The long road from
world-class research to
better health outcomes

Their answer has spawned an innovative medical device, a BC-based biotech company, international clinical trials, and the potential to someday soon save thousands of lives around the world.

But their journey has by no means been a straight line.

Determined to make anaesthesia safe for everyone, the pair devised and built a prototype oximeter to measure a patient’s blood oxygen saturation using an ordinary mobile phone – an innovation with great promise to make a life-saving technology affordable and accessible in all settings.

With a home-built prototype in hand, the researchers carried out early tests in Uganda that showed the device’s potential.

While Ansermino saw the phone oximeter's capability in the field for anaesthesia, he realized the device had many other potential applications. A chance conversation over coffee with his colleague Peter von Dadelszen led to an “accident of research."

Describing his work on a risk-assessment model for pre-eclampsia, a serious elevation of blood pressure during pregnancy, von Dadelszen noted that the women who experienced the greatest complications suffered from low oxygen saturations — precisely the outcome the phone oximeter was created to measure.

Recognizing the synergy in their projects, the two researchers integrated phone oximetry into a predictive model of pre-eclampsia risk. The partnership has grown into a large international trial in four countries — India, Pakistan, Nigeria, and Mozambique — with more than 80,000 women enrolled.

Expanding the phone oximeter's scope stands to benefit many more patients, but also increases the costs of bringing the device to market.

"We can solder this together in our basement and prove a concept, but there’s a huge step in actually making that into a commercial product," Ansermino says. "What we really needed was to establish a company to manufacture these devices."

Enter Tom Walker, an experienced BC-based biotech entrepreneur, who saw the news coverage of the device and was excited by the possibilities. Working with Ansermino’s team, Walker spearheaded development of a start-up company, LGT Medical, focused on producing the device.

But he didn't come with money, we still had to go to Grand Challenges Canada to try and raise some of the funds.

The team also attracted funds from local investors, enabling them to move forward with development of a commercial version of the phone oximeter.

"We're still not there yet," says Ansermino. "It's like with all start-ups, we don't have enough revenue to sustain us, so we're still looking for ways to keep this going for a few years so we can build sales and get to the stage where we are sustainable as a company."

Backed by an MSFHR Scholar Award and a grant from the US National Institutes of Health, Nielsen and his team spent five years perfecting a test that could filter through thousands of genes expressed by breast cancer. Their work identified a list of 50 genes that could be measured efficiently from biopsy specimens to classify tumours into one of four main sub-types.

"We had for the first time these tools that generated huge amounts of data, but we needed to turn that data into information, and information that we could use to help people," Nielsen says.

The resulting test – called PAM50 – had immense clinical potential. Accurately classifying tumour sub-types would allow physicians to make targeted treatment decisions that could save lives and reduce costs.

But a test that works in the lab is not the same as a test that can be commercially marketed and used to make life-or-death decisions in the hospital.

For their investment of five years of time and resources, Nielsen’s team had achieved proof of concept. The next challenge was to figure out how that concept could be scaled up for maximum impact.

The testing required to validate a discovery for regulatory approval is not only repetitive, but expensive. Researchers must show analytical validity – consistent results across a range of conditions – as well as clinical validity – a test or device’s ability to accurately predict patient outcomes in repeated use.

Public grant funding won’t typically cover the types of studies required for regulatory approval. So, for many researchers, the only way to navigate this complex process is to enlist a commercial partner.

Nielsen formed a partnership with Seattle-based NanoString Technologies that opened the door to commercializing his PAM50 breast cancer test. It also opened his eyes to the private sector’s approach to milestones, timelines, and strategic decisions.

Devoting precious time to the demands of commercialization can be a career liability for researchers who operate in a world where publication success and funding depend more on novelty and innovation than on following through on technical details. For Nielsen, the salary support of an MSFHR Scholar Award provided protected time for the test development phase of research.

“It’s an opportunity to do things that are somewhat higher risk for your career but ultimately give us a better chance of really moving research forward into health care and helping the patients of British Columbia and indeed of the world,” he says.

With the support of MSFHR and his commercial partner NanoString, Nielsen has achieved approval for the PAM50 test from Health Canada, the U.S. Food and Drug Administration, the European Union, and a host of other jurisdictions, including Hong Kong and New Zealand.

Like many researchers whose work touches on key policy areas, Janssen found the publication of her findings marked the end of one long and rigorous process and the beginning of another.

For more than a decade, she had been building an evidence base to inform the conversation around home birth and midwifery regulation in BC, Canada, and around the world.

Janssen’s evaluation of BC’s home birth demonstration program in the 2000s led to the addition of home birth as an option for low-risk women under the jurisdiction of the College of Midwives of BC. But despite the evidence, many jurisdictions and professional associations continued to recommend against home birth.

Previous studies had been limited by short timeframes and small samples, and Janssen realized that the home birth policy debate sorely needed long-term follow-up data in a large population.

"Policy requires rigorous studies that are reproducible, that involve large groups of representative people, and that’s what we provided," she says.

