Bracing for Biosimilars

Kuyler Doyle, Principal Consultant, Campbell Alliance Tony Lanzone, Vice President, Managed Markets Practice Fahti Khosrow-Shahi, Senior Vice President, Brand Management Practice

Introduction
Could generics finally be coming to the biotechnology sector? Amendments proposing pathways for regulatory approval of follow-on-biologics have passed committees in both the House of Representatives and Senate and are currently up for consideration as part of healthcare reform legislation. However, complexities related to the production of biologics will make the approval and commercialization of follow-on biologics a very different process than that used with small molecule generics. A handful of follow-on biologics are already offered in European and American markets, but have yet to cause significant brand erosion. Despite ongoing regulatory and commercial uncertainties, Big Pharma and small molecule generics companies have been making strategic moves to enter into the biosimilar arena. This article will examine the current movement toward an abbreviated approval pathway for followon biologics in the US and will assess the potential impact on current biotechnology products. In addition, the article will provide some insight into what commercial and reimbursement decision makers for biotechnology companies should be doing to prepare for the arrival of biosimilars.

Biosimilars vs. Small Molecule Generics

Many of the worlds largest pharmaceutical companies got their start as chemical companies, utilizing advances in the separation and synthesis of chemicals to create products for medicinal purposes. Modern day production of small molecule drugs occurs through a chemical process that allows the compound to be manufactured relatively inexpensively in large-scale batches while remaining pure. Since small molecule drugs are manufactured through a chemical process and can be structurally replicated, they lend themselves to be made into generic drugs by other companies after patent expiry.

The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) established a process to allow generic drug manufacturers to pursue an abbreviated New Drug Application (ANDA) process, while providing market exclusivity incentives for innovator pharmaceutical companies to continue research and development in pursuit of new therapeutics. The Federal Food, Drug, and Cosmetic Act (FDCA) was amended to allow regulatory approval of generics in the absence of clinical trials if the company can demonstrate a conserved chemical structure and bioequivalence, typically through small bioavailability studies (section 505(j)). With modern DNA technology, the drug industry has seen a shift from the classical small molecule drug toward an increased use of the biologic. Biologics can be hundreds of times the size of small molecules and of increased complexity. These products, frequently proteins, are produced via living cells and must be purified in a process that is more costly than that used for small molecules. Cells used to produce the protein can be mammalian in origin or from bacteria, yeast, plant, or even 1

insect cells. As synthesis occurs through a biologic process and requires separation of the active drug from crude cellular material, the end product is never completely pure and there can be variation between productions. Protein products are also typically more susceptible to degradation than small molecules, which can lead to further variations. Through naturally occurring processes inside the cell, proteins are frequently modified after production, including the addition of sugars through glycosylation. The choice of cells for use in manufacturing of the biologic can have major effects on if and where sugars are added to the protein. Not only do changes in cells affect the sugars, but even subtle changes to growth conditions in a conserved expression system can influence glycosylation patterns. Glycosylation modifications to a biologic drug hold the potential to impact the efficacy and safety of the drug. Differences in sugar placement on a protein can alter how a protein folds, what it binds, stability, biological activity, pharmacokinetics, and whether it is recognized as foreign by the immune system.

Bracing for Biosimilars

Changes to manufacturing processes inherently create changes in the structures of the more complex biologic drugs. Biotechnology companies must conduct testing when they alter their production capacity or process, and the FDA takes this seriously. The FDAs scrutiny is well exemplified in the recent saga of Genzymes Myozyme. Following efforts to scale up batches of the drug with a larger bioreactor, the FDA noted differences in product glycosylation and required Genzyme to submit a new BLA for the product under a different brand name (now Lumizyme), delaying market entry. This demonstrates how closely a biologic product can be linked to the process of producing it. Antibody therapeutics add further difficulty to the biosimilar issue since they are highly glycosylated and structurally complex, with multiple features that impact clinical outcomes. Although a biosimilar antibody would need to remain the same at the basic sequence level, differences in production might

lead to process-related impurities or glycosylation alterations that could vary the structure and alter clinical safety and efficacy. Because of the uncertainties surrounding what analyses are necessary to convincingly demonstrate biosimilarity and what differences might be allowable, the EMEA is still developing specific guidelines for approving antibody therapies. Meanwhile, Dr. Reddys Laboratories already markets Reditux in India as a biosimilar replacement therapy for Roches MabThera (Rituxan in US from Genentech/Biogen Idec). Although small and relatively simple proteins may be easier to replicate than larger ones, differences in production platform, conditions, and equipment can all lead to variations in product. Therefore, follow-on biologics will rarely be identical to the innovator product. This is why these drugs have been given the moniker of biosimilar and many avoid the biogeneric designation altogether. Follow-on biologics can be considered analogous to small molecule

generics, but are difficult to prove as exactly the same as originator product. As such, the regulatory authorization of follow-on biologics cannot follow the precedent set by small molecule generics.

