Can the Reference Biologic manufacturer, file an ANDA for a Follow-on?

Question asked on Linked in:
Following patent expiry, can the Reference Biologic manufacturer, file an ANDA for a Follow-on? Does competition need always to come from outside?

Commented as follows:

Christopher O. • First, in the US the notion of an ANDA for biologics is not applicable, especially after enactment of the Biologics Act in 2010. Nor are applications under 505(b)(2) generally permisssible for "biologic products" under the new Act.

A reference product sponsor can always "rebrand" its product or change its pricing to compete with follow-on manufacturers, either before or after patent expiry. Given its investment in its brand and the probable small reduction in price, accompanied by a reduction is profit, it is hard to imagine why such a sponsor would ever choose to do so.

In the small molecule world, where pricing is very diiferent and volume more important, "authorized generics" have become a significant part of the market. It seems unlikely that, for the forseeable future, a reference product sponsor would create an "authorized follow-on biologic" to market at the same time as its reference product (especially since the follow-on would likely have the same labelling as the reference product, perhaps apart form a trade name, and the marketing effort would away from product differentiation to demonstrate interchangeability).

Neha P. • Thanks for clarifying Christopher. It seems the referece sponsors do not face as big a threat if the possibility of "rebranding" exists (if ever needed). However, I am still a bit unclear on the ANDA issue, was not Enoxaparin (Sandoz) approved under one in the US?

Michael A. S. • Enoxaparin was not originally approved under a BLA, but an NDA. Thus, an ANDA is possible if, as Momenta/Sandoz persuaded FDA, they could show that their active ingredient was the "same" (not similar as under the new Biosimilars law) to the branded product.

Hareesh P. • @ Neha - Chris did answer your question well. Just wanted to add another perspective, whenever the Innovator gets into authorized generics they do so thru' their generics team (ex. Sandoz for Novartis, Hospira for Abbott etc) and they do with a branded generic or a generic name and diff packaging via a diff field force. Also, one of the practices in the industry is to source the authorized generic thru' an alliance or contract the mfg out ...essentially both the Innovator product and authorized generic are not manufactured from the same site. Guess with Biologics, as we move forward there would emerge the concept of "Authorized Biosimilars" too .... but it is still early days !!!

Atul S. • I agree in wholesome with Christopher, @Hareesh, the process is anyway downstream in striking cost efficiencies, which will follow similar patterns but would be very slow in pace or you may never know it would be a similar-similar of Biosimilar to the ref products.....!!

Christopher O. • It is correct that Sandoz' enoxaparin product was approved based on an ANDA, and that the FDA found sufficient "samness" to permit a finding that the the active ingredient in the generic drug product is the same as the active ingredient in the RLD.

In response to Aventis' citizens petition, objecting to that approval, the FDA said that "an ANDA applicant for generic enoxaparin must provide sufficient
information to show that the generic drug product contains the "same" active ingredient (enoxaparin) as Lovenox. We have concluded, based on our evaluation of current data and other current relevant scientific information and our scientific experience and expertise, that the following five criteria (or standards for identity) together provide suffcient information to conclude that generic enoxaparin has the "same" active ingredient as Lovenox:

Equivalence of physicochemical properties

Equivalence of heparin source material and mode of depolyierization

Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species

Equivalence in biological and biochemical assays

Equivalence of in vivo pharacodynamic profile ..."

The FDA went on to discuss each of these factors in great detail.

The factors that the FDA may use to assess "sameness" of two other future products may well be different. But the enoxaparin approval may serve as a guidepost for determinations of "sameness" of future products that are not primarily manufactured using cell-based techiques, no matter how large.

It is important to note that, in very recent comments about the FDA's future regulatory approach to biosimilars applications, an FDA official specifically referred to the enoxaparin approval (suggesting to me that it may be a model, even for applications under the Biologics Act).

After enactment of the Biologics Act, with narrow exceptions, an application for approval of a "biological product shall be submitted" under the terms of the Act, and not under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) (i.e., not as an NDA, ANDA or a 505(b)(2)). A "biological product" is defined by 42 USC 262(i), as "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide)or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings."

As I understand what the FDA has said about enoxaparin, it is manufactured through depolymerization of heparin, which, in turn, is prepared by processes involving extraction from animal tissues (i.e., porcine intestinal mucosa or bovine lungs).

