A Progress Report on the Regulatory Environment
Meenakshi Rao and Anthony Rebuck
Quintiles, Asia Pacific
In 2013 it is anticipated that there will be significant growth in the use of biosimilars in the biologics segment. By the end of the year, biosimilars will account for 5% of all biologics in worldwide – up 16-fold from 2011 when biosimilars accounted for only three-tenths of 1% of the biologics segment.1 This trend is even more dramatic when one looks at the use of biologics overall to treat disease. In 2006 only 14.7% of all prescription medicines were biologics; by the end of 2013 biologics (including biosimilars) will account for 25% of all prescription medicines – a 70% increase in seven years.
In this paper we examine the regulatory environment surrounding the development of biosimilars, the recent changes and the remaining challenges that face drug developers who aspire to play in the new game.
All of the 14 biosimilars that have been approved by the European Medicines Agency fall into one of only three classes: human growth hormone (two); colony-stimulating factors (seven); and erythropoietin (five).2 The oldest of biologics, insulin, still hasn’t been approved as a biosimilar, nor has interferon alpha. Furthermore, due to their complexity, neither of these drugs is expected to be available as a biosimilar in 2013.
Biosimilars vs. Generics
Biosimilars are not generics by another name. Biosimilars are variable; a variable product can never be identical to a reference product. Biosimilars are subsequent versions of innovator biopharmaceutical products, with identical primary amino acid sequences, made – following patent expiry – by different companies. A biologic is a preparation that has been synthesized from a living organism such as a bacterium or yeast. By contrast, a generic is an exact copy of a small molecule, made by the process of chemical synthesis that has gone off patent. Neither generics nor biosimilars are to be confused with “biobetters,” which are biologics that have been modified by protein engineering to give lower dosing frequency and better pharmacokinetic, and pharmacodynamic profiles with a reduced risk of immunogenicity.
Naturally, biologics are more complex than small molecules. Aspirin, for example, has a molecular weight of 180 Daltons and contains no amino acids. Even the simplest of biologics, such as Calcitonin, which is produced from yeast or bacteria, has a molecular weight twentyfold greater than aspirin and has 32 amino acids. A monoclonal antibody of the IgG class – produced from mammalian cells – is a vastly more complicated molecule, with a molecular weight a thousand fold greater than aspirin and containing more than a thousand amino acids.
To paraphrase British Prime Minister Harold Macmillan in his speech in Cape Town in 1960, ‘The Winds of Change are blowing through the Regulatory Authorities’.
On March 23, 2010, President Obama signed into law The Biologics Price Competition and Innovation Act (BPCI Act). From that moment, an abbreviated licensure pathway for biological products was created, as was a refreshing collegial, helpful atmosphere in the corridors in Silver Springs, Maryland, and Canary Wharf, London, headquarters of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) respectively.
There are two facts for which there is a degree of certainty: First, the regulatory approval for biosimilars will be a longer process than for generics. Second, the time will be shorter than for traditional small molecules and the patented biologics. There, the certainty ends.
Regulatory approvals for biosimilars are progressing at different rates across the world. When the guidelines were first introduced in 2004, European authorities (EMA) were unambiguous in stating that the criteria for approval of generic products were not sufficient for biological medicinal products. If, for example, there are differences in raw materials or manufacturing processes of biosimilar and reference products, results of preclinical tests or clinical trials relating to these conditions have to be provided. The EU requires that step-by-step head-to-head comparison at the levels of quality, safety and efficacy be undertaken to demonstrate biosimiliarity with the reference product.
The EMA was also the first to set precedent guidelines for biosimilar approvals for certain product classes, such as insulins; it recently followed up with draft guidance for monoclonal antibodies. The World Health Organization (WHO), in order to encourage regulatory harmonization across markets, also finalized guidance in 2010. Many countries are now following suit, forming their own guidance, referencing either the EMA or WHO. Canada and the United States have both issued draft guidance, while Brazil, Japan and India have issued final versions. Work is under way in China, but at the time of writing many other countries, Russia for example, has no specific pathway for biosimilars.