Using British Columbia's unique and world-leading health data resources, Janssen assembled a complete database of all home birth outcomes over a five-year period. By comparing these to midwife- and physician-attended home births for women of comparable low-risk status, she was able to assess the relative rates of perinatal death and adverse outcomes.

We’re a very data-rich country. In British Columbia, we have Population Data BC, and it was necessary to use that data, combined with data from Perinatal Services BC, to look at our outcomes... access to those data sources was critically important to us.

The study, published in 2009 made an emphatic case for the safety of home birth attended by regulated midwives in BC. Not only was the rate of death low and comparable to hospital birth, the rates of obstetric interventions and adverse outcomes were in fact lower.

Janssen knew her study could inform policy development at the provincial, national, and international levels, but she needed to get the word out. Working with UBC’s media relations team, Janssen issued a press release highlighting the study’s findings. The response was astonishing.

“We had saturation of every major newspaper in North America, every syndicated evening news show, every major radio network,” she says. “It went all over the world very, very quickly."

It also became a hot topic discussed on social media and blogs, igniting a public conversation about home birth. For her efforts, Janssen received the UBC President’s Award for Public Education through Media.

But the real reward was the surge in awareness among policy-makers. Backed by the study’s strong data, BC's midwifery legislation became a model for setting regulatory standards in the Prairie provinces, the Atlantic provinces, and the North. Internationally, legislation to ban home birth that had been before the Australian parliament was withdrawn in light of the study’s evidence.

In BC, the College of Physicians and Surgeons made the unparalleled landmark decision to allow its members to conduct birth at home. And the Ministry of Health affirmed its support for home birth and midwifery, with then-health minister Margaret MacDiarmid recommending the option.

Finally, after more than a decade, the evidence was speaking for itself.

Three doses was the approved global standard, but not necessarily the optimal number. “The cost of getting a vaccine from development through to being licenced is huge,” says Dobson. “The companies don’t want to disadvantage themselves by using fewer doses than would show a result.”

If a two-dose regimen could be proven effective, the impact would be massive. Fewer doses would mean greater compliance and lower delivery costs – effectively, more girls could be immunized for the same investment of resources. It’s an exciting prospect in Canada and a potential game-changer in the developing world.

To answer the question, Ogilvie and Dobson needed to conduct a large study involving thousands of girls, assemble a talented interdisciplinary team, and earn the support of clinicians, policy-makers, and public health specialists. Fortunately, they were in the right place.

“I think one of the things that made this study unique and feasible was that we did it in British Columbia,” Ogilvie says, rattling off half a dozen provincial institutes that supported the work*. “We tapped into all of those infrastructures and all of that expertise to build the team, to build the methodology, to do the analysis, to do the roll-out. Having worked in other provinces, I know those don’t exist everywhere.”

Equally valuable were the national collaborations they fostered with researchers in Quebec and Nova Scotia that allowed them to expand the study’s scope.

“We’ve been asked this question many times: could you have done this study in any other country?” says Dobson. “And the answer is: I’m not sure that we could, because there’s such good collaboration across Canada and across these different clinical specialties.”

Their study, published in April 2013, proved that over a three-year follow-up period, two doses were not only effective, but actually conferred stronger immunity in girls (ages 9-13) than the standard three-dose regimen did in young women (ages 16-26).

Even with this strong evidence for the benefits of two doses, there was no guarantee their recommendation would be adopted as policy.

“There’s in-built conservatism, and quite rightly, about changing an immunization schedule away from what’s been licenced for the product,” says Dobson, “and so it is a leap of faith to use less than the three doses.”

Convincing policy-makers to take that leap of faith was their next task. But for Ogilvie and Dobson, the process of persuading policy-makers had started even before their research question was settled.

With the introduction of the HPV vaccine in 2006, it was widely recognized that the vaccine would have resource and policy implications for governments.

At a summit attended by public health experts, clinicians and Canadian researchers from the vaccine and cancer fields, the question of optimal dosing emerged as a top priority with broad support among scientists and policy-makers alike.

MSFHR, the BC Ministry of Health, and the governments of Quebec and Nova Scotia provided funds to Ogilvie and Dobson’s team to evaluate the relative safety of a two-dose regimen. The early buy-in from government partners meant that following the publication of their results in April 2013, provincial governments were interested in the conversation about the public health case for two doses.

By starting with a research question that was highly relevant, that was actually prioritized by a group of clinicians, policy-makers, public health specialists, and by doing that kind of research, you start to have that knowledge translation charted out.

- Gina Ogilvie

This conversation at the provincial level began to feed into a broader global dialogue about the optimal dosing schedule.

Data from the BC-led study enabled the vaccine’s manufacturer to obtain licensing from the European Medicines Agency for a two-dose regimen, which in turn caught the attention of the World Health Organization. Based on the available evidence and the commitment to a 10-year follow-up study by Ogilvie and Dobson’s team, the WHO revised its HPV policy guidelines in December 2014 to recommend a two-dose vaccine for girls aged nine to 13.

“We went from a study that was looking at the blood response to two doses versus three doses, and we ended up with a World Health Organization recommendation that two doses be the standard dosing regimen,” says Dobson. “That is an amazing story."