Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development. 
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

"For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

In your case, you are proposing to conduct a investigational study and not using the drug in the course of a medical practice by a physician treating a patient. Therefore to conduct a study for an unapproved use of a marketed drug, you need an IND. 

------------------------------
GRSAOnline
------------------------------

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

The answer is "it depends".  Despite the fact the study is in an unapproved indication, it does not need to be done under an IND IF (and this is a big "IF") the safety of the drug can be described by the US PI.  This means that the dose and schedule are the same and a medical argument can be made the patient population under study will react to the drug in the same way as the labeled population.

Another consideration is how you intend to use the data from this study.  If there is a good chance the data will support a supplemental application for the new indication, then it needs to be done under an IND.

------------------------------
Dan Mannix, PhD
Washington, DC
------------------------------

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

To add to this thread, the emphasis is unapproved indication and patient risk.  If the indication is unapproved, the study requires an IND and the safety data from the approved used may or may not be supportive to the unapproved indication. The key sentence in the referenced guidance is "use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient".  If the intent is to eventually seek approval for the indication, then I agree it is an investigational study and an IND is appropriate. Please also consider the important aspect of safety reporting and compliance under the proposed scenario.  If something unexpected or worse, a death, under the unapproved use occurs, the FDA will need to be notified and then that can open a world of compliance issues and FDA scrutiny.  

My recommendation is to file the IND, it is not complicated considering the drug is approved; it makes the paper work less complicated and lowers and regulatory/compliance risks.

Best,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States
------------------------------

Original Message:
Sent: 24-Dec-2021 16:29
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The answer is "it depends".  Despite the fact the study is in an unapproved indication, it does not need to be done under an IND IF (and this is a big "IF") the safety of the drug can be described by the US PI.  This means that the dose and schedule are the same and a medical argument can be made the patient population under study will react to the drug in the same way as the labeled population.

Another consideration is how you intend to use the data from this study.  If there is a good chance the data will support a supplemental application for the new indication, then it needs to be done under an IND.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

This message was posted by a user wishing to remain anonymous

Dear OP,
Most likely you need an IND. At minimum you need to submit something to get ok from the FDA! That something could be "medical argument" (in my opinion there is no such thing as statement or narrative of "medical argument' without submitting the published literature in a formal way)  or justifying as to why the new Indication safety profile would be similar to the approved indication plus the most critical point as to why the approved drug would work for the new indication with the same strength, dosing schedule etc (basically the basis for your proposed 100 patient study i.e. do you have any nonclinical data to support or published literature to support the therapeutic dose for the new indication ELSE there is a huge risk of sub therapeutic dose given potentially risking the patients who may have other approved drugs for the new indication!!! etc.....)......................I don't see there are many "if"s that would support a non IND study for your new indication (plus you did not specify how different from the primary indication)........ Be ready to file an IND once you hear back from the FDA. Good luck!
Original Message:
Sent: 24-Dec-2021 16:29
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The answer is "it depends".  Despite the fact the study is in an unapproved indication, it does not need to be done under an IND IF (and this is a big "IF") the safety of the drug can be described by the US PI.  This means that the dose and schedule are the same and a medical argument can be made the patient population under study will react to the drug in the same way as the labeled population.

Another consideration is how you intend to use the data from this study.  If there is a good chance the data will support a supplemental application for the new indication, then it needs to be done under an IND.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

This message was posted by a user wishing to remain anonymous

In the absence of specific information on the drug and planned study, since the study is not for treatment use, rather to evaluate the drug's utility for further development in an unapproved indication, the study would seem to be putting a new (unlabeled) population at risk even if the dosing is according to the current labeling.  Therefore, this study of an unapproved indication would need to be conducted under an IND, whether the commercial entity sponsors it, or if an investigator serves as the sponsor.
Original Message:
Sent: 24-Dec-2021 16:29
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The answer is "it depends".  Despite the fact the study is in an unapproved indication, it does not need to be done under an IND IF (and this is a big "IF") the safety of the drug can be described by the US PI.  This means that the dose and schedule are the same and a medical argument can be made the patient population under study will react to the drug in the same way as the labeled population.

Another consideration is how you intend to use the data from this study.  If there is a good chance the data will support a supplemental application for the new indication, then it needs to be done under an IND.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

An IND is required when a drug is involved in a clinical investigation and is not exempt from the regulations.

An IND is required when a drug is involved in clinical investigation and is not exempt from regulations.
Supplemental IND is another route that can be followed for additional indication of the already approved drug which can take years and is also an expensive process.

------------------------------
Sangeeta Underwood
Bioengineer
Frederick MD
United States
------------------------------

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

Dear Sangeeta,

Can you clarify what a "supplemental IND" is and cite a regulation that allows for such a strategy?