The United States passed the BPCI in March 2010, as a part of Affordable Care Act, which amended section 351 of Public Health Services Act for biologics and created a new licensure pathway 351(k) for biosimilars. The FDA uses a risk-based, totality of evidence approach (Figure 2) for the evaluation of biosimilars; including structural and functional characterization, non-clinical evaluation, human pharmacokinetics and pharmacodynamics data, clinical immunogenicity data and clinical safety and effectiveness data.
Biotechnology: A Brief Recap
Notwithstanding the fact that we have been enjoying the fruits of biotechnology ever since beer was first brewed 7,000 years ago – with penicillin produced by fermentation 70 years ago – it was the food and energy crisis of the 1970s that stimulated a search for biological solutions to the global social upheavals. The breakthrough was genetic engineering.
The 1970s: Advances in basic biotechnology
In 1972, two scientists met over pastrami sandwiches and talked about whether they could clone plasmids and introduce them into E. coli. Thus, modern biotechnology was born, when bacteria were genetically engineered to produce human insulin. Herb Boyer and Stanley Cohen had shown that it was possible to take a human gene and introduce it into a bacterium which then expressed multiple copies of that gene. Boyer obtained venture capital and formed Genentech, recently purchased by Hoffman-La Roche for US$46 billion. Boyer could not have made his great breakthrough without the enzymes, or biological scissors that cut DNA into little “snips,’ (Single Nucleotide Polymorphisms) a discovery for which Smith, Nathans and Arber received the 1978 Nobel Prize.
1980s: Commercial biotech companies
Genetic engineering now started to capture public fascination … and fear. On the one hand, recombinant DNA seemed to have the potential to offer solutions to world hunger and the oil crisis. On the other hand, some experiments were thought to be so dangerous, that for a while there was a moratorium on research outside certain laboratories and it was forbidden to release modified organisms into the environment. Eventually, in 2000, the U.S. National Research Council published guidelines regarding genetically modified tomatoes, soybeans and cotton.3
The pharmaceutical industry seized on human growth hormone, followed by interferon which was seen as a new miracle cure for certain viral diseases and cancer. The late 1980s saw only synthetic insulin, human growth hormone, hepatitis B vaccine, alpha-interferon, and tissue plasminogen activator approved by the FDA.
1990s-2010: Biologic drugs in the market
Within a decade, a further 120 recombinant protein drugs were approved by the FDA. It has been estimated that during this period, more than US$350 billion was invested in biotech. Global sales of biologics in 2005 were US$50 billion and have been growing at 17% a year. By 2002 FDA had approved 36 new biologics followed by 37 in 2003; 40 in 2004; and 39 in 2005. By 2010 over half of the approved drugs were biologics.4 5
While traditional big pharma had been unable to realize much in the way of innovation over the decade, biopharmaceuticals were growing rapidly, with the most spectacular performance in the treatment of breast cancer, focusing on subsets of the total population. By 2009, five of the 10 best selling drug in the world – Enbrel, a recombinant product, and the monoclonal antibodies Remicade, Avastin, Rituxan and Humira – were biologics. Back in big pharma, R&D investment almost tripled over a 10-year period while Phase II success rates fell to 18 % in 2007 from 28 % in 2006.6
Challenges in Clinical Trials
Lest the impression has been given that the game is being delayed by the referees, let us be clear that the clinical development of biosimilars is also fraught with difficulties. For a start, the clinical trials are usually large, requiring 600 to 2000 patients. Secondly, the patients are singularly unenthusiastic about volunteering for the studies if the innovator product is widely available. They receive only lukewarm encouragement to enter trials from investigators who see no new science for publications or presentations. Thus, the Phase III studies must be conducted only in territories where the innovator product is approved but not generally available. Finally, health agency guidelines invariably require the use of comparator drugs that are authorized in that territory, thereby increasing the number of trials that need to be conducted for approvals.
When are clinical trials needed?
It depends. A trial is required if there are extensive structural and functional differences between the reference product and the biosimilar. For example, how well do the observed differences in non-clinical pharmacology and toxicology predict differences in clinical outcomes? Does the mode of action of the reference product correlate to the disease pathology? What is the extent of clinical experience with the reference product and its therapeutic class? Are there well established, sensitive clinical endpoints?
The scope and the magnitude of the clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies. The frequency and the severity of safety risk in the reference product will influence the design of the clinical program for the biosimilar.
Lessening or narrowing the scope of clinical studies (human PK/PD, clinical immunogenicity, or clinical safety /effectiveness) should be scientifically justified by the sponsors.
What are the recommendations for PK/PD?
For products with short half-life, a cross-over immunogenicity studied will be needed, and for those with a long half-life, greater than five days for instance, a parallel design is recommended. The statistical requirements for biosimilars are in no way different from those needed for safety and efficacy in innovative product trials. If a trial is required, it must be shown that the proposed product is not inferior to the reference product. The recommended dose should not be higher than in the labeling for the reference product because of safety concerns.
The good news is that once a biosimilar has been shown to satisfy efficacy and safety for one indication, extrapolation to other indications may be granted without further studies if the mechanism of action and target receptors are similar. Furthermore, if PK and bio-distributions are similar for different patients and for each condition of use and differences in toxicity are unlikely, under these conditions extrapolation of indications may be considered.
Even when the mechanism of action in different indications are less understood, (Low Molecular Heparins licensed for treatment in prophylaxis of deep vein thrombosis as well as prevention of acute coronary syndromes such as unstable angina) European regulators have suggested establishing equivalent efficacy for extrapolation of the indication; prevention of venous thromboemboslism in surgical patients with high risk.
Provisions for Exclusivity
Given the complexity of the biologics development the innovator products have been given 12 years of exclusivity for the licensure of the first reference product during which a biosimilar application 351(k) may not be approved (Figure 1). In addition, a biosimilar application 351(k) may not be submitted until four years after the date of the first licensure.
The first interchangeable product approved in the US is granted at least one year of exclusivity, and during this exclusivity period the subsequent biological product relying on the same reference product cannot be licensed as interchangeable. Exclusivity period is based on the date of approval, date of first commercial marketing and patent litigation milestones.
The EU provides an 8-year data exclusivity period with 10-year market exclusivity, which may be extended by an extra year for new indication offering significant clinical benefit in comparison with existing therapies for reference products. The data and market exclusivity periods commence from the date of first marketing authorization granted in the community. Per these provisions for marketing application submitted in 2005, the exclusivity provisions will be expiring earliest in 2013.
A Biosimilar Application to FDA
- 351(k) or a Biosimilar application must include information demonstrating that the biological product:
- is biosimilar to a reference product
- utilizes the same mechanism(s) of action for the proposed condition(s) of use — only to the extent known for the reference product
- condition(s) of use proposed in labeling have been previously approved for the reference product; and
- has the same route of administration, dosage form, and strength as the reference product
- that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
- there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
Key Factors in the Future of Biotech
A number of important factors will determine the future of biotechnology: affordability of drugs for patients who need them most, personalized medicine, stem cell/gene therapy and the fact that many biologic drugs will be coming off patent. An increase in the use of biomarkers will be seen as regulatory processes for their qualification in “context of use” become more transparent.
Currently, the cost of Herceptin for the treatment of breast cancer is US$36,000 per patient, per year – significantly higher than the per capita GDP of most countries. Clearly it is unacceptable to develop expensive new medicines that are accessible to only a small minority of patients who can afford them.
Neither gene nor stem cell research is the focus of the present article, but the patent issue certainly is. During 2012-13, Enbrel, Epogen, Remicade, Avonex, Rebif, Humalog, Neupogen and Cerezyme will experience patent expiry. The annual aggregate market size of these drugs is US$26 billion.7 Looking further into the future, by 2019, these medicines will be joined by biologics currently treating lymphoma, diabetes, rheumatoid arthritis, colorectal and breast cancer, not to mention such life-saving treatments as stimulators of blood white cell production.
