ERIC CLAASSEN

20% ACADEMIC-80% ENTREPRENEUR Involved in 18 B.V.’s and consulted for 110 paying clients over last

ten years, worked on Immunology Lactic Acid Bacteria since 1987

CHAIR “Businessmanagement and Entrepreneurship in the Life Sciences” Athena Institute VRIJE UNIVERSITEIT Amsterdam (2001…..)

MEDICAL FACULTY ERASMUS UNIVERSITY ROTTERDAM Immunologist & Prof Knowledge Valorisation (1994….)

“ENTREPRENEUR IN RESIDENCE” ROTTERDAM SCHOOL OF MANAGEMENT

(BEDRIJFSKUNDE)

Baba Vasilka Tudor Vasilka

Beneficial effects?

Eli Metchnikov (Nobel prize 1908)

No randomised placebo controlled trials of parachute use.

An example of underpowered and non-compliance studies. Food testing with ITT or Per Protocol studies?

V A L I D I T Y

B I A S

Meta-analysis of RCTs

Randomised

controlled trial (RCT)

Observational studies (case-control, cohort)

Observational studies

(case report, case series)

Experimental studies

Hierarchy of evidence Science – Clinical Trial paradox

Glaxo chief: Our drugs do not work on most patients BY STEVE CONNOR , SCIENCE EDITOR

MONDAY 08 DECEMBER 2003

• "The vast majority of drugs - more than 90 per cent - only work in 30 or 50 per cent of the people," Dr Roses said. "I wouldn't say that most drugs don't work. I would say that most drugs work in 30 to 50 per cent of people. Drugs out there on the market work, but they don't work in everybody."

Therapeutic area: drug efficacy rate in per cent

• Oncology: 25 • Alzheimer's: 30 • Incontinence: 40 • Hepatits C (HCV): 47 • Rheumatoid arthritis 50 • Migraine (prophylaxis) 50 • Migraine (acute): 52 • Diabetes: 57 • Schizophrenia: 60 • Cardiac Arrythmias: 60 • Asthma: 60 • Depression (SSRI): 62 • Analgesics (Cox-2): 80

A=strong, B=positive controlled trials but

some negative

studies, C= some

positive but not enough for certainty

Recommendations for Probiotic Use or: ‘A’ claims (Floch 2011)

• Infectious diarrhea children • AAD (antibiotic associated diarrhea) • Pouchitis • Ulcerative Colitis (maintenance) • Immune response • Atopic Eczema

Lynne V. McFarland

Meta-analysis of probiotics For the prevention of Antibiotics Associated Diarrhea (ADD) Note: no ITT significance in any!

Eradication Helicobacter pylori

Tong et al. Aliment Pharmacol Ther 2007;25:155–168

Eradication Helicobacter pylori

Effective • L acidophilus • Bifidobacterium • L casei

Tong et al. Aliment Pharmacol Ther 2007;25:155–168

Commercial (supermarket)

probiotics reduce pouchitis by 55% over

period of 5 years !

Health Maintenance of Athletes with Supermarket Probiotics

Mike Gleeson et al.

School of Sport, Exercise & Health Sciences Loughborough University, UK

Financieel dagblad 30 augustus 2011

Prof Dr Henk van Loveren EFSA Panel: “This does not mean that products with those claims do not work, but that their effect is not demonstrated”

EFSA process is moving target

contrary to accepted pharma

registration (FDA & EMA)

Take home messages

1. Food is not pharma (prevention vs cure; healthy vs diseased; pharma is not 100% effective)

2. Moving target is not acceptable (pre-IND meetings!)

3. EFSA rejection does not mean it does not work (person/PP vs population/ITT)

4. Industry targets: overpowered and compliant studies. shape up or ship out

First Overpowered study 2012: 500+ AAD Volunteer study

Ouwehand et al., in press

Antibiotic-associated diarrhea (AAD) incidence by study group. Low dose 4.17×109 colony forming units (CFU), High-dose: 1.70×1010

CFU, Placebo: microcrystalline cellulose.

0

5

10

15

20

25

Placebo Low dose High dose

AA

D in

cide

nce

(%)

P=0.005P=0.08P=0.28

SLIDES FOR DISCUSSION

Duration of diarrhoea

9 RCTs, n=1714, WMD -23 h (-38 to -7) Szajewska et al. update 2010

23

EVIDENCE FOR PROBIOTICS PREVENTING ACUTE URTI (THE COMMON COLD)

Probiotic intervention better than placebo:

Odds ratio for number of participants experiencing at least one URTI episode: 0.58 (0.36 – 0.92; 95% CI)

three URTI episodes: 0.53 (0.36 – 0.80)

Rate ratio of URTI episodes: 0.88 (0.81 – 0.96)

Antibiotic prescription: 0.67 (0.45 – 0.98)

No difference from placebo:

Mean duration of URTI episode: -0.29 (-3.71 – 3.13)

CONCLUSION: Benefit in using probiotics to prevent acute URTIs

Hao et al 2011 Cochrane database of Systematic Reviews 2011, Issue 9: CD006895

2011 Cochrane Systematic Review

10 trials involving 3451 people (infants, children, adults)

• ‘Healthy’ Shift-workers Probiotics and resistance to infections

•Gastro-intestinal and respiratory

25

Percentage change in saliva IgA

-40

-20

0

20

40

60

80

Beforetraining

After 3weekstraining

Aftercombatcourse

After 1 weekrecovery

PROPLA

47 army cadets

Daily 100 ml L. casei DN-114 001 probiotic drink or placebo for 3 weeks training, followed by a 5-day combat course

No difference in incidence of respiratory illness

Significant saliva IgA decrease only in placebo group

EFFECT OF A PROBIOTIC ON RESPIRATORY INFECTIONS AND SALIVA IGA DURING INTENSE MILITARY TRAINING

Tiollier et al 2007 Military Med 172: 1006-1011

26

0

1

2

3

PRO PLA

Number of URTI episodes

P=0.005 P=0.004

EFFECT OF PROBIOTIC ON URTI INCIDENCE IN AN ATHLETE COHORT

Gleeson et al 2011 Int J Sport Nutr Exerc Metab 21: 55-64

PLA = more people with URTI + during more weeks + URTI episodes

Antibiotic (3-14 days) Study product (3-14 + 7 days)

Check: Compliance Stool diary

Follow up (4 weeks after antibiotic)

503 Randomized

167 Placebo

168High dose

168 Low dose

146 completed

160 completed

144 completed

11 lost to follow-up

11 withdrew consent

2 consumed yogurt

3 consumed yogurt

12 withdrew consent

6 lost to follow-up

5 consumed yogurt

1 withdrew consent

1 lost to follow-up

1 death