Influenza Clinical Research – Influenza Challenge – Viral Challenge

Influenza research - wcct


 

About WCCT Global Influenza Clinical Research Capabilities:

WCCT Global is the first US contract research organization (CRO) capable of conducting Influenza Clinical Research. WCCT Global has built this influenza challenge capability based upon its longstanding successful history (established in 1998) of rapid enrollment of volunteers both healthy and targeted patient populations into complicated, specialized clinical trials. Therefore, WCCT Global is uniquely poised to support the development of antiviral drugs and vaccines for the treatment of a number of respiratory and enteric viral infections. WCCT Global recognizes that the Human Viral Challenge Model has become widely accepted as an alternative to traditional early stage field trials to show the efficacy of antiviral and vaccine therapeutics. Although WCCT Global will continue to participate in field trials, it is dedicated to providing the “Healthy Volunteer Flu Challenge Option” for those firms that wish to evaluate early vaccine or antiviral prototypes in this clinical setting.

WCCT Global will perform Influenza Clinical Research studies in a controlled quarantine environment in the WCCT Costa Mesa, CA Clinical Pharmacology Unit (CMCPU). The CMCPU is designed specifically for research and to do inpatient studies. The CMCPU has 30 private rooms and can be fully devoted at any time to running a flu challenge study. The unit contains large open phlebotomy areas, ECG rooms with multiple procedure stations, various subject entertainment options (DirecTV, computers, internet, DVD players and movies, ping pong, foosball, PlayStation 2, etc.), two spacious PK sample lab processing areas, large and comfortable monitor stations with phones and high speed internet access, a securely locked ambient and refrigerated drug storage room, two pharmacy dosing and storage areas with a study drug laminar flow hood, secure medical records and CRF storage rooms. The 30- semi-private rooms have air ventilation ducts configured so that there is no cross ventilation with the rest of the building.

The WCCT Challenge Virus (Wild-type A/California/2009 H1N1 PDM) was isolated from a combined nasal/throat swab obtained from a 3 year-old male child who presented an influenza-like illness during the 2009 flu season. In addition to evaluating acute respiratory illnesses in the child and his family members during the initial encounter, information on current and past medical history, travel history and social history was systematically recorded. The original isolate was subsequently passaged in specific-pathogen free (SPF) eggs under current Good Manufacturing Practices (cGMP) conditions. Appropriate qualification procedures, release specifications and analytical procedures for the WCCTG-A/California/H1N1 2009 challenge virus have been carried out to confirm lack of adventitious agents and suitability for clinical use. The virus has been used in clinical studies with excellent viral shedding rates in multiple clinical studies and with no safety concerns. Challenge studies using this virus can be performed in the US at WCCT’s dedicated influenza challenge facility based in Costa Mesa, CA or in Europe with a WCCT affiliated site based in the United Kingdom. An active FDA Drug Master File (DMF) for the WCCTG-A/California/H1N1 2009 challenge virus is available to the Sponsor for cross referencing purposes. The WCCTG-A/California/H1N1 2009 challenge virus Investigator Brochure (IB) is also available for Sponsor Review.

WCCTG Operations for performing Challenge Procedure Monitoring Trial

Typically, volunteers will spend 10 to 15 days in the WCCTG CMCPU. Individual clinical studies may involve multiple CPU admissions, depending on the required size of the study. In order to generate the target number of volunteers for a given trial, WCCTG may screen hundreds to thousands of potential volunteers which have been generated by the WCCTG – In-Site® and via appointments at dedicated screening locations. This recruitment strategy allows WCCTG to deliver what the sponsor requires, ideally involving as few volunteers in trial as possible.

In addition to the protocol and sponsor’s guidelines, WCCT has extensive SOPs and work instructions that cover all study related procedures – informed consent, screening, lab collection/processing, personal protective equipment, and subject confinement, to name a few. We have dedicated Quality Assurance staff onsite to ensure staff compliance with policies and processes. Trained medical staff is always available to monitor subject safety. For a human challenge study, subjects are generally screened within 28 days prior to randomization and will be confined to the unit based on the sponsor’s requirements.

