Recruitability and Retention: The Challenges of Vaccine Trial design

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Suzanne Elliott28July 2015

World Health Organization declared smallpox eradicated in 1979

http://www.wired.com/science/discoveries/news/2008/05/dayintech_0514

May 14, 1796: Jenner Tests Vaccination on Human Subject

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Vaccination“the most effective and cost effective health tool ever invented” 1

1.Gates B. Annual letter from Bill Gates. The Bill & Melinda Gates Foundation; 2001: 9. http://www.gatesfoundation.org/annual-letter/2011/Documents/2011-annual-letter.pdf

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Q-Pharm’s Vaccine Trial History• Infectious disease and autoimmune disease

• Genetically modified vaccine trials

• Pharmacodynamic vaccine-vaccine interaction studies

• Healthy Volunteers & Patient Groups

• Vaccine delivery routes - SC, IM, ID, comparisons

• Complex laboratory processing

– Plasma, PBMC, Pre-Prep CK, punch Bx

• Approved vaccines:

– IMOJEVTM (Japanese Encephalitis Vaccine) - Sanofi Aventis

– JESPECT(R) (Japanese Encephalitis Vaccine) - Intercell AG

– Intanza(R), (Intradermal Influenza Vaccine) - Sanofi Pastuer

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Q-Pharm Vaccine Studies

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Therapeutic area Prevention or treatment study?

Year trial commenced No. pts vaccinated Approximate Recruitment period

Influenza H1N1 H5N1-AvianH1N1UniversalH7N9-AvianH1N1 (Quadrivalent, novel Ag)

Prevention 200520072010

2012* 2013* 2014*

60 (E, D)50 (S)

200 (E, S)48 (S, LTF)98 (S, LTF)

50 (E, S, LTF)

2 weeks 1 week

2 weeks 2 weeks2 weeks

5 months

Herpes Simplex Virus Prevention Therapeutic

2013* 2015**

20 (DE, S,LTF)Ongoing aim 40 (PD, LTF, D)

3 weeks Ongoing

Human Papilloma Virus Prevention 2005* 30 (S,LTF) 2-4 weeks

Japanese Encephalitis Prevention 2004 2005*

20072007

108 (V, PD)64 (DE)100 (NI)

70 (S)

4-6 weeks4 weeks

4-6 weeks1 week

Malaria Prevention 2008*2008*

45 (DE)36 (DE)

1-2 months 4 weeks

Coeliac Disease Therapeutic 2009*2012*2013*

2 (DE, PD)10 (DE, PD)4 (DE, PD)

1 month1 year

8 months

Dengue Fever Prevention 2010 139 (S, PD) 7 working days

Ross River Virus Prevention 2011 100 (S) 3 weeks

Group A Streptococcus Prevention 2012* 10(S) 2 months

Cholera Prevention 2014 103 (NI, PD S) 2 weeks

Ebola Prevention 2015* 76 (PD, DE,S,LTF) 6 working days

E - Elderly, D - Delivery modality; V-Vaccine/Vaccine interaction; * Phase 1, ** Phase 2, PD-pharmacodynamic DE - Dose Escalation, NI - Non-Inferiority ; S – Safety; LTF - Long Term Follow up

Q-Pharm Vaccine Studies

www.qpharm.com.au

Therapeutic area Prevention or treatment study?

Year trial commenced No. pts vaccinated Approximate Recruitment period

Influenza H1N1 H5N1-AvianH1N1UniversalH7N9-AvianH1N1 (Quadrivalent, novel Ag)

Prevention 200520072010

2012* 2013* 2014*

60 (E, D)50 (S)

200 (E, S)48 (S, LTF)98 (S, LTF)

50 (E, S, LTF)

2 weeks 1 week

2 weeks 2 weeks2 weeks

5 months

Herpes Simplex Virus PreventionTherapeutic

2013* 2015**

20 (DE, S,LTF)Aim 40 (PD, LTF, D)

3 weeks Ongoing

Human Papilloma Virus Prevention 2005* 30 (S,LTF) 2-4 weeks

Japanese Encephalitis Prevention 2004 2005*

20072007

108 (V, PD)64 (DE)100 (NI)

