaprasad and Stone, 1992 as event-based, where time is measured relative to a series of important events that may pose a threat or opportunity for the company.²¹ Applying this event-based view of strategy to patent-holding biologic pharmaceutical companies, the short- or long-term time horizon of their strategy can be measured by the time required to prepare new pharmaceuticals for market and the temporary lifetime of their patents.

11

Chapter 3: Regulation of Biosimilars. Comparison of FDA, EMA, and PDMA

3.1 Introduction

This section discusses the regulation of biosimilar drugs in the US, Europe, and Japan. The primary focus is the market licensing process established by these markets‟

main pharmaceutical regulatory agencies: the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japan‟s Pharmaceutical and Medical Devices Agency (PMDA). These agencies directly influence the US$590 billion pharmaceutical markets over which they have jurisdiction;⁹ the regulations from these agencies are also closely followed by regulatory agencies of other countries around the world.

This section will first introduce the three regulatory agencies. The approaches these agencies take with respect to generic drugs is briefly described, along with the challenges posed by the new class of biologic drugs. Each regulatory agency‟s approach to biosimilars is then discussed in further detail. This section concludes with the main observations found in comparing the three agencies.

3.2 Regulatory Mandate of FDA, EMA, and PDMA

The FDA is responsible for ensuring that drugs, vaccines and other biological products and medical devices are safe and effective.²² The FDA also has a goal of advancing public health by supporting product innovations. The formal step in which the FDA is asked to consider approving new drugs is called the New Drug Application (NDA). The NDA includes all animal and human data, and information about how the drug behaves in the body and its manufacturing process.²³ The Prescription Drug User Fee Act (PDUFA) gives the FDA the authority to collect user fees for NDA submitted to the FDA‟s drug review agency, the Center for Drug Evaluation and Research

12

(CDER), and the biological product review agency, the Center for Biologics Evaluation and Research (CBER). With this fee-collecting authority, the CDER and CBER are required to meet certain performance metrics related to the review of new drug applications.²⁴

The EMA‟s main responsibility is the protection and promotion of public health through evaluation and supervision of medicines.²⁵ The EMA acts as the centralised review body, responsible for providing an opinion to the European Commission on whether the medicine should be marketed or not. The European Commission then provides the centralised marketing authorisation for European Union (EU) states. EMA reviews and European Commission marketing authorisations are compulsory for the following categories of medicines:

 human medicines for the treatment of HIV/AIDS, cancer, diabetes,

neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases;

 medicines derived from biotechnology processes, such as genetic engineering;

 advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines;

 officially designated 'orphan medicines' (medicines used for rare human

diseases).²⁶

The PMDA is responsible for protecting public health by assuring safety, efficacy and quality of pharmaceuticals and medical devices.²⁷ Similar to the EMA, the PMDA provides a review report to Japan‟s Ministry of Health, Labour and Welfare which has final authority for whether the applicant drug can be marketed in Japan. The

13

PMDA‟s drug reviews encompass all new drugs, generic drugs, over-the-counter drugs, and quasi-drugs.²⁸

All three agencies have a role in providing pre-submission guidance and consultations (when the drugs may be in various stages of clinical trials), as well as post-market pharmacovigilance, where drugs are monitored in the community setting for adverse events.^28,29,30

3.3 Regulation of Traditional Generic Drugs and the Challenge of Biosimilars Generic drugs, in principle, contain the same amount of the same active ingredient and have the same indications, dosage, and administration, and the same route of administration as those of its brand-name reference drug.²⁸ Recognizing the potential welfare gains from having price competition in the generics market, the US government passed the Hatch-Waxman Act in 1984, establishing the Abbreviated New Drug Application (ANDA) which expedited the FDA approval process of generic drugs.³¹ After the establishment of ANDA, applicants no longer needed to conduct clinical trials of the generic drug to demonstrate safety and efficacy. The main evidence required from applicants is proof of bioequivalence to the brand-name reference drug;

that is, the generic version delivers the same amount of active ingredients into a patient‟s bloodstream in the same amount of time as the brand-name drug.

Currently the FDA, EMA, and PDMA share a similar abbreviated approval process for generic drugs, in which the main evidence requirements are bioequivalence studies.^28,32,33 The safety and efficacy studies conducted for the brand-name drug can be used to demonstrate safety and efficacy of bioequivalent generic drugs. The agencies still regulate quality and manufacturing processes to the same standards as brand-name

14

drugs; also, the applications are only to be submitted after the brand-name drug loses patent protection.

