High quality clinical trials and optimal processes will always be the ultimate goal for drug development. One of the most important barriers to realize this goal, is patient recruitment. It is a challenge for any type of study phase or design.
We asked ourselves:
- What are the classical challenges and practices for patient recruitment and are these comparable to Viral Challenge studies?
- Are there additional hurdles for recruitment in Viral Challenge studies (e.g volunteers, regulatory)?
- What are their benefits of using the new challenge approach and how to overcome the additional hurdles?
Two case studies about influenza and rhinovirus will be described as examples.
1. Comparison with other study designs
Overall Recruitment Challenges
In many cases, volunteers have a lack of awareness regarding clinical trials. They don’t have an understanding of clinical studies and are afraid of being considered as a guinea pig. If they have a disease / illness, they are afraid, they will receive sub-standard care and get a placebo, often on top of their usual treatment. Or there could be other barriers such as language, literacy, or cultural.
There can be recruitment issues with the study site or protocol. Sometimes the criteria for study inclusion or exclusion can be too restrictive. At the beginning the site physician made an assumption on the number of subjects that would participate and then find that he has fewer subjects interested then thought due to different reasons like lack of interest form candidates, very strict in- and exclusion criteria. Many times study sites participate in multiple clinical studies and you end up with studies competing for the same volunteer population. Also the design of the studies and the type of molecule play an important role. For trials with vaccines and biologics, the long period of follow-up could be a barrier to participation.
Standard Recruitment Practices:
To recruit volunteers, sites have options that can best work for their facility and community.
- Advertising (print, radio)
- Network of physician / specialists
- Call center, direct mailing
- Social media / Patient websites (clinicaltrials.gov, centerwatch.com)
- Partnerships with academia / universities
- Patient associations
2. Comparison with viral challenge
In viral challenge studies the same barriers to recruitment and the same techniques are used to increase recruitment
a. Additional hurdles in viral challenge studies
Viral Challenge study design
Viral challenge testing is a new way to obtain proof-of-concept for the effectiveness of an anti-viral drug or vaccine early in phase 1, right after the initial safety and PK/PD assessments, leading to faster go-no-go decisions.
These study are mostly conducted in healthy volunteers but can be performed in patients as well. The study uses an established virus challenge strain that is a attenuated form of the wild type virus that will theoretically have milder symptoms. The volunteer is inoculated with the virus and depending on the virus tested, is then quarantined for a prolonged period.
Influenza Case Study
This was a Phase I, open-label validation study, in healthy volunteers for a H1N1 strain, with a dose escalation in 3 cohorts, needing 36 volunteers for enrollment. The duration was 29 days, with 10 days in the isolation unit after inoculation. Volunteers were prescreened for negative antibody titer using the HAI test. They could have not had a influenza vaccine in prior 2 years and could have contact with anyone immunosuppressed, under 5 or over 65 years of age or someone pregnant for 2 weeks following the challenge study.
A recruitment letter has distributed to 6382 volunteers in the database. 239 volunteers have positively reacted and subscribed themselves for the screening. 219 subjects actually took part in the screening (26 have canceled before the screening visit or did not show up). Of those, 90 volunteers cleared screening, 123 screen failures (57% screen failure rate) due to criteria for negative antibody titer. Then 61 volunteers moved forward, 32 screen failures (52% screen failed due to antibody titer (exposed to influenza between screen 1 and 2) and other inclusion /exclusion criteria. The final enrollment number was 29.
Rhinovirus Case Study
This was a Phase 1, randomized, double-blind, placebo-controlled study looking for 12 healthy volunteers (part 1) and 60 asthmatic subjects (part 2).
The study duration was 56 days with 10 days in the isolation unit. Study volunteers need to have a body weight between 40 – 125 kg and a BMI between 19 - 32 kg/m2. Volunteers need to test negative for serum neutralizing antibody to Human Rhinovirus -16 (HRV) .They need to have a positive serology for Herpes Virus 1 (HSV) with no signs or symptoms of active infection and not currently receiving prescription treatment. They could not have regularly used tobacco within 6 months of screening or have a history of smoking ≥ 10 pack years or equivalent, or a positive urine cotinine test at screening.
For part 1, the healthy volunteer part, enrollment, recruitment letters were sent to the volunteer database with over 8.000 subjects. We screened 160 volunteers, 147 screen failure (91.8% screen failure rate) due to positive HRV16 titer and/or negative HSV titer. The final enrolment was 12 subjects.
For part 2, the patient’s part, enrollment, recruitment letters were sent to the patient database, advertisement, flyers and physician network. SGS screened 54 asthma patients, 54 screen failed (100% screen failure rate) mostly due to a positive HRV16 titer and/or negative HSV titer. In a small number of patients, other reasons for screen failure were: withdrawal of consent, not qualifying for other inclusion criteria like spirometry.
Interpretation of case studies
There is much higher screen failure rate, even more in patients in this case (100 %) compared to most other study types. This high failure rate is to a large extent due to the exclusion of volunteers/patients having not the right antiviral profile. The strict and longstanding isolation conditions are not an additional barrier, at least not in a clinical pharmacology unit where participants are used to strict conditions for their participation a clinical trial.
b. Benefits of new approach
New approaches outside of large-scale field trials are more and more considered to provide early evidence of proof-of-principle in humans. Proof-of-concept challenge testing in general, provides a carefully controlled, systematic, and efficient group of methodologies in which a number of variables can be controlled or even eliminated, with the subjects continuously monitored in a sequestered environment.
Performed in an experimented and dedicated equipped clinical pharmacology unit, such new approach makes it feasible to:
- set up different challenging techniques (e.g. virus, histamine, LPS) in healthy volunteers and in patients,
- quarantining during prolonged periods,
- screening large volunteer populations for difficult selections,
- using complex laboratory techniques for collection of different body samples and preparation for biomarker analysis (virus, protective antibodies and cellular immunity)
- detailed assessment of immune parameters that help in identifying immunological correlations of infection and illness.
Looking at the recruitment challenges and practices for volunteers and patients for clinical trials, we did not see major differences between the viral challenge study design and other study phases or designs. Recruitment does not decline because of the specific requirements of viral inoculation and quarantining.
However the screen failure rate was at least 5-10 x higher than in other study types, depending of course on protocol inclusion / exclusion criteria, So for being successful, it is absolutely necessary to have a large database of volunteers and to approach a much larger sample of candidates than usual. Therefore including viral challenge testing in the activities of a large clinical pharmacology unit with a huge volunteer/patient database offers the best guarantee for a successful recruitment.
Overall, Viral Challenge Testing helps to optimize the overall drug development process enabling:
- Smaller sample size required to obtain meaningful results with this model that is substantially lower than for community-based studies of naturally acquired infection.
- Savings in the clinical development costs for new vaccines or antiviral agents.
- Avoiding initial efficacy studies in much larger populations, that are time-consuming and often dependent on epidemic infection periods environment.
- Minimizing safety risks for infected volunteers and protecting the outside world from a possible spread of infection.
- Facilitating the development of prophylactic as well as therapeutic new small and large molecules and vaccines, as well as early safety assessment in healthy volunteers and patients with respiratory disease.
- Faster go-no-go decisions for phase IIb and III trials
The technique is not only very helpful as proof-of-concept for effectiveness, but also in some cases as proof-of-mechanism for new targets e.g.in asthma.
SGS Life Science Services