Anticancer Antibodies Pose Complex Challenges for Drugmakers: An Interview With Martin Van Trieste

Martin Van Trieste

Senior Vice President of Quality

at Amgen

As anticancer antibody therapies have evolved into ever more highly engineered and complex structures, so have the manufacturing processes that pave the way for their widespread clinical use.

Today, many of the most widely used oncology drugs are biologics, broadly defined as agents produced from living organisms rather than chemical synthesis. By 2016, eight of the top 10 best-selling drugs worldwide for all disease states including cancer are expected to be biologics, industry analysts predict.¹

The expanding use of these therapeutics has prompted much debate about biosimilars, which are versions of original, proprietary drugs but differ sharply from traditional generics in part because biologics are developed from unique cell lines. Although the FDA devised a pathway for biosimilars last year, Fitch Ratings analysts believe biosimilars approved through those regulations will not be launched in the United States before 2015 and that it will take several additional years for the market to develop more fully.¹

Against this backdrop, Amgen has been vigorously reaching out to practicing oncologists, hematologists, and pharmacists to demonstrate and explain its manufacturing processes. The company showcased its technology at the 2013 American Society of Clinical Oncology Annual Meeting in June with interactive displays of the multifaceted process of developing biologics from cell lines to distribution. That marked the debut of an educational website, www.biotechnologybyamgen.com.

Amgen’s portfolio includes several biologics used in treating patients with cancer, notably pegfilgrastim (Neulasta), filgrastim (Neupogen), panitumumab (Vectibix), and denosumab (Xgeva).

Last year, the company announced plans to develop and commercialize “on a worldwide basis” biosimilar versions of other branded drugs, including bevacizumab (Avastin), trastuzumab (Herceptin), rituximab (Rituxan), and cetuximab (Erbitux).²

In an email interview with OncologyLive, Martin Van Trieste, senior vice president of Quality at Amgen, discussed some of the key issues involved in the manufacture of biologics.

OncologyLive: With the website unveiled at ASCO, Amgen seems to be making a concerted effort to reach practicing oncologists and hematologists with information about the company’s processes for manufacturing biologics. Why has Amgen taken this approach?Van Trieste:As countries around the world confront aging populations with increasing rates of chronic disease, a reliable supply of high-quality medicines, including biologic medicines, has never been more important.

Even small variations in the complex biologics manufacturing process can potentially alter safety and efficacy of these medicines. It takes considerable expertise, experience, and investment to ensure reliable supply of biologics for patients.

Through Biotechnology by Amgen, we are highlighting Amgen’s commitment to its goal of reliably supplying quality medicines and its investment in manufacturing processes and key practices that have helped Amgen to avoid drug shortages (as defined by the FDA) of its own medicines.

Expertise, experience, investment, and track record should be considered by all those involved in the provision of biologic medicines.

What is important for US oncology specialists to know about the manufacture of brand-name biologics and biosimilars?

Over the years, it has become evident that even organizations with significant expertise and manufacturing experience can face hurdles in dealing with the inherent complexity in producing biological medicines.

Maintaining a consistent supply of safe and effective biological medicines requires expert staff, advanced science, and sophisticated technology throughout the manufacturing process and supply chain. It also requires high standards for compliance with regulatory requirements and an organizational culture that values quality.

To put this into context, between 2005 and 2016, Amgen expects to invest approximately $1.5 billion in numerous strategies to help ensure that high-quality biologics get to the patients who need them. We are also leading the way forward to the next generation of biotech manufacturing, which includes a $200 million investment in a new, world-class manufacturing facility in Singapore as part of our Manufacturing of the Future (MoF) initiative.

Do you foresee a time when prescribing physicians, particularly those who treat patients with cancer, will want or need to evaluate the source of a biologic medicine before prescribing it? That is, will they want to make a value judgment on the manufacturer and, if so, what mechanisms would they use for going about it?

Healthcare professionals have a responsibility to know what medicines they are prescribing and—especially in the case of biologics— need to better understand the importance of manufacturing.

In the United States, the FDA sets manufacturing requirements, licenses only those companies that can meet these requirements, and maintains a broad inspection program to safeguard the drug supply.

Amgen’s website details the complexity of manufacturing biologics. Please highlight some of the key challenges in making these medicines safely, particularly when it comes to oncology drugs.

The manufacturing process is important for all drugs, but this is particularly so for biological medicines. The key challenge in their manufacture is that they are far more complex structurally and difficult to characterize, produce, and reproduce than most small molecule pharmaceutical compounds. Even small variations in the manufacturing process can potentially alter the medicine’s safety and efficacy, and negatively impact reliability of supply.

Can the development of biosimilars help alleviate drug shortages and, if so, how?

Amgen is committed to helping biosimilar medicines become a reality for patients by supporting science-based regulatory decision regarding biosimilars. As this new class of biologic medicines is introduced into healthcare systems worldwide, there must be an uncompromising commitment to patient safety. This starts with high regulatory approval standards and ongoing manufacturer accountability.

