Reinventing research institutions? Check out PDPs

I hang out in one particular corner of the world that talks about how to fund science, manage research, and build new research institutions. There are different intellectual tendrils that draw people into this happy muddle, but the shared interest once you get here is in scientific and technological progress for humanitarian benefit rather than just making money. That means starting high ambition organisations to solve problems that don’t fit traditional market incentives. Whether that organisation is for-profit or non-profit or some third thing doesn’t matter as much as what it works on and who’s doing the work.

I hang out in a second group with mostly different members to the first: global health. We talk about the big infectious killers – malaria, tuberculosis, pneumonia, diarrheal diseases, HIV/AIDS – and what to do next in the battle to defeat them. We talk about how to make battery-powered microscopes and paper strip diagnostic tests, and how to get vitamin A supplements to rural kids. This part of the world has a laundry list of scientific and technical problems that are unsolved and have no traditional market incentive to solve them, because they don’t often affect rich people.

This post is me introducing friends to each other, nervous they’ll hit it off and laugh at each other’s jokes. In particular I want to acquaint my first friends with a twenty-eight year institutional experiment of the second’s:

Product development partnerships

Last month the International Vaccine Institute (IVI) announced that SKYTyphoid, a typhoid vaccine, had been prequalified by the WHO – meaning it can now be used around the world. The vaccine was designed many years ago, when IVI adapted earlier work from the NIH, attaching a polysaccharide from typhoid bacteria onto a toxoid from completely other bacteria (diphtheria) so that your immune system notices the typhoid part more. Then IVI licensed that invention to three companies in Indonesia (Bio Farma), Bangladesh (Incepta), and South Korea (SK bioscience) – I presume with an agreement that they'd sell the vaccine in lower income countries at a reasonable price. With SK bioscience, they ran clinical trials in Nepal and the Philippines, funded by the Gates Foundation, to check the vaccine works as well as the other ones on offer for typhoid. It does. Now SK bioscience is manufacturing the vaccine, and more kids around the world will be protected from fevers, diarrhea, and death.

IVI is a Product Development Partnership, or “PDP”. Indeed, it’s the first one of the modern global health era. PDPs are nonprofit institutions designed to make drugs and vaccines that pharma won’t alone. They’ve helped make products used by hundreds of millions of people, with development costs lower than pharma’s, saving millions of lives.

Ever heard of a PDP? Google product development partnership and you get a list of links to dry text. At the time of writing this, there’s no Wikipedia page (anyone in the mood to fix that?), so you wouldn’t think PDPs are “a thing”. There’s no YouTube explainer video with splashy animations, no blogs talking about why PDPs are stupid and overhyped or inspiring and ingenious, no Wall Street Journal article announcing the latest leadership change at one.

I guarantee you PDPs are a thing. In fact, there are a dozen of them, with budgets mostly ranging from $30 million a year to $100 million a year. Get ready for the AO (acronym onslaught). There’s DNDi (drugs against neglected diseases), FIND (new low-cost diagnostics), IVI (lots of vaccines), IAVI (HIV/AIDS and TB vaccines), IPM (gels and rings to kill HIV), IVCC (new insecticides against mosquitoes), MMV (new malaria drugs), TB Alliance (new TB drugs), PATH (lots of stuff, including a sub-acronym MVI on malaria vaccines), GARDP (drugs to fight antibiotic resistance), CEPI (vaccines before future pandemics), ETC (et cetera).

They usually have a technical goal related to a new or improved product they want to develop, often defined by a “target product profile” (TPP) or by “preferred product characteristics” (PPC). For example, when deciding what leads to support in the TB vaccine pipeline, the global health community has mostly coalesced around a goal for something that’s at least 50% efficacious in adults and adolescents, 3 doses or fewer, and formulated in a way that’s affordable for low- and middle-income countries (page 18-20).

PDPs will often track a pipeline of leads developed by themselves and other groups, supporting the ones they think are most promising for achieving the desired goal. Some have their own labs, some don’t. Most work with academic labs and pharma companies, and contract with Contract Research Organisations and Contract Manufacturing Organisations to carry out clinical trials and formulate chemicals to standard.

Sometimes PDPs broker deals with new manufacturers to introduce a new product like SKYTyphoid, or to bring the costs down of an existing one. Sometimes they start further upstream, and develop canonical tests – in one particular dish, one particular animal – so you can compare how your new drug performs head-to-head against other drugs. That way the scientific community knows how the data was generated and doesn’t have to rely on press releases about wonderful, novel results.

Lessons learned from twenty-eight years

Sometimes PDPs achieve their goals. Take malaria drugs. (Maybe you have taken malaria drugs.) Swallowing a pill sounds easy, but there’s a problem: they taste gross – “bitter pill to swallow”, and all. Normal people get over this problem, but kids aren’t normal people. Kids are also most at risk of dying from an infection, since their immune systems are less developed. To address this, MMV helped the pharma company Novartis reformulate their drug Coartem into Coartem Dispersible, a cherry-flavoured tablet that dissolves in water. That makes a tasty drink, and might save your kid’s life.

You can’t make much money from children sipping malaria drugs, which means chemically tricky, clinically risky product development like this doesn’t happen often. But in the years since Coartem Dispersible was introduced, it has saved hundreds of thousands of children’s lives.

Pfizer’s R&D budget is around $11 billion a year. MMV’s is… $80 million.

