Safety Concerns Related to Global Biosimilars Drug Development
An initial unfortunate experience in the late 1990s served as an alert to the inherent risks of making apparently small changes to a biological product. The changes by the manufacturer to the formulation of erythropoietin, marketed as Eprex (epoetin alpha), resulted indirectly in the induction of an immune response, which manifested as a dramatic increase in the frequency of cases of pure red cell aplasia,1 requiring some patients to have blood transfusions and dialysis.2 Subsequently, the problem was resolved, but this salutary lesson may have has contributed to the rigorous approach of the European Medicines Agency (EMA) to establishing the similarity of both the structure and activity of biosimilars to those of the innovator or reference product.3 It is recognized that stringent pharmacovigilance procedures are required to detect potential differences in safety signals between biosimilars and their reference products.4
Historically, European and Canadian regulatory authorities have taken global leadership roles in biosimilar drug development.5 For example, EMA published test procedures and acceptance criteria for biological products in 1999.6 Demonstration of biosimilarity was restricted not only to physicochemical properties, but also required comparison of potency using pharmacodynamic (PD) endpoints and measures of efficacy and safety in patients with those of a reference product. A thorough investigation of immunogenicity was critical to address safety implications associated with changes in manufacturing. Although this early guidance addressed some of the critical concerns associated with biologic products, the first EMA general guideline on biosimilar products was not published until 2004.7
As of April 2014, biosimilars have been on the market for eight years with 300 million patient days, according to Paul Greenland of Hospira, chair of the European Generic medicines Association (EGA) European Biosimilars Group (EBG) Biosimilars Market Access (EBG-MAG).8 They are being used in the EU, Canada, Japan and Australia, and have the potential to improve health outcomes while minimizing costs to patients and global healthcare systems.9 There is a potential for price discounts of 10–51% over reference product prices.10
In the 10 years since the first EMA general guideline was published, no untoward safety effects have been reported to discourage global biosimilar development. Following the draft guidelines, published in 2012,11 the US Food and Drug Administration (FDA) issued a new draft guidance, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product12 in May 2014,which is one of several under development to establish a clear biosimilar pathway. However, as of June 2014, no biosimilars have been approved in the US via the 351(k) pathway, identified as the key biosimilar route to market approval in 2010. According to IMS, the delay in the availability of biosimilars in the US is resulting in forecasted demand for specialty medications—the often costly, complex medications prescribed in chronic care settings—continuing to increase at a double-digit pace until the end of this decade.13 The US regulatory situation is further complicated by state legislation on biosimilar substitution; in 2013, 28 bills were introduced in 18 states, and five were enacted in Florida, North Dakota, Oregon, Utah and Virginia.14
In 2009, the World Health Organization (WHO) published biosimilar guidelines based on those of EMA, and now influences biosimilar regulatory frameworks worldwide.15 Barbara Milani and Sara Gaspani of Médecins Sans Frontières (Doctors Without Borders) recently called for increased input from international bodies such as WHO; they proposed an extension to the WHO prequalification system for biologic/biosimilar drugs that previously improved access to generic antiretroviral medicines for HIV treatment. Milani and Gaspani assert this approach, would give emerging countries access to safe and effective pegylated interferon alpha and other essential biological medicines.16
Currently, the global biosimilars market includes monoclonal antibody (mAb) biosimilars, insulins, interferons, erythropoietins, filgrastim, somatropin and follicle-stimulating hormone. Of these, the mAb and insulin markets are forecast to record the highest growth rates. These two segments are expected to represent 46% of the global biosimilars market by 2018, when many leading brands will have lost their patents.17
As a result of pending patent expiries, wide variation in the sophistication of different market regulations and varying access to biological products, the biosimilar clinical trial industry is booming.18 Reports vary, but the number of biosimilar candidates in the global pipeline appears to be around 900 (see BII figure of 916),19 but has been reported to be as low as 305 if only trials in the clinic are counted.20 Only 28 clinical trials involving the search term “biosimilars” are listed on clinicaltrials.gov.21
Based on the authors’ experience in evaluating investments in biosimilars and portfolios of biosimilars and writing clinical developing plans, five major scenarios could result in untoward safety signals––such as immunogenicity––during biosimilar drug development and marketing. An untoward safety event could lead the entire biosimilar industry to pause and thus delay the availability of cheaper copies of biologic medicines for patients around the world.
