Pegasys earned the distinction of being one of the first MNC pharma patents to be granted in India in the wake of the 2005 amendments.The point of this post is not to assess the validity of the patent, but to ask as to why no compulsory license has been filed as yet? After all, the patent was granted in 2006 and 3 years have already elapsed. The patent is not being worked in India, as the product is merely imported from Switzerland. An ideal case for one of our generic majors to have taken a shot under section 84 and applied for a compulsory license (CL)?
Unfortunately, none have done so till date…. despite the huge windfall likely to be generated from this drug.
Apparently, “patients with chronic Hepatitis C, who need a six-month course of treatment of pegylated interferon alfa2a, have to purchase it at a cost of approximately Rs. 4, 36,000 [USD 8,752.38 ] (available at a discounted price of Rs. 3, 14,496 or USD 6,313.28 ).”
The market is clearly a lucrative one. The shot under section 84 (claiming a compulsory license under since the patent is not being “worked” in India) is a plausible legal shot. Why then are companies refraining from going this route?
Perhaps CL is too lame an option for our companies? Why then have they not undertaken a brazen “at risk” Cipla strategy and introduced a low cost drug in the market claiming refuge under “public interest”. And perhaps even mounted a serious challenge to the validity of the patent and claimed the non-existence of a strong prima facie case, as would warrant a temporary injunction?
What ails here? Are the Indian generics (apart from Wockhardt, which is now experiencing its own set of financial troubles) not competent enough to come up with a follow on biologic version? Is it too expensive? Do regulatory hurdles pose a problem? Is there an abbreviated pathway that the DCGI follows to assess the safety and efficacy of a follow on biologic?
Or is there something wrong with our compulsory licensing machinery? Is the procedure too complicated and cumbersome that Indian companies do not even want to touch it with a barge pole?
Natco did face the brunt of the system earlier on in its enthusiasm to be the first Doha licensee in India. Unfortunately, Natco failed..not because the CL procedure was cumbersome or faulty, but because Natco’s application itself was faulty i.e. Nepal just did not bother with issuing any notification suggesting a public health problem as would warrant supplies of the drug from India.
Or does this inaction have to do with a simple “invent around” strategy that is being worked out with the help of British scientists and the Indian government?
Perhaps some of our insightful readers can shed more light on this issue. For if we don’t crack this simple riddle, we’ll end up barking up the wrong tree and claiming that the Indian CL procedure is to blame.
Solving this puzzle will also help the DIPP come up with more nuanced policy suggestions for compulsory licenses (they’ve got their figures wrong in several paragraphs of their well crafted and researched note, but have articulated the legal issues and concerns quite well).
Or perhaps we needn’t bother wasting our time with such issues…for these are nothing more than flights of fancy…on the wings of a mythological horse..
Dear Shamnad,
yes you are right, in fact, 3 years since the patent was granted, it is surprising to see no Indian company opted for CL….DIPP has invited comments from stakeholders regarding draft paper on CL….let’s see how we respond to comments now….we keep on shouting for CL must be used, but when opportunity knocks at the door, nobody comes forward….then why shout on high prices on such products, when remedial measures have been there to counteract such prices….
Tks Manish,
In fact, if one takes a look at the list of pharma patents that are on the IPO website now (http://www.patentoffice.nic.in/iponew/Patent_PharmaProduct_2005_06_2009_10.pdf)
one will find that there are more than 500 pharma patents granted before September 2007! Even assuming that there are 50 pharma products corresponding to these 500 applications and about 10 drugs that are really market worthy to go after, its surprising that not a single CL has been applied for!
I particularly want share some of my experiences of those days when I was working as a scientist in a Biologics Research unit in a well known Indian generic company. I want to through some light on crucial aspects affecting business of Biotech drug industry.
Although, I am chemistry graduate with post graduation in Bio-analytical sciences, I have handled both Biotech and Pharma (chemically synthesized drugs & their formulations) Patenting work in my next career. Thus, it strongly encouraged me to touch the subject from other angles also rather than restricting our views in discussing only on possibility of complications in legal provisions of patent act which are bothering Indian generic companies.
