Earlier in Nov 2012, Campaign for Affordable Trastuzumab (an association of breast cancer survivors, NGO’s and health activists) had addressed a letter to the Prime Minister demanding that appropriate measures be taken to ensure that Trastuzumab is made accessible and affordable to the general public. Prashant had blogged about it over here. Shortly thereafter Trastuzumab was recommended for CL by the health ministry and the DIPP is still deliberating the issue of CL.
As reported by Nivedita Menon of Kafila, in a fresh letter, the association of breast cancer survivors, NGO’s and health activists has urged the Commerce Minister to commemorate International Women’s Day 2013 with an announcement of CL for Trastuzumab/Herceptin.
 |
| Image from here |
The letter reiterated the need for affordable Trastuzumab, considering that the incidence of HER2+ breast cancer, especially among young women in India is increasing rapidly. Trastuzumab is priced at Rs. 55,000 to 75,000 per 440 mg dose and a recommended course of 12 injections is unaffordable even to some of the most affluent Indians. The letter stated “We are mystified by the delay in the issuance of a notification under Section 92 of the Patents Act to initiate the process of compulsory licensing for Trastuzumab”
The entire text of the letter can be accessed here. Following are some issues raised in the letter:
Patent hindrance
The letter states that the patent is hindering local manufacturers from investing and developing a biosimilar version of Herceptin.
A cursory patent check with Indian patent office website, shows that Trastuzumab is patented in India as IN205534 (which claims a composition comprising a mixture of anti-HER2 antibody and one or more acidic variants) and expires in 2019. Apart from this, I believe Roche is pursuing another patent application 7990/DELNP/2009 (which claims a product containing vinflunine and trastuzumab as a combined preparation for simultaneous, separate or sequential use in treating a neoplasm in a mammal). A pre-grant opposition for this has already been filed by Indian pharmaceutical alliance-IPA. It should be noted that some of approved labels suggest a combination therapy of Herceptin with other anticancer drugs for metastatic breast cancer.
Roche-Emcure deal
In the letter, the campaign lashed out at Roche stating that their voluntary price reductions from Rs.1.2 lakh to Rs 75,000 are merely means to stifle competition. The letter also stated that the there was nothing positive about the Roche-Emcure deal. To quote “Perhaps the Honourable Minister for Chemicals & Fertilisers was not aware of these details when he stated in the Lok Sabha that Roche would be bringing the price of Trastuzumab down to Rs.75,000/- per dose under an upcoming deal with Emcure for local manufacture. Considering that the present MRP of the drug is Rs.75,000/-, and it is already being offered by retailers for 55,000/- per dose, we fail to see anything to cheer about in the Roche-Emcure deal.”
On draft policy of Department of Pharmaceuticals
The letter expressed displeasure over the recent draft policy released by DOP on pricing of patented drugs. They criticized the price negotiation policy proposed by the Govt. entity and said that it completely ignores global experience with regard to price negotiation. Price reduction achieved by negotiation is much lesser than price reduction achieved by promoting generic competition. Citing the Thailand CL example the letter states that price negotiation methodology is time consuming and only yields short term benefits.
The letter concludes on a distressing note “We are disappointed that eight years later, despite sharp increases in the number and prices of patented drugs, the Government of India is so reluctant to use the provision of compulsory licensing under Sections 92 and 100 of the Patent Act to expand generic competition, bring down prices and expand access.”
Will we be able to traverse the technological barriers and yet offer a significant price reduction-?
As I have mentioned before, Herceptin is considerably more complex than some of the currently developed follow on biologics. The challenges in its development are manifold. Unlike traditional small molecule drugs, in biosimilar development “the process is the product” and each step is critical. Host cell type selected to express the protein, along with culture medium and growth conditions influence product characteristics and determine the safety and efficacy of the resulting product. A study comparing 11 epoetin products from Korea, China, India and Argentina revealed substantial differences in in vivo bioactivity ranging from 71% to 226% (due to variations in isoform distribution), with 5 products failing to meet their own specifications!
Even relatively simple traditional small molecule generics have faced several quality issues, so things get more and more complicated with biosimilars. As reported here, a paper by Bond and Saggi points out that, after Thailand issued a CL (for Kaletra; innovator: Abbott) the quality of generics developed by GPO-Vir was not up to the mark. Likewise after voluntary licensing efforts with Merck failed, Brazil issued CL for AIDS drug Efavirenz, but due to lack of technological expertise, they had to import the drug.