Complexities of a Follow-on Biologic Regulatory Pathway

A drug manufacturer can currently seek market approval for a follow-on biologic through existing regulatory channels after patent expiration, although there is currently no abbreviated pathway established in the US that parallels that of small molecules. Earlier this year, several bipartisan bills went before Congress in an attempt to put one in place, including the Promoting Innovation and Access to Life Saving Medicine Act (H.R. 1427, Waxman-Pallone-Deal-Emerson) in front of the House of Representatives (with a Senate companion bill S. 726 sponsored by Schumer, Collins, Brown, and

Table 1 Comparative Look at Select Key Components of Biosimilars Legislation Proposed in Healthcare Reform
Select Key Component Affordable Health Care for Americans Act (H.R. 3962)
12 years data exclusivity for new biologic 6 month extension possible with pediatric indication

EMEA Biosimilar Guidelines

10 years for new biologic (8 years data exclusivity, 2 year market exclusivity) 1 year extension for new indication EMEA cannot guarantee biosimilar is interchangeable Substitution is determined on a national basis Potential to retain nonproprietary name Based upon molecular characteristics and determined by World Health Organization (WHO)

FDCA Section 505 (from Hatch-Waxman Act)

5 years data exclusivity for new chemical entity 6 month extension possible for pediatric indication

Exclusivity

Interchangeability

FDA determines

Interchangeable

Nonproprietary Name

Follow-on biologic receives distinct name

Generic retains nonproprietary name of originator product

Clinical Trials

Needed unless FDA deems not necessary

Efficacy and safety comparability study against originator required

Not required bioequivalence data sufficient

Immunogenicity Testing

Needed unless FDA deems not necessary

Needed for each indication

Not required

Table 2 EMEA-Approved Biosimilars

Product Class
Human Growth Hormone (HGH / Somatotropin)

Originator Product
Pfizer Genotropin Lily Humatrope

Company: Product
Sandoz: Omnitrope

Nonproprietary Name

somatropin Biopartners: Valtropin

Erythropoietin (EPO / Epoetin)

Sandoz: Binocrit Medice Arzneimittel Ptter: Abseamed Sandoz: Epoetin alfa HEXAL J&J Eprex Hospira Enterprises: Retacrit Stada Arzneimittel AG: Silapo

epoetin alfa

epoetin zeta

Granulocyte ColonyStimulating Factor (G-CSF / filgrastim)

Amgen Neupogen

Ratiopharm GmbH: Ratiograstim, Filgrastim ratiopharm CT Arzneimittel GmbH: Biograstim Teva Generics GmbH: Tevagrastim Sandoz: Zarzio None on market: three applications withdrawn from Marvel LifeSciences

filgrastim

Insulin

Lily Humulin Products

human insulin

Martinez), and the Pathway for Biosimilars Act (H.R. 1548, Eshoo-Inslee-Barton). Disparities in the bills demonstrated disagreements on some key components. One primary difference between the bills was the amount of data exclusivity time given to an innovator company that markets a new biologic drug. Data exclusivity prohibits the use of the innovators completed safety and efficacy studies from being used to reduce the number of trials needed for an abbreviated biosimilar application. As data exclusivity has the potential to outlast patent protection and ensures a baseline time period to recoup its investment before biosimilar competition, this is an area of key interest to biotechnology companies. The Waxman bill proposed five years of base data exclusivity for a new biologic, with possible six-month extensions for pediatric or additional indications. The Eshoo bill provided a base of 12 years of data exclusivity for a new biologic, and two more years for an additional indication and a potential to extend six months with a pediatric indication. Biotechnology companies and the Biotechnology Industry Organization (BIO) feel strongly that longer

