The ongoing biosimilar litigation between Roche and Indian generic companies is becoming more contentious with every passing day. ET’s Prabha Raghavan reported on July 15 that both Roche and Biocon are now suing each other for contempt before the Delhi High Court. As Rahul had reported earlier over here, Justice Manmohan Singh had passed orders in an earlier litigation restraining Biocon and its partner Mylan from using the name Herceptin (or associated Indian trademarks) while marketing its drug although he did permit both companies to use the INN Trastuzumab. As I explain in an earlier post critiquing the judgment, it is rather odd to allow the defendants use the INN but not the trademarks owned by Roche since the purpose of the INN is to signify that the drugs are in fact the same.
In any case, as per the ET report, Roche “took issue with the mention of Herceptin (sold as Herclon in India) by Biocon at an international scientific conference related to the results of clinical trials on its trastuzumab” on the grounds that Biocon was restrained from making such references by the Delhi High Court. Roche apparently also argued “alleged contempt over Biocon using the name ‘Herceptin’ in the approval process of its trastuzumab drug in the US”. While I seriously doubt the sustainability of the second claim since the Indian court cannot regulate Biocon’s conduct in territories beyond its jurisdiction, the first claim regarding Biocon’s reference to Herceptin is likely to cause problems for Biocon. The reason for this, I speculate, is the confusion caused by the Division Bench which heard the appeal against Justice Manmohan Singh’s judgment. The DB’s first day order accessible over here is confusing. It says that both parties would be governed by the position prior to Justice Manmohan Singh’s judgment on April 15, 2016 i.e. the legal position on April 14 would continue to regulate the parties. I’m not sure of the legal position on April 14 in this case because there has been a long series of litigation/appeals between both parties since Justice Manmohan Singh’s first ex-parte injunction on February 5, 2014. This mess could have perhaps been avoided if the Division Bench was more precise with the wording of its order. In any case, Justice Hima Kohli has scheduled the contempt petitions for November – the true intent of the contempt application I suspect is to influence the hearing that was conducted today before the Division Bench – I don’t know of what happened today in court.
The ET article also reports that Biocon has also filed a contempt application “alleging Roche of making disparaging statements leading to a distorted impression of the Indian biotech company”. Quite frankly, disparagement is a separate cause of action warranting a separate lawsuit and I’m not sure how this is covered under contempt law.
The other series of interesting litigation ongoing before the Delhi High Court is the litigation launched by Roche against Hetero, in May, over the launch of a biosimilar of Roche’s Avastin. Rahul had blogged about it over here. This case was originally before Justice Valmiki Mehta who had asked Roche to explain its rights were affected by Hetero’s launch of a biosimilar. As I explained in an earlier post Justice Manmohan Singh had claimed Roche’s civil right was affected, although he really doesn’t explain the nature of this civil right.
Before the next date of hearing, the roster of the High Court changed and Justice Mehta was moved out of the original side of the Delhi High Court. Thereafter the case was posted before Justice Hima Kohli – when the case came up before her on July 8, 2016 Hetero apparently argued that the case was ‘part-heard’ by Justice Mehta which meant that a new judge could not hear the case until Justice Mehta released the matter from his board. Roche disputed this account. Justice Mehta has a tough reputation and is known to reject suits quite liberally at the preliminary stage and it is quite likely that Roche doesn’t want the matter to be heard by him. He’s also supposed to be transferred to Gujarat High Court which means that the arguments could be disrupted half-way. Regardless of how he rules, I don’t think this matter would qualify as part heard because Justice Mehta had only framed the issue that he wanted to hear arguments on. He didn’t actually hear any substantive arguments. In any case Justice Hima Kohli ordered the suit to be placed before Justice Mehta on July 15 – the court order of that day isn’t available on the High Court’s website. Any tips would be welcome.
[Update 23:45, July 21, 2016: A reader has updated us that the case is going to be heard by Justice Kohli on August 23 on the points of issuance of notice or objections thereto].
I have a slightly different view here. In your previous post you say “If two drugs can legally use the same INN, it mean that the drugs are same”– This statement might be true for small molecule generics but not for biosimilars. Biopharmaceuticals are complex medicinal products which are markedly different from small molecule drugs. Since its manufacture involves a biological system, each biologic is a unique product and the product characteristics largely depend on the manufacturing conditions. Even slight differences in cell lines, temperature, and culture media used to synthesize the biologic can have an impact on the final product. INN’s, work well for chemical drugs which are substantially reproducible- but there are a lot of inconsistencies in assigning INN’s for biopharmaceuticals, because each biologic is different and unique. People are wary about using the same INN’s for biologics. WHO is infact debating assigning a biological qualifier to each INN to distinguish one manufacturer’s product from another. http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf . If you see interferon nomenclature in US, lower case alphabets are assigned to differentiate one manufacturer’s product from another (e.g. interferon beta-1a and interferon beta-1b) .Since India is not a highly regulated market and biosimilars are not rigorously evaluated for similarity with the innovator product- I understand Roche’s grouse. If the biosimilar product uses the exact same INN and also claims similarity to Herceptin®, it is very likely to be automatically substituted by some clinicians, which might be detrimental to patients in some cases at least!
