Pharma’s Cutting Edge

Pharma’s Cutting Edge Vol. 4 Number 3 - March 2006

Review of EMEA Biosimilars Guidelines

Last month EMEA (the European Medicines Agency) released final guidelines containing details of clinical, nonclinical and quality expectations for biosimilar protein therapeutics (aka generic biologics, aka biogenerics, aka follow-on biologics or proteins). These guidelines were themselves as expansion of the general guideline released in September 2005 and of two earlier documents, a note for guidance containing nonclinical and clinical issues (December 2003) and a quality guideline (also December 2003). All of these documents are conveniently located on a single page on the EMEA website.

As of today, two biosimilar proteins have been recommended for approval by the CHMP (Committee for Human Medicinal Products, the human medicines technical component
within EMEA), both somatropins (growth hormones): Omnitrope (Sandoz) and Valtropin (BioPartners). Based on CHMP’s specific guidelines for insulin and G-CSF biosimilars, we can infer that registration dossiers have been submitted for biosimilars in these categories (potentially adversely affecting primarily Novo Nordisk and Hoffman-La Roche, respectively). Other widely used therapeutic proteins that are susceptible to biosimilar competition in Europe today, owing to patent expiration, are erythropoeitin (Eprex, Janssen) and interferon-alpha2b (IntronA, Schering-Plough). We can expect CHMP guidelines for biosimilars for these drugs soon. In addition to Sandoz and BioPartners, companies that stand to gain in the near-term from the EMEA’s actions are listed in this PharmaWeek article.

In the U.S., FDA has been considering its own guidance for follow-on biologics (biosimilar) developers and manufacturers for some time. It’s hinted that a draft guidance will be forthcoming this year. Sandoz isn’t holding its breath waiting for FDA to get its act together on this issue. It sued FDA in September last year, asking the Court to rule that FDA must act on its application for Omnitrope now, one way or another. FDA asked the Court to dismiss the suit in November. So far, no further action has occurred. In the meantime, U.S. observers can learn from the CHMP’s guidelines, as it is likely that scientific guidance from FDA will be similar.

My goal in this issue is to provide an overview to these recent guidelines, focusing on the key issues. I’ll discuss them in the order of general guideline, nonclinical, clinical and quality and then touch on the specific product guidelines. I realize that this is a long post, but it’s far shorter than the original guideline documents, and it isn’t every year that a completely new category of drug marketing authorization comes to fruition.

General Guideline

Scope

• Theoretically covers all biologics, including vaccines, blood-derived products, antibodies, etc.

Application of “similar biological medicinal products approach:”

• differs from the standard generics approach as it is based on a comparability exercise rather than a demonstration of bioequivalence
• is more likely to be applied (and to be successful with) highly purified biologicals, such as recombinant proteins
• must fulfill quality, safety and efficacy requirements (discussed later)
• results in products that are similar but not in generic equivalents, necessitating the need for clear product identification to facilitate pharmacovigilance.

Choice of reference product

• Active substances must be similar (structure and function).
• Reference product must be approved in the Community (meaning the countries embodied by the EMEA).
• Pharmaceutical form, strength, and route should be the same; differences will have to be justified.

Note on immunologicals (e.g. vaccines)

• Vaccines and allergens are complex and unlikely to be well characterized molecularly.
• They will therefore consider them on a case-by-case basis.

Note on blood or plasma-derived products

• Such products have complex and variable physico-chemical, biological and functional characteristics.
• Therefore, such products must satisfy safety and efficacy requirements as found in BPWG “new products” guidance note and related documents.

Other biologicals

• Cell and gene therapy products will be considered in the future.

My take away: Although the similar biological approach is potentially relevant to all biological medications, in fact, the current guidelines are intended primarily for development of biosimilars referenced to well-characterized recombinant protein therapeutics, including monocloncal antibodies.

Nonclinical Guideline

General (applicable to clinical as well)

• Within a biosimilar MAA (marketing authorization application) dossier, each indication for use will be considered separately.
• Efficacy and safety for each indication will either have to be demonstrated or an extrapolation from one indication to another justified.