Making Biosimilars for Biotech molecules (Biologics) is totally different than the drugs produced by chemical synthesis. Though, India has a “so called” good lab set up and state of art infrastructure for biotech research, most of the times reproduction of the “lab scale research results” at manufacturing site is very difficult. Especially, the biotech drugs manufacturing has never been so easy. There are so many hidden secretes which are never disclosed in the patent disclosure. The patent law also does not mandate for such disclosure as they are so minute and are generally considered as known things to a person skilled in the art. One can not produce a batch scale quantity by simply reading the patent. There are no. of factors which decides the way in which these molecules behave. Even a minute change in manufacturing conditions impact a lot.
One can argue that the same is true with the chemically synthesized drugs. I absolutely agree with such opinions. Up to some extent, it is accepted if these changes affect only the final yield. But, if such changes affect the quality of product, then it is very difficult to go ahead with the consistent manufacturing. Unlike chemical industry, when we talk about biotech industry, a highly qualified scientist or a highly experienced and skilled person also most of the times feel helpless in the mysterious behavior of the biomolecules.
Continued………
……..Continued
Below are the very few and simple examples which show the challenges in consistent reproduction of Biomolecules:
1. A minute deviation in pH (from the set limit) of a solvent used in particular step of processing can result to denaturation of a biomolecule.
2. Chromatography is the widely used technique for purification of biomolecules. In case, the stationary phase material used in the chromatographic columns is changed or the water/solvent used in mobile phase is purchased from different vendor (although, it is of same quality) the yield as well as the quality of the product changes.
3. The most important observation is regarding the assay of the product. For deciding the shelf life of a product, its degradation pattern and assay is monitored under controlled conditions for certain period. But, it is seen that the Biomolecules show mysterious “Zic-zic” pattern (as opposed to normal linear degradation pattern). Reasoning of such unexpected outcomes is very difficult, lengthy and many times unexplainable.
Above are the very few examples. There are lot many things which seems minor, but actually are of great importance.
These things may result in considerably lengthy period required for registration of “safe and effective biologic drug” to FDA.
The cost of production in Biologics is also very high as opposed to chemically synthesized drugs. I have seen the company investing crores of Rupees at research stage for production of just 1.5 liters batch of a biologic drug.
The company can easily manufacture no. of chemically synthesized drugs in a year in the same manufacturing facility by alternatively switching over the production of those drugs (as per market requirements).
But, in case of Biologics, frequent switching over may lead to complications with respect to yield and quality. Thus, you need lot of time, dedicated efforts and lot of money to overcome all these difficulties and for producing Biologics with consistent yield and consistent quality.
Thus, in my opinion the major concern of generic companies is financial wealth and manufacturing difficulties and not the so called compulsory complications. In fact, it is a one of the attractive opportunity given to generic industry.
I see two probable reasons!
One could be that Generics the so called “Savior of Public” do not have the courage to file CL for the simple reason that it might amount to admission of validity of the patent. If they fail to get CL for some reason, they might loose their right to challenge the validity of the patent in a counter claim when the patentee sues for infringement.
The second reason could be why take the trouble of getting CL when our Courts as well as Government are ready to grant them FREE LICENSE!
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Parag has given a good understanding of the technical issues and Varun also touched upon few others. My post below will be an add-on. I will randomly touch upon some superficial aspects. I am slightly off topic from Compulsory Licensing which is the subject matter of the post, but this will give you some idea about why companies will tread with caution when it comes to manufacturing generic biopharmaceuticals (biosimilars) irrespective of the fact that the product is off-patent or available for CL
IP issues for a biopharmaceutical product are very complex. There may be patents on nucleotide sequences, amino acid sequences, promoters, expression systems, manufacturing process, formulation, platform technologies etc. Each of these can potentially block competitors. Even if the patent expires it will be very difficult to exactly replicate the teachings of the patents, especially the process patents. That is the reason a biopharmaceutical generic can never be identical, it can only be similar. Hence the name biosimilar. Performing an FTO for biopharmaceuticals is a very tough job. It becomes more difficult when your end product uses lot of platform technologies and is having several components (for example a multivalent conjugate vaccine).