High-quality, reliably supplied biosimilars offer additional therapeutic choices to patients and other key stakeholders; however, development and supply of these complex medicines is scientifically challenging and capital intensive. Successful manufacturers need to have significant expertise, infrastructure, and investment capital to successfully develop these molecules.

Please clarify/expand upon Amgen’s plans to develop biosimilars as described in the company’s 2012 annual report.

Amgen is a pioneer in the field of biologic medicines. We believe in the role that biosimilars can play in providing additional treatment options for some patients, so we are continuing to pursue opportunities to serve patients in this rapidly evolving field. Amgen is wellpositioned to produce and supply safe and effective biosimilars.

Our primary focus is to continue discovering, developing, manufacturing, and commercializing innovative medicines to treat grievous illnesses.

Are the biosimilars that Amgen is developing in oncology intended for the US market?

Amgen will determine the best approach to making our products available on a country-by-country basis. Overall, launch timing will vary by products and geographies depending on a variety of factors, including but not limited to patent expiries of the originator products, development timelines, regulatory requirements, etc.

Since biosimilars first became available in Europe years ago, what issues have surfaced and what lessons might be helpful to the US?

A couple of points on Europe—first, that it is a complex amalgamation of widely varied healthcare systems.

Second, the biosimilars approach has changed quite a bit in the European Union (EU) since its beginning in 2006. Now both regulators and manufacturers are increasingly transparent with physicians, patients, and pharmacists about the biosimilarity method, specific products being used, postmarket data, and use of clinical data to support a finding of similarity versus re-establishing safety and efficacy.

The European Medicines Agency is publishing a significant number of articles so that everyone has a really good understanding of what biosimilars are and are not. This is probably a good learning experience—that patient and physician confidence is important for uptake and that transparent data, decision-making, and recordkeeping facilitate that confidence.

We have seen that the penetration of biosimilars in Europe varies by country, reflecting, among other things, local pricing and reimbursement policies, stakeholder influence, and attitudes toward their adoption and use.

A recent report from the European Commission shows that biosimilars are helping improve competition and may be increasing access to biologic medicines for patients.³

Are there concerns over keeping track of adverse events that patients encounter with biosimilars, particularly over time?

Amgen believes that healthcare systems globally must ensure all biologic medicines, including biosimilars, can be rapidly and accurately identified by national regulators, healthcare providers, and patients.

In fact, regulations are being tightened to improve identification and traceability of biologic medicines. For example, in 2012, the European Commission introduced a pharmacovigilance directive, which was the biggest change to the regulation of human medicines in Europe since 1995.

It is now a legal requirement for EU member states to take all necessary measures to clearly identify the biological medicines that are prescribed, dispensed, and sold in their country. A similar naming program is recommended by the WHO and national regulatory bodies, such as the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA).

There has been debate on legislative levels in various US states about substituting cheaper biosimilars for brand-name biologics. Major pharmaceutical companies, including Amgen, have argued that biosimilars should not be automatically interchangeable with brand-name biologics, and that pharmacists should keep records of substituted medicines for at least five years. What is Amgen’s rationale for such arguments?

As a company planning to commercialize biosimilars, Amgen supports the state biosimilars legislation and believes it is necessary because state laws leave unaddressed the substitution of biologics that the FDA deems interchangeable.

The biosimilars legislation in the US states is about increasing patient access to biologic and biosimilar medicines in a way that maintains patient medical records and facilitates manufacturer accountability.

Biosimilars are not generic drugs; to the contrary, they are expected and allowed to have greater flexibility in design than generics while demonstrating equivalent efficacy and noninferior safety. However, they are viewed as having the potential “to lead to an expanded market and greater consumer access.”⁴

The legislation is intended to establish a clear, orderly system for introduction of biosimilars.

Importantly, the legislation also implements a provision of the federal biosimilars law authorizing automatic substitution of biologic medicines determined by the FDA to be interchangeable. The Federal Trade Commission has noted that interchangeable products may stimulate price competition, and we expect this could become relevant as experience is gained with biosimilars.

A video featuring Joe Miletich, MD, Amgen’s senior vice president of Research & Development, provides additional insight. (Available at http://www.youtube.com/watch?v=wL3k5D8Azrw).

Reference

1. Bostwick J, Kirby B, Zbinovec M, Neuberger M. Trekking the path to biosimilars: forging ahead. www.fitchratings.com. Fitch Ratings special report. Published August 5, 2013. Accessed October 29, 2013.
2. Amgen. 2012 annual report and 10-K. http://goo.gl/yFp36Y. Published April 4, 2013. Accessed October 29, 2013.
3. European Commission. Consensus Information Paper 2013: What you need to know about biosimilar medicinal products. http://tiny.cc/jqrn5w. Published April 21, 2013. Accessed October 29, 2013.
4. Federal Trade Commission. Emerging health care issues: follow-on biologic drug competition. http://tiny.cc/u1qp5w. Published June 2009. Accessed October 29, 2013.