Posted: 03 Nov 2015 03:56 AM PST
By Wes Siegner –
Effective October 30, 2015, FDA issued a stay on certain food provisions of the final guidance, “Investigational New Drug Applications—Determining Whether Human Research Studies Can Be Conducted Without an IND” (IND Guidance). FDA announced the stay in the Federal Register notice, 80 Fed. Reg. 66907 (Oct. 30, 2015). The stay has been issued for certain provisions of subsection VI.D.2 “Conventional Food,” and all of subsection VI.D.3 “Studies Intended to Support a Health Claim;” with the stated exception to studies for food intended to reduce the risk of disease in medically vulnerable populations (individuals less than 12 months of age, those with altered immune systems, and those with serious or life-threatening medical conditions).
To our knowledge, this is the first time FDA has issued a stay on a final guidance. The possible explanation may be that before this, no one ever saw a need to issue a stay for a guidance, which on its face “does not create or confer any rights for or on any person and does not operate to bind FDA or the public.”
Regardless of whether a stay is necessary, the stay does address some of the problems that this guidance posed. Nonetheless, FDA’s guidance, were FDA to enforce its terms, still exceeds its statutory authority by requiring INDs for foods, including medical foods, when studied for intended uses as food under the provisions of the Federal Food, Drug, and Cosmetic Act (FDC Act).
History
We have followed this guidance through its tortuous history and have blogged on its evolution here, here, here, here, and here. The IND Guidance was published in draft and announced in the Federal Register on October 14, 2010. The draft guidance included a section on dietary supplements, but did not discuss food in detail. References to Generally Recognized as Safe (GRAS) substances was mentioned in the FAQ section, and in a reference to botanical products marketed as food in the Appendix to the draft guidance. FDA issued the final guidance and announced availability in a Federal Register notice on September 10, 2013. Subsections VI.C. “Cosmetics” and VI.D “Foods” (which included a section on dietary supplements) appeared for the first time in the final guidance.
The public found the “notice and comment process” confusing and after receiving multiple comments on subsections VI.C and VI.D, FDA reopened the comment period on February 6, 2014. The comment period closed April 7, 2014. FDA received comments from medical, scientific, and food associations; academia; trade organizations; individual companies; public interest organizations; and individuals in response to reopening. Our blog post after the reopening of the comment period announced concerns from sixty university-based nutrition department heads strongly opposing the confusing guidance. The researchers, like many other commenters, were concerned with the possible effect the guidance could have to stifle food research, that it would be overly burdensome to institutional review boards, it was issued outside the scope of FDA’s statutory authority and it contradicts the statutory definition of food, and that the new subsections were added without any notice contrary to FDA’s own procedures.
The Stay
In the Federal Register notice, FDA states that they “…generally do not intend to seek INDs for studies in the stayed categories while the stay is in effect…. This stay does not affect investigations of conventional foods or dietary supplements studied for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Products intended for such uses meet the definition of a ‘‘drug’’ at section 201(g)(1)(B) of the FD&C Act; such investigations will continue to be subject to IND requirements.”
The stay has been issued for portions of subsection VI.D.2 “Conventional Food,” (which pertains to clinical studies intended to evaluate a food’s effect on the structure or function of the body, and a sentence in the fourth paragraph concerning clinical studies intended to evaluate a non-nutritional effect on the structure or function of the body) and all of subsection VI.D.3 “Studies Intended to Support a Health Claim;” with the exception of clinical investigations intended to evaluate whether a food substance may reduce the risk of a disease in medically vulnerable populations. This exception is stated in bold text in a box immediately above the stayed paragraph. While it seems clear from a policy perspective to protect medically vulnerable populations, we question the legal basis for this exception. As previously mentioned, requiring an IND for food research intended to support a health claim (whether for the general population, or a vulnerable population) appears to exceed FDA’s legal authority.
Subsection VI.D.2 as it pertains strictly to nutritional effects of medical foods is stayed (see VI.D.2, third paragraph). However, the portion of the guidance that required an IND for the study of a medical food for a medical food use – that is for the dietary management of a disease or condition in compliance with the statutory definition – is not stayed (see VI.D.2 last paragraph). Also in the last paragraph of section VI.D.2, FDA states that “an investigation intended to evaluate the effects of a medical food on a disease would require an IND.” See IND Guidance at pages 13 and 14.