70 (S)

4-6 weeks4 weeks

4-6 weeks1 week

Malaria Prevention 2008*2008*

45 (DE)36 (DE)

1-2 months 4 weeks

Coeliac Disease Therapeutic 2009*2012*2013*

2 (DE, PD)10 (DE, PD)4 (DE, PD)

1 month1 year

8 months

Dengue Fever Prevention 2010 139 (S, PD) 7 working days

Ross River Virus Prevention 2011 100 (S) 3 weeks

Group A Streptococcus Prevention 2012* 10(S) 2 months

Cholera Prevention 2014 103 (NI, PD S) 2 weeks

Ebola Prevention 2015* Ongoing 76 (PD, DE,S,LTF) 6 working days

E - Elderly, D - Delivery modality; V-Vaccine/Vaccine interaction; * Phase 1, ** Phase 2, PD-pharmacodynamic DE - Dose Escalation, NI - Non-Inferiority ; S – Safety; LTF - Long Term Follow up

Influenza

JE - GMO

Dengue- GMO

HSV2- DNA vaccine

Public Scrutiny of Clinical Trials

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Time Magazine22.04.02

http://www.abc.net.au/ra/innovations/stories/s1904518.htm

7 May  2007 

Vaccine 1

Vaccine 2 EOS

Vaccine 2 EOS

Screening

Screen and

Vaccine 1

Vaccine Trial Design

Vaccine 3

EOS

Follow-up

Screen and

Vaccine 1Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

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Study Design

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• Study Design – number of vaccinations

• Schedule of follow-ups• Participant time in the clinic? (live virus/GMO, Ph 1 v Ph 3)

• Blinding (staff & subjects)• Clinical sampling & procedures

(bloods [volume], ± Urine/Saliva, injection site photos, diary cards, Thermometer, ruler)

- Staff time for sample processing - limitation Nos./day

Nature of the Trial Vaccine Products

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• Seasonal timing with local flu season

• Pre-existing immunity (Pre-screening)particularly relevant - infected with non-

symptomatic disease• What are the benefits to the volunteer?

Health monitoringAccess to registered vaccines (ie: JE, YF, Influenza)

Challenges - GMO Vaccine Regulatory• Biosafety – IBC, OGTR – Licensed dealing to NLRD/LD• Agency – TGA• NHMRC – HREC• AQIS – Containment• OGTR – Participant education

Facilities Storage and Transport Laboratory – OGTR status, Disposal Trial logistics - complexity

daily viral samples Mosquito repellent, information

Staff TrainingPC2AQISOGTR

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OGTR requirement/RegistrationOGTR License: GMO Vaccine

Sanofi Pasteur Files for Approval in Thailand and Australia of IMOJEVTM, Single-dose Japanese Encephalitis Vaccine

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Inclusion/Exclusion

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• Age• Contraception

Abstinence (females) for a phase 1 vaccine? Same-sex relationships Male contraception

• Lifestyle – elevated CK (exercise)

• Urine Drug Screening (alcohol and cotinine)• Pathology (& physiology)

(@ screen or baseline)

“ NCS @ the discretion of the investigator”

Contraception

• In female subjects either childbearing potential terminated by surgery or one-year post-menopausal, or a negative serum pregnancy test during screening and the willingness not to become pregnant during the study period and 30 days after the last vaccination by practicing reliable methods of contraception as specified in protocol.

• Females of child bearing potential must have a negative serum pregnancy test at visit 0 and be practicing an acceptable method of birth control during the study. Urine pregnancy tests will be conducted at each subsequent study visit. Acceptable methods of birth control include barrier methods (including male and female condoms), diaphragms (cervical caps) with intravaginal spermicide (including jellies, foams and suppositories), intra-uterine devices, hormonal contraceptives, abstinence or same sex relationships. Non-childbearing potential includes being surgically sterilized or postmenopausal with no menstrual bleeding for at least one year prior to the study.