Thanks

------------------------------
Glen Park PharmD
Vice President, Regulatory Affairs and Quality Assurance
New York NY
United States
------------------------------

Original Message:
Sent: 27-Dec-2021 10:42
From: Sangeeta Underwood
Subject: Investigator Initiated Studies_requirement for IND

An IND is required when a drug is involved in a clinical investigation and is not exempt from the regulations.

An IND is required when a drug is involved in clinical investigation and is not exempt from regulations.
Supplemental IND is another route that can be followed for additional indication of the already approved drug which can take years and is also an expensive process.

------------------------------
Sangeeta Underwood
Bioengineer
Frederick MD
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

Original Message:
Sent: 12/28/2021 7:11:00 AM
From: Glen Park
Subject: RE: Investigator Initiated Studies_requirement for IND

Dear Sangeeta,

Can you clarify what a "supplemental IND" is and cite a regulation that allows for such a strategy?

Thanks

------------------------------
Glen Park PharmD
Vice President, Regulatory Affairs and Quality Assurance
New York NY
United States
------------------------------

Original Message:
Sent: 27-Dec-2021 10:42
From: Sangeeta Underwood
Subject: Investigator Initiated Studies_requirement for IND

An IND is required when a drug is involved in a clinical investigation and is not exempt from the regulations.

An IND is required when a drug is involved in clinical investigation and is not exempt from regulations.
Supplemental IND is another route that can be followed for additional indication of the already approved drug which can take years and is also an expensive process.

------------------------------
Sangeeta Underwood
Bioengineer
Frederick MD
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study. 

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States
------------------------------

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar".

Having said all this, there are certainly more upsides than downsides by conducting any such study under an IND.  If this is to be done as an IST and the investigator doesn't want to deal with an IND by him- or herself alone, then make it a collaborative agreement instead where your company and the investigator share the IND obligations.

------------------------------
Dan Mannix, PhD
Washington, DC
------------------------------

Original Message:
Sent: 27-Dec-2021 13:56
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

This message was posted by a user wishing to remain anonymous

"The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar"."

So you are implying that in the above scenario an IND is not required??? Especially when you have so many drugs approved for 2nd line MBC and you imply that an oncologist would administer an unapproved drug (although approved for 3rd line) to the 2nd line MBC patient population for which the drug is not approved??? 
Just so you are aware, in the oncology practice, only when the 2nde line MBC patients becomes refractory or not responding to the approved drugs, only then you are allowed to administer an unapproved drug with preliminary dose/response information that should have been obtained in a phase 1 study. Your scenario cited above is most unlikely even from the IRB standpoint specifically in the oncology clinical practice! 


Original Message:
Sent: 28-Dec-2021 11:45
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar".

Having said all this, there are certainly more upsides than downsides by conducting any such study under an IND.  If this is to be done as an IST and the investigator doesn't want to deal with an IND by him- or herself alone, then make it a collaborative agreement instead where your company and the investigator share the IND obligations.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 27-Dec-2021 13:56
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

First, I am not saying an IND would not be required.  I am saying that it would be easier to make the argument that the approved US PI could describe patient safety for an IST in, say, second line metastatic breast cancer, when the drug is approved for third line metastatic breast cancer (as opposed to a study in allergic rhinitis) and thus an IND might not be needed.  But as I also said previously, it would still be better to conduct any study in this situation under an IND.

Second, in the context of oncology drug development, clinical trials are conducted in numerous tumor settings from early disease (neoadjuvant / adjuvant and front line metastatic) through late disease (relapsed / refractory metastatic).  Patients can choose whether they want to receive SOC or enroll in a clinical trial at any setting.  Certainly an oncologist cannot administer an unapproved drug outside the setting of a clinical trial.

------------------------------
Dan Mannix, PhD
Washington, DC
------------------------------

Original Message:
Sent: 28-Dec-2021 12:21
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar"."

So you are implying that in the above scenario an IND is not required??? Especially when you have so many drugs approved for 2nd line MBC and you imply that an oncologist would administer an unapproved drug (although approved for 3rd line) to the 2nd line MBC patient population for which the drug is not approved???
Just so you are aware, in the oncology practice, only when the 2nde line MBC patients becomes refractory or not responding to the approved drugs, only then you are allowed to administer an unapproved drug with preliminary dose/response information that should have been obtained in a phase 1 study. Your scenario cited above is most unlikely even from the IRB standpoint specifically in the oncology clinical practice!


Original Message:
Sent: 28-Dec-2021 11:45
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar".

