DYANN WIRTH: Hello, I'm Dyann Wirth.
I'm Professor of Immunology and Infectious Disease at The Harvard TH
Chan School of Public Health.
And today I'm talking with Dan Hartman of the Bill and Melinda Gates
Foundation.
Dan, welcome.
DAN HARTMAN: Well thanks, Dyann.
It's a pleasure to be here.
DYANN WIRTH: As director of Integrated Development,
what does that mean in the context of malaria eradication versus product
development?
DAN HARTMAN: So in product development, we are constantly
thinking about how to pull all of the different pieces
together, whether it's a clinical plan, a regulatory strategy,
a manufacturing plan, a toxicology plan.
Thinking about the sequence of these various activities
and how to do that in the most efficient, cost effective way.
As I look at all of the research being done on malaria,
they tend to be one off.
We're going to answer this question, and then we're
going to answer the other question, and then the subsequent question.
And you have a whole bunch of questions being answered,
but how do you integrate all of those different results
into a cost effective way to eradicate malaria?
How do you think about the combination of various vector control tools?
Do I need bed nets, and IRS, and newer vector control tools?
Or can I substitute?
And how do you think about that?
Well if I have an effective vector control,
do I need to do mass drug administration?
And in what type of population?
And in what type of setting?
High intensity?
Low intensity?
Indoor?
Outdoor?
There are so many different covariates, and so many pieces of information,
that I think this is a great opportunity to do model based global health
and try to say, what type of an environment in my entering?
What type of information do I have?
And what is the most cost effective way to utilize the tools as opposed to,
just being add on therapy.
DYANN WIRTH: So when Bill and Melinda Gates in 2007
announced their goal to eradicate malaria, I was in the room.
And I remember thinking, no, it's too hard.
The biology, the transmission is one case leads to 100.
And then as I thought about it, I realized
it was a paradigm shift, that now you had
to think not about a disease but actually eradicating
a biological organism.
And that's a very different thing.
And I think that paradigm shift you see reflected now
in the research and the implementation.
We are now focusing much less on disease.
Clearly disease is important, but we're focusing much less on disease
than we are on how do we get rid of the organism and its transmission.
DAN HARTMAN: As I've been working with the team,
and we fund a fair amount of research, the one question that we always ask
is, how will this help us eradicate malaria?
And that's been interesting to think through that, and the grants
that we make, and how we're approaching all of our work as opposed
to thinking like a physician, like I am, to OK, I see a patient,
I treat a patient.
DYANN WIRTH: You've talked a bit about evaluating the current tools in terms
of, will they contribute to eradication.
But where do you see the holes in the toolbox?
Where are the missing tools?
DAN HARTMAN: As I've been looking at and trying to evaluate the current toolbox,
one of the things that I would love to see us develop,
is something that is less reliant on human behavior
because I think human behavior is so difficult to change.
And if we look at polio, there is a human behavior
required for the eradication of polio.
You have human behavior on the part of the vaccinators.
They have to go out, they have to find everybody on the planet, the places
that they're challenged most.
Their end game is areas with social strife.
And in malaria because of the vector, there
may be opportunities to think about a tool that
doesn't require one human being interacting
with another or one human being taking the medication for a given
period of time.
And we know adherence, even in the best situations, is challenging.
What if we could alter the vector with minimal human behavior?
DYANN WIRTH: It's an interesting idea.
It gives the opportunity to think in a completely different way,
not focus at all on the parasite but focus on the vector.
DAN HARTMAN: I think other things that we're looking to do,
is to reduce the reliance on continuous medication for P Vivax.
Can we go from a 14 day regimen to a single dose?
The single dose would be, I think, beneficial in multiple different ways,
both for treatment because the most common regimen is
a BIB, three days in a row.
What if you could do that in a single day?
What would happen to resistance?
Because you would be getting a full dose in a single day,
as well as thinking about mass drug administration.
If that's a tool that would help us eradicate malaria,
it's a lot easier to do mass drug administration
if you're giving a single dose than if you have to come back multiple times.
