Oral-lyn, the first buccal insulin – taken through the inner lining of the mouth – has been approved to be part of the US Food & Drug Administration’s treatment investigational drug programme. This programme is meant to give early access to investigational drugs to patients who have life-threatening or serious medical conditions and have been failed by existing therapies. Such patients are not already part of ongoing clinical trials to prove the drugs’ safety and efficacy. Oral-lyn’s maker – Canadanian biotech firm Generex – is currently conducting phase three trials on Oral-lyn.
A Generex press release says under a structured protocol, Generex Oral-lyn will be provided to patients with serious or life-threatening Type 1 or Type 2 diabetes mellitus, with no satisfactory alternative therapy available for the treatment of diabetes, and who are not eligible to participate in the company’s ongoing global Phase III pivotal clinical trial.
Only selected doctors who are part of the treatment protocol will be allowed to prescribe it.
Now, this is the same buccal insulin that was forced off the market by the Drugs Controller General of India, and rightly so. Oral-lyn, branded Oral Recosulin in India, was being made commercially available for both type 1 and type diabetes without any trials having been conducted here, according to the newspaper Mint. Generex’s Indian partner Shreya Life Sciences had managed to get approval from the current DCGI Dr Surinder Singh’s predecessor Dr Venkateswarulu (who recently passed away). In March it announced that Shreya had secured over 100 orders in the first month of marketing “reflecting the demand for a pain-free” insulin.
When Recosulin was approved here, the only other country that it was available in was Ecuador. Lately, Algeria has been added to that list.
This is an example of how companies can be only as good as the regulators who govern them. Or what explains the completely different paths that the same product has taken in two markets. Sure, no new product goes through full-blown trials for every market, but first-time launches are usually approved here on the basis of phase three trials done locally. Approvals from either the US FDA or EMEA also are deemed important. This time, though, caution seems to truly have been thrown to the winds.
Interestingly, Generex still says it makes Oral-lyn available in India, in its press release.
Apothecurry 
Very interesting points here. I had spoken to a Generex official earlier this year. He said Generex recognized the power of emerging markets much before the Big Pharma did and so introduced its products first in these markets.
That could be seen as a good way to say that semi-regulated markets give product licenses faster with less stringencies. And once sales picks up, there is enough data to go to the bigger regulated markets.
Once again, the DCGI – like in the case of Albupax – seems to have gone wrong in approving the product first and then ordering its withdrawal.
Also, after the oral insulin, Generex claims it has worked on a chewable metformin ! Watch out.
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Vikas, agree with you mostly. However I see one difference between Albupax and Oral-lyn. The former was approved after trials here- however abbreviated – and the reason for revoking the licence was higher-than- permissible levels of endotoxins found much later, ostensibly. That was more of a manufacturing issue than an inherent product safety concern, to the best of my knowledge. Of course, as always, the DCGI has given no written communication to the world at large which is completely in character for that office. Like you had noted earlier, training sessions for CDSCO officials should include a session on transparency.
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Oral recosulin is available in India here:
http://mukeshmedicalhall.com/medilist.php?mname=R&page=6
or here:
http://www.apollopharmacy.in/index-2.html
Shreya already reported a successful trial in India (presented in October 2009 at the IDF in Montreal, poster 1446), and this delivery method has proven safe in Phase I, II and (thus far) III trials in the US. The drug, of course, is insulin, which isn’t too controversial, unless inhaled. This is not inhaled — it is sprayed on the lining of the mouth.
Until I hear otherwise, I’m inclined to believe that LiveMint was less than thorough in its reporting, and you might do some fact checking yourself.
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I’d like to draw your attention to the following quote in one of the livemint series on the subject:
“Clinical trials for Oral Recosulin were not conducted in India. But we are currently conducting in India (a) phase IV trial,” said Ram Shelat, director (domestic business) at Shreya Life Sciences in an email. Livemint directly quoted a written communication from the company so I am willing to believe this isn’t fabricated. I have also double-checked with the reporter on that article and it was in fact a written quote and she had seen other official documents that showed no trials were conducted, prior to approval, she says.
Phase four suggests post marketing surveillance not clinical trials. In the meantime, Shreya’s website http://www.shreya.co.in/?q=node/29&cat_id=17 has no mention of this product in its ‘diabetes range.’
Secondly, it doesn’t matter whether the product has proven safe in earlier phases of trials. It hadn’t been approved in any developed country on the basis of those trials yet. Now if the DCGI’s office had followed due process and required statistically significant phase three safety and efficacy trials in India before approval I don’t think anyone would have had cause for complaint even if the product wasn’t in the US or European markets.
In the meantime, thanks for the info on Shreya’s poster presentation though am not sure what sort of trial you are referring to and on how many subjects, what its endpoints were and whether they were met. It would also help if you could disclose whether you’re connected to either Shreya or Generex in any way directly or indirectly, but I leave that to you.
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I appreciate that you checked with the reporter. Whether the drug should have been approved is academic — it was approved. The question is, if the DCGI doesn’t actually state publicly that the approval has been revoked, how can you tell whether it was? Did you verify that with the DCGI? As mentioned, it’s still available for purchase in the pharmacies above. Also, the pricing authority hasn’t revoked it’s pricing. And it’s on the marketing page (the How We Work page) — not the product page — of Shreya’s web site.