exclusivity times are critical to cover the high costs of development failures and to keep the innovative process churning. Conversely, the Federal Trade Commission issued a report in which they found no need for twelve- to fourteen-year market exclusivities, citing that patent protection, market-based pricing, and likely slow brand erosion in the follow-on biologic market should suffice in recouping investments for development and commercialization of new products. The Obama administration provided their opinion that seven years would be a fair compromise. Drug interchangeability is another pressing issue with regard to follow-on biologics. Both proposed bills allowed the FDA to determine if the biosimilar is interchangeable with the branded product. This point will help determine whether a pharmacy will be able to switch to the biosimilar without consent of the physician or patient, which could impact branded sales. Contributing to this debate, the Waxman bill allowed the biosimilar to maintain the nonproprietary pharmaceutical nomenclature while the Eshoo bills called for all follow-on biologics to have a distinct name due to inherent differences. The Eshoo bill sought to identify and distinguish the 3

biosimilar from the branded product, in addition to any future follow-on biologics of the same classification. Use of a different nonproprietary name could complicate the ability for the pharmacy to easily interchange products without patient consent. Another point of contention was in regards to the hurdles needed to demonstrate biosimilarity. The Waxman bill provided the FDA with the authority to determine whether there is a need for clinical studies to test a biosimilar, while the Eshoo bill required clinical trials but allows the FDA to waive them if deemed unnecessary. In addition, the Eshoo bill required immunogenicity testing to ensure that any differences in glycosylation do not cause an immune response that could be harmful to the patient. Groups like BIO claim that stringent testing would help ensure the safety of the patients, while generic advocates claim these are merely stall tactics to keep a biosimilar off the market. Safety concerns for changes to biologics are not unfounded. Slight variations in formulation to Johnson & Johnsons recombinant erythropoietin (EPO) drug Eprex in 1998 led a small percent of chronic kidney disease patients to lose their immunological toler-

Bracing for Biosimilars

Table 3 Recent Pharmaceutical and Generic Company Acquisitions of Technology Platforms and Products for Biologics
Pharma Company Acquisition / Partner
Glycofi

Platform / Product
Engineered yeast strains that can enhance production of therapeutically active biologics through control of protein glycosylation Discovery of antibodies for therapeutics and diagnostics Follow-on biologic pipeline and manufacturing facility Albumin technology that allows biologics to remain longer in body, requiring fewer injections and maintaining a steady dose Injectable generics technology Chinese company specializing in R&D and manufacturing of biologics Joint venture to develop, manufacture, and market biosimilars Biologic pipeline Antibody therapeutics Antibody therapeutics Biologic and vaccine product portfolio and pipeline Biologics manufacturing plant Biotechnology drug discovery and optimization technology (from Haptogen) Biologic pipeline for neurologic disorders Technology platform for developing longer acting biologics and a diabetes drug pipeline New platform technology for targeted biologics and a cancer drug

Merck

Abmaxis Insmed

CoGenesys Sicor

Teva
Tianjin Hualida Lonza MedImmune

AstraZeneca
Cambridge

GSK

Domantis

Wyeth

Pfizer

Rinat Biorexis

Bristol-Myers Squibb

Adnexus Therapeutics

ance, resulting in antibodies against EPO. Antibody production neutralized the effects of the drug and the patients own EPO, leading to the development of pure red cell aplasia (PRCA), a condition characterized by resistance to therapy and absence of red blood cell precursors in the bone marrow leading to severe anemia. This example highlights how small changes to biologics could impact both safety and efficacy. As healthcare reform discussion proceeded in committee hearings, greater support for the amendments swayed towards the 12 year exclusivity. An amendment with language largely taken from a previous bill sponsored by Ted Kennedy passed

the Senate Health, Education, Labor and Pensions (HELP) committee (Hatch-Enzi-Hagan amendment) by a 16 to 7 vote. Eshoo altered her bill to reflect that of the Senate, passing the House Committee on Energy and Commerce 47 to 11. This amendment made it into the Affordable Health Care for Americans Act (H.R. 3962; key biosimilar provisions in Table 1) that passed the House, and the Senate has adopted largely similar language for their healthcare reform bill, although the issue of nonproprietary nomenclature is not addressed. However, some members of Congress and the Generic Pharmaceutical Association remain vocally opposed to the current language. With disparate opinions on the incentives needed to spur 4

innovation while allowing biosimilar competition that could reduce costs, it remains to be seen what the final legislation might include.