The emergence of complex, large-molecule, biologic drugs in the 1990s and 2000s presents a challenge to the relatively straightforward regulatory treatment of traditional generic drugs. Biologics are made in living organisms to produce proteins to treat diseases, often by genetically modifying cell constructs or cell lines.³⁴ The

manufacturing process for biologics is highly complex, involving several factors that make it difficult for competing firms to produce copies of the brand-name biologic drug, even after the drug‟s patent has expired:

 Biologic manufacturers have their own master cell bank producing

unique cell lines replicated for manufacturing, often under a proprietary process;

 The physical and clinical properties of the medicine are sensitive to small

variations during the manufacturing process. Small changes to the properties of biologic medicines can cause serious harm to a patient by way of unwanted immune responses;

 Production requires a high level of monitoring and quality testing:

typically around 250 in-process tests for biologics compared to around 50 tests for traditional small-molecule medicines.³⁵

Due to the nature of the manufacturing process of biologic drugs, copies of biologic drugs produced by unrelated manufacturers will not be bioequivalent to the reference product. Regulatory agencies needed to develop special regulations for these biosimilar drugs, as the minimum standard of bioequivalence used for traditional generic drugs could not be used to evaluate marketing approvals for this class of medicine. At the same time, the safety and efficacy of biosimilars are still a high

15

concern for regulators because small variations in the biologic product can have a significant impact on the safety and efficacy profile of the drug.

The next three subsections describe the biosimilar regulations developed specifically for the US FDA, EMA, and Japan PDMA.

3.4 Regulation of Biosimilars by the US FDA

The US FDA‟s regulatory pathway for biosimilar approvals are the result of amendments to the Public Health Service Act (PHS Act) introduced by the Patient Protection and Affordable Care Act, signed into law in 2010. The amendments as part of the Biologics Price Competition and Innovation Act (BPCI Act) create an

abbreviated licensure pathway for biological products that are demonstrated to be

“biosimilar” to or “interchangeable” with an FDA-licensed biological product (section 351(k) in PHS Act).³⁶ To date, no biosimilars have been approved for market under this abbreviated pathway; however, numerous biosimilars are in various stages of

investigation prior to final submission of the 351(k) application for FDA‟s right-to-market decision.³⁷

The 351(k) application includes information demonstrating that the applicant product is:

 Biosimilar to a reference product that is licensed for sales in the US;

 Utilizes the same mechanism of action for the proposed conditions of use, only to the extent known for the reference product;

 Conditions of use proposed in labeling have been approved for the reference product;

 Has the same route of administration, dosage form, and strength as the reference product.³⁶

16

The main criteria for approval under the abbreviated pathway - biosimilarity - is defined to mean “that 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”.³⁶ The sponsor must include information demonstrating biosimilarity including data from analytical studies, animal studies, and one or more clinical studies. The FDA can determine at its

discretion whether certain studies are not necessary for demonstrating biosimilarity.

Market approval with the higher standard of comparability to the reference product - interchangeability - allows the biosimilar to be substituted for the reference product without the intervention of the prescribing healthcare provider. In order to meet the standard of interchangeability, the applicant must provide sufficient information to demonstrate biosimilarity, and also to demonstrate that the product can be expected to produce the same clinical result as the reference product in any given patient.

Furthermore, if the product is switched with the reference product, the risk in terms of safety or diminished efficacy is no greater than the risk of using the reference product without such switch.³⁶ The higher evidence requirements for a biosimilar to be approved as an interchangeable product underscore the greater uncertainty inherent in using biosimilars for the same line of treatment. However, the interchangeable label is necessary for biosimilars greater acceptance in the market vis-à-vis the brand-name reference biologic.

FDA‟s biosimilar regulation also specifies the exclusivity period for the first-to-be licensed reference biologic product (12 years) during which biosimilars referencing the product may not be approved for market. The reference biologic also has a initial 4-year exclusivity period during which biosimilars may not submit the 351(k)

17

application.³⁵ Similar to the FDA‟s first-to-market generic exclusivity period, there will be an exclusivity period for the first interchangeable biologic, during which subsequent biosimilars may not be determined to be interchangeable. The length of this exclusivity period may vary depending on the date of first marketing and patent litigation

milestones.³⁷

The following diagram shows the main features of FDA‟s biosimilar regulation under the BPCI Act‟s abbreviated licensing process:

Figure 3.1: Main Features of US FDA Biosimilars Regulation

3.5 Regulation of Biosimilars by the EMA

The European agency has the longest history of biosimilar regulation, with the current overarching guidelines for biosimilar reviews being in effect since October 2005.

As the early leader of biosimilar regulations, the EMA‟s guidelines are influential for other non-European countries‟ adoption of biosimilar market license regulations. The EMA‟s overarching guidelines set the basic principles for evaluating „similar biological medicinal products‟ based on comparability studies with a licensed reference product, as opposed to bioavailability studies used for traditional generic drugs. The biosimilar

18

must have the same pharmaceutical form, strength, and route of administration as the reference product, with any differences justified by additional studies on a case-by-case basis.³⁸

An important distinction between EMA‟s advice and the FDA is the EMA does not give advice on whether a biosimilar is interchangeable/substitutable with the reference product.³⁹ Individual member states must make the decision on

interchangeability of the biosimilar because it touches on the regulations of professional practice among health care providers, which is the jurisdiction of the member states.

The EMA‟s guidelines recognize that that acceptance of a biosimilar product, as being a „similar biological medicinal product,‟ will depend on technology of the

analytical procedures, the manufacturing process, and clinical and regulatory

experiences.³⁸ Each of these factors will evolve over time and vary across the spectrum of biologics. The EMA guidelines, therefore, specify product-class specific guidance which is made over time.

To date, the EMA has published product-class guidance for 9 classes of biologics. Overarching evidence requirements are also listed, while the specific requirements are published within the product-class guidance forms. Table 3.1 below shows classes of biologic drugs for which the EMA has published class specific guidelines:

19

Table 3.1: Biologic Product Classes Covered by EMA Guidelines for Biosimilars

Documents can be downloaded at EMA‟s webpage for scientific guidelines on biosimilars.⁴⁰

An example of different standards for evidence for different classes of biologics is the extrapolation of indications, which describes cases when studies on a biosimilar in use for one indication can be used to determine biosimilarity of the drug in use for a different indication. For example, in the Extrapolation of indications section in the guidelines for interferon beta, the EMA states that:

Extrapolation of clinical efficacy and safety in confirmed RRMS (relapsing-remitting multiple sclerosis) to the other indications of the reference medicinal product in MS is possible on the basis of the totality of the evidence provided from the comparability exercise. (Ref# CHMP/BMWP/652000/20100, Pg 8)⁴⁰

Product Class Effective Date Topics Covered in

Guidelines Biosimilars containing recombinant

follicle-stimulating hormone September 2013

Biosimilars containing interferon beta September 2013 • Non-clinical studies (in vitro, in vivo, toxicological) Biosimilars containing monoclonal

October 2009 (effective revision date to be determined)

Biosimilars containing recombinant

interferon alpha April 2009 • Extrapolation of indications

Biosimilars containing recombinant human insulin and insulin analogues

June 2006 (effective revision

date to be determined) • Pharmacovigilance plan

Biosimilars containing somatropin June 2006

Biosimilars containing recombinant

granulocyte-colony stimulating factor June 2006

• Clinical studies (pharmacokinetics, pharmacodynamics, clinical efficacy, clinical safety)

20

The EMA‟s guidance for interferon beta biosimilars does not require specific studies for proving biosimilarity with the reference product used in other indications of MS. On the other hand, in guidance for monoclonal antibodies (mAb) biosimilars, which have indications for wider array of diseases, EMA‟s guidance lists a number of cases where further studies are required to extrapolate to different indications, including challenges faced when the mAb is licensed both as an immunomodulator and as an anticancer antibody (Ref#EMA/CHMP/BMWP/403543/2010).⁴⁰ In such cases, the EMA may require separate studies demonstrating comparability for the different indications rather than an extrapolation of the data.

EMA‟s biosimilar review process allows submissions of applications at earliest 8 years after the reference biologic received its initial marketing authorisation through the centrally-licensed process (licensed by European Commission) or by any individual member state.⁴¹ This period of „data-exclusivity‟ is longer than the 4 year period

specified by FDA regulation.

3.6 Regulation of Biosimilars by the Japan PDMA

Japan‟s Ministry of Health, Labour and Welfare issued guidelines for PMDA review of biosimilars in March 2009. Since this date, two biosimilar products have been approved in Japan: Somatropin BS s.c. and Epoetin alfa BS.⁴² Although the two

products were submitted to PDMA before 2009 in the same pathway as new biologics, they both experienced shorter review times as a result of the new biosimilar guidelines.

The PDMA guidelines refer to biosimilars as “follow-on” biologics, developed to be comparable in quality, safety, and efficacy to and existing biologic approved for sale in Japan. The PDMA approach to evaluating follow-on biologics is generally the same as the EMA, whereby the evidence that the applicant provides demonstrates

21

comparability with the reference product in terms of quality, safety and efficacy. Any differences in quality should be demonstrated with existing information to have no

comparability with the reference product in terms of quality, safety and efficacy. Any differences in quality should be demonstrated with existing information to have no