Having said all this, there are certainly more upsides than downsides by conducting any such study under an IND.  If this is to be done as an IST and the investigator doesn't want to deal with an IND by him- or herself alone, then make it a collaborative agreement instead where your company and the investigator share the IND obligations.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 27-Dec-2021 13:56
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

This message was posted by a user wishing to remain anonymous

"that the approved US PI could describe patient safety for an IST in, say, second line metastatic breast cancer, when the drug is approved for third line metastatic breast cancer (as opposed to a study in allergic rhinitis)"

How on earth an approved US PI for 3rd line MBC could describe safety for 2nd line MBC without having done a study???

Dear OP, please post the FDA's feedback once you hear back! IND would be required in your situation, that would be my RA assessment. Good luck!
Original Message:
Sent: 29-Dec-2021 09:48
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

First, I am not saying an IND would not be required.  I am saying that it would be easier to make the argument that the approved US PI could describe patient safety for an IST in, say, second line metastatic breast cancer, when the drug is approved for third line metastatic breast cancer (as opposed to a study in allergic rhinitis) and thus an IND might not be needed.  But as I also said previously, it would still be better to conduct any study in this situation under an IND.

Second, in the context of oncology drug development, clinical trials are conducted in numerous tumor settings from early disease (neoadjuvant / adjuvant and front line metastatic) through late disease (relapsed / refractory metastatic).  Patients can choose whether they want to receive SOC or enroll in a clinical trial at any setting.  Certainly an oncologist cannot administer an unapproved drug outside the setting of a clinical trial.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 28-Dec-2021 12:21
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar"."

So you are implying that in the above scenario an IND is not required??? Especially when you have so many drugs approved for 2nd line MBC and you imply that an oncologist would administer an unapproved drug (although approved for 3rd line) to the 2nd line MBC patient population for which the drug is not approved???
Just so you are aware, in the oncology practice, only when the 2nde line MBC patients becomes refractory or not responding to the approved drugs, only then you are allowed to administer an unapproved drug with preliminary dose/response information that should have been obtained in a phase 1 study. Your scenario cited above is most unlikely even from the IRB standpoint specifically in the oncology clinical practice!


Original Message:
Sent: 28-Dec-2021 11:45
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar".

Having said all this, there are certainly more upsides than downsides by conducting any such study under an IND.  If this is to be done as an IST and the investigator doesn't want to deal with an IND by him- or herself alone, then make it a collaborative agreement instead where your company and the investigator share the IND obligations.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 27-Dec-2021 13:56
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

As correctly stated by Dawn Marie in an earlier posting, there are five conditions that have to be met for a study to be exempt from an IND.  One of these is the following: The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product.  

This is a medical judgement and, as such, RA professionals will need to get physician colleagues in their companies to opine on whether or not they believe there is a significant increase in risk of use of the approved drug outside its approved indication, where the risk is described in the US PI.  

Having said this, the person who posted the question originally will need to determine whether the other conditions are met as this condition alone will not exempt the need for an IND by itself.  All in all, however, conducting the study under an IND is probably the safe way to go.

------------------------------
Dan Mannix, PhD
Washington, DC
------------------------------

Original Message:
Sent: 29-Dec-2021 10:03
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"that the approved US PI could describe patient safety for an IST in, say, second line metastatic breast cancer, when the drug is approved for third line metastatic breast cancer (as opposed to a study in allergic rhinitis)"

How on earth an approved US PI for 3rd line MBC could describe safety for 2nd line MBC without having done a study???

Dear OP, please post the FDA's feedback once you hear back! IND would be required in your situation, that would be my RA assessment. Good luck!
Original Message:
Sent: 29-Dec-2021 09:48
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

First, I am not saying an IND would not be required.  I am saying that it would be easier to make the argument that the approved US PI could describe patient safety for an IST in, say, second line metastatic breast cancer, when the drug is approved for third line metastatic breast cancer (as opposed to a study in allergic rhinitis) and thus an IND might not be needed.  But as I also said previously, it would still be better to conduct any study in this situation under an IND.

Second, in the context of oncology drug development, clinical trials are conducted in numerous tumor settings from early disease (neoadjuvant / adjuvant and front line metastatic) through late disease (relapsed / refractory metastatic).  Patients can choose whether they want to receive SOC or enroll in a clinical trial at any setting.  Certainly an oncologist cannot administer an unapproved drug outside the setting of a clinical trial.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 28-Dec-2021 12:21
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar"."

So you are implying that in the above scenario an IND is not required??? Especially when you have so many drugs approved for 2nd line MBC and you imply that an oncologist would administer an unapproved drug (although approved for 3rd line) to the 2nd line MBC patient population for which the drug is not approved???
Just so you are aware, in the oncology practice, only when the 2nde line MBC patients becomes refractory or not responding to the approved drugs, only then you are allowed to administer an unapproved drug with preliminary dose/response information that should have been obtained in a phase 1 study. Your scenario cited above is most unlikely even from the IRB standpoint specifically in the oncology clinical practice!


