NVGH Typhoid Vaccine Clinical Trial: Bringing clinical trials to patients

International diplomacy is not a requirement one normally finds in NIBR job descriptions. However, in addition to scientific, clinical and technical expertise, it's exactly what Audino Podda, Head of Clinical Research and Regulatory Affairs, and M. Qasim Rana, Clinical Program Manager, Novartis Vaccines Institute for Global Health (NVGH) in Siena, Italy demonstrated to win approval for a clinical trial in Pakistan for a new NVGH conjugate vaccine, Vi-CRM197, to prevent typhoid fever in developing countries.

Typhoid fever is difficult to estimate. Globally, according to the WHO, 16-23 million people suffer from typhoid fever each year with 90% of cases reported in Asia. Each year, typhoid fever causes 200,000 deaths, mostly in children. Hoping to reduce these figures, NVGH scientists and colleagues in South Asia have focused on how to best address this endemic disease. Audino remarked, "Recent epidemiological studies have shown a higher incidence of typhoid fever in young children and suggested that immunization programs target children under two years old. However, current approved vaccines are not appropriate for children this young." 

After successful initial Vi-CRM197 clinical trials in Europe, NVGH submitted applications for a clinical trial in India and Pakistan, among the South Asian countries where the vaccine is most needed. With ethical approval already obtained from the Aga Khan University IRB and the Pakistani National Bioethics Committee, the NVGH team faced a major set back when their Pakistani colleagues informed them that the Pakistani government issued a ban on all clinical trials, including the NVGH trial for reasons unrelated to the NVGH study. It was a complicated situation because the Pakistani government had never previously approved phase 1-3 vaccine clinical trials.

Making the Case in Pakistan
Faced with this challenge, Qasim traveled to Islamabad, Pakistan to work with his colleagues on a solution. As a citizen of Pakistan and knowledgeable of how the government works, Qasim met with the Director General of the Ministry of Health and learned that any change in the decision on the ban on clinical trials rested with the National Assembly of Pakistan's Standing Committee of Health—a high-level group of heads of various national health related institutes and politicians, whose influence is not easily accessed. However, Qasim persevered by contacting members of the national assembly and eventually received an invitation to present his case before the Standing Committee of Health.

“The result of Qasim’s impassioned speech was the unanimous agreement by Pakistan’s Standing Committee of Health to lift the ban on all clinical trials in the country."

In January of 2011, Qasim spoke before the Standing Committee at the Parliament House of Pakistan amidst much media coverage. His address focused on the great cost of typhoid fever in South Asia—lives lost and the high cost of treating the disease—and how the new NVGH vaccine could help reduce the local disease burden. Qasim noted how the vaccine would improve the lives of so many Pakistanis as well as so many other South Asians. However, none of this could happen without the ability to carry out the NVGH clinical trial in areas where the disease is endemic.

"In Bangladesh, India and Pakistan, poor hygienic conditions make this water-borne disease so deadly. People, especially young children, are vulnerable to getting the disease from drinking water, milk (which is unpasteurized), and from the bazaar culture where they buy their fresh and prepared foods," said Qasim. The vaccine addresses this reality and by preventing people from getting sick it reduces the financial burden of families, most of which do not have health insurance.

The result of Qasim's impassioned speech was the unanimous agreement by the Committee to lift the ban on all clinical trials in the country. "The Committee members were openly touched by what they learned and how the vaccine could help Pakistani people and neighboring countries. They also understood how vaccines such as this could help not only the health of the country but also the economy. The Committee also agreed that there should not be a ban on clinical trials in Pakistan that are conducted in adherence with legal, ethical and scientific standards. They are open to similar vaccine clinical trials in the future," added Qasim.

Clinical Trial Begins
Two days after Qasim's presentation, the NVGH team received government authorization to begin the trial at the Aga Khan University (AKU) of Karachi, one of the largest and best universities in South Asia. "Following the safe immunization of the adult cohort of the trial, the AKU clinical investigators have now started to immunize the children, who are the target population for this vaccine.

In May 2011, the first infants (9 months) have been immunized in Pakistan with the NVGH Vi-CRM conjugate vaccine and, concomitantly, with the measles vaccine. For the first time in Pakistan, clinical investigators have vaccinated young children that previously could not be immunized with currently available typhoid vaccines. The NVGH vaccines were administered in the context of a regular EPI vaccination visit, an approach that in clinical practice will reduce delivery costs and will increase vaccination coverage.

"Upon completion of clinical trials, the vaccine will be licensed and the World Health Organization (WHO) will ultimately pre-qualify it," added Audino.

This extraordinary turn of events is a credit to the teamwork of NVGH and their colleagues at AKU. "I believe that our commitment to this project, particularly Qasim's speech to the Standing Committee, communicated well the dire public health need for this vaccine to fight typhoid fever and that it can be the start of improving overall health conditions in Pakistan and neighboring countries," remarked Audino. "This new vaccine will hopefully contribute to saving a significant proportion of about 200,000 lives currently lost yearly to typhoid fever," added Audino.

"I am overjoyed by the results we have had in gaining approval for the clinical trial and for the results it is yielding. I am also pleased that this opportunity has led to continued collaboration with the Pakistani health authorities. The Standing Committee of Health invited us to attend another meeting to provide feedback on Pakistan's legislation on clinical trial regulations... I look forward to advancing future clinical trials in the region," said Qasim.

"Only a few years after the start of NVGH operations, we are in Phase 2 clinical trials in the target population of our first vaccine, fulfilling criteria of accessibility to developing countries’ children, which is part of our mission,” concludes Audino.