Scenario 1: Marketing Approvals Based on Small Clinical Trials
Recent news reports suggest favorable government regulation will help allow greater access to products destined for biosimilar status.22 However, disparity among the global regulatory agencies remains. While the US appears to be taking an ultra-conservative approach, with largely non-prescriptive regulatory guidance issued in 2012 and 2014 and each biosimilar sponsor being handled individually by FDA, other countries are forging ahead, sometimes with more limited safety dossiers.23
Sponsors of biosimilar products argue, on the one hand, overly restrictive regulatory requirements stifle innovation and advancement, and on the other, too lax a clinical trial environment may result in an untoward safety outcome.
Taking India as an example, Mylan’s Herceptin biosimilar recently was approved in that country based on data from just 132 patients,24 while Mylan also is conducting a 600-patient Phase 3 trial in Europe25 that will be used for other global submissions. The difference in the number of patients required for different safety databases could reflect the confidence different regulators place in each safety dossier, but smaller numbers of patients from which to judge overall safety may mean the ultimate proving ground for safety, including immunogenicity, could be the global marketplace.
Scenario 2: Outsourcing Manufacturing
Even with advanced analytical methods, biologic products remain difficult to make. Recognizing this fact and the significant capital required to conduct clinical trials to assess safety and biosimilarity (IMS estimates biosimilar trials cost $20—100 million (US) excluding manufacturing costs26), many biopharmaceutical companies have partnered with chemical or manufacturing companies to obtain expertise, share risk or obtain additional sources of capital. In addition, not all manufacturing facilities are created equal. In the authors’ experience, there is a variance between International Conference on Harmonisation (ICH) countries and those that have not yet achieved ICH harmonization.
Since many of the largest companies have grown through acquisitions, the supply chain may not be optimized. For example, biologic manufacturing may involve multiple stages, each occurring at a different site or in a different country. In such cases, the propensity for variation increases and may result in unacceptable inconsistency between batches.
Scenario 3: Pressure for Speed to Market
Speed to market remains a key concern for all biosimilar product manufacturers, given the intense pressure to cut the cost of biologic medications, rapid increases in global competition for patients to participate in clinical trials and approaching patent expiries.
Although there are multiple possible routes to biosimilar approval, depending on a biologic’s complexity and mechanism of action (MoA), the general Western paradigm is to conduct a Phase 1 trial to obtain safety and bioequivalence data, then conduct at least one Phase 3 trial prior to filing for registration. That having been said, the authors have seen some companies begin Phase 3 trials simultaneously with Phase 1 trials in an attempt to shorten time to approval. This makes sense from the standpoint of the same amino-acid sequence and similar molecular structure, in essence, only being confirmed, not determined. However, an unexpected safety issue arising in such a development program would leave the company exposed to a high degree of liability. Indeed, defending such a development strategy following the emergence of a major safety issue might prove challenging.
To balance the pros (speed to market) with the cons (potential for untoward safety issues), some companies are developing internal guidelines to take a more risk-based approach to Phase 3 clinical trials with respect to clinical safety assessments in what they deem an adequate number of patients or volunteers.
Scenario 4: Trials in Emerging Markets
Companies running biosimilar clinical trials need motivated, educated and informed investigators to fulfill patient recruitment requirements. A recruitment paradigm that reflects a combination of factors, including the variability associated with access to expensive biologics, has resulted in pharmaceutical company recruitment strategies that often involve patients in emerging markets (where access to biologics is more limited) to enhance enrollment and thus gain speed to market. This can be a win-win for the pharmaceutical company and the patient, but only if Good Clinical Practices are maintained throughout clinical drug development, within the boundaries of sufficient biostatistical powering to determine biosimilar efficacy and a satisfactory safety dossier.
