Label Changes - how about afrezza?
May 5, 2015 18:07:20 GMT -5
ezrasfund, kball, and 1 more like this
Post by Deleted on May 5, 2015 18:07:20 GMT -5
Changing the label on afrezza would be a boon to us. As such I'm revisiting what it takes to get a label changed. I recall the following but please correct/add as appropriate as I may be missing something here. I tried to pull relevant info from the regs for those that don't have the time to read the details, but I'd prefer if you just read it for yourself and bring your view to the table. That is, I'm not trying to "help" anyone here. I am looking for meaningful discussion on the issue of label changes.
What part of the label would we want changed and can it actually be changed?
1. Black Box - The black box warning for Afrezza prohibits it from prescribed to people with lung diseases, in particular chronic obstructive pulmonary disease and asthma, as well as smokers and recent smokers. I'm guessing this will never get changed due to the diseases involved and the fact that afrezza is inhaled. Can't see a path forward for a label change on this one but maybe someone else can shed a perspective here.
2. Lack of ability to put on the label that afrezza is fast acting. Definitely can be changed.
3. Lack of ability to put on the label that afrezza offers superior control to other insulins. Definitely can be changed.
4. FDA didn't include that afrezza produces less hypoglycemia events compared to other insulins on the label. Definitely can be changed.
All the regulatory info below is pulled from here: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.70 which outlines Sec. 314.70 Supplements and other changes to an approved application.
My understanding of getting a label change is that a label change regarding a negative event can be done at any time (that is, a change that's more conservative than the approved label) via a supplement and submitted to the FDA for review but the pharma company can go ahead and do the conservative changes while waiting for FDA comment and approval.
The regs provide several pathways forward for label changes through either the supplemental process or the annual reporting process.
The regulations separate out "major" changes from "moderate" changes from "minor" changes. I've included details from the regs below, but, pretty sure from reviewing the regs again that what SNY/MNKD wants is not a major change. But it might be a moderate change and if not moderate, a minor change. SNY would most assuredly discuss with the FDA in advance which avenue would best serve the purpose.
I've bolded my own written text. The italics are quotes from the regs. Extra spaces between Major, Moderate, and Minor descriptions.
The major changes category is defined as follows:
(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes) . (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.
The major change category doesn't appear to apply to label changes.
Moderate Changes are defined as follows:
(c) Changes requiring supplement submission at least 30 days prior to distribution of the drug product made using the change (moderate changes). (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. If the supplement provides for a labeling change under paragraph (c)(6)(iii) of this section, 12 copies of the final printed labeling must be included.
In reading further in the moderate changes category, it includes the following which SNY may or may not be able to utilize to get an afrezza label change:
(iii) Changes in the labeling to reflect newly acquired information, except for changes to the information required in 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish any of the following:
(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness; or
(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.
(D) and (E) appear most relevant for SNY with afrezza.
If SNY submits a supplement for the label change under this section, they must comply with the following:
(3) A supplement submitted under paragraph (c)(1) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is to be made. The supplement must be labeled "Supplement--Changes Being Effected in 30 Days" or, if applicable under paragraph (c)(6) of this section, "Supplement--Changes Being Effected."
The requirements below must include the following with the submission:
(i) A detailed description of the proposed change;
(ii) The drug product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to assess the effects of the change;
(v) The data derived from such studies;
Minor Changes are defined as follows:
(d) Changes to be described in an annual report (minor changes) . (1) Changes in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with 314.81(b)(2).
The category a label change under the minor definition is:
(ix) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form; and
(x) An editorial or similar minor change in labeling, including a change to the information allowed by paragraphs (b)(2)(v)(C)(1 ) and (2 ) of this section.
(3) For changes under this category, the applicant is required to submit in the annual report:
(i) A statement by the holder of the approved application that the effects of the change have been assessed;
(ii) A full description of the manufacturing and controls changes, including the manufacturing site(s) or area(s) involved;
(iii) The date each change was implemented;
(iv) Data from studies and tests performed to assess the effects of the change; and,
(another requirement about natural drugs but that wouldn't be applicable to afrezza)
What stands out to me is the requirement to provide data from studies and tests to provide support to whatever label changes are requested. The FDA won't accept video's posted on you tube (yes, I realize that's a negative comment but it is also a true comment and not meant to be negative or positive - just the facts as it where) nor will the FDA accept anecdotal information. The FDA has in the past accepted literature reviews but that typically involves drug combinations where the individual drugs were approved in the past, now are being combined or used in a different manner than what it was approved for. Otherwise, SNY is going to have to produce trial results - maybe run additional trials, maybe take from trials already done supplemented with new limited data (meaning obtained quickly but through a more formal process than you tube video's) or simply wait till the post approval studies are done and utilize that data for labeling changes.