Scope (applicable to clinical as well)

• Covers biosimilar applications for recombinant proteins only and only when no changes are introduced in the manufacturing process.

Nonclinical study program

• Studies should be done prior to clinical studies.
• Should be designed to detect response differences between the reference and biosimilar, not just responses per se.
• In vitro receptor-binding or cell-based [binding] assays should normally be done.
• In vivo studies should measure the pharmacodynamics relevant to clinical use.
• At least one repeat-dose toxicity study should be conducted.
• Toxicokinetics should include antibody titers, cross reactivity and neutralizing capacity
• Other routine types of tox studies are NOT normally required.

Clinical Guideline

General

• Test product should be studied clinically using the final manufacturing process, unless justified and supported by additional data.
• Clinical comparability is done in stages, much like a traditional program.

Pharmacokinetics

• Clinical comparability pharmacokinetic (PK) studies should NOT necessarily mimic a standard comparability design that focuses on absorption and bioavailability. Rather, such studies should also include exploration of clearance and elimination.
• Choice of design must be justified and careful attention should be paid to issues such as elimination half-life.
• The acceptance range to conclude clinical comparability should be defined and justified.

Pharmacodynamics

• The pharmacodynamic (PD) effects should be compared in a population where “possible differences can best be observed.”

When will PK/PD studies alone suffice to determine clinical comparability:

• when PK of the reference product is well characterized
• when PD properties (e.g. binding to receptor) of the reference product are well characterized
• when the PK/PD relationship of the reference is well characterized
• when a PD marker exists and the PK/PD relationship using the marker is well known.
• when the PD marker is a well characterized surrogate of the clinical outcome of interest
• when the dose range is chosen to demonstrate assay sensitivity (see ICH E10 for a discussion of assay sensitivity)
• when the PK and PD margins defining clinical comparability are defined and justified a priori. Read the rest of this entry »
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It’s about time, but never too late for Sandoz to celebrate the approval of the GH “biosimilar” known as Omnitrope. The CHMP opinion is the required precursor to EC approval. If approved, Omnitrope will be the European Union’s first approval since biosimilar guidelines were issued there over a year ago. In the U.S., Sandoz (parnet Novartis) is suing FDA to advance action on the 505(b)(2) NDA for the drug. FDA guidance for accelerated approval pathways for recombinant drugs is expected later this year.

When John Jenkins (FDA Director of Office of New Drugs) testified to the Institute of Medicine this past week that: “I don’t know that we’re ready at this point to say we are going to completely change the paradigm and start asking for databases 10 times bigger than they have been,” he wasn’t suggesting that current safety database sizes were “adequate”. What he was suggesting is that: “There could be a lot of really unintended consequences to what sounds like an easy, good idea.” In other words, he is justifiably concerned that a knee-jerk reaction to highly publicized safety recalls of new drugs is going to create unintended health hazards, chief of which is delayed access to important new medicines.

So, is this a justified concern, or is it kowtowing to industry, as industry opponents are sure to claim? Here are some facts to consider. Safety database size is determined by several factors that are described in detail in ICH Guidance E1A and FDA Guidance on Pre-Marketing Risk Assessment. The most important factor is the minimum exposure size needed to detect an adverse event “signal”. A signal is usually regarded as a single event. A simple rule of thumb is that a single adverse event occurring with a frequency of 3/X, where X is the drug-exposed population, will be evidenced with chronic dosing 95% of the time. So, for instance, the minimum recommended chronic dosing (i.e. 6 months) exposure of 300 subjects in ICH E1A will essentially rule out a safety signal occurring with a frequency of 1/100 (1%) if said signal is not evidenced during the studies. This is the minimum requirement. Most safety databases resulting in approval of the most widely used drugs are much larger. In the Vioxx case, the original NDA contained exposure to rofecoxib of 1396 subjects treated for at least six months at any dose. So, this size was sufficient to rule out a safety signal occurring with a frequency of about 0.2% with 95% confidence. Read the rest of this entry »