Dr. Karen Wai Senior Director and Head of Feasibility and Site Identification Asia, Quintiles
Dr. Elvira Zenaida P. Lansang Patient and Site Services Manager, Asia, Quintiles
Introduction: The Shift of Vaccine Clinical Trials to Asia Pacific
In recent years, Asia Pacific has become an increasingly important region in which to conduct clinical trials. Some typical benefits of conducting clinical trials in Asia Pacific vs. North America or Western Europe, for example, include lower costs and increased patient recruitment, resulting in increased efficiency and shortened development timelines. In general, there is an upward trend in the number of clinical trials being performed in Asia Pacific. This shift also has been observed in vaccine clinical trials. There is a 12% increase in the number of open industry-sponsored active interventional vaccine clinical trials in Asia Pacific, when compared against the overall percentage (see Figure 1).
Feasibility is a crucial step in determining a country's potential in regards to a specific clinical trial's goals. It is defined as the process of assessing the alignment of the clinical trial in terms of study design, dose of investigational product, comparator, patient type, with the local environment and assessing the potential of conducting the clinical trial in a specific country. When evaluating the feasibility of vaccine clinical trial protocols, what specific parameters must one consider?
The eligibility criteria for preventive vaccine clinical trials typically involve healthy volunteers. Recruitment is less of an issue when compared to studies requiring patients with a particular disease. Furthermore, knowing the required age group will help in determining the proper investigators and healthcare facilities, hereafter referred to as "sites", for inclusion. A trial requiring volunteers in the pediatric, adult and elderly age groups will require both pediatric and adult sites. Feasibility conducted for an influenza study in Southeast Asia and East Asian countries showed that the recruitment rates across age groups may differ, and typically, recruitment tends to be easier for the younger population compared to the elderly. Some barriers towards recruiting elderly subjects include reluctance to participate in clinical trials, concerns regarding side effects, and increased morbidity and mortality. To be able to better assess the impact of patient type on future recruitment, it is recommended that past recruitment performance for protocols requiring similar patient populations be reviewed.
Alignment of design with the standard of care
A critical factor when evaluating the feasibility of a preventive or therapeutic vaccine protocol is it's concordance with a country's immunization schedule. Furthermore, alignment with the immunization schedule is defined not only by the age when the vaccination is administered. One must also consider that the frequency of vaccination is similar to the recommended frequency in the country. If the vaccination schedule is aligned with the immunization schedule in the country, there is a higher likelihood of obtaining regulatory and ethics committee approval. Among Southeast Asian countries, the Philippines has one of the highest number of vaccine trials ever conducted. It can be a potential country for a diphtheria, pertussis, tetanus (DPT) vaccine protocol that has a vaccination schedule of 6-10-14 weeks. DPT is part of the Philippine national immunization program and the vaccination schedule in the protocol is similar to the country's childhood immunization schedule. Furthermore, in areas where indigenous or traditional health practices prevail over Western medicine, the uptake of vaccination, including participation in vaccine clinical trials is expected to be challenging. Cultural beliefs that influence healthcare decisions are additional considerations.
Properties of the investigational product and the comparator
Properties can refer to the dose of the drug under study, the type of comparator (whether placebo or active control, and if an active control, whether it is registered in the country), or the availability/ reimbursement status of the comparator drug. In most countries, a placebo arm is only possible if the vaccine under study is not part of the existing schedule of the national immunization program. In Thailand, five out of seven trials for preventing HIV infection were placebo controlled. Conducting pure placebo-controlled HIV vaccine trials is ethical because there is no existing effective vaccine. However to meet the ethical obligations and to decrease the risk of developing HIV infection, behavioral interventions that are known to be effective in reducing the risk needs to be provided. In addition, the reimbursement status and ease of access to the investigational product and comparator will also impact willingness of volunteers to participate. Clinical trials for vaccines that are already part of a country's national program of immunization or are available to people at no or minimal cost will have recruitment challenges. In such populations, the access to the vaccine under study is high. For such trials, there is minimal medical benefit for them to participate in the study.
The availability of high-quality sites that have access to large subject populations is important to assess a country's potential and feasibility for clinical trials. A vaccine clinical trial with large subject numbers often requires multiple global or regional trial sites]. Furthermore, sites that have access to healthy populations such as schools and communities are essential for preventive vaccine trials. The involvement of commune health stations and local health centers located within communities are effective strategies for recruiting healthy volunteers in the Philippines, Thailand and Vietnam. A sponsor's marketing strategy also plays a role in country selection. Emerging markets have potential to be the largest global market for pharmaceutical sales, and this has undoubtedly shifted the focus of clinical trials into these countries. Countries such as Vietnam, Indonesia and the Philippines have been flagged to be among 11 emerging markets that have conducted a total of 44 industry-sponsored vaccine clinical trials in the last five years, a 29% increase when compared to prior years.
Other parameters for consideration include the seasonality of the disease being investigated (if applicable), and the overall benefit of the vaccine to the population.