Hi Madhulika,
But in this case the regulator and the court allowed both parties to use the same INN without any distinction right – in which case they must have been convinced the products are similar enough to be presumed biosimilar, in which case why not allow them to refer to the innovator’s tradename.
I understand your point that the process to make biologics is different from small molecules but I’m presuming all these biosimilar regulations, including the Indian ones, presume that a biosimilar comes pretty close to the original – or at least close enough to allow the clinicians substitute the innovator product with the biosimilar. Otherwise there is really no point in regulating these products is there?
Regards,
Prashant
Hey Prashant,
I believe the “biosimilar” version of trastuzumab was approved in India using an ad-hoc abbreviated pathway which is usually followed for small molecules (only phase III trials). I dont think the biosimilars were in accordance with the Guidelines issued in 2012.
Regards,
Madhulika
Hey Prashant,
The biosimilar version of trastuzumab was approved using an ad-hoc abbreviated pathway that is used to approve small molecule drugs (only phase III trials). They were not in accordance with the guidelines released by CDSCO in 2012.
Hi Madhulika,
That’s troubling information – if its true then Biocon-Mylan should have been stopped from using even the INN trastuzumab.
Regards,
Prashant
Hey Prashant,
It all boils down to the differences between biologics and small molecules. This WHO document sums it up perfectly “‘It is recognised that biosimilar ’ is a regulatory and legal term and is distinct from the INN assignment process for biological substances.”
“In the opinion of the US FDA, interchangeability and traceability do not fall under the remit of the INN Committee , but rather are issues for the regulatory
authority, industry and other pertinent health authorities within the country. Regulatory mechanisms should be in place to prevent inappropriate and potentially dangerous substitutions of biological medicines”
Link to the WHO document: http://www.who.int/medicines/services/inn/BQ_FP_meeting_final.pdf
In my opinion, same INN does not necessarily mean that the biosimilar is interchangeable- but claims to similarity might encourage automatic substitution.
This article lends further perspective, http://scroll.in/article/754277/a-new-class-of-drugs-is-here-but-india-is-dangerously-inept-at-dealing-with-them
Regards,
Madhulika
Dear Madhulika:
It would be fair to assume that whatever trial/ approval related tests that Biocon did were initiated prior to 2012 since the Order notes that approvals came through in 2013. So, you mean to say that every biosimilar approved from 2000 through 2012 is therefore suspect?
Dear ZRS,
Yes I would say they are suspect for most part!
For small molecules, their structure is accurately known and analytical techniques can be used to demonstrate that the molecules are virtually identical . This is the reason why most regulatory agencies around the world, allow assessment of bioequivalence in lieu of full clinical trials (abbreviated pathway). If two drug products are shown to be bioequivalent (i.e. AUC within 80 to 125%), it is expected that will have the same therapeutic effect and can be automatically substituted. Some simple biologics (small peptides recombinant insulin and recombinant human growth hormone) have also been approved using an abbreviated pathway because their structure can be identified and well characterized.
On the other hand Monoclonal antibodies (mabs) and some recombinant proteins are highly complex 3D structures with varying glycosylation profiles and conformational changes. Their structures CANNOT be fully identified or characterized using existing analytical techniques . In order for a monoclonal antibody to be approved as a biosimilar – it should show chemistry, manufacturing, and control (CMC) comparability in addition to pre-clinical and clinical comparability with the reference biologic. The main difference is that for small molecule generics the manufacturing process does not impact the final product, whereas for biosimilars the process is the product.
Allowing such complex antibodies like trastuzumab (C6470 H10012 N1726 O2013 S42) to be approved using the abbreviated approval pathway that is used for small molecules like sunitinib malate (C26 H33 F N4 O7) is outrageous. As we all know, mabs can cause severe immunogenicity issues and placing cost savings above patient safety is dangerous to say the least!
-Madhulika
Hi Prashant
I guess the fight was on bio similarity and patient sample size issues only since there were no patent hurdles for the same in India.
Regards
Shaklain
Hi Shaklain,
True there were no patent hurdles – the fight was on whether Biocon-Mylan complied with the Biosimilar Guidelines.
Regards,
Prashant
Hi Madhulika,
In that case, the WHO really shouldn’t be prescribing INNs for biosimilars right?
Regards,
Prashant
Hey Prashant,
Yes I agree. WHO is seriously debating, introducing a biological qualifier to the INN name that uniquely identifies the biosimilar by manufacturer. In EU, INN based prescription for biologics is not permitted.
Unlike a small molecule generic drug whose chemical structure is exactly identical to the reference listed drug, a biosimilar is never going to be an exact replica of the reference biologic much and thus cannot be automatically substituted.
Regards,
Madhulika