WCCTG offers a comprehensive clinical trial service offering – from protocol design to Clinical Study Report publication. With over 15 years’ experience in clinical trials, WCCT Global has extensive knowledge encompassing Phase 1a, 1b and 2a studies conducted to US and international standards. The WCCT Global database of several thousand volunteers plus the Proprietary Recruitment department call “In-Site, which enables sponsors the ability to rapidly and cost-effectively carry out studies with specific deadlines, such as the seasonal requirements for the Flu Vaccines

WCCTG Recruitment/Screening Capabilities and Timelines

In an influenza vaccine trial conducted in influenza season of 2012, WCCT Global’s site was asked to identify subjects who did not have a presence of detectable pre-existing antibodies to the vaccine component as determined by an HAI titer of ≤ 1:20 against circulating H1N1-like viruses. WCCT Global demonstrated its recruitment capabilities by increasing the advertising through general media advertising and internet advertising. With this strategy, WCCT Global placed over 1,500 calls to the community which resulted in over 600 screening appointments. Of the 600 appointments, 335 came in for evaluations which resulted in 37 randomized subjects in 2 groups. Based on this experience, WCCT Global has developed a recruitment strategy enabling enrollment of consecutive 30-volunteer cohorts. As an example, below are some metrics that we recommend for a Human Challenge Model trial which would enroll 36 sero-negative healthy volunteers.

Activity Number of Volunteers Assumptions
Calls to Make 4170 At 5:1 call to appointment ratio
Total # of Appointments for Screening 833 Schedule 40% or more  screening appointments to cover potential no-shows
Total # to Screen 500  
Estimated # of screen fails 450 90%  SF range set depending on final I/EC
Cleared 50 At 10% cleared cushion
Estimated # alternates 9 At 20% admission cushion
Enrolled/randomized  Into Trial 36  

WCCT Global Staff and Experience

All WCCT Global lab staff are IATA certified and trained to process a wide range of samples. They are familiar with time sensitive processing such as PK and antibody processing, sputum samples, flash freezing, and 24 hour urine collection. WCCT has the ability to perform a diagnostic tests for influenza, either rapid antigen or PCR via nasal swabs or washes. The methodology will be determined by the sponsor’s requirements.

Safety experience in young adults

It is unknown exactly how many experimental influenza virus studies have been carried out in young healthy adult volunteers. However, it is well know that a commercial enterprise that only does experimental viral challenge studies in volunteers in the UK has been in existence since 1989. Generally, all volunteers :

  • Are selected based upon a predetermined HAI titer level
  • Are quarantined for 7 to 10 days
  • inoculated, intranasally, with a live virus that has been proven to cause the viral syndrome in other human experimental studies or in a proven animal model
  • Are medically monitored 24/7 during the quarantine and full lifecycle of the induced illness
  • Viral Shedding
  • Physical examinations (plus ECG and vital signs)
  • Reactogenicity questionnaires
  • Laboratory safety studies and often other “biomarkers” of disease or drug action

They have not reported a serious safety problem attributable to the virus challenge, to date. Furthermore, Carret et al published an extensive review of the worldwide literature of reported outcomes of experimental influenza virus infection in healthy volunteers from 1965 to 2005. Seventy-one papers describing 56 different studies, 79 different subgroups, and 1,280 different participants were selected for thorough review. In all the studies, the participants were young adults aged between 18 and 40 or 50 years, except in one study (15), where the age ranged up to 65 years. A total of 199 (12 subgroups) participants had pre-HAI antibody titers to the challenge strain of at least 1/16 or were not selected according to their pre-HAI antibody titers. The routes of challenge were intranasal instillation in most studies. Throat sprays were also used in three studies, and aerosol inhalation was used in one study. The inoculum ranged between three and 7.2 log10 median tissue-culture infective doses. Most papers reported IRB committee approval or collection of written, informed consent from each participant. In almost all studies, participants were individually confined for 1 week. Most studies included daily follow-up with daily nasal washing and collection of clinical signs and symptoms. The follow-up period ranged from 3 days prior to inoculation to 14 days after inoculation.

Again, there was no reported serious safety outcome highlighted in the discussion.

Therefore, WCCTG concludes that the experimental influenza challenge model, if carried out as described, above, provides no more risk to the volunteer than any other clinical trial that we have been offering to our sponsors.

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