So again, I think that also relates to taking the human behavior factor out
of it.
DYANN WIRTH: Good.
In fact, one of the challenges, as we talk about products,
whether it's genetically engineering mosquitoes, or it's new drugs,
or vaccines, one of the big issues is the regulatory issues.
How do you take things from discovery and get them approved?
Particularly, in situations where it's a new idea.
It's not something that the industry has done before or rarely does.
And I know that you think about this a lot,
and I'm wondering what your perspective is, what the approach will be?
DAN HARTMAN: One of the things that we try to do
and are doing more frequently today is, integrated development of which,
integrated development includes, what is your regulatory strategy.
And it's really hard to plan if you don't know
what your end is going to look like.
So early interactions with regulators, talking to them
about new products, what could these products be,
what could the endpoints be, and then developing a strategy on how
to get there in the most effective way.
Again remembering, that most products fail.
So if you don't know where you're going, and you
don't know what the steps are going to get there, if you do
fail you're likely to fail late as opposed to failing early,
which is a very expensive endeavor.
Being able to make a clear case as to why
you think a product would be safe and effective
or have an appropriate risk benefit in a given situation,
is obviously necessary.
And then having the open discussions with various regulatory agencies,
and sometimes I see us thinking more developed world regulatory agencies.
But what we really need to do is to go to the communities
that we work and get their perspectives on a risk benefit.
DYANN WIRTH: I think that's a very important point
because it is a different population that's
going to uptake almost everything that's developed
during this phase of the elimination and eradication campaign.
DAN HARTMAN: I had a fascinating discussion with one of my colleagues
from Senegal, and he was telling me about malaria in the 1990s.
And he was one of the chief physicians at this hospital in Senegal.
And chloroquine resistance hit their area, and they said,
I would sign 20 to 50 death certificates a day.
I don't have that experience, and a lot of regulators in the developed world
don't have that experience.
So when you start thinking about risk and benefit,
unless you have that perspective and you've lived in those communities,
it's really hard to have that.
So that's one of the things that we're starting to do.
Especially with novel products, is really get out into the communities
where they're going to be used and get their perspectives early on
and try to have, whether it's WHO, stringent regulatory agencies
from developed worlds, national regulatory agencies from countries
where it will be utilized eventually, all have that discussion together.
We've made some really good progress in that area.
We've been working on a project called African Regulatory Medicine
Harmonization, which is taking a regional approach to a country
approach for product introduction.
DYANN WIRTH: Because most of the countries
don't have a very well-developed regulatory agency.
There are a few, but for the most part in Africa,
in particular, other than South Africa, I
think there's relatively little local expertise in country.
But from a regional perspective, that could be of interest.
DAN HARTMAN: We're trying to do multiple things with this approach.
So one is to get a critical mass, as you were describing.
So if we can take the East African community,
pull their resources and their best people
together, and have them do Dossier reviews, that's a positive thing.
The way it works, we've had it set up right now
as we're bringing in other regulators, whether it's
Swissmedic, or folks from WHO, or other stringent regulatory agencies
to help answer questions that they might have.
And they're also relying on other stringent regulatory agency reviews.
So instead of starting from scratch, they're
looking at somebody else's report, ideally, and saying, OK,
do I agree with this report as opposed to having
to dig through an entire dossier?
And the whole purpose of that is to make sure you have a quality review
and make sure it's timely.
But it also benefits manufacturers.
I was a manufacturer in my old role, and I
wanted to submit a drug to Sub-Saharan Africa, I would have over 50 dossiers,
that I would have to prepare and submit, and get questions back
from 50 countries, respond to all 50 for a market with very
marginal turn on that.
Well we can create a system where we have four or five regional areas
and you can drop in four or five dossiers, as opposed to 50,
get back four or five sets of questions and have a general format
that everybody's agreed to.
That would dramatically reduce the burden on the manufacturers.