From reading through SNY's docs on the 1st quarter of 2015, there's no mention of any afrezza trials nor is there a mention of SNY going after approval in any other country. While I would like to think that SNY is playing the long game, it would be good to understand what they consider to be the optimal sequence of these events - EU application, label change, and post approval studies. So far, it's pretty quiet on all three. As this year progresses I'll be looking for direction and clarity on these issues.
What part of the label would we want changed and can it actually be changed?
1. Black Box - The black box warning for Afrezza prohibits it from prescribed to people with lung diseases, in particular chronic obstructive pulmonary disease and asthma, as well as smokers and recent smokers. I'm guessing this will never get changed due to the diseases involved and the fact that afrezza is inhaled. Can't see a path forward for a label change on this one but maybe someone else can shed a perspective here.
2. Lack of ability to put on the label that afrezza is fast acting. Definitely can be changed.
3. Lack of ability to put on the label that afrezza offers superior control to other insulins. Definitely can be changed.
4. FDA didn't include that afrezza produces less hypoglycemia events compared to other insulins on the label. Definitely can be changed.
All the regulatory info below is pulled from here: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.70 which outlines Sec. 314.70 Supplements and other changes to an approved application.
My understanding of getting a label change is that a label change regarding a negative event can be done at any time (that is, a change that's more conservative than the approved label) via a supplement and submitted to the FDA for review but the pharma company can go ahead and do the conservative changes while waiting for FDA comment and approval.
The regs provide several pathways forward for label changes through either the supplemental process or the annual reporting process.
The regulations separate out "major" changes from "moderate" changes from "minor" changes. I've included details from the regs below, but, pretty sure from reviewing the regs again that what SNY/MNKD wants is not a major change. But it might be a moderate change and if not moderate, a minor change. SNY would most assuredly discuss with the FDA in advance which avenue would best serve the purpose.
I've bolded my own written text. The italics are quotes from the regs. Extra spaces between Major, Moderate, and Minor descriptions.
The major changes category is defined as follows:
(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes) . (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.
The major change category doesn't appear to apply to label changes.
Moderate Changes are defined as follows:
(c) Changes requiring supplement submission at least 30 days prior to distribution of the drug product made using the change (moderate changes). (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. If the supplement provides for a labeling change under paragraph (c)(6)(iii) of this section, 12 copies of the final printed labeling must be included.
In reading further in the moderate changes category, it includes the following which SNY may or may not be able to utilize to get an afrezza label change:
(iii) Changes in the labeling to reflect newly acquired information, except for changes to the information required in 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish any of the following:
(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness; or
(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.
(D) and (E) appear most relevant for SNY with afrezza.
If SNY submits a supplement for the label change under this section, they must comply with the following:
(3) A supplement submitted under paragraph (c)(1) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is to be made. The supplement must be labeled "Supplement--Changes Being Effected in 30 Days" or, if applicable under paragraph (c)(6) of this section, "Supplement--Changes Being Effected."
The requirements below must include the following with the submission:
(i) A detailed description of the proposed change;
(ii) The drug product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to assess the effects of the change;
(v) The data derived from such studies;
Minor Changes are defined as follows:
(d) Changes to be described in an annual report (minor changes) . (1) Changes in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with 314.81(b)(2).
The category a label change under the minor definition is:
(ix) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form; and
(x) An editorial or similar minor change in labeling, including a change to the information allowed by paragraphs (b)(2)(v)(C)(1 ) and (2 ) of this section.
(3) For changes under this category, the applicant is required to submit in the annual report:
(i) A statement by the holder of the approved application that the effects of the change have been assessed;
(ii) A full description of the manufacturing and controls changes, including the manufacturing site(s) or area(s) involved;
(iii) The date each change was implemented;
(iv) Data from studies and tests performed to assess the effects of the change; and,
(another requirement about natural drugs but that wouldn't be applicable to afrezza)
What stands out to me is the requirement to provide data from studies and tests to provide support to whatever label changes are requested. The FDA won't accept video's posted on you tube (yes, I realize that's a negative comment but it is also a true comment and not meant to be negative or positive - just the facts as it where) nor will the FDA accept anecdotal information. The FDA has in the past accepted literature reviews but that typically involves drug combinations where the individual drugs were approved in the past, now are being combined or used in a different manner than what it was approved for. Otherwise, SNY is going to have to produce trial results - maybe run additional trials, maybe take from trials already done supplemented with new limited data (meaning obtained quickly but through a more formal process than you tube video's) or simply wait till the post approval studies are done and utilize that data for labeling changes.
From reading through SNY's docs on the 1st quarter of 2015, there's no mention of any afrezza trials nor is there a mention of SNY going after approval in any other country. While I would like to think that SNY is playing the long game, it would be good to understand what they consider to be the optimal sequence of these events - EU application, label change, and post approval studies. So far, it's pretty quiet on all three. As this year progresses I'll be looking for direction and clarity on these issues.