There are many difficulties associated with manufacturing biosimilars. Biopartners application for marketing approval of biosimilar interferon was rejected by EMEA after reviewing for over an year citing CMC concerns. Establishing how similar a biosimilar is a major issue since you do not have all the minute know-how of the process of the innovator. Indian regulators do not have stringent approval process. There are published reports that Streptokinase from Indian manufacturers is of substandard quality. I know of another biosimilar molecule being sold in the market with lot of impurities. Developing a biosimilar is time consuming too. It will take at least 3-4 years to commercialize a biosimilar product. Unfortunately you will also face several bottlenecks in your way!
Pegylated interferons (in general):
There are two pegylated forms of interferons in the market pegasys (Roche) and peg-interon (Schering). The oldest patents related to pegylated technology are held by Enzon which were licensed by Schering. Roche also has some patents related to pegylation chemistry. Schering & Roche fought for several years in US before cross-licensing their patents which put an end to the dispute. There are also patents related to formulation of both pegasys and peg-interon (I know of one filed in India too). There is lot of intricate chemistry involved in pegylation. Moreover yield of pegylated protein is also another major issue I have noticed. Although these patents will not come in the way especially in India, and with the availability of CL provision in Indian Patent Act, the only reason I can attribute in not coming out with a biosimilar version of this molecule by Indian Cos is the complexity associated with biosimilars in general, and peg-ifn in particular.
Indian companies having strong R&D teams can only take up the challenge of producing a biosimilar product. You also need to invest a lot in the manufacturing facilities. I know of few pharma companies who faltered after entering into BT bandwagon without realizing the true nature of biotech molecules.
Sy
not able to publish my long comment
Part1
Parag has given a good understanding of the technical issues and Varun also touched upon few others. My post below will be an add-on. I will randomly touch upon some superficial aspects. I am slightly off topic from Compulsory Licensing which is the subject matter of the post, but this will give you some idea about why companies will tread with caution when it comes to manufacturing generic biopharmaceuticals (biosimilars) irrespective of the fact that the product is off-patent or available for CL
IP issues for a biopharmaceutical product are very complex. There may be patents on nucleotide sequences, amino acid sequences, promoters, expression systems, manufacturing process, formulation, platform technologies etc. Each of these can potentially block competitors. Even if the patent expires it will be very difficult to exactly replicate the teachings of the patents, especially the process patents. That is the reason a biopharmaceutical generic can never be identical, it can only be similar. Hence the name biosimilar. Performing an FTO for biopharmaceuticals is a very tough job. It becomes more difficult when your end product uses lot of platform technologies and is having several components (for example a multivalent conjugate vaccine).
There are many difficulties associated with manufacturing biosimilars. Biopartners application for marketing approval of biosimilar interferon was rejected by EMEA after reviewing for over an year citing CMC concerns. Establishing how similar a biosimilar is a major issue since you do not have all the minute know-how of the process of the innovator. Indian regulators do not have stringent approval process. There are published reports that Streptokinase from Indian manufacturers is of substandard quality. I know of another biosimilar molecule being sold in the market with lot of impurities. Developing a biosimilar is time consuming too. It will take at least 3-4 years to commercialize a biosimilar product. Unfortunately you will also face several bottlenecks in your way!
Sy
Part2
Pegylated interferons (in general):
There are two pegylated forms of interferons in the market pegasys (Roche) and peg-interon (Schering). The oldest patents related to pegylated technology are held by Enzon which were licensed by Schering. Roche also has some patents related to pegylation chemistry. Schering & Roche fought for several years in US before cross-licensing their patents which put an end to the dispute. There are also patents related to formulation of both pegasys and peg-interon (I know of one filed in India too). There is lot of intricate chemistry involved in pegylation. Moreover yield of pegylated protein is also another major issue I have noticed. Although these patents will not come in the way especially in India, and with the availability of CL provision in Indian Patent Act, the only reason I can attribute in not coming out with a biosimilar version of this molecule by Indian Cos is the complexity associated with biosimilars in general, and peg-ifn in particular.