First and foremost, as FDA makes clear at the very outset of all “guidance,” neither the original final nor the more recent version with certain provisions stayed is legally binding on industry or FDA. The guidance merely reflects FDA’s “current thinking on this topic.” Nonetheless, in certain circumstances, such as conducting a study with funding from the National Institutes of Health, for practical purposes “guidance” may be read as the rule of law.
In some respects the stay is a victory for stakeholders conducting studies in the area of food research. However, the uncertainty as to whether the stayed provisions might be removed, modified or reinstated remains, and, if the intent here is to provide clarity (as the guidance is not legally binding), then FDA needs to further stay or revise the guidance with respect medical foods, and potentially health claims, to make it clear that such studies are not “drug” studies and FDA is not authorized to require an IND.
FDA has not issued a closing date for comments to this notice. Comments may be submitted to Docket No. FDA–2010–D–0503. We intend to follow the comments and keep track of any FDA follow-on action.
Effective October 30, 2015, FDA issued a stay on certain food provisions of the final guidance, “Investigational New Drug Applications—Determining Whether Human Research Studies Can Be Conducted Without an IND” (IND Guidance). FDA announced the stay in the Federal Register notice, 80 Fed. Reg. 66907 (Oct. 30, 2015). The stay has been issued for certain provisions of subsection VI.D.2 “Conventional Food,” and all of subsection VI.D.3 “Studies Intended to Support a Health Claim;” with the stated exception to studies for food intended to reduce the risk of disease in medically vulnerable populations (individuals less than 12 months of age, those with altered immune systems, and those with serious or life-threatening medical conditions).
To our knowledge, this is the first time FDA has issued a stay on a final guidance. The possible explanation may be that before this, no one ever saw a need to issue a stay for a guidance, which on its face “does not create or confer any rights for or on any person and does not operate to bind FDA or the public.”
Regardless of whether a stay is necessary, the stay does address some of the problems that this guidance posed. Nonetheless, FDA’s guidance, were FDA to enforce its terms, still exceeds its statutory authority by requiring INDs for foods, including medical foods, when studied for intended uses as food under the provisions of the Federal Food, Drug, and Cosmetic Act (FDC Act).
History
We have followed this guidance through its tortuous history and have blogged on its evolution here, here, here, here, and here. The IND Guidance was published in draft and announced in the Federal Register on October 14, 2010. The draft guidance included a section on dietary supplements, but did not discuss food in detail. References to Generally Recognized as Safe (GRAS) substances was mentioned in the FAQ section, and in a reference to botanical products marketed as food in the Appendix to the draft guidance. FDA issued the final guidance and announced availability in a Federal Register notice on September 10, 2013. Subsections VI.C. “Cosmetics” and VI.D “Foods” (which included a section on dietary supplements) appeared for the first time in the final guidance.
The public found the “notice and comment process” confusing and after receiving multiple comments on subsections VI.C and VI.D, FDA reopened the comment period on February 6, 2014. The comment period closed April 7, 2014. FDA received comments from medical, scientific, and food associations; academia; trade organizations; individual companies; public interest organizations; and individuals in response to reopening. Our blog post after the reopening of the comment period announced concerns from sixty university-based nutrition department heads strongly opposing the confusing guidance. The researchers, like many other commenters, were concerned with the possible effect the guidance could have to stifle food research, that it would be overly burdensome to institutional review boards, it was issued outside the scope of FDA’s statutory authority and it contradicts the statutory definition of food, and that the new subsections were added without any notice contrary to FDA’s own procedures.
The Stay
In the Federal Register notice, FDA states that they “…generally do not intend to seek INDs for studies in the stayed categories while the stay is in effect…. This stay does not affect investigations of conventional foods or dietary supplements studied for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Products intended for such uses meet the definition of a ‘‘drug’’ at section 201(g)(1)(B) of the FD&C Act; such investigations will continue to be subject to IND requirements.”