It could be that, at the time Lovenox was approved under an NDA, a regulator may well have judged that, because it is a low-molecular-weight heparin, enoxaparin is something other than a "biological product" within the statutory definition set forth above. I haven't reviewed the Lovenox NDA approval (NDA 20-164) to learn why the FDA approved it under an NDA rather than a BLA, or wther the issue was even considered. Once Lovenox was approved under an NDA, it makes some sense for an application for approval of a generic equivalent to have been made and approved under an ANDA. I am not sure how frequently this might occur in the future, at least for products that, whatever their molecular weight or structure, are not manufactured solely using chemical synthesis (including synthetic biological techniques).

So, it would seem that your question is far from naive and may have been more complex than my initial response suggested. I hope this discussion has been helpful.

As always, the views expressed jn this post are mine alone, and do not necessarily reflect the views of my law firm, Schiff Hardin LLP, or any of its partners or clients.

Neha P. • Thanks a lot everyone for your input. This discussion was certainly helpful.

Atul S. • @ MR Cristopher, in isolation (or for that matter for Enoxaparin) or any heparin product still is a bit different in terms of its source (production), I suppose things would be entirely different in other cases of big molecules.

Ronald A. R. • I think it very possible we may see more "authorized" biosimilars and true biogenerics in the U.S. and other major markets than most presume.

For example, if I headed a reference product manufacturing/marketing company with a biologic facing U.S. patent and data exclusivity expiration, I'd seriously consider having one or more U.S. licensees or captive/related/proxy companies bring out a biosimilar/biogeneric, and even meet or slightly beat the price of competing biosimilars. This way, the competition never gets traction in the marketplace, while I retain dominant market share. As the ref. product manufacturer, I would presumably have at least a decade of experience making the product, fully paid-off manufacturing facilities, economies of scale and low manufacturing costs that few, if any, upstart competitors will be able to beat. In this context, rather than lose say 20-40% (pure guesses) sales of my ref. product to biosimilar competitors, I can price the competition out of the market (particularly, if mine is a genuine interchangeable biogeneric), and perhaps even prevent competitors from bothering to develop competing biosimilars. Yes, my profit margins will go down due to the cheaper biosimilar/biogeneric, but probably not as much if I were to allow others to launch biosimilars. Why would I want to allow others to disrupt my monopoly on the product? For example, in the context of facing serious competition in the U.S market, would Amgen (and J&J) really lose much by bringing out its own biosimilar/biogeneric version(s) of EPO? I think it very possible that given the alternative - multiple competing biosimilars - a reference product company can make more profit by retaining its reference product monopoly vs. losing both substantial revenue and commanding market share to biosimilar competitors.

Am I off-base in my reasoning?

Neha P. • Hi Ronald, actually that is exactly the kind of thought process that led me to pose the question. I agree to you completely. A reference sponsor does not seem to lose too much, if the cards are played right.

Christopher O. • Although it is only a matter of opinion, at this point, I disagree with the suggestion that a reference productmanufacturer will "lose say 20-40%" of sales of a reference product to biosimilar competitors. It will be much greater, although the price drop will not be as significant as such "branded" manufacturers have experienced with Hatch-Waxman generics. Any price decrease, particularly if bosimilars are demonstrated to be nearly as effective as the reference products (or maybe better), with similar levels of safety/toxicity, the formularies will shift prescriptions, to the extent that they can effectively exert economic force, from a reference product to a biosimilar. If a biosimilar is deemed by the FDA to be an "interchangeable," the effect will be more pronounced.

In the Hatch-Waxman world, the shift, because of Medicaid/medicare through the formularies, is 80%. Authorized generics probaly account for more than 10% of total sales, at a price higher than generic small-molecule drugs, but lower than the reference product.

If a similar pattern appears with biosimilars, understanding of the obtacles to direct competition that will likely exist as a result of potential labelling and other regualtory requirements, the share of the market that may be capture by biosimilars is likely to be much greater than 20% - 40% of the reference product sponsor's sales. I believe that experience in the EU with biosimilars may support this estimate See, e.g., http://www.urchpublishing.com/articles/biosimilars_should_capture_significant_share_biologicals_market_europe.html and http://decisionresources.com/News-and-Events/Press-Releases/BAS-11410-(1).

It is the fear of such market degradation that is at the root of efforts by reference product sponsors to obain a lengthy data exclusivity period, or multiple exclusivity periods, and to seek exacting FDA regulation of biosimilars (such as requirement in all cases for many and expensive human clinical trials).

As always, the views expressed in this post are mine alone and do not necessaarily reflect the views of my law firm, Scchiff Hardin LLP, or any of its partners or clients.