Original Message:
Sent: 28-Dec-2021 11:45
From: Dan Mannix
Subject: Investigator Initiated Studies_requirement for IND

The key is how is the patient population different.  If the drug is approved for some type of cancer and you want to study it in allergic rhinitis, then the populations are certainly different.  But if the drug is approved for third line metastatic breast cancer and you want to study it in second line metastatic breast cancer, then an argument could be made that the populations are "similar".

Having said all this, there are certainly more upsides than downsides by conducting any such study under an IND.  If this is to be done as an IST and the investigator doesn't want to deal with an IND by him- or herself alone, then make it a collaborative agreement instead where your company and the investigator share the IND obligations.

------------------------------
Dan Mannix, PhD
Washington, DC

Original Message:
Sent: 27-Dec-2021 13:56
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

"The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))."

A new unapproved indication for the marketed drug involves studying (or conducting a study)  the drug for new patient population, correct?
Sorry, there is/are no "ifs" for the question raised by the OP initial question, you do need an IND. Thus the OP needs to follow or comply with the above last CFR citation: "If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).

If you do comply with the above in case you don't agree with those posts that strongly said an IND is required in your situation, and hear back from the FDA, please post that decision on this thread! I am 100% certain the FDA would require an IND citing one example that it involves a safety issue because the new indication is for new population (i.e. not approved in the original approved NDA indication) especially the new proposed indication may already have other approved drugs to treat so exposing them to this unapproved drug (for the new indication) in this study requires IND.
Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

Excellent Response!

------------------------------
Glen Park PharmD
Vice President, Regulatory Affairs and Quality Assurance
New York NY
United States
------------------------------

Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"

Superb discussion and information on this topic. From my reading, filing an IND is the "safest" (lowest risk) approach. 

Thank you for all the invaluable insights and experience,

Dar

------------------------------
Darlene Rosario MBA, RAC
Principle Consultant
Ventura CA
United States
------------------------------

Original Message:
Sent: 28-Dec-2021 08:04
From: Glen Park
Subject: Investigator Initiated Studies_requirement for IND

Excellent Response!

------------------------------
Glen Park PharmD
Vice President, Regulatory Affairs and Quality Assurance
New York NY
United States

Original Message:
Sent: 27-Dec-2021 11:48
From: Dawnmarie DeFazio
Subject: Investigator Initiated Studies_requirement for IND

If you review a guidance (we also use checklists we developed for such), sometimes it is a no. A lot of the IIT will not want to change the labeling, no intent to report the outcome to the FDA or support a change in the advertising. So it is exempt from having to get an IND from FDA. However, you also have to make sure it really will not be used for any FDA submission (if there is data being shared with the maker of the drug, you will want to limit the use of data if shared in contracts. Although real world data is used but if they plan to do the label change, advertisement change, dosage/route change, you have to get an IND. Very grey for the determination but the IRB usually makes that decision when they review the study.

https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-%28INDs%29-Determining-Whether-Human-Research-Studies-Can-Be-Conducted-Without-an-IND.pdf


Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study
in support of a new indication, (2) use it to support any other significant change in the
labeling of the drug, or (3) use it to support a significant change in the advertising (for
prescription drugs only) for the drug?


Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily
depends on the intent of the investigation and the degree of risk associated with the use of the
drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND
requirements if all of the criteria for an exemption in § 312.2(b) are met:
• The drug product is lawfully marketed in the United States.
• The investigation is not intended to be reported to FDA as a well-controlled study in
support of a new indication and there is no intent to use it to support any other significant
change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant
change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or
other factor that significantly increases the risk (or decreases the acceptability of the risk)
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the
investigation is not intended to promote or commercialize the drug product).
The potential sponsor or sponsor-investigator of a planned clinical investigation using a
marketed drug is responsible for determining whether the investigation meets the criteria for an
exemption.9
If there is uncertainty about whether the exemption criteria are met, the potential
sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND
regulations (§ 312.2(e)).





------------------------------
Dawnmarie DeFazio
Director
Pittsburgh PA
United States

Original Message:
Sent: 22-Dec-2021 10:55
From: Anonymous Member
Subject: Investigator Initiated Studies_requirement for IND

This message was posted by a user wishing to remain anonymous

I have been approached with a plan to use  a lawfully marketed drug for an unapproved use in a sponsored-investigator initiated study.
The drug will be evaluated in about 100 people for an unapproved use in order to evaluate its utility for further development.
I will pursue IRB agreement, but is an IND necessary? My read of the guidance " New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND" suggests that there is room for interpretation
"...For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient"