dean
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Post by dean on Aug 20, 2015 17:35:52 GMT -5
There has been quite a bit of discussion and speculation about the status of Afrezza in Europe and in particular its status with the European Medicines Agency (EMA). Although not an expert, I've had experience with the process of obtaining EMA approval for the sale of human-use drugs in the EU. Here is information you may find useful in your assessment of where Sanofi is in getting approval to sell Afrezza in Europe. Assuming Afrezza is not designated for a fast track designation which is unlikely, the time from requesting approval to being approved would be at least 210 days (there are often requests by companies for time extensions to respond to EMA questions and there are "clock stop" days during several EMA evaluation events).
1. Sanofi/Mannkind could elect to seek approval for Afrezza in individual European countries through each country's medicine regulatory agencies. Typically, that doesn't happen for countries that are part of the EU. Instead those countries would seek approval through the unified process available via the EMA. There have been a few exceptions where some EU members sought approval separate from, or in parallel with, the EMA because it wanted to approve a particular drug sooner than what could be expected through the EMA process. The UK comes to mind as an example.
2. Key terms; - MAA = Marketing Authorization Application
- Applicant = Drug company that submitted the MAA
- CHMP = Committee for Medicinal Products for Human Use (CHMP) is the organization in EMA that conducts safety/efficacy evaluations and makes approval/rejection recommendations on new drug applications.
- Rapporteur/Co-Rapporteur = Rapporteurs lead the evaluation and recommendation process for the CHMP. One or two Rapporteurs are assigned to each MAA. Rapporteurs are representatives of an EU country, are voting members of the CHMP, are seen as opinion leaders, and are a powerful force during the entire process.
- Day 80 Rapporteur/s Report = Each Rapporteur reports to the CHMP on their evaluation of the drug, primarily on factors relating to safety and efficacy. This report also goes to the applicant.
- Day 120 List of Questions (120 LoQ) = CHMP sends the applicant an evaluation report and questions about the drug under consideration. Primary factors are safety and efficacy.
- Day 150 Rapporteur/s Report = Rapporteurs send individual and joint reports to the CHMP on their opinion on the answers provided by the applicant to the 120 LoQ. This report also goes to the applicant.
- Day 180 List of Outstanding Issues (180 LoOI) = CHMP sends the applicant an evaluation report, further questions and identification of issues not yet resolved by the applicant.
- Day 210 = CHMP makes an approval or rejection recommendation to the EMA after consideration of the applicants written and oral (hearings) responses to the 180 LoOI.
3. During the evaluation process, the EMA is very transparent to the companies that apply for drug approval. It is up to the company, during the evaluation, on how transparent it wants to be with the public. In my experience the EMA announces new MAA's on its website shortly after they are received. When the EMA makes a decision it will be made public and its rationale for approving or rejecting the MAA will be available to the public.
4. Generally, the EMA will give a new name to the applicant’s drug that is different from, but often similar to, the U.S. brand name. Afrezza, as a silly example, could be called Adeza. However, the U.S. brand name Afrezza will be abundantly referred to in all the reports.
5. I am not aware of any launched FDA approved drug that went before the EMA approval process with an anonymous/secret filing and its U.S. brand name not disclosed in the MAA.
6. Shown below is a flow diagram of the EMA approval process:
-Dean
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Post by longstocking on Aug 20, 2015 18:37:26 GMT -5
There has been quite a bit of discussion and speculation about the status of Afrezza in Europe and in particular its status with the European Medicines Agency (EMA). Although not an expert, I've had experience with the process of obtaining EMA approval for the sale of human-use drugs in the EU. Here is information you may find useful in your assessment of where Sanofi is in getting approval to sell Afrezza in Europe. Assuming Afrezza is not designated for a fast track designation which is unlikely, the time from requesting approval to being approved would be at least 210 days (there are often requests by companies for time extensions to respond to EMA questions and there are "clock stop" days during several EMA evaluation events).
1. Sanofi/Mannkind could elect to seek approval for Afrezza in individual European countries through each country's medicine regulatory agencies. Typically, that doesn't happen for countries that are part of the EU. Instead those countries would seek approval through the unified process available via the EMA. There have been a few exceptions where some EU members sought approval separate from, or in parallel with, the EMA because it wanted to approve a particular drug sooner than what could be expected through the EMA process. The UK comes to mind as an example.
2. Key terms; - MAA = Marketing Authorization Application
- Applicant = Drug company that submitted the MAA
- CHMP = Committee for Medicinal Products for Human Use (CHMP) is the organization in EMA that conducts safety/efficacy evaluations and makes approval/rejection recommendations on new drug applications.