Regarding the study in India — the title is,
“A 12 week phase IV study of recombinant human regular insulin metered dose buccal spray on subjects with type 2 diabetes who are suboptimally controlled while on oral antidiabetic agents”
You can find the description and authors here:
Click to access WDC_programme_book.pdf
These are the authors — they should be able to get you the endpoints and details:
P. Talwalkar1, A. Bhansali2, A. Jha3, R. Walia2, S. Gupta4, S. Srikanta5, S. Chowdhury6, P.V. Rao7, V. Seshiah8.
1S L Raheja Hospital, Diabetology, Mumbai, India.
2Postgraduate Institue of Meidcal Education and Research, Endocrinology, Chandigarh, India.
3Shreya Life Sciences Pvt Ltd, Medical, Mumbai, India.
4Diabetes Care and Research Centre Pvt. Ltd, Diabetology, Nagpur, India.
5Jnana Sanjeevini Medical Center, Diabetology, Bangalore, India.
6Institute of Postgraduate Medical Education & Research, Endocrinology, Kolkata, India.
7Nizam’s Institute of Medical Sciences, Endocrinology, Hyderabad, India.
8Dr V Seshiah Diabetes Care & Research Institute, Diabetology, Chennai, India.
I own shares in Generex, but am not in any way affiliated with Generex or Shreya.
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Also, details on the Phase IV study were highlighted here:
http://seekingalpha.com/instablog/112537-r-j-steffens/36434-oral-lyn-versus-afresa-how-generex-will-win-over-mannkind
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Thanks for disclosing your equity interest in Generex.
Now for the further points that you have raised.
1. I don’t believe for a moment that whether or not the drug should have been approved is an ‘academic’ question alone. The answer to that question is extremely relevant to Indian patients who take all drugs on the assumption that someone in authority has done a thorough job of reviewing their safety and efficacy profile. According to the DCGI’s and the company’s statements no phase three trials had been completed on Indian patients at the time of approval. Nor was this the case in any other developed mkt it appears. This is unsettling to say the least regardless of whether the product eventually turns out to be safe and effective at the end of clinical trials being done elsewhere. I mean if all it took for a drug/delivery approval was initial studies in phase one and two to prove without doubt that the product is ready to be taken by patients why do we have a phase three requirement anywhere in the world. I am not particularly enamoured by western regulators but India’s DCGI has in fact had a history of taking signals from Europe and/or the US on matters of product approval. It is noteworthy that it did not do so this time. (And by the way, India does not have a great track record on pharmacovigilance). That is the whole point of my post.
2. The DCGI went ‘on-the-record’ to livemint that the office had suspended Shreya’s import licence in April last year and this is what I referred in my post. Shreya also admitted to the paper that it had decided not to proceed with the post-marketing surveillance, and would stop sales of the product. If Shreya – or DCGI – changed its mind, when, and why I do not know, but I plan to check out now that you’ve brought it to my attention so watch this space.
3. According to the trader that you sent me a link to, the product is ‘readily available.’ But I still need to check out whether it was withdrawn and reintroduced or whether the company and the DCGI did not follow through on what they said to Mint for reasons best known to them.
4. Ultimately, the onus lies on the regulator but frankly nothing stops the company from doing a phase three local trial before seeking approval.
5. Also, much as it should, the DCGI’s office does not issue press statements about many of its actions something that this blog has pointed out.
And one more thing, I have nothing against the product so long as it comes to market the right way.
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Something really fishy here ! How is it that the product was ordered to be pulled off, trials were directed and then the product is back on the shelves.
It happens only in India. DCGI, Shreya, et al – tough to understand what’s going on.
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Gauri – I think you might be onto a very intriguing story here. GNBT has been very very tight lipped about the matter, which raises more questions and suspician. Some questions that need to be answered:
1. How did this product gets approved without any phase iii trials being completed in India or anywhere else for that matter? While there may have been no safety issues in phase i and ii sometimes safety signals don’t emerge until larger and long term studies are done in phase iii. It has been reported that the product causes numbness and burning in the mouth. It has also been reported that it causes dizziness during dosing. Phase iii should shed more light on whether these side-effects could cause potential health problems.
2. Who (Sherya or Generex, or both) were involved with the regulatory approval process with the India officials?
3. Was there any unethical conduct by company officials in obtaining regulatory approvals?
4. How is it that this product is still on the market today?
Any light you could shed on the continued mystery of this product in India would be very interesting to read. Good luck.
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The report in today’s Mint newspaperhttp://www.livemint.com/2010/02/10000457/Probe-on-as-oral-insulin-shows.html on Shreya’s insulin conveys nothing. The DCGI’s move of launching an investigation is pure vanila and inconsequential. The investigation should be specific on how the controversial drug reached the market when a Phase III trial was ordered. The idea should be to pin down the blame conclusively.
Ironically, the DCGI came up with the same statement on Albupax, eight months after it was approved by his own office.
Tough answers are never easy to find. The news reporters who have access to influential people should use that “privilege” to crack open the facts, than turn into mouthpieces.
As Gauri noted earlier there is nothing against the product but the regulations should be neatly understood and followed.
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Initially asked to conduct phase 3 trials, somewhere down the line the company was given waiver from phase 3 and allowed to do phase 4. somethings one knows but they just can’t be published
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