Regulatory Open Forum

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------

Hello Dar,

The designation was initially proposed as a way to accelerate the regulatory process for products that show early clinical evidence of substantial improvement over existing therapies.  yes its true companies have had little guidance on how FDA makes this determination, since FDA does not make public its rationale for granting or denying individual requests for designation.

The program was still in a transition phase. The newness of the program meant that even products that were in later stages of development (i.e., Phase 3) are being granted the designation despite the fact that the program was originally designed for drugs in early clinical development (i.e., Phase 1 and 2).

History
Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential  breakthrough therapies.

Designation
Sponsors can request Breakthrough designation at the time of investigational new drug application (IND) submission or anytime after, and the FDA has sixty days to respond to this request.

Designation Process (timing and content of request)

• First of all preliminary clinical evidence is required for designation.
• The pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet Breakthrough Therapy criteria and the contents of a designation request.
• The potential timeline of a request based on an agreement about the preliminary clinical evidence needed and the content of IND
• A request for Breakthrough designation should describe what category of Breakthrough therapy the investigational agent would fit into by including a summary of the disease the therapy aims to treat, expected outcomes for that patient population, and the existing (if applicable) therapies available to treat the disease.
• It should also describe how it meets the criteria for Breakthrough designation by describing the scientific rationale and mechanism of action of the investigational agent, and describing the early phase clinical studies and results of those studies

Designation Process (FDA Response)
Requests for Breakthrough designation will be reviewed by senior officials in the office of the Center Directors. We propose that the FDA should have the flexibility to consult external expertise. These experts could also be consulted for later discussions on the appropriate design of clinical studies, if necessary.

In the event of a negative decision, the FDA should issue a non-designation letter that explains the FDA's rationale and provides recommendations of what criteria would need to be met in order for the product to be considered for Breakthrough designation.

Upon Designation
Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine the most efficient path forward.

Crieteria for Breakthrough Designation

1) The diseases under study will be serious (either debilitating or life-threatening) and no established SoC exists or the current accepted SoC yields poor clinical outcomes (such as low response rates, lack of durability, limited survival, inadequate symptom control, severe acute or chronic effects, reduced quality of life).

2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting.

3) The potential Breakthrough Therapy under consideration could be designated on the basis of early data suggesting a superior clinical therapeutic index compared to SoC in a similarly defined population.

4) The potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease

Categories of Breakthrough Therapies

1) Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established SoC or available concurrent control exist.

2)Drugs that provide substantial therapeutic improvement over existing, established SoC for conditions with poor outcomes, which may be defined by a clinical or biologic subset of disease.

3)Drugs that provide a substantial therapeutic index advantage over a SoC with well characterized efficacy and safety in a similarly defined population (e.g., a non-cardiotoxic anthracycline, antibody-drug conjugates).

4)Drugs that dramatically enhance the activity or tolerability of an existing regimen (e.g., boceprevir and teleprevir treatments for Hepatitis C).

5)Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation/pathway alteration could be considered eligible for Breakthrough designation in a different tumor type with the same mutation/alteration based on substantial clinical efficacy in the additional tumor type.


Hope this will Help

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 08-30-2013 17:37
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------

Dar,

As for "specific requirements for data and format," it can be reasonably identified and addressed by using available information.  For example, http://wp.me/P33LGu-1au

Once you have come up with the list of requirements in view of your organization's developmental plan and planning, you may want to present your plan to FDA as a pre-IND meeting or whatever stage of meeting applicable, and then fine-tune your plan and finalize.  Then take action to the next step!

-------------------------------------------
President and Principal
http://www.regulatorydoctor.com
Riner VA
United States
-------------------------------------------






Original Message:
Sent: 09-04-2013 11:26
From: Amit Jain
Subject: BreakThrough Therapy Designation


Hello Dar,

The designation was initially proposed as a way to accelerate the regulatory process for products that show early clinical evidence of substantial improvement over existing therapies.  yes its true companies have had little guidance on how FDA makes this determination, since FDA does not make public its rationale for granting or denying individual requests for designation.

The program was still in a transition phase. The newness of the program meant that even products that were in later stages of development (i.e., Phase 3) are being granted the designation despite the fact that the program was originally designed for drugs in early clinical development (i.e., Phase 1 and 2).

History
Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential  breakthrough therapies.

Designation
Sponsors can request Breakthrough designation at the time of investigational new drug application (IND) submission or anytime after, and the FDA has sixty days to respond to this request.