Indian companies having strong R&D teams can only take up the challenge of producing a biosimilar product. You also need to invest a lot in the manufacturing facilities. I know of few pharma companies who faltered after entering into BT bandwagon without realizing the true nature of biotech molecules.
Sy
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Dear Parag, Varun and Anon:
I must thank you all profusely for raising the quality of discussions on this blog. Sadly, of late, comment quality has taken a serious dip and I’ve been thoroughly disheartened and demoralised….as one of the purposes of this blog was to really engender discussions and critical thinking on various IP issues.
I always knew that we had a wonderful reservoir of extremely talentend and insightful commentators…Varun Chhonkar, Aditya Kant and Yogesh Pai are names that come immediately to mind…sadly many others are averse to revealing their names and post as anonymous.
I felt that that if this fine medley of IP stakeholders put their heads together, we would revolutionise IP policy in this country. With this latest bunch of well thought out and articulated comments, you’ve more than vindicated my belief and I have much to thank all of you for.
From your various comments, two key issues stand out. Firstly you’ve highlighted the difficulty of creating and manufacturing follow on biologics of a good enough and consistent standard and quality. Secondly, you’ve pointed to the fact that the “patent” terrain of innovative bioligics is uncertain and any follow on player venturing into this domain must be very careful about navigating this patent maze, so as not to fall foul of the law.
Now I have two basic queries for you:
1. What is the current standard for approving bio-similars in India. I know of at least 2 biosimilars that were approved in India (filgrastim and reditux were approved in favour of Dr Reddys).
Does the Indian DCGI have an abbreviated pathway for such approvals? Or does it insist on clinical trials afresh (perhaps executing an entire Phase III?). Or some version of an abridged version of Phase III trials?
The government appears to be moving such approvals to the proposed Biotech Regulatory Authority of India (BRAI)? But is this a good idea. Why should this authorty under the control of DBT be asked to determine safety and efficacy of biologics? Wouldnt it be far better to ramp up bio expertise at DCGI and ask them to do this. Safety and efficacy is predominantly a “health” issue. And this function ought to be retained with the Ministry of Health (DCGI works under the aegis of the Ministry of Health).
in any case, whoever controls the regulatory function for biologics, must come up with a standard quickly…and make this standard a transparent one known to all.
2. In terms of the uncertainty surrounding patents that cover various aspects of a biologic drug, can’t we simply insist that every drug that is approved must be forced to disclose all patents that apply to it or that it implicates in some way. Any failure to disclose this information before teh regulator would impact the enforcement of the patent before courts. I made a similar recommendation a while back in a Mint piece noting that:
http://www.livemint.com/articles/2008/07/09215015/The-potency-of-a-middle-path.html
“an innovator company that applies for drug approval is obligated to disclose all its patent registrations/applications for products/processes relating to the drug. The office of the DCGI displays this on its website. Much like the Orange Book in the US, the public can access it and check which drugs are covered by what patents.
The benefits of such a database cannot be emphasized enough. Absent such a database, correlating patents with drugs will prove an arduous task, particularly in the context of biopharmaceuticals. It would not only aid transparency around pharmaceutical patents in the world’s largest democracy, but also enable a more effective deployment of the patent opposition mechanism.”
Shamnad: sometimes it helps being anonymous because of various reasons, I hope you understand. What is important is the quality of comments irrespective of whom it comes from. Recently we have seen lot of disgraceful comments on spicy ip. I hope commentators stick to the issues concerned without being personal. Even though I comment as anonymous, I always sign as “Sy”, as I did in my previous post (6:34 AM). In fact I comment very rarely. Since biosimilars and their IP position interests me, I could not stop myself from commenting.
There are several biosimilar/follow-on biologics approved in India. Notable ones are Insulin, Erythropoietin, Streptokinase, interferon, GCSF or filgrastim, rituximab (redutix), rec HBsAg vaccine. Unlike chemical molecules full characterization of a biologic is extremely difficult. Therefore, a simple bioequivalence study cannot replace clinical trial in case of biosimilars.