- Rapporteur/Co-Rapporteur = Rapporteurs lead the evaluation and recommendation process for the CHMP. One or two Rapporteurs are assigned to each MAA. Rapporteurs are representatives of an EU country, are voting members of the CHMP, are seen as opinion leaders, and are a powerful force during the entire process.
- Day 80 Rapporteur/s Report = Each Rapporteur reports to the CHMP on their evaluation of the drug, primarily on factors relating to safety and efficacy. This report also goes to the applicant.
- Day 120 List of Questions (120 LoQ) = CHMP sends the applicant an evaluation report and questions about the drug under consideration. Primary factors are safety and efficacy.
- Day 150 Rapporteur/s Report = Rapporteurs send individual and joint reports to the CHMP on their opinion on the answers provided by the applicant to the 120 LoQ. This report also goes to the applicant.
- Day 180 List of Outstanding Issues (180 LoOI) = CHMP sends the applicant an evaluation report, further questions and identification of issues not yet resolved by the applicant.
- Day 210 = CHMP makes an approval or rejection recommendation to the EMA after consideration of the applicants written and oral (hearings) responses to the 180 LoOI.
3. During the evaluation process, the EMA is very transparent to the companies that apply for drug approval. It is up to the company, during the evaluation, on how transparent it wants to be with the public. In my experience the EMA announces new MAA's on its website shortly after they are received. When the EMA makes a decision it will be made public and its rationale for approving or rejecting the MAA will be available to the public.
4. Generally, the EMA will give a new name to the applicant’s drug that is different from, but often similar to, the U.S. brand name. Afrezza, as a silly example, could be called Adeza. However, the U.S. brand name Afrezza will be abundantly referred to in all the reports.
5. I am not aware of any launched FDA approved drug that went before the EMA approval process with an anonymous/secret filing and its U.S. brand name not disclosed in the MAA.
6. Shown below is a flow diagram of the EMA approval process:
-Dean
Thank you for the detailed explanation of the EMA approval process. How does the UK PIII trial relate to EMU approval, if at all? (see link): www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4631 |
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Post by peppy on Aug 20, 2015 19:24:35 GMT -5
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dean
Newbie
l
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Post by dean on Aug 20, 2015 19:56:12 GMT -5
longstocking - The UK is an EMA member state and may be conducting Sanofi sponsored Afrezza trials for the EMA. See quote below from EMA website at www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
"The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area (EEA) in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union."
When an FDA approved drug is submitted to the EMA for approval, typically the EMA will accept the clinical trials conducted for the FDA. There are times when additional studies are requested by the CHMP for a controversial drug, even though that drug was approved by the FDA, but the request comes to light in the Day 80 or Day 120 reports. Not before the MAA is submitted. And Afrezza is not in the controversial drug category. I wouldn't be surprised that the UK studies are sponsored by Sanofi and will be included in a Sanofi MAA to request an expanded label for Afrezza sales in the European Union.
-dean
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Deleted
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Post by Deleted on Aug 20, 2015 20:29:19 GMT -5
longstocking - The UK is an EMA member state and may be conducting Sanofi sponsored Afrezza trials for the EMA. See quote below from EMA website at www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
"The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area (EEA) in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union."
When an FDA approved drug is submitted to the EMA for approval, typically the EMA will accept the clinical trials conducted for the FDA. There are times when additional studies are requested for a controversial drug, even though the FDA approved the drug in the U.S., but that request comes to light in the Day 80 or Day 120 reports. Not before the MAA is submitted. And Afrezza is not in the controversial drug category. I wouldn't be surprised that the UK studies are sponsored by Sanofi and will be included in a Sanofi MAA to request an expanded label for Afrezza sales in the European Union.
-dean
The US trial data proved non-inferiority and did not grant Afrezza Ultra Rapid Acting status. Is there any way to take the US trial data and parse it for the EU to validate superiority and Ultra Rapid claims or would this require an entirely new trial or could there be some abridged trial which could be completed with less subjects / site to expedite the process? |
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dean
Newbie
l
Posts: 21
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Post by dean on Aug 20, 2015 20:50:48 GMT -5
longstocking - The UK is an EMA member state and may be conducting Sanofi sponsored Afrezza trials for the EMA. See quote below from EMA website at www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
"The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area (EEA) in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union."
When an FDA approved drug is submitted to the EMA for approval, typically the EMA will accept the clinical trials conducted for the FDA. There are times when additional studies are requested for a controversial drug, even though the FDA approved the drug in the U.S., but that request comes to light in the Day 80 or Day 120 reports. Not before the MAA is submitted. And Afrezza is not in the controversial drug category. I wouldn't be surprised that the UK studies are sponsored by Sanofi and will be included in a Sanofi MAA to request an expanded label for Afrezza sales in the European Union.