The stay has been issued for portions of subsection VI.D.2 “Conventional Food,” (which pertains to clinical studies intended to evaluate a food’s effect on the structure or function of the body, and a sentence in the fourth paragraph concerning clinical studies intended to evaluate a non-nutritional effect on the structure or function of the body) and all of subsection VI.D.3 “Studies Intended to Support a Health Claim;” with the exception of clinical investigations intended to evaluate whether a food substance may reduce the risk of a disease in medically vulnerable populations. This exception is stated in bold text in a box immediately above the stayed paragraph. While it seems clear from a policy perspective to protect medically vulnerable populations, we question the legal basis for this exception. As previously mentioned, requiring an IND for food research intended to support a health claim (whether for the general population, or a vulnerable population) appears to exceed FDA’s legal authority.
Subsection VI.D.2 as it pertains strictly to nutritional effects of medical foods is stayed (see VI.D.2, third paragraph). However, the portion of the guidance that required an IND for the study of a medical food for a medical food use – that is for the dietary management of a disease or condition in compliance with the statutory definition – is not stayed (see VI.D.2 last paragraph). Also in the last paragraph of section VI.D.2, FDA states that “an investigation intended to evaluate the effects of a medical food on a disease would require an IND.” See IND Guidance at pages 13 and 14.
i. When an IND is not required
While the stay is in effect, FDA will not “generally” require an IND for conventional foods and dietary supplements for the following types of studies:Conventional Foods (including medical foods)
- Clinical studies designed to evaluate whether a conventional food may reduce the risk of a disease, intended to support a new or expanded health claim, and conducted in a population that does not include individuals in the medically vulnerable population;
- Clinical studies designed to evaluate a non-nutritional effect of a conventional food on the structure or function of the body.
Dietary Supplements
- Clinical studies designed to evaluate whether a dietary supplement may reduce the risk of a disease, intended to support a new or expanded health claim, and conducted in a population that does not include individuals in the medically vulnerable population.
ii. When an IND is required
The guidance remains in effect and FDA will require an IND for clinical studies used to evaluate: Conventional Foods (including medical foods)
- Clinical studies designed to evaluate a conventional food’s ability to diagnose, cure, mitigate, treat, or prevent a disease[1], except for studies designed to evaluate whether a conventional food reduces the risk of a disease, intended to support a health claim, and conducted in a population that does not include the medically vulnerable population;
- Clinical studies designed to evaluate whether a food substance reduces the risk of a disease, intended to support a new or expanded health claim, and conducted in a population that includes individuals in the medically vulnerable population.
Dietary Supplements
- Clinical studies designed to evaluate a dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent a disease, id., except for studies designed to evaluate whether a dietary supplement reduces the risk of a disease, intended to support a health claim, and conducted in a population that does not include individuals in the medically vulnerable population;
- Clinical studies designed to evaluate whether a dietary supplement reduces the risk of a disease, intended to support a new or expanded health claim, and conducted in a population that includes individuals in the medically vulnerable population.
Cosmetics
- Clinical studies designed to evaluate a cosmetic’s effect on the structure or function of the body or its ability to diagnose, cure, mitigate, treat, or prevent a disease.
First and foremost, as FDA makes clear at the very outset of all “guidance,” neither the original final nor the more recent version with certain provisions stayed is legally binding on industry or FDA. The guidance merely reflects FDA’s “current thinking on this topic.” Nonetheless, in certain circumstances, such as conducting a study with funding from the National Institutes of Health, for practical purposes “guidance” may be read as the rule of law.
In some respects the stay is a victory for stakeholders conducting studies in the area of food research. However, the uncertainty as to whether the stayed provisions might be removed, modified or reinstated remains, and, if the intent here is to provide clarity (as the guidance is not legally binding), then FDA needs to further stay or revise the guidance with respect medical foods, and potentially health claims, to make it clear that such studies are not “drug” studies and FDA is not authorized to require an IND.
FDA has not issued a closing date for comments to this notice. Comments may be submitted to Docket No. FDA–2010–D–0503. We intend to follow the comments and keep track of any FDA follow-on action.
[1] Section 201(g)(1)(B) of the FDC Act, 21 U.S.C. 321(g)(1)(B), “(1) The term “drug” means (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
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