Designation Process (timing and content of request)

• First of all preliminary clinical evidence is required for designation.
• The pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet Breakthrough Therapy criteria and the contents of a designation request.
• The potential timeline of a request based on an agreement about the preliminary clinical evidence needed and the content of IND
• A request for Breakthrough designation should describe what category of Breakthrough therapy the investigational agent would fit into by including a summary of the disease the therapy aims to treat, expected outcomes for that patient population, and the existing (if applicable) therapies available to treat the disease.
• It should also describe how it meets the criteria for Breakthrough designation by describing the scientific rationale and mechanism of action of the investigational agent, and describing the early phase clinical studies and results of those studies

Designation Process (FDA Response)
Requests for Breakthrough designation will be reviewed by senior officials in the office of the Center Directors. We propose that the FDA should have the flexibility to consult external expertise. These experts could also be consulted for later discussions on the appropriate design of clinical studies, if necessary.

In the event of a negative decision, the FDA should issue a non-designation letter that explains the FDA's rationale and provides recommendations of what criteria would need to be met in order for the product to be considered for Breakthrough designation.

Upon Designation
Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine the most efficient path forward.

Crieteria for Breakthrough Designation

1) The diseases under study will be serious (either debilitating or life-threatening) and no established SoC exists or the current accepted SoC yields poor clinical outcomes (such as low response rates, lack of durability, limited survival, inadequate symptom control, severe acute or chronic effects, reduced quality of life).

2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting.

3) The potential Breakthrough Therapy under consideration could be designated on the basis of early data suggesting a superior clinical therapeutic index compared to SoC in a similarly defined population.

4) The potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease

Categories of Breakthrough Therapies

1) Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established SoC or available concurrent control exist.

2)Drugs that provide substantial therapeutic improvement over existing, established SoC for conditions with poor outcomes, which may be defined by a clinical or biologic subset of disease.

3)Drugs that provide a substantial therapeutic index advantage over a SoC with well characterized efficacy and safety in a similarly defined population (e.g., a non-cardiotoxic anthracycline, antibody-drug conjugates).

4)Drugs that dramatically enhance the activity or tolerability of an existing regimen (e.g., boceprevir and teleprevir treatments for Hepatitis C).

5)Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation/pathway alteration could be considered eligible for Breakthrough designation in a different tumor type with the same mutation/alteration based on substantial clinical efficacy in the additional tumor type.


Hope this will Help

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 08-30-2013 17:37
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------

Amit,

I have all this information and thanks for confirming its accuracy; however I was hoping to get information on direct experience with the RFD process that led to a positive response (BTD-granted) or negative response (BTD-not granted).  Are there any key learnings that can be shared that would improve the process, data packages, interactions, etc? For example, were the packages 20 pages with cross references to the IND, were data in a certain format, were statistics from an external consultant or directly from the SAP or TFLs, was there any interaction with the review Division prior to submission of the RFD for endorsement or support, were the data just graphics - Kaplan Meier curves supporting the clinical endpoints with cross reference to the IND, what kind of confirmatory statistics did FDA conduct, how were the communications?

If industry is not willing or able to share; I guess that in itself is telling; every organization will go it alone and forge the trail for their own product(s).

Best regards,

Dar



-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------






Original Message:
Sent: 09-04-2013 11:26
From: Amit Jain
Subject: BreakThrough Therapy Designation


Hello Dar,

The designation was initially proposed as a way to accelerate the regulatory process for products that show early clinical evidence of substantial improvement over existing therapies.  yes its true companies have had little guidance on how FDA makes this determination, since FDA does not make public its rationale for granting or denying individual requests for designation.

The program was still in a transition phase. The newness of the program meant that even products that were in later stages of development (i.e., Phase 3) are being granted the designation despite the fact that the program was originally designed for drugs in early clinical development (i.e., Phase 1 and 2).

History
Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential  breakthrough therapies.

Designation
Sponsors can request Breakthrough designation at the time of investigational new drug application (IND) submission or anytime after, and the FDA has sixty days to respond to this request.

Designation Process (timing and content of request)

• First of all preliminary clinical evidence is required for designation.
• The pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet Breakthrough Therapy criteria and the contents of a designation request.
• The potential timeline of a request based on an agreement about the preliminary clinical evidence needed and the content of IND
• A request for Breakthrough designation should describe what category of Breakthrough therapy the investigational agent would fit into by including a summary of the disease the therapy aims to treat, expected outcomes for that patient population, and the existing (if applicable) therapies available to treat the disease.
• It should also describe how it meets the criteria for Breakthrough designation by describing the scientific rationale and mechanism of action of the investigational agent, and describing the early phase clinical studies and results of those studies

Designation Process (FDA Response)
Requests for Breakthrough designation will be reviewed by senior officials in the office of the Center Directors. We propose that the FDA should have the flexibility to consult external expertise. These experts could also be consulted for later discussions on the appropriate design of clinical studies, if necessary.

In the event of a negative decision, the FDA should issue a non-designation letter that explains the FDA's rationale and provides recommendations of what criteria would need to be met in order for the product to be considered for Breakthrough designation.

Upon Designation
Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine the most efficient path forward.

Crieteria for Breakthrough Designation

1) The diseases under study will be serious (either debilitating or life-threatening) and no established SoC exists or the current accepted SoC yields poor clinical outcomes (such as low response rates, lack of durability, limited survival, inadequate symptom control, severe acute or chronic effects, reduced quality of life).

2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting.

3) The potential Breakthrough Therapy under consideration could be designated on the basis of early data suggesting a superior clinical therapeutic index compared to SoC in a similarly defined population.

4) The potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease

Categories of Breakthrough Therapies

1) Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established SoC or available concurrent control exist.

2)Drugs that provide substantial therapeutic improvement over existing, established SoC for conditions with poor outcomes, which may be defined by a clinical or biologic subset of disease.

3)Drugs that provide a substantial therapeutic index advantage over a SoC with well characterized efficacy and safety in a similarly defined population (e.g., a non-cardiotoxic anthracycline, antibody-drug conjugates).

4)Drugs that dramatically enhance the activity or tolerability of an existing regimen (e.g., boceprevir and teleprevir treatments for Hepatitis C).

5)Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation/pathway alteration could be considered eligible for Breakthrough designation in a different tumor type with the same mutation/alteration based on substantial clinical efficacy in the additional tumor type.


Hope this will Help

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 08-30-2013 17:37
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------

Dear all

If anyone has the answers, you could consider writing this down, not just as an answer in this forum, but as a RAPS article. Please contact me if you have any questions

Siegfried 

-------------------------------------------
Siegfried Schmitt
Principal Consultant
PAREXEL
Braintree, Essex
United Kingdom
-------------------------------------------






Original Message:
Sent: 09-05-2013 17:20
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Amit,

I have all this information and thanks for confirming its accuracy; however I was hoping to get information on direct experience with the RFD process that led to a positive response (BTD-granted) or negative response (BTD-not granted).  Are there any key learnings that can be shared that would improve the process, data packages, interactions, etc? For example, were the packages 20 pages with cross references to the IND, were data in a certain format, were statistics from an external consultant or directly from the SAP or TFLs, was there any interaction with the review Division prior to submission of the RFD for endorsement or support, were the data just graphics - Kaplan Meier curves supporting the clinical endpoints with cross reference to the IND, what kind of confirmatory statistics did FDA conduct, how were the communications?

If industry is not willing or able to share; I guess that in itself is telling; every organization will go it alone and forge the trail for their own product(s).

Best regards,

Dar



-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------






Original Message:
Sent: 09-04-2013 11:26
From: Amit Jain
Subject: BreakThrough Therapy Designation


Hello Dar,

The designation was initially proposed as a way to accelerate the regulatory process for products that show early clinical evidence of substantial improvement over existing therapies.  yes its true companies have had little guidance on how FDA makes this determination, since FDA does not make public its rationale for granting or denying individual requests for designation.

The program was still in a transition phase. The newness of the program meant that even products that were in later stages of development (i.e., Phase 3) are being granted the designation despite the fact that the program was originally designed for drugs in early clinical development (i.e., Phase 1 and 2).

History
Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential  breakthrough therapies.

Designation
Sponsors can request Breakthrough designation at the time of investigational new drug application (IND) submission or anytime after, and the FDA has sixty days to respond to this request.