In comparison, in some Western countries, willing investigators are less readily available. This situation is, in part, a reflection of the ability of patients to obtain biologic products outside the clinical trial setting. However, high co-pays in countries such as the US and Japan may motivate clinical trial participation to lower the out-of-pocket costs of therapy.
As mentioned above, only 28 biosimilar trials are listed on clinicaltrials.gov (a mandatory US reporting structure).This large disparity between trials conducted and reported in US databases and those reported in the global marketplace (n=30 vs. n=900+) is a reflection of heavy US lobbying efforts by originators trying to block biosimilars27,28 and these factors:
- ease of access to the originator product
- perceived likelihood of regulatory approval
- number of patients required for regulatory approval
- cost of regulatory filing (including number of patients and trials required for approval)
- availability of government funding
- regulatory clarity
Scenario 5: Lack of Specific Regulatory Guidance and Biosimilar Approvals in the US
The lack of a precedent––and the potential for an untoward safety signal in the world’s largest market––has led FDA to follow an ultra-conservative approach weighed down by heavy anti-biosimilar lobbying efforts.29,30
FDA’s approach can be viewed as positive in the sense that safety remains a top concern. Without additional guidance, clinical development and commercial risk increase and can lead to delays for potential product approvals.
The authors have witnessed the impact on clinical development and manufacturing progress from a lack of clear US regulatory guidance. With a lucrative available market , some companies have forged ahead with the goal of penetrating the US marketplace using EU guidelines, which are more specific, as a platform. While this strategy allows companies to advance drug development, it has, unfortunately, proven duplicative or non-productive, slowing down their products’ speed to market and typically requiring multiple meetings with FDA to obtain the required regulatory advice.
In addition to the lack of specific biosimilar guidelines, clear guidance on topics such as interchangeability and transition does not exist. This lack of transparency has led to the existing US case-by-case basis approach to biosimilar regulation. When forced to develop products on a case-by-case basis, companies with adequate resources clearly will have an advantage over those without.
Summary
As increasing numbers of highly successful biologics come off patent, biosimilars remain a promising area for continued investment. With lucrative first-mover advantages in the larger markets at stake, companies are keen to be first.
The intense focus on speed to market by biosimilar developers has resulted in a disparity among countries with regard to global biosimilar drug development programs.
Although an unfortunate safety experience occurred early in the development of biologics, biosimilar drug development has proven safe over a timespan of more than a decade, despite wide regulatory variance among different jurisdictions. On one hand, in the US, biosimilar drug development has not resulted in any approvals yet via the 351(k) pathway. On the other hand, driven mostly by the desire to bring cheaper copies to their citizens, many other countries are forging ahead. These countries are advancing and approving biosimilars. With such a spectrum of regulatory sophistication, there is the possibility for an untoward safety signal, which could result from or be affected by:
- marketing approvals based on small clinical trials
- manufacturing outsourcing
- pressure for speed to market
- trials in emerging markets
- lack of specific regulatory guidance and biosimilar approvals in the US
References
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About the Authors
Raymond A. Huml, MS, DVM, RAC, is executive director and head of global biosimilar strategic planning for Quintiles Inc.’s Global Biosimilar Unit. He can be reached at [email protected]. Nigel Rulewski, MD, DCH, DRCOG, is vice president and head of Quintiles Inc.’s Global Biosimilars Unit. He can be reached at [email protected].
Acknowledgments: The authors wish to acknowledge Jeffrey Spaeder, MD, Quintiles chief scientific and medical officer, for his thoughtful insights on the issue of safety while conducting biosimilar trials, and Jill Dawson, PhD, consultant to Quintiles Corporate Communications, for her editorial assistance while preparing this manuscript.
Cite as: Huml R, Rulewski N. “Safety Concerns Related to Global Biosimilars Drug Development.” Regulatory Focus. June 2014. Regulatory Affairs Professionals Society.