-dean
The US trial data proved non-inferiority and did not grant Afrezza Ultra Rapid Acting status. Is there any way to take the US trial data and parse it for the EU to validate superiority and Ultra Rapid claims or would this require an entirely new trial or could there be some abridged trial which could be completed with less subjects / site to expedite the process? scotta - I could only speculate in giving an answer to your question. What I do not know is if there is a mechanism with the EMA, like there is with the FDA to negotiate criteria for trials before the trials begin. If there is, Sanofi would be wise to do as you suggest and maybe, just maybe, that is what the UK trials are all about.
-dean
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Post by longstocking on Aug 20, 2015 21:02:39 GMT -5
longstocking - The UK is an EMA member state and may be conducting Sanofi sponsored Afrezza trials for the EMA. See quote below from EMA website at www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
"The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area (EEA) in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union."
When an FDA approved drug is submitted to the EMA for approval, typically the EMA will accept the clinical trials conducted for the FDA. There are times when additional studies are requested by the CHMP for a controversial drug, even though that drug was approved by the FDA, but the request comes to light in the Day 80 or Day 120 reports. Not before the MAA is submitted. And Afrezza is not in the controversial drug category. I wouldn't be surprised that the UK studies are sponsored by Sanofi and will be included in a Sanofi MAA to request an expanded label for Afrezza sales in the European Union.
-dean
Appreciate the quick response. If in fact Sanofi is currently conducting Afrezza trails for the EMA via UK P-III, AND they have reported positive results for both July 15th and August 15th as detailed in the report near the bottom of the page at the link I provided earlier, what is a likely (or maximum assuming smooth process without questions/revisions/etc) timeline for EMA approval, ASSUMING that EMA would accept FDA test results AND UK P-III results? I understand we are talking hypothetically here, but appreciate your insight. I just am hoping to get to the bottom of the theories that EMA approval may be forthcoming within Sept-Oct time frame. If it is obvious to you that there is no possibility of that occurring, please let us know. Again, thanks for sharing your expertise. |
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dean
Newbie
l
Posts: 21
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Post by dean on Aug 20, 2015 21:20:12 GMT -5
longstocking - The UK is an EMA member state and may be conducting Sanofi sponsored Afrezza trials for the EMA. See quote below from EMA website at www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
"The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area (EEA) in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union."
When an FDA approved drug is submitted to the EMA for approval, typically the EMA will accept the clinical trials conducted for the FDA. There are times when additional studies are requested by the CHMP for a controversial drug, even though that drug was approved by the FDA, but the request comes to light in the Day 80 or Day 120 reports. Not before the MAA is submitted. And Afrezza is not in the controversial drug category. I wouldn't be surprised that the UK studies are sponsored by Sanofi and will be included in a Sanofi MAA to request an expanded label for Afrezza sales in the European Union.
-dean
Appreciate the quick response. If in fact Sanofi is currently conducting Afrezza trails for the EMA via UK P-III, AND they have reported positive results for both July 15th and August 15th as detailed in the report near the bottom of the page at the link I provided earlier, what is a likely (or maximum assuming smooth process without questions/revisions/etc) timeline for EMA approval, ASSUMING that EMA would accept FDA test results AND UK P-III results? I understand we are talking hypothetically here, but appreciate your insight. I just am hoping to get to the bottom of the theories that EMA approval may be forthcoming within Sept-Oct time frame. If it is obvious to you that there is no possibility of that occurring, please let us know. Again, thanks for sharing your expertise. lonstocking - my experience has been 210 days after MAA submittal. I don't know of any shortcuts.
-dean
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Post by BlueCat on Aug 21, 2015 1:41:34 GMT -5
5. I am not aware of any launched FDA approved drug that went before the EMA approval process with an anonymous/secret filing and its U.S. brand name not disclosed in the MAA.
-Dean
And from this, I infer you mean to say it is not likely we'll see an approval anytime in 2015 since it is unlikely that this was secretly filed/withheld from public? Dean - not familiar with your background, but have you tracked that closely on all filings/approvals with the EMA that your sample would be indicative? I could imagine that MNKD may be interested in keeping this under wraps. Certainly mgt is aware of the manipulation and the interests like Karp, and a history phone calls and another CRL at Christmas. O yea. I'd be keeping it quiet. |
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Deleted
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Post by Deleted on Aug 21, 2015 5:57:05 GMT -5
The US trial data proved non-inferiority and did not grant Afrezza Ultra Rapid Acting status. Is there any way to take the US trial data and parse it for the EU to validate superiority and Ultra Rapid claims or would this require an entirely new trial or could there be some abridged trial which could be completed with less subjects / site to expedite the process? scotta - I could only speculate in giving an answer to your question. What I do not know is if there is a mechanism with the EMA, like there is with the FDA to negotiate criteria for trials before the trials begin. If there is, Sanofi would be wise to do as you suggest and maybe, just maybe, that is what the UK trials are all about.