Designation Process (timing and content of request)

• First of all preliminary clinical evidence is required for designation.
• The pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet Breakthrough Therapy criteria and the contents of a designation request.
• The potential timeline of a request based on an agreement about the preliminary clinical evidence needed and the content of IND
• A request for Breakthrough designation should describe what category of Breakthrough therapy the investigational agent would fit into by including a summary of the disease the therapy aims to treat, expected outcomes for that patient population, and the existing (if applicable) therapies available to treat the disease.
• It should also describe how it meets the criteria for Breakthrough designation by describing the scientific rationale and mechanism of action of the investigational agent, and describing the early phase clinical studies and results of those studies

Designation Process (FDA Response)
Requests for Breakthrough designation will be reviewed by senior officials in the office of the Center Directors. We propose that the FDA should have the flexibility to consult external expertise. These experts could also be consulted for later discussions on the appropriate design of clinical studies, if necessary.

In the event of a negative decision, the FDA should issue a non-designation letter that explains the FDA's rationale and provides recommendations of what criteria would need to be met in order for the product to be considered for Breakthrough designation.

Upon Designation
Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine the most efficient path forward.

Crieteria for Breakthrough Designation

1) The diseases under study will be serious (either debilitating or life-threatening) and no established SoC exists or the current accepted SoC yields poor clinical outcomes (such as low response rates, lack of durability, limited survival, inadequate symptom control, severe acute or chronic effects, reduced quality of life).

2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting.

3) The potential Breakthrough Therapy under consideration could be designated on the basis of early data suggesting a superior clinical therapeutic index compared to SoC in a similarly defined population.

4) The potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease

Categories of Breakthrough Therapies

1) Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established SoC or available concurrent control exist.

2)Drugs that provide substantial therapeutic improvement over existing, established SoC for conditions with poor outcomes, which may be defined by a clinical or biologic subset of disease.

3)Drugs that provide a substantial therapeutic index advantage over a SoC with well characterized efficacy and safety in a similarly defined population (e.g., a non-cardiotoxic anthracycline, antibody-drug conjugates).

4)Drugs that dramatically enhance the activity or tolerability of an existing regimen (e.g., boceprevir and teleprevir treatments for Hepatitis C).

5)Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation/pathway alteration could be considered eligible for Breakthrough designation in a different tumor type with the same mutation/alteration based on substantial clinical efficacy in the additional tumor type.


Hope this will Help

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 08-30-2013 17:37
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------

Hello Dar,

Excuse me if i didn't answer you earlier, As far as my experience with "BTD" is kind of typical comparing to the other expedite approaches include: Accelerated approval, Fast track, Priority review. You also mentioned in earlier comment that only 25 BTD-Granted out of total 82 BTD application from Oct,1 2012 that means (30%possibility of grant). Again like i said program still in a transition  phase, and agency came up with a narrow guidelines of RFD. Questions you asked are very specific, Somehow they are confidential and might vary from every other organization strategically.

RFD process:Communication with FDA: You may initiate discussion for consideration of a BTD at the time of IND submission or at any time thereafter prior to receiving marketing approval NDA.
pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet BTD criteria and the contents of a designation request;

For a Grant things to be consider:  

• Proposed effective time line
• preliminary clinical evidence(most Important)
• content of IND(with BTD format)
• RFD either prior to IND or before IND
• Request for decision (required)
• In case of negative decision FDA  issue a non-designation letter that explains the FDA's rationale and provides recommendations.

were the packages 20 pages with cross references to the IND? Yes
were data in a certain format? yes, especially for RFD (just giving you an outline)

• BTD would fit into IND by including a summary and therapy aims to treat,
• Patient population,
• Overview of existing therapies,
• Describe how it meets the criteria for BTD,
•  Potential clinical development (early phase studies)

Were statistics from an external consultant or directly from the SAP or TFLs?
Ideally, statistics were based on SAP(prospective/retrospective).

Was there any interaction with the review Division prior to submission of the RFD for endorsement or support?
Pre-IND meeting

What kind of confirmatory statistics did FDA conduct, how were the communications?
Abbreviated or condensed development;
Earlier and more frequent communication;
You'll be dealing with senior reviewers and cross- disciplinary review team

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 09-05-2013 17:20
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Amit,

I have all this information and thanks for confirming its accuracy; however I was hoping to get information on direct experience with the RFD process that led to a positive response (BTD-granted) or negative response (BTD-not granted).  Are there any key learnings that can be shared that would improve the process, data packages, interactions, etc? For example, were the packages 20 pages with cross references to the IND, were data in a certain format, were statistics from an external consultant or directly from the SAP or TFLs, was there any interaction with the review Division prior to submission of the RFD for endorsement or support, were the data just graphics - Kaplan Meier curves supporting the clinical endpoints with cross reference to the IND, what kind of confirmatory statistics did FDA conduct, how were the communications?