Biosimilar Impact on European Markets

The EMEA has an established abbreviated regulatory pathway for biosimilars and the first product hit the market in Europe in 2006, with several additional products following soon after (Table 2). To gain approvals for biosimilars, simply demonstrating bioequivalence was determined insufficient. The

EMEA requires clinical trials, including comparability studies to the originator product, to demonstrate safety and efficacy. The manufacturer must also demonstrate comparable immunogenicity. Guidelines were established to provide further details on specific needs for demonstrating biosimilarity for four primary product classes. This was instituted due to the differences in complexity of the molecules and history of safety issues, such as the PRCA associated with EPO. More complex product classes with a record of side effects require more stringent demonstration of safety. In many European countries, pharmacists automatically dispense the generic form of the branded product that the physician has prescribed. However, the EMEA has made clear that a biosimilar is not the same as a generic drug and handed the interchangeability issue over to individual countries, most of which do not allow this practice. Some countries, including large markets France and Spain, have gone so far as to pass legislation that outlaws automatic substitution of biosimilars for the originator products. The physician must now provide explicit instruction on which product to use, or the pharmacist must call the physician for consent to switch, even when the nonproprietary name is the same. Clearly this places the onus back upon the physician and requires the physician be well versed in product differences. Thus far, two human growth hormone (HGH) products, five erythropoietins (EPO), and four granulocyte colony-stimulating factor (G-CSF) biosimilars are on the market in the EU (Table 2). The EMEA has denied the market approval application for two products from BioPartners, Alpheon and Biferonex, biosimilar versions of interferons alfa-2a and beta-1a, respectively. Of note is that the nonproprietary name for erythropoietin biosimilars Retacrit (marketed by Hospira) and Silapo (Stada) were not allowed to match that of the originator product epoietin alfa (Table 2), demonstrating the potential challenge to biosimilar companies pursuing drug interchangeability. The launch of biosimilars in the EU has yet to have a major impact on market shares of existing drugs. Sandoz HGH biosimilar Omnitrope has only grabbed a small piece of the market despite its branded competitors having raised prices, and even with additional launches of Omnitrope in convenient pen devices. Although it did not gain regulatory approval through the abbreviated pathway, Shires discounted EPO product Dynepo never gained

significant market share and the company recently discontinued marketing the drug. The limited success is largely due to the fact that branded products have been entrenched in the market for years with positive results while there is some apprehension to biosimilars as they are new and without a track record of safety and effectiveness in practice. Further, the relatively modest discounts of 25-30% have not been enough incentive for patients and physicians to switch products, making it difficult for biosimilars to gain significant market share. Despite relatively minor market penetration as a whole, Germany may be seen as the early adopter due to extreme pricing pressures leading to biosimilar acceptance by the Federal Healthcare Committee. Erythropoietin biosimilars in Germany have steadily increased market share and led to a reduction in branded product prices and loss of sales. The increasing acceptance of biosimilars in Germany likely demonstrates future trends in Europe, where countries will bow to pricing pressures of biologics and will shift toward biosimilars once the safety and effectiveness profiles of early marketed products are better demonstrated. A reversal of interchangeability restrictions could have a profound impact on future sales of branded products.

in between. With the increasing likelihood of a regulatory pathway becoming a reality in the near future, these companies have been establishing their presence in the biosimilar space through the creation of subsidiaries, partnering, or acquisition of companies. Novartis Sandoz has been a pioneer in the field and has biosimilar offerings already on the market. Merck and generic company Teva have each made bold acquisition and partnering moves to be major players in the field. These follow-on biologics companies are actively developing products to be at the front line when given the nod of approval from the FDA. With predictions that future drugs will be dominated by biotechnology products, entering into the biologics realm is a sound strategy for pharmaceutical companies. Investment in platform technologies could allow companies to develop follow-on biologic drugs in ways that are quicker and less costly than the aging methods developed by innovator companies, allowing less expensive manufacturing that could allow price reductions while maintaining margins. Developing biosimilars also allows pharmaceutical companies to enter the biologics space while pursuing targets with proven markets and mechanisms of action. Many of the companies entering into the biologics arena are not merely looking to copy existing products once they go off patent. Marketers at these companies realize that patients and physicians may be entrenched with existing products and difficult to convert through modest discounts. Instead, some companies are looking to use their platform technologies to develop biobetter drugs that actually provide advantages over well-characterized existing products. Clearly, biosimilars and biobetter products being marketed by experienced pharmaceutical companies have the potential to significantly threaten the bottom lines of biotechnology companies.

Interest in Biosimilars from Big Pharma

Due to inherent challenges, the demands for launching follow-on biologic drugs are beyond those required for small molecule generics. The need for a sizeable property, plant, and equipment investment and know-how in intellectual property law, clinical development, regulatory interactions, manufacturing, and marketing, requires deep pockets and extensive experience to bring a biosimilar to market. Although several large generic companies are trendsetters in pursuit of biosimilar opportunities, the increased demands for financial backing as well as development and promotion expertise in the burgeoning market have recently led to a follow-on biologic shopping spree from Big Pharma. With an eye toward biologics due to shifting industry trends, many of the largest pharmaceutical and generic drug companies have been acquiring biotechnology platform technologies over the last few years (Table 3). In doing so, pharmaceutical companies have gained valuable intellectual property for platforms to create biologic drugs, whether they are novel, follow-on, or somewhere 5

Potential Impact of Follow-on Biologics on US Markets

Many global companies have biosimilar development programs underway (Table 4), and several are waiting to enter the US market. Sandoz tested the waters for biosimilar acceptance in the US with its introduction of Omnitrope in 2007, approved under a 505(b)(2) abbreviated approval pathway for new drugs similar to previously approved products. The FDA determined that this pathway was acceptable

Bracing for Biosimilars

Table 4 Representative Biosimilar Companies and Product Focus

Company
Teva / Sicor / Barr (Teva world HQ in Israel)

HGH
DEV

EPO
DEV DEV MKT

G-CSF
MKT DEV DEV DEV

Insulin
DEV

Interferon
DEV DEV

Hep B SK; tPA* Vaccine

mAb

Other

North America

Merck BioVentures Hospira Maxygen Cangene (Canada) Sandoz

MKT MKT

DEV (CTLA4-Ig)

DEV MKT DEV MKT DEV MKT

Europe

Ratipharm / BiogeneriX Stada / Bioceuticals Bioton / BioPartners Biocon Dr. Reddys Laboratories Ranbaxy
MKT, DEV

DEV MKT DEV MKT MKT MKT MKT MKT MKT MKT MKT MKT DEV DEV

MKT MKT, DEV

DEV MKT (SK) MKT (Rituximab) DEV

India

Wockhardt Shantha Biotech Intas Biopharmaceuticals Reliance Life SciGen (Singapore HQ, offices globally)
MKT

MKT, DEV MKT MKT MKT MKT MKT MKT (SK); DEV (tPA)

MKT MKT DEV

MKT

MKT

East Asia

Nippon Chemical Reseach (Japan) LG Life Sciences (Korea) 3SBio (China)

MKT MKT MKT

MKT MKT

MKT MKT MKT (IL-2)

MKT: Product(s) on Market (includes less regulated markets than US, EU) DEV: Product (s) in Development Note: List is representative and not complete. Development programs are not published by many companies. *SK streptokinase; tPA = tissue plasminogen activator China has many biotechnology companies, most of which produce biosimilars

since Human Growth Hormone (HGH) is a relatively simple, non-glycosylated protein. The application included supporting clinical data, but the FDA still only ruled on its approval after a lawsuit forced them to make a decision. Since then, Omnitrope has captured only 1% of the market. Cangenes HGH product Accretropin also recently received US approval and will be interesting to monitor as the market crowds. The Omnitrope example demonstrates that follow-on biologics may face similar early challenges in the US as have been seen with their introduction in the EU. Several factors have the potential to inhibit a rapid uptake of early follow-on biologics in the US. Since the process of manufacturing biologics is relatively expensive, there is less room for cutting costs that would enable companies to sell them at greatly discounted prices. Thus, price reductions will not be as extreme as those found with small molecule generics and competition will be more akin to brandbrand than brand-generic. Physicians and patients who are comfortable with the proven safety and effectiveness of the branded biologic will likely be slow to switch to the biosimilar if the price differential is not substantial.

Although a discount of 10-30% from branded biologics may not be a large motivating factor for physicians and patients, this is a significant sum to payers. Payers will take a quick interest in follow-on biologics as the discounts would add up to meaningful differences in their bottom lines. Payers will likely structure their formularies to create incentives for biosimilar prescribing behavior, such as greater out of pocket expenses for branded products, and may attempt to force mandatory substitution. A complicating factor to this strategy is that most biotechnology drugs are provided in the physician office or hospital setting, averting the retail pharmacy that would substitute the products. In addition, the current Medicare Part B structure provides a higher reimbursement rate to physicians for more expensive drugs, creating another reason to resist biosimilar prescription (although lawmakers are aware of this loophole and have proposed legislation to neutralize this factor). Omnitrope has demonstrated that follow-on biologic entry into US markets will likely not be rapid or easy. Physicians and patients will likely hold onto their reliable branded products in the short term. How-

ever, payer pressure may erode this loyalty with time, once safety and efficacy have been proven and financial incentives established. Further, the marketing machinery from familiar drug companies pursuing biosimilar markets may sway consumers to put more trust in their products. Without an abbreviated approval process in place, Teva recently filed a BLA for its biosimilar version of Amgens Neupogen. Clearly, biosimilars are poised to be a legitimate player in the US and global markets, and biotechnology companies will need to plan product lifecycle strategies that adjust to the new landscape.

