Generic Lovenox & An FDA Precedent: Pan Explains
9 CommentsBy Ed Silverman // July 30th, 2010 // 9:35 am
Last week, the FDA issued one of those surprise product approvals by giving a thumbs up to a generic version of Lovenox, a widely used bloodthinner sold by Sanofi-Aventis, much sooner than most people expected (see here and here). The move is something of a game-changer for the pharmaceutical industry and so we spoke briefly with Jonathan Pan, a senior associate at the Scientia Advisors consulting firm, about the implications…
Pharmalot: Why is this approval such an important development?
Pan: Well, it’s a $4 billion product for Sanofi-Aventis. That’s one reason it’s important. The second reason is the active ingredient is an extremely complicated molecule – a macro molecular that wraps around itself – which means it’s hard to characterize and hard to manufacture. So it requires a lot of technical expertise. Sanofi’s argument is that it’s too hard to make, that you can’t make the same exact molecule, although that argument is the same one that everyone makes about their biologic product…However, Lovenox is not a biologic like a protein or antibody. It’s much simpler but still relatively complex…Momenta and Sandoz somehow convinced the FDA that their product is equivalent in safety and efficacy to the original product without the need to fully characterize the structure and sugar changes in the active molecule.
Pharmalot: And there’s still no framework for approval.
Pan: Since there is no framework for regulatory approval for a biosimilar…the FDA is creating a precedent for a regulatory process…What’s most interesting is that, for a traditional small molecule, all I need to prove is that the chemical entity is equivalent and I can make an equivalent product. But this particular compound, which is a little more complex than a simple molecule with a fixed structure, is difficult to prove equivalence. So the FDA had to use some other proxy. What the FDA did was ask Sandoz and Momenta to create a robust clinical trial, although it was not as extensive as going through all three phases for a new product approval, but not as lacksadaisical as a small molecule generic. What people are trying to look at now is how much clinical trial work do I need to do without having to do all three phases? What is the minimum threshold on my product in order to show the FDA it’s equivalent to the original marketed product?
Pharmalot: What are the implications for all the players?
Pan: Until now, there have been assumptions that biologics may be too complex to characterize or understand. So there were barriers to entry. The companies, basically, saw this as a door to close off potential entrants to their markets and a means to extend the life of their products beyond the patent years….In this case, it’s not as though a purely generic company is manufacturing this. It’s really Novartis (which owns Sandoz). The large pharmas are also invested in this game to compete against each other… There is one caveat –Sandoz and Momenta filed this particular application under an ANDA. It’s almost a Paragraph IV filing in order to get a generic product. And the FDA doesn’t consider this class of product to be a biologic. So technically, it’s not a follow-on biologic. But what’s interesting is that using this particular route of approval creates a precedent for building out infrastructure for creating a follow-on or biosimlar approval process as mandated by health care reform. So if you’re a big pharma, you need to pay attention to that, of course.
Pharmalot: How so?
Pan: There are a lot of diff strategies one can employ…To protect themselves, bi g pharma will use the traditional protection process. They will create patent barriers either through new product formulations, new dosage formulations, new indications that are part of the labeling that grants exclusivity. Instead of saying a product is too complex to manufacture, I think the issue is coming down from the high clouds to the realm of a small molecule situation, where pharma companies have to play the old-fashioned line extension game.
Pharmalot: Are we likely to see many more, if not a flood of follow-on products now?
Pan: There were three different companies - Amphastar,Teva and Momenta - attacking the same point, and from what I hear, Teva is almost on the cusp of filing their particular product. As far as whether, this will be a floodgate, there may be a trickle at first. Once people understand the process. I think post-2012, most companies are going to start thinking about follow-on biologics…Remember, there are follow-on products elsewhere in the world. The US is unique. We don’t have the regulatory pathway allowing biosimilars. Epogen, for instance, is approved in Europe….
Most of the biologic patent expirations are coming in the next five to 10 years and to develop the infrastructure for those products, we’re in the right time for that now. It takes roughly five years to get a product on the market…so this is the perfect time for everybody in the market to start thinking about getting in the game. By then, the regulatory framework will likely be in place. Companies should be looking at this and gearing up for what eventually will be an avalanche that is coming…
Pharmalot: By the way, Is there any reason to think Sanofi might prevail in its lawsuit to stop the generic? (background here)
Pan: If I were the judge sitting on this case and thought Sanofi had a case, I probably would have enacted an injunction until Aug. 17, when the proceedings are to begin. So that tells me that at least the judge seems to indicate the FDA made a reasoable determination of equivalency of safety and followed guidelines for the generic approval process. I think Sanofi had no choice but to file the suit. It only makes good business sense and any delay they win is an obvious benefit for them. But the generic has more or less gained some traction in the market. I can’t predict which way it will go, but Sanofi’s argument may not hold water…
Nathan
Great interview Ed! This really is a groundbreaking event for the pharma industry. Given that more and more early R&D is devoted to biologics, this issue has major issues on healthcare costs over the coming decades.