-dean
Thank you Dean. |
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Post by mnholdem on Aug 21, 2015 8:19:38 GMT -5
To establish superiority, placebo injections would have been required. The FDA's lead physicians did not allow them and was soundly criticized at ADCOM for not introducing that protocol after having worked with Afrezza for ten years.
I don't see how the FDA trial data can be re-assessed to establish superiority without those placebo RAA injections. Just my opinion, as there may be other ways around the problem.
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Post by poodlebytes on Aug 28, 2015 6:20:26 GMT -5
It is mind-boggling that we can not find any reference to where Afrezza is with the EU approval. I managed to find a PowerPoint presentation, in French, that stated on slide 121 (?) that "MAA was submitted directly" Whatever that means or inferred - perhaps the studies we see were resultant from that. From what I read many of the FDA studies would be accepted for MAA too. I also know that triles in Europe have been going on for years. Around 2010 (I believe) a MNKD ex-employee filed charges that MNKD falsified trial data in Ukraine (or ?) - turns out the accuser was full of it and retracted the allegations. (this was around same time as infamous shareholder lawsuit)
In a nutshell I'd trust Dr. Mann with my life - it is only my blind-faith that I support who he picked as leaders - otherwise I'd pulled my life-savings out a long time ago. A lot of secrets, FUD-fodder for sure but Dr. Mann is no spring chicken and will make sure his $1B large investment and name-sake Inc. will prevail.
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Post by dreamboatcruise on Aug 28, 2015 10:22:55 GMT -5
To establish superiority, placebo injections would have been required. The FDA's lead physicians did not allow them and was soundly criticized at ADCOM for not introducing that protocol after having worked with Afrezza for ten years. I don't see how the FDA trial data can be re-assessed to establish superiority without those placebo RAA injections. Just my opinion, as there may be other ways around the problem. This may indeed be part of the hold up in starting new trials to show superiority. It would seem that to reveal the true extent of Afrezza's superiority would require a protocol that includes follow up doses and thus precludes a true double blind since you couldn't have people do a follow up dose of Novolog an hour after a meal or you'd end up with many of them in the hospital at the 4 hour mark. Maybe there is some clever way of designing the study to get around this. Though it seems if a trial were done with early T2, such as our friends the Spiros, superiority could be shown without follow up doses. It seems that much thought needs to be put into what they wish to prove based on how they wish to market, and I'm sure that this has been a constant topic of discussion with MNKD and SNY. |
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Post by jpg on Aug 28, 2015 10:44:12 GMT -5
I do not understand the issue of follow up doses being a problem in trial design?
There are very simple and elegant ways around this and there is absolutely no reason for needing (or even wanting) follow up prandial injections.
This is, to me at least, a non issue and has nothing to do with why a superiority trail can't or isn't being done.
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Post by mnholdem on Aug 28, 2015 10:56:36 GMT -5
It's true that one of Afrezza's remarkable benefits is the level of safety with which a diabetic can use it for additional adjustment doses. In fact, I think a paper was recently published to that effect, the abstract making its appearance at this year's ADA.
But what I was thinking about data gleaned from previous FDA trials was that the FDA skewed the A1c results by mandating Afrezza be administered way too early which, in retrospect, caused the number of hypoglycemic excursions to exceed the RAA comparator and resulted in a false impression of the risk for hypoglycemia. Same with the trial where the comparator was oral medication. Afrezza was better, but the data should have shown it to be MUCH better.
My point is that there is little in the FDA trials data that Sanofi will be able use to challenge the FDA that Afrezza is superior. It will take additional post-marketing studies to accomplish label enhancement. I'm crossing my fingers that Sanofi may be working closely with the initial group of endocrinolists/diabetologists that they appear to have focused on at launch and that empirical data is being gathered and peer reviewed for release to support the claim of Afrezza's superiority in efficacy over the current RAA insulin Humulog and Novolog, paving the way for Tier 2 coverage and lifting current marketing restrictions.
To jpg's point, post-marketing studies can be conducted to easily show superiority. My initial questions was whether data from the FDA trials could be used to support that claim. My conclusion is no old data is useful - the FDA screwed us royally - and that new trials/studies will be needed to make a claim of superiority. |
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