Therapeutic Vaccines: A Case Study of Oncology Vaccine Trials
Vaccine clinical trials are largely focused on preventive or prophylactic applications, but in recent years, there has been growing interest for therapeutic vaccines. Therapeutic vaccines under clinical development are mainly for oncology. They are designed to work by stimulating the host immune response against specific types of cancer. Cancer vaccines have low side effects, making them an appealing form of treatment when compared with standard cytotoxic chemotherapy.
Dendreon's Provenge (sipuleucel-T), a dendritic cell for metastatic castration-resistant prostate cancer was the first therapeutic cancer vaccine to receive FDA approval. This is a personalized cancer vaccine that requires extraction of a patient's antigen presenting cells by leukapheresis, incubation of these cells with antigen prostatic acid phosphatase and granulocyte-macrophage colony stimulating factor, and re-infusion of the PAP-labelled blood cells into the patient. This is heavily dependent on centers that are highly specialized and have the capability to perform these procedures. Although clinical trial sites that were involved in the development of Provenge were located in North America and Western Europe, it is possible for sites in more developed Asia Pacific countries such as Australia, Japan, South Korea, China and Taiwan to have the capability to execute.
Other technologies for the development of cancer vaccines (i.e. those using recombinant microorganisms or oncolytic viruses, DNA and gene therapy based products, etc.) allow for mass production, making worldwide distribution a lot easier. Many sites in Asia Pacific are capable of conducting such trials. An example is the Phase III study for L-BLP25 in Asian patients with unresectable non-small cell lung cancer (INSPIRE) which involved 47 sites across Asia Pacific, including in China, South Korea, Taiwan, Hong Kong and Singapore. These sites can be tapped for other therapeutic cancer vaccines in the future.
Similar to any clinical trial, the availability of the target patient pool is an important consideration when selecting sites for cancer vaccine trials. Sites must also have the necessary cold chain facilities. In addition, the principal investigator and site staff involved must be capable of complying with protocol requirements. One of the reasons cited for the failure of a Phase III lung cancer vaccine trial that initially showed promise during early phase trials was the lack of understanding and commitment from the participating centers. In spite of training provided, many sites administered the vaccine subcutaneously and incompletely, rendering it completely ineffective.
Progression-free survival (PFS) and overall survival (OS) are some endpoints that are evaluated in cancer vaccine trials. It is important to note that for global and multi-regional oncology trials, the mean anticipated PFS/ OS in the control group might be significantly shorter in a subset of patients from developing countries when compared to the US and Europe due to sub-optimal and underdeveloped standards of care. This is particularly true for Asian countries where medications/ healthcare are not reimbursed.
According to clinicaltrials.gov, 6% of interventional cancer vaccine studies conducted globally (77 trials) involves sites in Asia Pacific, with majority being located in Japan, Australia, China and South Korea. Nearly half (33 trials) are ongoing which backs up claims that Asia Pacific is viewed as a more favorable region for conducting these trials in recent years.
The Asia Pacific region continues to hold much promise for the conduct of vaccine trials. Evaluating the feasibility of a vaccine clinical trial protocol, whether preventive or therapeutic, is essential. A thorough review of a vaccine protocol utilizing the five feasibility parameters is necessary to ensure study success. Doing so would allow one to identify the best bag of countries to deliver the clinical trial.
Note: 'Pacifica' defined by ClincialTrials.gov as region that includes Australia, New Zealand, Papua New Guinea and Fiji.
About the Author
Dr. Karen Wai is currently the Senior Director and Head of Feasibility and Site Identification Asia at Quintiles in Singapore. She leads a team responsible for feasibility, site identification and KOL mapping across Asia Pacific. Karen is a physician by training, acquiring a MB,BCh,BAO degree from Trinity College Dublin, Ireland. She also obtained her Masters in Business Administration from UCD Michael Smurfit Graduate Business School, Ireland. Prior to joining Quintiles, Karen was working as a physician in both the public and private healthcare sector. Karen has direct management and operational experience in European, African and Asian environments. She has also served as Medical and Scientific Advisor for over 60 different clinical trial protocols in the following indications: oncology, neurology, cardiovascular, anti-infective and rheumatoid arthritis. Using her medical and safety background she is now focused on ensuring efficiency and quality during the initial planning of a clinical trial with regards to sites and investigators.
Dr. Elvira Zenaida P. Lansang is currently the Manager of Patient and Site Services Asia for Quintiles in Singapore. She leads a team of patient and site services specialists responsible for delivering accurate and robust feasibility studies for clinical trials involving countries in Asia. Elvira is a physician by training, acquiring her Doctor of Medicine and Bachelor of Science in Psychology degrees from the University of the Philippines. Prior to joining Quintiles, Elvira practised medicine as a physician in the private healthcare sector and was involved in various healthcare policy reform projects in the Philippines.
Elvira has also published several peer-review research papers on Asia-Pacific clinical studies in the areas of rheumatoid arthritis, vaccines and pediatrics. Using her medical and safety background Elvira is now focused on ensuring efficiency and quality during the initial planning of a clinical trial with regards to sites and investigators.
Click here for the complete issue.