As this article rightly states “The friction between cost and patient care is rarely discussed by those who see biosimilar drugs exclusively as a cost-savings mechanism. But the blinders of cost-containment must never be permitted to obscure the twin therapeutic pillars of safety and efficacy.”
Also ,not everybody responds positively to Herceptin therapy, overexpression or amplification of HER2 is correlated with poor patient outcomes. It is therefore imperative to identify patients with HER2+ breast cancer and select patients who will benefit from Herceptin therapy, by using reliable diagnostic tests. This adds another dimension to cost effectiveness i.e. cost and availability of standardized diagnostic tests (especially the fluorescent in-situ hybridization (FISH) test) to identify the patients that will benefit from therapy.
The rigorous clinical trials for testing safety and efficacy entail a huge investment. Considering all this I believe that, the magnitude of price reduction, achieved by biosimilars (especially Herceptin) will be far lesser than their generic small molecule drug counterparts.
I must say that it is a quite one-sided piece which depicts a possible downside of CL strategy in India. Who said that a CL will automatically ensure quality production of generic and biosimilars? It nevertheless opens a window and licensees should thereafter comply with stringent regulatory requirements. If such requirements are not there, or lack implementation accordingly then it does not mean that CL strategy fails. If India cannot take a lead on this front with such a robust generic industry then we should simply dump the idea of a CL anywhere in the world. This is what IFPMA would like to see!
This is indeed a great piece Madhulika! Very comprehensive, covering all possible aspects of CL for Herceptin in India. I think you have clearly provided both sides of the matter. I am not sure if Anonymous has read the post properly! Personally I do not think IFPMA has more rights than DCGI (at least in India). So I guess if anyone wants to sell any drug product in India, it is up to DCGI to grant permission. It will be interesting to see how IFPMA plays a role here. I think you have clearly mentioned about the complications of a biosimilars. I have worked on combination product (long acting drug eluting medical devices) registration in India and clearly had a tough time convincing DCGI about the regulatory standards! I can clearly imagine all the possible problems with a biosimilar registration!
Anon:
Nature and complexity of invention play an important role in effective utilization of CL and I just wanted to say that in case of complex biosimilars like Herceptin, price reduction margin may be not be that significant.
If the price reduction margin is huge, we should ensure that we don’t end up compromising on safety and/or efficacy. There is nothing costlier than a failed therapy.
A robust generic industry –Yes we have , but robust biosimilars industry –I think not!
I am wondering whether this patent really covers Herceptin as sold in India. It claims composition of two Anti HER 2 Mabs, one being acidic variant. I suppose that would mean change of one or two amino acid sequence. But still, Is herceptin composition of two Mabs?I don’t think so. Though Heceptin itself is acidic or acidic variant of ‘parent’ Anti-HER 2 Mab.
Rahul:
If you read carefully this is not a composition patent at all, the patent in fact relates to a method of purification where a product molecule must be separated from a very closely related contaminant molecule (acidic variant).
The acidic variants are predominantly deamidated anti-HER2 antibody, with minor amounts of other acidic variants. In preparations of anti-HER2 antibody obtained from recombinant expression, about 25% of the anti-HER2 antibody is deamidated (contaminants).
Very cleverly worded-this patent claims a mixture of anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of the acidic variant(s) is less than 25%.
So in the manufacture of biosimilar Herceptin, you obviously have to ensure that the contaminant (acidic variant) percentage is less than 25% in order to meet safety and efficacy standards. If you go about doing that you will fall within the scope of this patent.
I would say that this patent very much covers Herceptin.
Madhulika
It is true that the patent basically pertains to process as mentioned in the “field of invention” part of the patent specification. But herceptin’s trastuzumab’s sequence itself is ‘”acidic” with said variations in the particular amino acid art specific positions. I have not come across herceptin’s process and composition as such (as indicated by you or in the patent) presented for regulatory submissions, over the internet, I will consult with our scientists and regulatory team to check how it actually goes in terms of “contaminants” in the actual Herceptin formulation. There is no explicit information on this.
Madhulika
I found out few chromatograms of Herceptin and its drug susbtance. Both show several peaks with respect to trastuzumab (in terms of mol. wt.) . I also checked its specs which shows various “impurities” which are actually variants and one of them is acidic variant (From peak). This is indeed Herceptin’s patent.
Rahul,
As expected 🙂
Thanks for confirming.