Fear versus fear: understanding vaccination rates

All opinions are my own and do not necessarily reflect those of Novo Nordisk.

h/t to @edyong209 for the heads up on the study.

If it seems like plagues from bygone years are coming back, well, you’re right!  Due to growing objections within the United States to vaccination efforts, we are seeing a number of infectious diseases arising that even ten years ago we might have said were eradicated in the US.   The problem may seem larger than it is simply because we get so much more news so much more quickly and easily than we used to.  However, so far there have been 159 cases of measles, which is the highest yearly count since the mid-90s.  And there are still 3.5 months to go in 2013.  Texas has been in the news quite a bit recently for clusters of measles and whooping cough–both diseases with good vaccines that prevent infection when used correctly.

There are a number of reasons why parents choose not to vaccinate their children and one of these seems to be a lack of familiarity with these preventable diseases.  Once almost everyone got the measles and kids got really sick; some died.  Now, the idea of infectious diseases might seem quaint, distant and nonthreatening to parents with no frame of reference.  And of course, once a child gets a disease it’s too late.  A particularly scary report suggests even some younger doctors feel that infectious diseases aren’t such a big deal.

So you might think that this recent study, and others like it showing that the Human Papilloma Virus (HPV) vaccine is clearly reducing HPV infections throughout the body should be promoted even more strongly by public health officials.  Why?  Because HPV is known to cause cancer.  And if there’s anything that evokes the immediacy of fear in the area of health issues, it’s cancer.  That may not be the correct path however, and I’ll get to that in a minute, but first I just want to talk about the research.

The research study was a double-blinded clinical trial in which  7,466 women were inoculated at random with either an HPV vaccine or a control vaccine to hepatitis A.  At the end of the trial, the women were checked for evidence of oral HPV infections.  The vaccine had an estimated vaccine efficacy of about 93%, meaning it reduced infection rates about 14-15 fold.  This study is the first to demonstrate that HPV vaccinations can prevent oral HPV infections in addition to those at the cervix and other locations, as has been shown previously in other research.

That HPV infection is linked causally to the development of some cancers has been shown repeatedly.  Oral HPV infections contribute to the majority of oropharyngeal cancers. When these vaccines were developed, this was the basic argument:  that giving this vaccine to women would result in a decrease in HPV infections and subsequently a decrease in various cancers.  However, as has happened with many vaccines such as the Measles-Mumps-Rubella (MMR) shot, the scientific rationale became overshadowed by a number of other, unanticipated societal factors.

With the HPV vaccine, as Beth Skwarecki (@BethSkw) astutely pointed out on PLOS Blogs, maybe the key issue that wasn’t given enough attention in planning the vaccine rollout is that they way you get HPV is by having sex, and the age at which you should ideally give a person a vaccine is when they are 11 to 12 years old.  Or, to think about it another way, just when girls are starting to begin the maturation process into young women and parents have to face the reality that there is a good chance their child will be having sex sometime in the next 5-10 years.

And that’s scary.  Scarier than the possibility that your child might get cancer 20, 30 years down the road because he or she did not get vaccinated for HPV.  Beth also helpfully links to writing by David Ropeik about how fear can trump common sense with respect to things like, for example, vaccines.

It’s already known that people are lousy about understanding probability, and when you add an element of fear to this misunderstanding, one can see how vaccination campaigns even for something as straightforward as HPV face an uphill battle.

I mean, cancer!  If you can’t get people behind a preventative measure for cancer, what can you do?

And that is the question.  It’s not enough to just say that vaccinations should be mandated.  Sure government could do that, but the consequences could be quite large in terms of anger and pushback.  Would it have helped if in the beginning Merck had not pressed so strongly for every girl to be vaccinated?  Maybe, as some analyses after the fact suggest Merck involvement increased suspicion that all this was just some Pharma boondoggle.  That’s a post-hoc justification though, which I tend to distrust.

Ultimately it seems the answer will have to come from some combination of using subtler methods for incentivizing parents and better understanding of what people are afraid of.  Because right now it seems like even the fear of cancer isn’t enough.

