DISCUSSION GROUP 4 REPORT

ISAPP 2015

GEORGETOWN UNIVERSITY

What is the future of probiotics in USA? Regulatory challenges.

Group members 1. Dan Merenstein, Georgetown University Medical Center

2. Mary Ellen Sanders, ISAPP

3. Pat Hibberd, Massachusetts General Hospital, Boston

4. Andi Shane, Emory

5. Richard Oberhelman, Tulane

6. Girish Deshpande, Nepean Hospital Sydney

7. Peter Marks, FDA CBER

8. Chris Elkins, FDA CFSAN

9. Jennifer Patro, FDA CFSAN

10. Linda Duffy, NIH-NCCIH

11. Martin Hahn, Hogan Lovells

12. Sarah Roller, Kelley Drye & Warren LLP

13. Diane Hoffmann, Univ Maryland

14. Tina Tan (rapporteur) - Georgetown University

15. Greg Leyer, UAS

16. David Keller, Ganeden Biotech

17. Maeve Murphy, General Mills Inc

18. Solange Henoud, Lallemand Health Solutions Inc

19. Thomas Tompkins, Lallemand Health Solutions Inc.

20. Berenice Ocampo Guevata, Mead Johnson Nutrition

21. Seema Mody, DSM

22. Danielle de Montigny, BioK+

23. Wafaa Ayad, Church & Dwight

Chairs

Clinical experts

Regulators

Lawyers

Industry experts

Research funding

Group photo

Objective

Improve current regulatory approach to human research on oral probiotics in the USA

Focus:

Human research

Oral

USA (next year – EU)

Probiotics (not prebiotics)

Key challenges

INDs required when not appropriate

Foods and supplements

When IND is appropriate

Impossible unless manufacturer cooperates

Limits investigator-initiated research

Difficult to obtain IND for foods

Phase 1 safety studies on well-studied probiotics

Everyone agrees that the goal is appropriate oversight commensurate with risk to human subjects.

Bureaucratic interference that prevents needed research or wastes money on unneeded safety studies benefits no one.

Consequences

Studies going outside the USA

Companies being advised to use CROs instead of academic PIs

Guidance's are not law

Companies advised not to seek federal funding

Probiotic research hindered

Scientists having to be vague about endpoints to prevent undue oversight

CBER, CDER and CFSAN

FDA issued a final guidance September 2013 that requires essentially all human research conducted on foods to be conducted as an investigational new drug (IND)

Exception is studies on taste, aroma, nutritive value and approved health claims

FDA re-opened comments through April 7, 2014

65 comments received

FDA response still pending

FDA-Center for Biologics (CBER) Request for Comment

https://www.federalregister.gov/articles/2015/03/31/2015-07273/early-clinical-trials-with-live-biotherapeutic-products-chemistry-manufacturing-and-control

Issued March 31, 2015. Comments due May 29, 2015

CBER action

CBER is proposing that a product label can serve as CMC info for an IND for commercial probiotics

This will facilitate investigator-initiated INDs

Comments (due May 29) – ISAPP will comment; you should, too

This does not address the issues of food research, unnecessary INDs or safety studies

87% of hospital formularies

surveyed carry at least one probiotic

Is research on food/supplement (not device, marketed drug, etc)1

Does research use healthy or at risk members of the general population ?2

Is research on endpoints that are (a) structure/function or (b) reduction of risk

of disease?3

Does PI or study sponsor indicate that research is part of a drug development

pathway?

YES

YES

YES

CBER

YES

NO

NO

NO

CFSAN

Is study on a commercially available probiotic?

Does local IRB consider it safe for the proposed

population?

YES NO. Safety is not

adequately demonstrat

ed for intended

use

FULL DISCUSSION NEEDED WITH CBER; LIKELY PHASE 1

STUDY NEEDED

PRODUCT LABEL SERVES AS CMC, WAIVER OR ABBREVIATED IND.

CAN PROCEED TO EFFICACY STUDIES

NO

Is probiotic adequately characterized to strain level (gene sequencing) AND is

probiotic quality adequate?4

NO

YES

YES

Is probiotic of a well-studied species with

history of safe or documented safety (e.g.,

GRAS, QPS list?) YES

NO

ISAPP 2015: Proposed decision tree for human research on probiotics

NO

Footnotes 1. Clarify what is meant by food/supplement (currently marketed, or food format or declared by PI to be food/supplement) 2. Need to discuss general population (include IBS, healthy people on antibiotics, others that would not be vulnerable subjects for probiotic

studies) 3. Since structure/function and reduction of risk of disease endpoints can be both drug and food, CFSAN would be appropriate oversight agency if

study PI/sponsor declares the research to be on a food/supplement 4. Approach to characterization can be developed and applied to probiotic research

Recommendations

New framework that considers vulnerability of study population and safety data

Subject Vulnerability

Low High

Strength of safety data (history of

use or research)

Strong safety info

CFSAN IRB enough

CBER IND discussion Full CMC not required

Unstudied safety

CBER IND Discussion

IND Phase 1 safety study

Suggested approach

Recommendations

New framework that considers vulnerability of study population and safety data

If provide one of the following, safety study not necessary for generally healthy population study

GRAS notice, or

New Dietary Ingredient Notification (NDIN)

Key points

Lawyers: substance category dictated by intent of vendor, not study endpoints

CBER has experience with streamlined IND process

Recognized value of better inter-agency communication (CBER and CFSAN)

2013 guidance on IND requirements has not been revised – we hope FDA will revise

Don’t forget possible food categories with more potential for claims Foods for special dietary use

Medical foods