We did a study about three years ago, looking
at the time it takes for a product to go through the entire regulatory system
and get to people in developing countries.
In developed countries, it's about nine to 12 months.
In developing countries, especially in Sub-Saharan Africa,
we found it's about four to seven years.
And it's usually approved in the developed
world, goes to WHO for pre-qualification,
then it goes to the national regulatory agencies for their review and approval.
Frequently, that none of those three groups
were taking advantage of prior reviews.
DYANN WIRTH: So they were doing de novo review each time?
DAN HARTMAN: De novo review each time.
And that obviously, lengthened it by 3x, just
if you did that in the ideal situation.
The other thing that we found is manufacturers
because they had to apply to each country.
The spread of their submissions of dossiers
was sometimes up to four years.
DYANN WIRTH: Right.
Because it had to fit into their workflow.
DAN HARTMAN: Exactly.
What we're trying to do through this harmonization effort,
is to support mutual reliance and minimize, I would say,
non-value added activity of applying to each different country as opposed
to regions.
And we've had some great success in East Africa.
And now this approach in this harmonization effort
is moving into West Africa.
South Africa already had started something on their own.
At WHO pre-qualification, we found that the drug side was relying on stringent
regulatory agency reviews, but the vaccine side wasn't.
And there was about a 13 month difference
in review time between drug and vaccines.
That was a relatively easy change to do and now the timelines are much better.
Looking at mutual reliance of national regulatory agencies
on either, WHO, or other stringent regulatory agencies reports,
has again streamlined it, single dossiers as opposed to multiple.
So all of these things have reduced the overall timelines by close to 50%,
to what they were three years ago.
DYANN WIRTH: And it also strikes me that there is an enormous capacity building
potential here because as this develops, perhaps, the Africans will even
be able to do standalone approval at the highest level
because at some point perhaps, that's the right strategy for registering
a product that's going to be either, primarily
or only used in a malaria endemic country.
DAN HARTMAN: I think that really is where we want to go.
And the regional approach makes sense to try
to stand up 50 plus high quality regulatory agencies
even within the next decade, I think would be almost impossible.
DYANN WIRTH: Exactly.
And also not productive because malaria is
going to have to be solved on a regional level.
The disease doesn't know borders.
That's something that's becoming accepted as a mode of interaction
between countries.
What advice would you give to people early in their career,
or even pre-career, what kinds of things do
you think are important for people to think about?
DAN HARTMAN: That's a great question.
I think that as scientists and physician scientists,
we underestimate the importance of leadership training.
I went through 15 years of post-high school education, and 99% of it
was science based.
The leadership component, is a totally different component,
and I think it's one that can be learned.
For the last almost 20 years, I read some type of leadership book
every quarter.
I take time out of my busy schedule to take some type of course
that I think will help my career development, whether it's I've
taken courses on implementation management, change management,
decision quality, a variety of leadership courses.
It has really helped my career and helped
me understand what good leadership looks like
and how I can constantly improve myself.
I think career development has to start with the individual.
Nobody is going to develop your career for you.
The sooner I realize that, then I could start taking control over my own career
development, understand what some of my areas of weakness
were, how am I going to fix those, and develop.
That has made a significant difference in terms of how I think, how I work.
Early on in my career, I think it was less important, but today most of what
I try to do is influence my environment.
And certainly, I try to do that through scientific discussions and arguments,
if you will.
But a lot of it is, I think, some of the softer
skills, whether it's an emotional intelligence component
or how do you think about decision quality, which is something
that we tend to overlook.
We think we all make great decisions, but you can actually tell,
did you have a quality process in your decision making at the time
you make the decision irrespective of outcome.
DYANN WIRTH: Interesting advice because I agree,
we don't spend a lot of time teaching people how to lead
or systematically how to make decisions.
We know how to test a scientific hypothesis or follow a protocol,
but we don't focus on how do you get to decisions,
and how do you lead people to decisions.
Well thank you very much.
It was wonderful that you could spend time with our students.
DAN HARTMAN: Thank you Dyann.