You have nicely summed up various comments and raised the two most pertinent issues related to the current debate.
Presently three players are involved in the approval of biotech drugs (new or follow-on) viz., DBT, Environment ministry & DCGI. There are subcommittees (IBSC, GEAC, RCGM etc.) under them to look after various aspects. A short phase III trial is necessary for a biosimilar. Since the regulatory frame work is too complex involving several players the idea of NBRA was mooted. It is also the industry demand that a single window clearance system be evolved. All therapeutic proteins derived from recombinant organisms has been excluded from the purview of proposed NBRA, they will continue to be approved by DCGI. It does not matter to industry “who approves what”. What is important is clear guidelines and single window clearance. Since major chunk of biosimilars, as proposed, will continue to be approved by DCGI, I would like to see DCGI issuing “product specific” guidelines as to quality, efficacy, & safety of follow-on biologics. Approval of biosimilars should be on a case (molecule) specific basis and purely on scientific merit without compromising on the quality, safety & efficacy standards. DCGI should also make available to public all the relevant documents that formed the basis of marketing approval (similar to European Public Assessment Reports provided by EMEA). This will increase public scrutiny and thereby prevent any standards of quality being compromised.
Patent terrain of biopharmaceuticals is indeed uncertain. I have at least looked at IP position of close to 15 molecules (these included therapeutic proteins, antibodies and few vaccines too) that have gone off-patent in different jurisdictions or will become off-patent in few years from now. I know how much I had to struggle! Your idea of having an Orange Book like listing is commendable and should be seriously looked into. Since DCGI’s role is restricted to the quality, safety & efficacy of the drugs, I am not sure if such a mandatory disclosure of patent information will be well received by the industry, it may even be challenged in a court of law. There is no orange book equivalent for biopharmaceuticals in US too. I personally would love to see that happen!
Sy
Dear Sy,
Once again, thanks for taking this debate to a more thoughtful plane and raising these pertinent issues.
On the issue of single window clearance, I am with you. At best the authority can seek guidance etc on teh matter from another authority that might have select competence in an area…however the regulatory approval itself should flow just out of one body. The reason I am concerned about which body does is …owes to a potential conflict of interest. DBT’s mandate is to increase the biotech potential and drive more science and commercialisation in this regard. I would therefore hesistate in recommending that a specialist body tasked with biotech regulatory approvals be housed under the control of the DBT. In fact, our own DCGI’s capacity for biologics sohuld be ramped up and it should be tasked with biotech regulatory approvals in so far as “health” related biologics (for human use) are concerned.
You’re right about a challenge to DCGI mandating patent information (without the parent statute permitting the call of such information)…one option would be to amend the DCA to mandate such information. The other is to amend the Indian patents act and simply have an added obligation on every patentee to disclose details of every product that co-relates to the patent. In fact, this should be across the board and not just for pharma. It will help us track the commercialisation of patents and how well they are working. The “working” requirements in fact could be tuned up to insist on this information as well. And we could take the lead in this regard….and perhaps its high time that the US and EU begin to follow our lead in some of these issues.
Dear Sy,
When you post, you also have the option of doing so under an “open” ID ..without revealing any further information about yourself (you can chose to hide information under blogger). Such an open ID would ensure that nobody hijacks your identity. When you sign in as anonymous and put in “sy” at the end of your comment, any other person could do so as well. We found this a lot with one of our regular insightful commentators, who would label himself as “frequently anon”. Some of the comments were clearly not upto the mark–and we suspect somebody else may have hijacked his identity. So do consider using an open ID.
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Thank you Shamnad for suggesting me to comment using an identity which is not subject to misuse. I have created a google account with a display name as “Sy’s comment” and would use the same for commenting. I hope nobody hijacks this, my pseudonymous identity!
Your suggestion makes sense that regulatory approval should flow from one authority. DBT & DCGI has got different mandates. Even with the proposed NBRA setup still a lot of biologics will end up being approved by DCGI. FDA also faced similar issues initially and subsequently went about establishing CBER (centre for biologics evaluation & research) to evaluate biologicals. But then again, after few years FDA moved therapeutic proteins and antibodies from CBER to CDER. Nevertheless both of them were and are part of FDA. In India also we can make a progress towards evolving a similar set up within DCGI’s framework.
