Scientific Considerations for Complex Drugs in Light of Established Regulatory Guidance

Agenda

* Presentation times are subject to change.

Abstracts

Small Molecules, Biologics and Non-biological Complex Drugs: An Overview of their Scientific and Regulatory Differences
Chris Holloway, BSc, PhD, ERA Consulting Group, London, United Kingdom

We are concerned here with "follow-on" or "me-too" products, i.e. medicinal products that attempt to mimic as closely as possible the attributes of an already approved and marketed innovative product. Such products are allowed an abridged development program for marketing authorization, after the patent life of the reference product has expired. For drug substances that are small molecules, "essential similarity" can be confirmed with a high degree of certainty, and out of this scientifically valid fact has evolved the regulatory concept of a generic drug, which requires no nonclinical animal testing and only confirmation of bioequivalence without a requirement for clinical trials to prove efficacy and safety. This approach, however, is not appropriate for biologics, as these are complex macromolecules with attributes that may be linked to their specific manufacturing process. For that reason, a different paradigm, that of a "biosimilar" product, has been developed for "follow-on" biologics, with a requirement for some nonclinical studies and clinical confirmation of comparability in terms of efficacy and safety, albeit abridged with respect to requirements for a completely novel biologic. The regulatory situation with regard to non-biological complex drugs (NBCDs) is less well defined, although it is generally recognized that a generic approach is also not appropriate for these products. In many ways, NBCDs represent an even more difficult case than "biosimilars", as there are more constraints on demonstrating structural and functional similarity. Furthermore, classical bioequivalence testing, even if technically possible, has little scientific meaning. For that reason, it is argued from the scientific perspective that regulatory requirements should take such limitations into account. In this overview, the need for a regulatory approach based on a solid scientific rationale will be discussed, and linked to current requirements for small molecular drugs, biologics and NBCDs that are intended as "follow-on" medicinal products.

Biosimilar Monoclonal Antibodies: Current European Developments
Jan Mueller-Berghaus, MD, Paul-Ehrlich-Institut, Langen, Germany

The concept of similar biomedicinal products (biosimilars) has been included in the legal framework for the authorisation of medicinal products in Europe since 2001. This framework of “biosimilar” medicinal products in Europe does not preclude the development of “biosimilar” monoclonal antibodies. Therefore the European regulatory system has recently been encountered and challenged by the first proposals for the development “biosimilar” monoclonal antibodies. The current legislation foresees a stepwise approach, starting at the level of pharmaceutical quality, advancing to non-clinical investigations and commencing with clinical trials. Two workshops at the European Medicines Agency (EMA) brought together the different stakeholders and advanced the understanding of the challenges inherent for this particular class of drugs. Although monoclonal antibodies are large molecules, the known structure-function relationship of these macromolecules may be particularly suited for the biosimilar approach. Specific controversies that will be discussed relate to the use of different expression systems, specific differences in glycosylation, difficulties for preclinical in vitro and in vivo studies and the discussion on the clinical development.

Coauthor: Christian Schneider, MD, Danish Medicines Agency, Copenhagen, Denmark

Insights into the Process of Establishing Regulations for NBCDs
Beatriz Silva Lima, PhD, iMED.UL, Lisbon University, Portugal

Non-Biological Complex Drugs (NBCDs) include medicinal products for which the active substance, like for biologics, consists of different (closely related) structures that can’t be fully quantitated, characterized and described by (physico)-chemical analytical means. Nanoparticle formulations, e.g., liposomes, iron sucrose, block copolimer mycelles, are under this definition. Consequently to the inherent structural variability of the components, adapted strategies to determine comparability of copies vs originator, and possibility and conditions for their interchange are needed. Indeed, in contrast to any generic formulations, the comparable pharmacokinetic profile (bioequivalence) cannot be sufficient to presume equivalent activity, since e.g., tissue and cellular biodistribution may be influenced by multiple structural aspects which may carry different levels of variability. The potential for differences on safety and efficacy need therefore to be carefully evaluated as a support for interchangeability. While the efficacy of putative copies can be studied in clinical trials, several aspects impacting on safety cannot be studied in humans, as is the case for differential tissue, and cellular distribution. Therefore, while for biologics the most relevant information is considered to derive from appropriate quality characterization and comparative human kinetics/efficacy/safety, for NBCDs a set of nonclinical studies in vitro and in vivo may need to be considered and conducted to support their equivalent level of safety and efficacy. An expert group of the European Medicines Agency is addressing the quality, nonclinical and clinical aspects to support equivalence between copies and originator NBCDs.

Experimental and Clinical Trial Evidence Needed for Follow-on Versions of Complex Drugs
Huub Schellekens, MD, PhD, Utrecht University, The Netherlands

The classical generic approach based on showing pharmaceutical equivalence (ie, identical active substances) and bioequivalence (ie, comparable pharmacokinetics) has been the basis of the introduction of many safe and effective alternatives to innovative medicines. However this approach can only be applied to products which can be fully characterized, with a known mode of action and for which serum levels correlates with efficacy. For off-patent versions of biologics the European Union and other regulatory agencies have introduced a new regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. The type of comparative clinical trials, the number of patients to be included and the clinical endpoint are dependent of the type of therapeutic proteins. However for other complex drugs such as the iron-carbohydrate drugs, liposomal drugs, heparins and the glatiramoids regulatory guidance is still mostly lacking. The type of biological and clinical data that would provide an acceptable level of confidence in the efficacy and safety of these products will be discussed.

