Clinical studies involving probiotics: When FDA's investigational new drug rubric applies-and when it may not

Gut Microbes

Volumn 3, Issue 6, 2012, Pages 485-489

  Degnan, Fred H ^a  

^a King and Spalding   (United States)

Author keywords

Drug definition; FDA; Institutional review board (IRB); Investigational new drug (IND); Medical food; Probiotics; Protocol

Indexed keywords

PROBIOTIC AGENT;

DIET SUPPLEMENTATION; FOOD; FOOD AND DRUG ADMINISTRATION; HUMAN; MEDICAL RESEARCH; NOTE; PRACTICE GUIDELINE;

DRUG APPROVAL; DRUGS, INVESTIGATIONAL; HUMANS; PROBIOTICS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 84868532355     PISSN: 19490976     EISSN: 19490984     Source Type: Journal    
DOI: 10.4161/gmic.22158     Document Type: Note

References (37)

1. Collado MC. Role of Probiotics in Health and Diseases, HANDBOOK OF PROBIOTICS AND PREBIOTICS, Lee, K.L. and Salminen, S. eds, John Wiley and Sons (2d Ed. 2009).
2. Food and Agriculture Organization of the United States. 2001, Health and Nutritional Properties of Probiotics in Food Including Powdered Milk With Live Lactic Acid Bacteria. http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf.
3. This commentary does not address issues that may attend government-funded research.
4. "New drug" is a statutory term of art.
5. See, infra, text accompanying footnotes 20 and 21 for discussion.
6. "Biological product" is also a statutory term of art.
7. See, infra, text accompanying footnotes 22 and 23 for discussion.
8. 21 U.S.C. 355(i)
9. 21 U.S.C. 301, et seq.
10. 21 C.F.R. Part 312.
11. In addition to its IND regulations, FDA has issued comprehensive regulations governing the role of institutional review boards ("IRB") with respect to reviewing clinical investigations within the IND rubric. 21 C.F.R. Part 56. The IRB regulations also apply to studies conducted within the investigation medical device rubric of the FDC Act as well as clinical investigations that support applications for research or marketing permits for products regulated by FDA including foods, dietary supplements, infant formulas, medical foods, and the like. Consistent with its IRB regulations, FDA also has issued extensive requirements with respect to ensuring that the rights and welfare of human subjects are protected and that subjects are fully informed about the risks, alternative treatments, and other relevant information before deciding to participate in any given clinical study. 21 C.F.R. Part 50. These "informed consent" requirements ensure that anyone undergoing a clinical study does so knowingly and voluntarily with a full understanding of the contours of investigation and secure in the knowledge that he or she may withdraw his or her consent at any time without penalty or recrimination.
12. Defined infra in text accompanying reference 27.
13. Defined infra in text accompanying reference 25.
14. Defined infra in text accompanying reference 21.
15. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM229175.pdf.
16. www.fda.gov/.../GuidanceComplianceRegulatoryInformation/Guidances/general/UCM292704.pdf.
17. Of course, any clinical study involving a substance meeting the definition of food or dietary supplement but focused on an endpoint involving the cure, mitigation, treatment or prevention of disease would not be exempt from the IND requirements.
18. "Draft Guidance for Industry: Complementary and Alternative Medicine Products and Their Regulation by the Food and Drug Administration," December 2006; www.fda.gov/RegulatoryInformation/ Guidances/ucm144657.htm.
19. Additional possible but less likely categories for probiotics include "medical device" and "cosmetic."
20. And, the category can be broken down even further into animal food or feed.
21. U.S.C. 321(g).
22. 21 U.S.C. 321(p).
23. 42 U.S.C. 262(i).
24. 21 C.F.R. 600.3(h)(1).
25. 21 U.S.C. 321(ff).
26. 21 U.S.C. 350b.
27. 21 U.S.C. 321(f).
28. 21 U.S.C. 321(s).
29. 21 U.S.C. 360ee(b)(3). FDA has, by regulation, expanded on the requirements for achieving "medical food" status, e.g., a medical food must be intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone. 21 C.F.R. 101.9(j)(8).
30. 21 U.S.C. 343(r).
31. Nevertheless, FDA has observed that health conditions can be based on research involving subjects who have the disease or condition at issue: Health conditions involve reducing the risk of a disease in people who do not have the disease that is the subject of the claim. FDA considers evidence from studies with subjects who have the disease that is the subject of the claim only if it is scientifically appropriate to extrapolate to individuals who do not have the disease. That is, the available scientific evidence demonstrates that (1) the mechanism(s) for the mitigation of treatment effects measured in the disease populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations and (2) the substance effects these mechanisms in the same way in both diseased and healthy people.
32. See, e.g., 21 CFR 101.72 - 101.83.
33. 58 Fed. Reg. 1993; 2478:2505.
34. 21 U.S.C. 321(g)(1)(B) [exempting "food" bearing a structure/function claim from part of the "drug" definition] and 343(r)(6) [exempting a "dietary supplement" bearing a structure or function claim from the definition of "drug"].
35. 21 C.F.R. 101.93.
36. See 65 Fed. Reg. 2000; 1000:1029.
37. In some cases, substances are excluded from the definitions of "food" and "dietary supplement," respectively. Pursuant to 21 U.S.C. 331(ll), it is unlawful to introduce into interstate commerce any food to which has been added an approved new drug or a licensed biological product or a drug or biological product for which "substantial clinical investigations had been instituted and for which the existence of such investigations has been made public." From the perspective of its framers, this prohibition makes sense-firms intending to risk significant time and money to develop new drugs and biological products should not have to worry that others may take advantage of their research to market a test substance as a food and thereby avoid any premarket approval requirements accompanying a new drug or a biological product. The scope of the prohibition, however, is not clear and FDA has not issued definitive guidance on how it intends to interpret the provision. A broad interpretation could have the unintended consequence of significantly discouraging companies from sponsoring clinical research for food and dietary ingredients. Pursuant to 21 U.S.C. 321(ff)(3)(B), a dietary supplement cannot be an approved drug, certified antibiotic, and licensed biological product or new drug, antibiotic, or biological for which substantial clinical investigation has been instituted under INDs and for which the existence of such investigation has been made public. Judicial case law has established that this prohibition applies to even components of a dietary supplement as well as to a dietary supplement itself. In sum, food ingredients or components, dietary supplements, and dietary supplement ingredients or components falling within the scope of either of these provisions cannot be accorded food or dietary supplement status and, as a result, cannot be investigated or subject to clinical study as if they were foods or dietary supplements. Thus, any clinical research of a substance excluded from the food or dietary supplement definition would, in all likelihood, fall within the IND rubric.