How to Prepare
The earliest biologics on the market are those under the most immediate threat. Companies marketing those products must systematically identify actions they can take to brace for the increase of followon biologic competitors (Table 5). Although some markets may be difficult for biosimilars to penetrate initially, updates to brand strategies will require thorough assessments of the competitive landscape, in-depth scenario planning, and new revenue forecasts that incorporate the emerging threats. Traditional lifecycle management tools can be employed in response to follow-on biologics, including pricing, product improvements, and authorized biosimilars. Biotechnology companies will need to explore pricing and contracting strategies that could minimize loss of market share while maximizing sales. New technologies to improve manufacturing and cut costs can be explored to help with pricing, although pursuing new processes will not always be worth the investment of equipment and bioequivalence studies. Organizations can also work to improve or expand the product line, either through second generation products with enhanced formulation or by development of a novel delivery system. One potential roadblock to this strategy is the threat of biobetter follow-on biologics that may also pursue a competitive advantage. Alternatively, a company may also help create an authorized biosimilar by licensing their technology to the manufacturer, thereby maintaining revenue that will help offset some of the lost market share. Reverse payment settlements to follow-on biologic companies that delay market entry may not be a viable option, as their legality remains questionable and the House of Representatives included language (Rush amendment) in its health reform bill to ban the practice.

Table 5 Preparing for Biosimilars

Area to Address Description
Pricing strategies Manufacturing improvements to cut costs Second generation product Novel delivery system Authorized biosimilar Medical Affairs to describe underlying scientific differences with follow-on biologics Marketing campaign detailing years of safety and effectiveness Contract for rebates with branded use Update value dossier and highlight risks that could offset follow-on biologic discounts Pursue extensive patent protection for early-stage technologies Carefully guard trade secrets that could differentiate branded product from follow-on in the future

Life Cycle Management

Physician and Patient Education

Payer Communication

Intellectual Property

Bracing for Biosimilars

Payer engagement will be critical to prepare for market entry of follow-on biologics. Product strategies related to the payer-specific value proposition and contracting will need to be revisited. The value proposition will need to be updated to fully inform payers of potential differences between biosimilars and their branded products. Cost effectiveness of the branded product will need to be highlighted, including details regarding proven health outcome benefits of the drug. Prices for the branded product will need to be justified with data demonstrating proven results. Rebate contracting for use of the branded product will also need to be carefully examined. Key payer accounts with broad market reach and influence for the indication should be approached for contracting in order to help maintain market share. In order to make informed treatment decisions, healthcare professionals will be searching for means to gain a thorough understanding of the issues

surrounding use of biosimilars rather than branded biologics. Medical Affairs teams will have the opportunity to educate physicians and key opinion leaders on the underlying scientific differences with follow-on biologics that could potentially alter safety and efficacy. Traditional marketing campaigns can also be launched detailing the many years that the drug has effectively treated many patients. These programs should focus on the differentiation of the branded product from the biosimilar. For products in early stage development, the threat of biosimilars is long-term. However, biotechnology companies should be planning strategically now through use of intellectual property protection. Not only should patents be pursued for composition of matter, method of use, formulation, and methods of manufacture, but trade secrets regarding manufacturing procedures that could potentially help differentiate the innovator product from a biosimilar should also be carefully guarded.

Conclusion
Follow-on biologics are on their way to the US. With the momentum for healthcare reform, it is only a matter of time until the legislation to support an abbreviated regulatory pathway is passed. As demonstrated in Europe, biosimilars will not have a straightforward path to immediate market success. However, with experienced pharmaceutical companies jumping into the game, competition will soon be a reality. Now is the time for biotechnology companies to develop strategies to prepare for the coming wave of biosimilars in order to maintain the commercial successes of their branded products. For questions or comments, contact: Fahti Khosrow-Shahi at fkhosrow@campbellalliance.com Telephone: (919) 844-7100 Toll Free: (888) 297-2001 www.campbellalliance.com

www.campbellalliance.com (888) 297-2001

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