Therapeutic Equivalence of Complex Drug Products: Case Study of Generic Calcitonin Nasal Spray Products
Sau (Larry) Lee, PhD, U.S. Food and Drug Administration, Rockville, Maryland

The Office of Generic Drugs of the US-FDA has reviewed and approved numerous generic complex drugs products, including synthetic peptide products, heparin and low molecular weight heparin products. In comparison to conventional "small molecule" drugs, review and approval of complex drug products under the Abbreviated New Drug Application (ANDA) regulatory pathway is considerably more challenging, particularly with respect to demonstration of pharmaceutical equivalence. To understand the underlying science used to evaluate these complex products, the standards for review and approval of synthetic generic calcitonin nasal spray products will be discussed. This presentation will focus on two key aspects of pharmaceutical equivalence for the synthetic peptide nasal spray product. The first aspect is drug substance sameness—a proposed generic salmon calcitonin product must be shown to contain the same active ingredient as its brand-name counterpart. The second aspect is comparability of product- and process-related factors that may influence immunogenicity (i.e., peptide-related impurities, aggregates, formulation, and leachates from the container/closure system). Using salmon calcitonin as an example, the importance of knowledge about the reference product and the integrated analytical technologies (i.e., an array of properly designed high-resolution analytical characterization methods, biochemical and/or biological assays) in the evaluation of complex drugs will be illustrated.

Scientific Challenges in Regulating Complex Biological Products in Emerging Markets
Ivana Knezevic, MD, MSc, PhD, World Health Organization, Geneva, Switzerland

Biotechnology derived medicinal products are presently the best characterized biologicals with considerable production and clinical experience. Availability of these products is critical for successful treatment of many life-threatening and chronic diseases. These products are often expensive for the majority of patients who need them most. The expiry of patents and data protection for the first generation of biopharmaceuticals, mainly recombinant DNA derived products, such as interferons, growth hormone and erythropoietin, was recognized as an opportunity for producing copies of these products as affordable medicines with a great potential for increasing access to them. The question that immediately arose was how should such copies of the originator products be licensed, bearing in mind that they are highly complex biological molecules produced by equally complex biological production processes with their inherent problem of biological variability. Copying biologicals is much more complex than copying small molecules and the critical issue was how to handle the licensing of products if relying in part on data from an innovator product. Since 2004 there has been considerable international consultation on how to deal with biosimilars and biological copy products. Much investment in the development of these products is now going on in many countries, including those with emerging economies. Following on the publication of WHO Guidelines on the evaluation of similar biotherapeutic products, a survey in 13 countries was conducted. It is clear that building the expertise and capacity in regulatory agencies as well as in manufacturing sites needs to be done.

Coauthor: Elwyn Griffiths, PhD, Kingston upon Thames, United Kingdom

Clinical Barriers to the Adoption of Biosimilars: A Lesson for Complex Drug
Andrew D. Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, New York

The Biologics Price Competition and Innovation Act of 2009 (BPCI) is a component of the Patient Protection and Affordable Care Act signed into law on March 23, 2010. BPCI provides a pathway for abbreviated approval of biological products that are demonstrated to be "highly similar" (i.e., biosimilar). A biologic product is considered to be biosimilar to a reference product if analytical studies demonstrated that it is highly similar to the reference product and utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed. Biosimilar also need to be compared to the reference product in clinical trials to demonstrate similar efficacy (the trials do not appear to require statistically equivalence). BPCI also allows biosimilar drugs to be deemed interchangeable with the originator product enabling substitution for the reference product by a pharmacist without notification of the prescriber. To date, the FDA has not provided detailed guidance regarding biosimilars in contrast to the EMA which provided guidance and has approved several biosimilars. However, in Europe the health care professional must determine interchangeability. A central question is what data would be persuasive to a clinician to overcome hesitation about biosimilars. Biologic agents are most commonly used in the treatment of cancer and account for a significant proportion of expenditures for cancer drugs. Biosimilars potentially will have a major impact on cancer care. Rituximab is a monoclonal antibody directed against CD20 expressed on human B cells. In 2010, the total expenditure for rituximab in the Untied States was 1.4B dollars. I will use rituximab as a case study examining the potential for a rituximab biosimilar and what hurdles I see for its adoption.

Follow-on Biologics — A Patient's Perspective
Janet S. Wyatt, PhD, RN, FAANP, Institute of Pediatric Nursing and Arthritis Foundation, Round Hill, Virginia

Since the 1990's more than 350 million patients have benefited from biologic treatments. Today there are over 650 new biologic medicines and vaccines being developed to treat over 100 diseases. While cost has often limited access to these miracle medicines in the US, the European Union together with Japan, Australia, Canada and others have pursued the development of bio-similar products, working to balance sound science and patient safety with the goal of delivering lower cost biologic therapies. While billions are at stake and politics and production issues lead the headlines, the needs of patients must be explored and their most pressing questions answered: Will a new biosimilar be the best and safest drug for me? Can I rely on this medicine to provide sustained long-term symptom relief and disease benefit without undue immunogenic side effects and adverse reactions, and... Can I return to my former biologic treatment (and get the same benefit) if this one fails?

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Directions to the Academy

Hotels Near 7 World Trade Center

Recommended partner hotel

Club Quarters, World Trade Center
140 Washington Street
New York, NY 10006
Phone: 212.577.1133

The New York Academy of Sciences is a member of the Club Quarters network, which offers significant savings on hotel reservations to member organizations. Located opposite Memorial Plaza on the south side of the World Trade Center, Club Quarters, World Trade Center is just a short walk to the Academy.

Use Club Quarters Reservation Password NYAS to reserve your discounted accommodations online.

Other nearby hotels