Dear All (especially Shamnad),
Thank you for this discussion. I am working in the field of Biotech patenting and Regulatory affairs. Cant resist myself to not participate in this discussion. As rightly pointed out by some members, Biosimilar production is a very different ballgame when compared to traditional organic chemistry. The process has 3 main steps.
1. clone development
2. Upstream process
3. Downstream process
clone development involves cloning the gene of interest in the plasmid and transfecting an E.Coli/CHO or other cell to produce a recombinant clone. The recombinant plasmid will multiply in the E.Coli cell. Once you get the good amount of plasmid in the E.Coli cell you should remove the plasmid from this cell and add it to other strain of E.Coli cell which can be used for production. This clone will be grown in the media and will be used for standardization of media composition, growth curve studies, expression studies and several other purposes. few successful clones are used for study in small scale fermenter studies. after you are satisfied on the yield of protein and stability of the process then you select that clone to make Master cell bank. Master cell bank will be used to prepare working cell bank and working cell bank will be used every time for the fermentation.
After fermentation the protein is produced in the inclusion bodies. this protein is then purified. inclusion bodies are isolated by centrifugation and use of enzymes. inclusion bodies are further purified by Tangential flow filtration and other techniques. This will give desired protein along with the other host cell proteins (proteins from bacteria). we have to remove host cell protein from the the desired protein. this is achieved by chromatography techniques. this is the most complex part of the process where you have to make the protein in the desired conformation. the protein in the bacteria is produced in the mis-folded conformation. to achieve the protein in desired conformation you have to refold the protein. this involves great complexity. the protein produced should be tested for in vitro bioassay, stability and other parameters. this should be done with reference article too to compare the properties of the our protein and innovator product.
To conclude it is very difficult to produce biosimilar of similar quality as the innovator product is. Thats why it takes significant amount of time.
Speaking about regulatory pathway for biosililar, This involves coordination between 3 agencies. DCGI, RCGM, FDA. The product development should start with approval from RCGM. you have to seek permission to develop from RCGM for the molecule which you want to develop. once you develop the molecule you need to submit the 5 batch data. After going through the 5 batch data and your protocols for toxicology they will give permission to conduct toxicology. once the toxicology is completed then you need to submit the toxicology data to RCGM who will recommend/ or will require additional data prior to recommending ct to DCGI. After you get the permission to conduct toxicology you have to get Licence to manufacture for test and analysis from local fda. The local FDA along with CDSCO zone will inspect the facility prior to giving test licence in form 29. After you conduct toxicology you have to get form 44 for conducting ct. Your protocols should be finalized for ct phase 3 on the molecule. this takes time to happen for some reasons which can not be discussed. after ct your product will get approval if it is found to be similar in efficacy (which is not the case every time as there are many cases for withdrawal of ct for biosimilars). after all this you get manufacturing licence for r-DNA product form 28-D from FDA.
CT for some biosililars take lot of time as there are stringent inclusion and exclusion criteria for patient recruitment. There are many Bureaucratic hurdles in the above processes. one example is that your protocol discussion will take at least 9 months for molecule like g-csf and insulin. the timeline for comment from dcgi is 3 month. There are many funny processes which happens during this approvals some of which are vary difficult to justify.
Dear all, suddenly with the CL on Nexavar now, this post has become very relevant. Why not a CL on pegylated interferon? The Post patent hearing against Roche has been posponed till april 14th and no news about the infrigement case from Schering Plough on ranbaxy and another phara company. Do any one of you have any updates on the infringement case?
I am not scientist like you all. Roche sells the same product in Egypt for 1998 USD for the 48 weeks duration, in georgia around 7000 USD..so why do they mainatain such pricing difference. in india with almost 17 to 18000 USD for the treatment period of 1 year, many people just cant afford it. I hope some company comes out for CL or Wockhardt wins the post patent grant application against alpha 2a.