The use of biologics and biosimilars to treat disease has grown substantially in recent years. This trend will continue for the foreseeable future. Evolving technologies and unmet medical needs are fueling the discovery and development of innovative biologics; while patent expirations, clearer regulatory pathways, and economic factors are driving the growth of biosimilars. The economic factors are especially keen in Asia (and other developing regions). With lower per-capita incomes relative to the West, the vast majority of individuals in Asia cannot afford branded biologics. Governments and other payer organizations in Asia are seeking evidence to make difficult reimbursement decisions, i.e. which offers better value, an innovative but higher cost biologic or existing lower-cost therapies, often generics. For both parties, biosimilars are part of the solution, combining innovation with substantially lower costs versus branded biologics.
About the Authors
Anthony Rebuck joined Quintiles in November 2011 and was instrumental in establishing the Strategic Drug Development Unit for Quintiles in Asia, which he is currently heading.
Dr. Rebuck brings more than 20 years’ experience in industry and academia involving health care issues and drug development, including significant projects in respiratory medicine and diabetes before joining Quintiles. He possess deep understanding of healthcare issues and the drug development process, from target product profiles in early discovery, through global clinical development, registration and market entry.
Prior to Quintiles, he held senior positions with several multinational pharmaceutical companies, including Pfizer where he was responsible for setting up its Phase I Clinical Research Unit in Singapore. He also was Vice-President and Regional Medical Director for GlaxoSmithKline (GSK) and Head of Clinical Development & Research in Pulmonary and Diabetes in the United States of America for SmithKline Beecham.
Dr. Rebuck received his medical training from the University of Sydney in Australia and held faculty positions at the University of Toronto, Canada. He authored numerous publications and is a fellow of the Royal College of Physicians and Surgeons of Canada, and is a Fellow of the American College of Physicians and Fellow of the Royal Australian College of Physicians.
Meenakshi (Meena) Rao has a Ph.D in Chemistry from University of Louisville, Kentucky (USA) and is currently the Director, Regulatory Strategist at Quintiles.
Prior to joining Quintiles, Dr. Rao was a Director of Regulatory Affairs for Novo Nordisk, Inc. based in United States, where she was instrumental in creating regulatory strategies and managing regulatory activities for a portfolio of GLP-1 analogs for diabetes and obesity. She was also responsible for reversing FDA’s decision and securing the approval of Vagifem®10mcg. She was instrumental in formulating regulatory strategies for key strategic products leading to successful approvals and launches in US and major EU markets.
With more than 20 years of pharmaceutical and healthcare industry experiences in the areas of drug discovery, pharmaceutical development, project management, clinical safety, chemistry, manufacturing and controls (CMC), regulatory affairs in small molecules and biologics. She has held various roles in regulatory affairs in in large and medium sized pharmaceutical companies. Dr. Rao has deep experiences in drug development and regulatory affairs across many therapeutic areas such as diabetes, obesity, inflammation, haemostasis, women’s health and oncology.
- Datamonitor February 2011
- Falk Ehman – EU Biosimilar Regulatory Framework II GCC Workshop on Similar Biological Medicinal Products (Biosimilars) 19-20 April 2011, Riyadh. Biosimilar Guidelines: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac058002958c
Directive 2001/83/EC as amended:
Reference for the Figure 1: Rachel E. Sherman CDER, Biosimilar Biological Products - Biosimilar Guidance webinar February 15, 2012.
Reference for Figure 2: Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, February 2012
- Committee on Genetically Modified Pest-Protected Plants, National Research Council. Genetically modified pests-protected plants: Science and Regulation (Washington, D.C. 2000). http://www.nap.edu/catalog.php?record_id=9795
- Shapiro RJ. The Potential American Market for Generic Biological Treatments and the Associated Cost Savings. February 2008. http://www.sonecon.com/docs/studies/0208_GenericBiologicsStudy.pdf
- Ernst & Young. Beyond Borders: Global Biotechnology Report 2005. http://www2.eycom.ch/publications/items/biotech-report/2005/2005_EY_Global_Biotech_Report.pdf
- Arrowsmith J. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Discov. 2011 May;10(5):328-9. doi: 10.1038/nrd3439.
- Pricewaterhouse Coopers. Biotech Reinvented: Where Do You Go From Here? 2011. http://www.pwc.be/en/pharma/pdf/2011/biotech-reinvented.jhtml
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