If industry is not willing or able to share; I guess that in itself is telling; every organization will go it alone and forge the trail for their own product(s).

Best regards,

Dar



-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------






Original Message:
Sent: 09-04-2013 11:26
From: Amit Jain
Subject: BreakThrough Therapy Designation


Hello Dar,

The designation was initially proposed as a way to accelerate the regulatory process for products that show early clinical evidence of substantial improvement over existing therapies.  yes its true companies have had little guidance on how FDA makes this determination, since FDA does not make public its rationale for granting or denying individual requests for designation.

The program was still in a transition phase. The newness of the program meant that even products that were in later stages of development (i.e., Phase 3) are being granted the designation despite the fact that the program was originally designed for drugs in early clinical development (i.e., Phase 1 and 2).

History
Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential  breakthrough therapies.

Designation
Sponsors can request Breakthrough designation at the time of investigational new drug application (IND) submission or anytime after, and the FDA has sixty days to respond to this request.

Designation Process (timing and content of request)

• First of all preliminary clinical evidence is required for designation.
• The pre-IND meeting would be an opportunity to discuss and agree on the evidence needed to meet Breakthrough Therapy criteria and the contents of a designation request.
• The potential timeline of a request based on an agreement about the preliminary clinical evidence needed and the content of IND
• A request for Breakthrough designation should describe what category of Breakthrough therapy the investigational agent would fit into by including a summary of the disease the therapy aims to treat, expected outcomes for that patient population, and the existing (if applicable) therapies available to treat the disease.
• It should also describe how it meets the criteria for Breakthrough designation by describing the scientific rationale and mechanism of action of the investigational agent, and describing the early phase clinical studies and results of those studies

Designation Process (FDA Response)
Requests for Breakthrough designation will be reviewed by senior officials in the office of the Center Directors. We propose that the FDA should have the flexibility to consult external expertise. These experts could also be consulted for later discussions on the appropriate design of clinical studies, if necessary.

In the event of a negative decision, the FDA should issue a non-designation letter that explains the FDA's rationale and provides recommendations of what criteria would need to be met in order for the product to be considered for Breakthrough designation.

Upon Designation
Upon designation, the FDA and sponsor would collaborate in a dynamic and cross-disciplinary process to determine the most efficient path forward.

Crieteria for Breakthrough Designation

1) The diseases under study will be serious (either debilitating or life-threatening) and no established SoC exists or the current accepted SoC yields poor clinical outcomes (such as low response rates, lack of durability, limited survival, inadequate symptom control, severe acute or chronic effects, reduced quality of life).

2) Breakthrough designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting.

3) The potential Breakthrough Therapy under consideration could be designated on the basis of early data suggesting a superior clinical therapeutic index compared to SoC in a similarly defined population.

4) The potential Breakthrough Therapy under consideration will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease

Categories of Breakthrough Therapies

1) Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established SoC or available concurrent control exist.

2)Drugs that provide substantial therapeutic improvement over existing, established SoC for conditions with poor outcomes, which may be defined by a clinical or biologic subset of disease.

3)Drugs that provide a substantial therapeutic index advantage over a SoC with well characterized efficacy and safety in a similarly defined population (e.g., a non-cardiotoxic anthracycline, antibody-drug conjugates).

4)Drugs that dramatically enhance the activity or tolerability of an existing regimen (e.g., boceprevir and teleprevir treatments for Hepatitis C).

5)Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation/pathway alteration could be considered eligible for Breakthrough designation in a different tumor type with the same mutation/alteration based on substantial clinical efficacy in the additional tumor type.


Hope this will Help

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 08-30-2013 17:37
From: Darlene Rosario
Subject: BreakThrough Therapy Designation

Since Jan 2013, over 25 breakthrough therapy designations have been granted by FDA to over 17 development compounds. The FDA has issued guidance on RFD but has not published specific requirements for data including format, etc.  Most information on the designation specifics are assumed from press releases from the companies being granted the designation and as expected bigger pharma companies have received a majority of the designations.  Moving forward this might change.

Are there any companies willing to share their experience with requesting breakthrough therapy designation including key learnings (do and do not) about the request, submission package and interactions with the FDA towards the designation.  For the companies that did not get the designation what advise would you have for other companies that are considering a RFD.

I look forward to your input,

Dar

-------------------------------------------
Darlene Rosario
Vice President RA and Quality
Biothera
Eagan MN
United States
-------------------------------------------