However, I would caution (as does Pan) that Lovenox is far, far simpler than more biologics that are entering the market today. It will be interesting to see what sort of clinical trials are required. Given the emphesis on safety today, it almost seems to me that the FDA may require trials to be designed to show a similar safety profile to the brand-name drug. This would throw a wrench in things because frequently safety issues are not found durring the initial phase-III trial. (they come up post-market) In theory, the phase III for a follow-on-biologic may end up being more costly than the phase-III that was originally done for approval!
Jonathan Pan
At Scientia Advisors, we currently have an article describing some of the issues which surround bioproduction (http://www.scientiaadv.com/review_2010-06-02.php), and how the industry is taking some of the complexity out of the system, effectively reducing the barrier to entry by removing the “complexity” issue. The next set of questions will be how to determine equivalance to the marketed product. As Nathan pointed out, the Phase III for a follow-on product may be more expensive than the Phase III for the marketed product. But, the question will remain is the Phase III of a follow-on biologic be less expensive than the total clinical trial regimen required for a new drug to be approved. I think that will be very interesting in the next coming years.
Jonathan Pan
jpan@scientiaadv.com
http://www.scientiaadv.com
Mike Shifflet
It is too easy for tag along companies to put products on the market. The human body is extremely complex and for companies to just infer that there product is safe and effective because there product is similar to the initial product does not provide enought public saftey. Judges, politicians and the public will not understand this until patients suffer. We need to slow down, perform the studies and evaluate the data. People want to have cheap and quality together and it just does not work that way.
M. Black
Call me a Sat AM quarterback, but this “molecule” is mired with proverbial landmines due to the nature of molecules manipulated to
achieve the end product. It’s in these type of processes where good people to turn to the dark side. Keep it simple from the development stage to prevent quality products to hopefully come.
I do hope it is successful.
M. Black
JaT
“frequently safety issues are not found durring the initial phase-III trial. (they come up post-market)”
I guess no amount of testing prior to putting a drug to the public could eliminate the truth of Nathan’s comment, but having been given a new formulation, there is just no getting past that this is potentially a horrible situation for consumers. I would honestly never take a newly approved product again. Not that I believe there should be no new products - just, tweaking and labeling changes might occur based on consumer reports and there are not enough protections for early consumers. Consumers should be warned that they are being given something that has yet to be tested outside of controlled studies done on people who might have been chosen like a well selected jury.
You always hear that you should contact MedWatch, the drug maker, and your doctor if you have troubles with a drug. What happens next (in my experience) seems to be more to the benefit of FDA and drug makers than for the consumer. Give me something tried and true - the alternative is scary.
SteveM
Re: JaT
You got that right. Eli-Lilly completed about 80 clinical trials for Cymbalta based on a search at the FDA clinical trials site. Yet they only reported study results for about a dozen of the completed trials.
I inquired to FDA about what Lilly’s results reporting requirements were and was told, none…nada…zilch…zip. The drug companies are free to selectively report (or not report) whatever trial results they want. So who knows what they see that they don’t tell you?
My only advice is to do a web search on the drug name and “side effects” and see what pops up. Also check out the drug name at WebMD, select the User Reviews and do a sort on “low satisfaction”. The anecdotal inferences accumulate pretty quickly for the pharmaco-train-wrecks.
pharmavet
Steve, every macromolecular recombinant DNA protein pharmaceutical product has been “manipulated” to some extent. For example, Humalog is a rDNA analogue of naturally occuring insulin that is synthesized with amino acid substitutions at two places on one of the insulin peptide chains. The result is the same efficacy without the allergic side effects of pork or beef insulin. PEGASYS is a pegylated alpha interferon for Hepatitis C that is made by attaching a strand of polyethylene glycol (PEG) to the interferon molecule. Pegylation prevents the body’s immune system from destroying the drug before it works. These have been great advances in medicine.
Even small molecules, both chemically synthetic (e.g. Synthroid) and “natural” (e.g. Armour Natural Thyroid) are made as the salt of the natural molecule.
Dr. Talluri
It is a very informative interview.
However the question still lingers” Did the approval come through for enoxaprin as a generic or a biosimilar or an entirely different pathway?
I am not sure through which pathway this “GENERIC” from Sandoz/Momenta is approved. It is another version of the low molecular heparin derived from the pig intestine heparin–perhaps purified by different mechanism, or was it considered a biosimilar. From the interview I gather it may have been.
I expressed my thoughts and questions on this in my blog dated 23 July:
http://krishnaonlifelivingandmedicine.blogspot.com/2010/07/is-lovenox-drug-or-biologic.html
Regulatory approval process has to evolve constantly. That is the only way to catch up with the ever changing picture of pharmacological world. Approval of another version of enoxaprin is one of those momentous occasions perhaps, we all debate, learn and eventually help set up the guidelines for future reference.
Bingo
Sandoz product was approved through an ANDA (077857). It is an AP rated therapeutic equivalent to Lovenox.