Biologics and biosimilars: Are they?

Several biologic products manufactured using recombinant DNA technology are nearing or have passed patent expiration. Generic biologics, also called “follow-on biologics” or “biosimilars,” are emerging, which has forced legislation enabling the FDA to approve follow-on biologics via an expedited approval process that would rely, at least in part, on knowledge of the original product’s safety and efficacy.

This expedited process is driven largely by the potential cost savings to the health care system. For a typical generic drug, FDA approval criteria require that the generic product match the pharmacokinetic and pharmacodynamic properties within a range of 80% to 125% of the branded product. Although the active ingredient of the generic is identical to the brand, the inactive ingredients typically differ. Because biologic products are usually large, complex molecules, the generic version is unlikely to be an exact replica, and thus comparative testing regarding protein content, activity, stability, integrity and immunogenicity is important.

Differences in agency classifications

In 2010, the FDA approved an abbreviated new drug application for a generic version of enoxaparin (Sandoz-Momenta Pharmaceuticals) against the reference listed drug Lovenox (Sanofi-Aventis). Although Sandoz filed the abbreviated new drug application in 2005, approval was delayed due to the complex regulatory and review process, and also due to a citizen petition filed in 2004 protesting acceptance of any application for generic versions until Lovenox was fully characterized.

Aparna Yerramilli

In the US, low–molecular-weight heparins (LMWH) are considered drugs, and thus, the new Sandoz and Momenta version is considered a generic. However, the European Medicines Agency considers enoxaparin to be a biologic and has not given approval for any biosimilar enoxaparin. The European Medicines Agency guideline document asserts that in vitro and preclinical properties of LMWHs cannot reliably predict the clinical behavior of LMWHs. Therefore, copies of currently approved LMWHs should be deemed as biosimilar and not generic LMWHs. The European Medicines Agency position clearly differs from that taken by the FDA and considers a biosimilar not identical to the innovator product because of the potential for differences in efficacy, biological activity and mechanism of action, even though molecules may be similar in terms of therapeutic equivalence.

Problems with pharmacokinetic study

Enoxaparin, with a molecular weight of about 4,200 dalton, is manufactured by alkaline beta-eliminative cleavage of the benzyl ester of heparin obtained from porcine intestinal mucosa. The complexity surrounding the approval of the generic version by the FDA stems from the complexity and the heterogeneity of the enoxaparin molecule. About 70% to 80% of the polysaccharide chains have between two and 12 sugars and have been fully characterized. The other 20% to 30% have more than 12 sugars and are not yet fully characterized, due primarily to technological hurdles and the large size of polysaccharide chains.

Due to difficulties in the physical detection of LMWHs, conventional pharmacokinetic studies cannot be performed. Instead, the absorption and elimination of LMWHs are studied by using pharmacodynamic tests, including the measurement of anti-FXa and anti-FIIa activity. The heterogeneity of LMWH is high, the mode of action is not completely understood and it is uncertain whether the physical detection markers are representative of the clinical outcome.

The European Medicines Agency currently has a requirement for adequately powered, randomized, double blind clinical trials to be conducted for every indication for which approval is sought. This would establish comparable efficacy and safety profiles for biosimilars and their branded counterparts. From a cost perspective, biosimilars, similar to generics, can provide an advantage of approximately 30% to 90% more than the cost of the innovator product. However, the cost advantage of these products compared with the innovator products becomes questionable if they have to undergo extensive, expensive clinical trials to get approved.

The five criteria the FDA used to establish the similarity of Lovenox and the approved generic enoxaparin sodium are:

• Equivalence of heparin source material and mode of depolymerization.
• Equivalence of physiochemical properties.
• Equivalence in disaccharide building blocks, fragment mapping and sequence of oligosaccharide species.
• Equivalence in biological and biochemical assays.
• Equivalence of in vivo pharmacodynamic profile.

This means that the generic version is completely substitutable with Lovenox for all of the indications for which it has FDA approval.

The three currently approved LMWHs are manufactured using different methods of heparin depolymerization; have distinguishable chemical and pharmacological properties; and hence, are not interchangeable as per the recommendations of the FDA, WHO and the American Heart Association.

Concerns with generic enoxaparin

Generic versions of enoxaparin are being used in many countries such as Brazil, Argentina, India and China. Most likely, the scientific basis for granting market approval for generics is the combination of their in vitro biochemical properties and pharmacodynamic profiles in healthy human volunteers. Some of these international generic versions have already been withdrawn by their manufacturers and/or regulators because of severe adverse events observed, although few details are available regarding the specific reasons for the withdrawals. These events led to the issuance of a consensus statement by the North American Thrombosis Forum on preapproval steps to be considered and/or implemented to assure both the safety and efficacy of follow-on biologics and generic LMWHs.

The concerns regarding biosimilars are many. The variability in quality, activity, contamination and stability must be addressed for individual products by the biosimilar manufacturers. Immunogenicity and the lack of adequate pharmacovigilance infrastructure in many countries is the biggest concern.

Moving forward, we will likely see many generic LMWHs approved for sale. It will remain a challenge for regulatory authorities to prevent another heparin contamination incident. The approval of generic enoxaparins should serve the primary purpose of cost containment without compromising patient safety. An active pharmacovigilance program will help to identify and monitor the safety and efficacy of these less expensive versions of enoxaparin.

Aparna Yerramilli, PharmD, is an associate professor at Sri Venkateshwara College of Pharmacy, Madhapur, Hyderabad, India.

Rhonda M. Cooper-DeHoff, PharmD, MS, is an associate professor at the University of Florida College of Pharmacy in Gainesville, Fla. and is the column editor for Cardiology Today’s Pharmacology Consult.

For more information:

• Harenberg J. J Thromb Haemost. 2009;7:1222-1225.
• Jackson CM. Clin Adv Hematol Oncol. 2010;8:163-167.
• Kalodiki E. Clin Appl Thromb Hemost. 2011;17:136-139.
• Ofosu F. Clin Appl Thromb Hemost. 2011;17:5-8.