And yet: plenty of projects don’t succeed; PDPs aren’t miracles. IAVI was founded the same year as IVI, but HIV vaccines have continued to prove harder to develop than typhoid vaccines. The Institute for OneWorld Health was absorbed by PATH in 2011, and I believe its activities have since mostly been shut down.

So enough, enough about what can go right (new life-saving drugs). What else can go wrong? PDPs can involve too many cooks in the kitchen, or particular cooks stirring the wrong pots. Decisions on how to develop a given PDP drug candidate involve:

{$} external philanthropic/government funders, either in large chunks of flexible funding or for specific clinical trials

{PDP} the non-profit PDP itself

{IP} the academic group and/or pharma company that originally developed the drug

{Maker} a manufacturer to make and sell the drug if it ends up working (sometimes the same company as {IP}, like Novartis and the malaria drug)

For SKYTyphoid that was: {$} = the Gates Foundation and the core government funders of IVI. {PDP} = IVI. {IP} = IVI itself with perhaps a little NIH. {Maker} = SK bioscience, with Bio Farma and Incepta coming up too.

That number of decision-makers can lead to disagreements, or too many lawyers, or just things going slowly when urgency is needed. Dynamics:

• Product development can speed up or slow down based on grant and donor cycles, rather than product quality. I.e. the system is getting failed by {$}. When richer countries cut aid spending, promising programs get slashed. If there is uncertainty about the future government funding landscape, product developers will not lean into their most ambitious plans. The system holds back.
• Too much funder power relative to PDP executive/staff power, even if you hold total funding fixed. I.e. {$} and {PDP} are out of whack. This problem is familiar in non-profit work writ large, and can be particularly acute for PDPs given global health R&D is so underfunded as a sector that the Gates Foundation has to support half or more of many PDP budgets. That makes the Gates Foundation’s decision on whether to renew their support high stakes, or even existential for a PDP.
• PDPs can be overly dependent on external partnerships with pharma companies to achieve their strategic goals, and have little control over those companies. I.e. {PDP} and {IP}/{Maker} get out of whack. In particular, the PDP may not be able to ensure rapid access to a new drug in the places where it’s needed most, even if it’s shown to work, if the company they’re working with doesn’t register the drug in that country or make enough of it or sell it cheaply enough – or if they hold on to ingredients for more profitable uses.
• PDPs can consolidate too much perspective and strategy for a field in one actor. I.e. too much power in a centralised {PDP}, instead of a dispersed set of {$}s and {IP}s. Then if the PDP makes a prioritisation mistake, future patients are in trouble.

Recent institutional innovations in non-profit drug development

Hilleman Labs is a joint venture between Merck and the Wellcome Trust taking vaccines from preclinical research through to phase 2 clinical trials for developing countries; GVGH does similarly but as an arm of GSK; MDGH is a fully independent non-profit developer of therapeutics, that goes through phase 3 (and 4!) too; KEMRI is a state corporation in Kenya that partners with funders and universities on all sorts of health research, including clinical trials; the Aurum Institute is a South African nonprofit that has run 100+ clinical trials for HIV and TB.

There are many models in global health R&D that differ from the PDPs. Here are the five institutional experiments from recent years I’m watching most closely:

1. In 2018, the Gates Foundation set up the Gates Medical Research Institute – working on translation and clinical trials, similar to a PDP, but where they have more control since it’s a wholly owned subsidiary of one foundation. (That said, the Wellcome Trust co-funded their largest effort to date.)
2. BioNTech is ploughing some of its COVID profits into malaria vaccine R&D. When you get a windfall, and have the expertise on staff, why not go after a global health product?
3. Novo Nordisk Foundation announced its Initiative for Vaccines and Immunity (NIVI) in December, to develop flu, strep A, and TB vaccines through to phase 2 trials, via a combination of a non-profit and an LLC.
4. Not specific to one institution, but there is a general push, especially after the pandemic, for more R&D and manufacturing capabilities in regions where the products get used. The Advancing Vaccine End-to-End Capabilities (AVEC) Africa office from IVI and African Vaccine Manufacturing Accelerator (AVMA) financing mechanism from Gavi are two examples.
5. The R21/Matrix-M malaria vaccine was developed by the Jenner Institute at Oxford further into manufacturing and clinical trials than usual for a university, then handed off to the Serum Institute to fund a phase 3 trial and mass produce. This made its development much quicker and cheaper than comparable vaccines. (Open Philanthropy supported the phase 3 trial sites too.)

I’m especially interested in seeing more of #5 get tried by innovative research institutes and universities, for vaccines and drugs. If that describes you, and you’re working on vaccines, consider going to the World Vaccine Congress in Washington D.C. or DCVMN in São Paulo to meet some vaccine company executives and see what makes them tick. There are similar conferences for small molecule and monoclonal antibody developers too, if you’re working on those instead.

Verdict

You do not get a verdict! It is a big topic, performance across PDPs varies, and I’m introducing friends, remember? Perhaps you can guess I’m more positive than negative on PDPs, but the purpose of this blog post isn’t to run an accounting. If you’re looking to reinvent research institutions, I hope you click some of the links above and form your own view on what’s been tried so far.

(That said… there is a verdict coming up soon from more careful analysts than me on global health R&D as a whole, if not PDPs specifically. Policy Cures Research and collaborators are assessing society's return on investment across the sector since 1999. Which were the new approved products that turned out to be the biggest deals, and were they worth the research money? They’ve released some materials you can play around with already.)

Thanks to Melinda Moree, Jamie Bay Nishi, Youngmi Cho, and Aerie Em for comments