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Contraception Agreement

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Contraception Agreement

If you are female and of child bearing potential whilst participating in this trial it is important that you practice an effective method of contraception from 1 month before screening and at least 1 month after your Day 60 date of the trial. The follow methods of contraception are considered to be efficacious:

Oral contraceptive medication Implanted / Injection contraceptive medication IUCD

Subject’s Screening No: S_______ Subject Name: ___________________________ Subject’s Initials:________ I am a female of childbearing potential and whilst taking part in this trial I agree to practice one of the following methods of effective contraception until 30 days following my Day 60 of this trial. (Subject must indicate the method by placing a tick in one of the following boxes).

Oral contraceptive medication

Implanted / Injection contraceptive medication

IUCD

Other (specify)____________________________________ Must be discussed with the Study’s Medical Monitor

Subject’s Signature: _____________________________ Date: ___________

Requirements during Study- Con Med Restrictions (annual flu vaccine, travel vaccines).

- Lifestyle Restriction Exercise

Any change to their exercise routine or initiate vigorous exercise from the time of their Screening visit until after Day 30. In particular, any exercise that may cause bruising or muscle strain (i.e. participating in contact sports or performing an aggressive work-out in the gymnasium) should be avoided.

Personal Hygiene – GMO vaccines Mosquito avoidance procedures – JE vaccine

- Smoking

- Alcohol

- Travel restrictions (especially for long and GMO vaccine trials)www.qpharm.com.au

Retention of vaccinated subjects on long trials• JE vaccine study (2005, 7 months; $465)- Dosed 149 subjects; 87% still contactable @ 7 mo- Non inferiority – Scr/3 vaccines (0,7,28), 6visits, PC@7mo

• Ross River Vaccine study (2011, 12 months; $450)- Dosed 96 subjects; 8 early withdrawals (3 lost to follow-up and 5

moved interstate or overseas)- Ph3 – Scr+Vacc1/ 2vacc (1,22),6 visits

• Avian Influenza vaccine study (2013, 13 months; $1000)- Dosed 98 subjects; only 1 early withdrawal (due to death in family).- Ph 1- Scr+Vacc1/2 vacc (0/21), 7 visits+ PC, 1 PC@ 13 mo

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Suggestions from the unit: Improving of recruitment of eligible volunteers

Respect for the volunteer

- they make the difference

- they can withdraw at any time

- any reason with no notification• great way to get free health check and money - no dirext contact w ebola..• Would love to participate if this won't cross line with my everyday job!• Do you work around work schedules?• Why do most trials have a maximum age limit ? People over 50 are not immune

from illness, obviously. It seems arbitrary and unfair. Plus, we usually have more money to spend on pills !

• am only guessing here but it's probably to do with the amount of time it takes for some one younger vs some one older to recover. For example hangovers

• can i still go to the nightclub once im infected?

Suggestions from the unit: Improving retention of vaccinated subjects on long trials

1) Respect for participant’s time and commitment

2) Consider trial length and participant requirements

3) Flexibility in sampling time windows.Healthy Participants – No real Benefit

>> Participant Payment

$ Payment

– time commitment

$ payment for 6 month F/U phone call – (AE’s/con meds/medical history).

+/- 6/12 month blood sampling

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Early Phase Trial Considerations:

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Nature of the product (NCE/vaccine)Chemical v Biologic Factors of Risk

– Mode of action– Nature of target– Animal model relevance

Participants: Healthy volunteers OR patients? ± Sentinel dosing – IF so – what time delay?

Guideline on strategies to Identify and Mitigate Risks for First-in-Man Clinical Trials with Investigational Medicinal Products (EMEA/CHMP/SWP/28367/2007)

Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006)

Guidance for Industry General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases (Docket No. FDA-2011-D-0855)

Thankyou

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Mervyn Eadie Clinic(Block 8, Level 6)Building located

directly behind CBCRC

Wayne Hooper Clinic and Outpatients Clinic

(Level 5, Clive Berghofer Cancer Research Centre

(CBCRC))

Suzanne Elliotts.elliott@qpharm.com.au