Why does the FDA authorisation of the first generic Lovenox, Enoxaparin Sodium Injection, cause so much interest these days?

THE FACTS:specific guideline in March 2009 which illustrates in
On July 23, 2010 the U.S. Food and Drugdetail which data are expected for a biosimilar LMWH.
Administration FDA approved the first generic versionThis guideline requires a PK/PD study in healthy
of Lovenox (enoxaparin sodium injection), anvolunteers plus a clinical efficacy/safety study in
anti-coagulant drug used for multiple indicationspatients being relevant for the clinical use of LMWH
including prevention of deep vein thrombosis. FDAsuch as those undergoing major orthopaedic surgery.
approved an abbreviated new drug applicationThe FDA has acknowledged the fact as well that
(ANDA) for Sandoz‘ product which is a genericenoxaparin is a biologically-derived product while
version of Lovenox, approved for Sanofi-Aventis incommenting on the approval of the first generic
1993. Enoxaparin, the active ingredient of Lovenox, isenoxaparin since it referred to the fact that the
a low molecular weight heparin (LMWH) withprocess can be more complex for a natural product.
approximately 4500 Da manufactured from heparinDespite this, FDA considered it justified to base the
by alkaline beta-eliminative cleavage of the benzylapproval of this biologically-derived product on the
ester of heparin. Other LMWHs are authorised whichANDA legal pathway which is nothing else than
use different methods of heparin depolymerisation.approving it with the criteria applied for a common
The heparin underlying the manufacture of LMWHs ischemical generic drug for the evidence of sameness.
derived from natural sources, mainly porcine intestine.FDA has, however, taken into account the nature of
The generic was developed by Sandoz and Momentaenoxaparin specifically in their review by adapting
Pharmaceuticals and applied for FDA approval in 2005these criteria by the following five criteria:
already. Prior to the approval, the FDA also had to1. Equivalence of heparin source material and mode of
review a citizen petition questioning the approvaldepolymerization
criteria for generic enoxaparin sodium injection and2. Equivalence of physiochemical properties
determined in response to it that it had a sound basis3. Equivalence in disaccharide building blocks, fragment
for the approval.mapping, and sequence of oligosaccharide species
All primary information related to the FDA decision4. Equivalence in biological and biochemical assays
including the approval letter and the response to the5. Equivalence of in vivo pharmacodynamic profile
citizen petition can be found here. 
On August 17, 2010, a U.S. federal judge hearing isThese five criteria would have been part of a
hold in response to Sanovi-Aventis‘ lawsuit filedEuropean dossier as well. The first three criteria are
against the FDA on July 26, 2010. It says that theused to ensure that the heparin source material, the
FDA has exceeded its authority given by thechemical reaction used in the manufacturing process,
mechanism of ANDA approval.and the structure (the distribution of molecular
THE ISSUE:weight, chemical composition and sequence) of the
Enoxaparin remains a biologically derived productactive ingredient, enoxaparin sodium, in the generic
despite the semi-synthetic manufacturing steps useddrug product is equivalent to that in the brand name
to depolymerize the heparin from which it iscounterpart, Lovenox. The difference lays in the
produced, the resulting low molecular weight and theinterpretation of the fourth and fifth criteria. FDA
structure which is possible to be well-characterised byused them to require the applicant to ensure that the
analytical methods. Products derived from a biologicalgeneric enoxaparin sodium has the same degree of
source are by definition complex, difficult to fullyanticoagulant activity as Lovenox. And based on all
characterise by analytical means and the relationshipthese five criteria FDA considered that the generic
of structure with clinical effect and safety is difficultenoxaparin sodium has the same active ingredient as
to determine by non-clinical investigations only. This isLovenox.
common understanding. Accordingly, the basis ofIn the EU guideline on biosimilar LMWH, the criterion
approval of a generic version of a biologically-derivedfive is also included, i.e. the requirement to conduct a
product needs to take this into account. In the EU,study in healthy volunteers to investigate the
the legal articles determining the pathways forpharmacokinetic/pharmacodynamic properties. FDA
authorisation of a generic version of a product withdid, however, not insist on the conduct of a clinical
chemical/synthetic or biological origin are thusefficacy/safety study in patients reflecting the clinical
different – see article 10 of the EU-Directive 2001use of enoxaparin as it would have been the case in
83 as published here.the EU in addition to the five criteria. The study is
Furthermore, there is a difference in terminology:required in the EU due to the heterogeneity of
generics are chemical or synthetic drugs whereas theLMWH and the uncertainty on the relevance of PD
generic version of a biologically-derived product is tomarkers for the clinical efficacy.
be called a biosimilar. The difference is furthermoreBy the way, the EU guideline is intended to be utilised
supported by the requirements for the scientific datafor all LMWH applied for authorisation as biosimilars,
to be submitted. The approach to develop a biosimilarindependently of an eventually demonstrated
requires a comprehensive comparability packagehigh-grade similarity (EMA) or sameness (FDA) of the
which includes – most importantly in the contextactive ingredient by other means than clinical testing.
of this case – also the requirement to conductThus, it does require the same grade of data as the
clinical studies comparative in nature with theFDA did in this case but plus the clinical study in
reference product as the control arm. For LMWH, thepatients.
European Medicines Agency EMA has adopted a