Sanofi-Aventis Sues The FDA Over Generic Lovenox
4 CommentsBy Ed Silverman // July 27th, 2010 // 8:05 am
Stunned by the FDA approval of a generic version of its best-selling Lovenox blood thinner, Sanofi-Aventis has filed a lawsuit in federal court, charging the agency with exceeding its authority, and acted arbitrarily and capriciously in granting Momenta Pharmaceuticals the right to market a drug (see background here).
In arguing its case, Sanofi claims the FDA is allowing a generic to be sold that is not similar in safety or efficacy to Lovenox, which generated $4 billion in sales last year. And so Sanofi is seeking a temporary restraining order to force the FDA to withdraw approval, which would prevent Momenta and its partner, the Sandoz generic unit of Novartis, from moving forward. Sanofi has moved aggressively before to thwart generic Lovenox, filing a citizen’s petition with the FDA in 2003 and again last year, although in that instance, the document was filed by scientists with ties to the drugmaker.
In a statement, a Sanofi spokeswoman says the drugmaker “believes the FDA approval of the Sandoz ANDA was not made in accordance with the agency’s statutory obligations. The company believes that this case poses a number of significant questions regarding the FDA review process for complex pharmaceutical products which are important to pursue.”
For instance, the lawsuit and accompanying memorandum claim the FDA dismissed, “without any rational justification or analysis, a wealth of scientific evidence establishing that small variations in the manufacturing process used to create low-weight molecular heparins (such as Lovenox) can result in significant changes to the structure and pharmacological properites of generic versions of the drug.”
A status conference was held yesterday and, according to a statement from issued this morning by Momenta, US District Court Judge Emmet Sullivan did not place any restrictions on the sale of Lovenox.
pharmavet
No TRO = weak case.
pharmavet
On the other hand, when in doubt, read the document. Based on historical precedent Sanofi may have a compelling argument. To quote the suit:
“This manufacturing process creates a highly complex collection of macromolecules with a chemical structure unique among branded LMWH’s currently on thwe market”.
This is very similar to the approach that American Home Products (aka Wyeth, aka Pfizer) took in defending Premarin against generic competitors for many years. The strategy was extremely successful, since no synthetic preparation could exactly replicate the combination of active and inactive ingredients in pregnant mare’s urine. As in the case of the LMWH’s it was a combination of both the ratios of the estrogen components in Premarin as well as their combination and activity in toto that made it impossible to synthetically replicate.
This created the legal and regulatory justification for keeping generic Premarin off the market for many years. If this is the basic approach embodied in the Sanofi lawsuit, they may have a shot at winning.
anonymous
Only if you believe that the end of the day Momenta and Sandoz did not fully characterize Lovenox and their generic is not a complete replication.
It isn’t like they haven’t had several years to work on it now!
Henriette
It´s definetly a hot topic! We just discussed it in our blog, too:
Why does the FDA authorisation of the first generic Lovenox, Enoxaparin Sodium Injection, cause so much interest these days?
Enoxaparin remains a biologically derived product despite the semi-synthetic manufacturing steps used to depolymerize the heparin from which it is produced, the resulting low molecular weight and the structure which is possible to be well-characterised by analytical methods. Products derived from a biological source are by definition complex, difficult to fully characterise by analytical means and the relationship of structure with clinical effect and safety is difficult to determine by non-clinical investigations only. This is common understanding. Accordingly, the basis of approval of a generic version of a biologically-derived product needs to take this into account. In the EU, the legal articles determining the pathways for authorisation of a generic version of a product with chemical/synthetic or biological origin are thus different – see article 10 of the EU-Directive 2001/83 as published here.
Furthermore, there is a difference in terminology: generics are chemical or synthetic drugs whereas the generic version of a biologically-derived product is to be called a biosimilar. The difference is furthermore supported by the requirements for the scientific data to be submitted. The approach to develop a biosimilar requires a comprehensive comparability package which includes – most importantly in the context of this case – also the requirement to conduct clinical studies comparative in nature with the reference product as the control arm. For LMWH, the European Medicines Agency EMA has adopted a specific guideline in March 2009 which illustrates in detail which data are expected for a biosimilar LMWH.
This guideline requires a PK/PD study in healthy volunteers plus a clinical efficacy/safety study in patients being relevant for the clinical use of LMWH such as those undergoing major orthopaedic surgery.
The FDA has acknowledged the fact as well that enoxaparin is a biologically-derived product while commenting on the approval of the first generic enoxaparin since it referred to the fact that the process can be more complex for a natural product. Despite this, FDA considered it justified to base the approval of this biologically-derived product on the ANDA legal pathway which is nothing else than approving it with the criteria applied for a common chemical generic drug for the evidence of sameness. FDA has, however, taken into account the nature of enoxaparin specifically in their review by adapting these criteria by the following five criteria:
1. Equivalence of heparin source material and mode of depolymerization
2. Equivalence of physiochemical properties
3. Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species
4. Equivalence in biological and biochemical assays
5. Equivalence of in vivo pharmacodynamic profile
These five criteria would have been part of a European dossier as well. The first three criteria are used to ensure that the heparin source material, the chemical reaction used in the manufacturing process, and the structure (the distribution of molecular weight, chemical composition and sequence) of the active ingredient, enoxaparin sodium, in the generic drug product is equivalent to that in the brand name counterpart, Lovenox. The difference lays in the interpretation of the fourth and fifth criteria. FDA used them to require the applicant to ensure that the generic enoxaparin sodium has the same degree of anticoagulant activity as Lovenox. And based on all these five criteria FDA considered that the generic enoxaparin sodium has the same active ingredient as Lovenox.
In the EU guideline on biosimilar LMWH, the criterion five is also included, i.e. the requirement to conduct a study in healthy volunteers to investigate the pharmacokinetic/pharmacodynamic properties. FDA did, however, not insist on the conduct of a clinical efficacy/safety study in patients reflecting the clinical use of enoxaparin as it would have been the case in the EU in addition to the five criteria. The study is required in the EU due to the heterogeneity of LMWH and the uncertainty on the relevance of PD markers for the clinical efficacy.
By the way, the EU guideline is intended to be utilised for all LMWH applied for authorisation as biosimilars, independently of an eventually demonstrated high-grade similarity (EMA) or sameness (FDA) of the active ingredient by other means than clinical testing. Thus, it does require the same grade of data as the FDA did in this case but plus the clinical study in patients.
The European Directive defining the legal pathways of a generic and biosimilar product requires differentiation based on whether the product is chemical or biologically derived. To acknowledge the fact that the sameness of biologically-derived products could not fully be proven based on analytical tests or surrogate PK/PD markers – therefore also the term similarity is used instead in the EU. However, reading the EU Directive again and again, there might be room for interpretation, i.e. when a biological fulfils the definition of a generic product given there. This has not yet been proven for an even less complex biosimilar than enoxaparin such as growth hormone but may be the case for the future?