3D printers, DIY Bio, French bistros and one possible future path for drug development

All opinions are my own and do not necessarily reflect those of Novo Nordisk

The Long Tail is Everywhere There’s Information

Several years ago I happened upon Chris Anderson’s great book The Long Tail.  He wrote about the amazing changes that were taking place in commerce because of the digitization and electronic dissemination of information.  Mix incredibly cheap (essentially free) data storage with the Internet and reasonable bandwidth, throw in the power of search and individual customization algorithms, and suddenly business models no longer had to rely on bulk consumption and the generation of popular hits.

The first industries to feel the change were in entertainment:  music, movies, books, where having a physical copy was once necessary to enjoy Madonna, Star Wars, or Carl Hiaasen’s latest thriller.  Digitization turned that upside down.  It became clear that what we’re really paying for is information, and it’s a lot harder for the entertainment industry (or any industry) to keep control over the dissemination of information than when they sold that information packaged in shiny plastic discs.

Anderson also described how in this digital world, and aided by the powers of personalized search, niche markets could not only survive but thrive.  Once, something like Tuvan Throat Singing was a niche musical form that you might have heard of on a trip to Siberia, but you’d have had no luck finding a CD at your local Tower Records (remember them?).  Now, you can not only find several tracks from iTunes or Amazon, you’ll also get suggestions for what else you might like based on your fondness for overtone singing.  Since it costs Amazon basically nothing to store the music and associated information, they can afford to have it available for the 20 people who might want to buy it.  Tally that up across all the niches in the world and it’s a hefty sum.

This is pretty neat.  But it’s still uncertain how the business of entertainment will shake out financially and logistically among the producers, distributors and promoters.  I’m not real fond of chaos like that in my professional life, and for a long time felt secure that my job–drug development scientist–was not in danger of becoming part of a long tail phenomenon.  Only now I’m not so sure. Continue reading

Supply chains in Drug Development?

This is a response I made to a recent post at Xconomy about the idea of drug development adopting a supply chain approach.  http://www.xconomy.com/san-diego/2013/05/31/test-the-supply-chain-model-this-market-driven-relationship-is-a-fail/.  All opinions are my own and do not necessarily reflect those of Novo Nordisk.

I really appreciate the ongoing conversation about how to fix the problems that appear to be facing drug development–specifically a lack of truly transformative, life- and health-changing new drugs.  I think the idea of a supply chain process in drug development is worth looking at.  However, I am not convinced it will actually fix the problem.

In this piece, Standish Fleming suggests a market driven process isn’t meeting the needs of drug development because the potential suppliers in the market (the startup biotechs) don’t have a clear view of what the eventual buyers (the pharma) really want as part of their strategic goals.  Alignment is often a good thing.  I believe many startups may not have a clear idea of what actually constitutes a good drug as many of them arise out of academia. This is not a criticism, just a statement of how the academic and industrial systems have different cultures, goals and knowledge bases. I also appreciate the point that, with capital harder to get via venture funds, pulling pharma in to replace that investment at an earlier stage requires some sacrifice of control on the part of the biotech, with a corresponding gain in risk sharing and predictability.

But I don’t think alignment is enough.  I worry instead that the key problem is one that’s been suggested by David Shaywitz and others–we just don’t understand enough about diseases to make the next generation of drugs.  It seems that the buyers themselves don’t have a clear idea of what is most likely to make a good drug.  As evidence, I’d suggest that if pharma really knew what they wanted, failures in Phase I-III would be far lower since drugs would never be tested in humans until pharma were sure of an 80-90% success rate.  Baseball aside, a 30% or lower success rate generally doesn’t make for a good business strategy, but that’s what we’ve got.  And I agree with the point that there are a lot of smart people working on the problem across pharma, so it’s not just a question of brainpower.

If pharma can’t easily predict what kinds of drugs will succeed, then this model may just swap out VC funding for pharma funding with the same net effect.  Also, the development of a drug is an incredibly long process.  For a pharma to be able to predict the market ten or more years ahead of time is adding another uncertainty yet.

Since I live in Seattle, I’d like to throw out the analogy of the Dreamliner.  A key reason the Dreamliner exists is because of 9/11.  Before that, Boeing was designing a supersonic passenger jet.  After 9/11, the pressure for nations to become more fuel-efficient to allow less involvement in the Middle East led Boeing to change course and design a plane that would instead be a model of efficient design.  So there’s an example in which changes in the market outside of a company’s control can render all its best plans moot.

Another point about the Dreamliner is that that project relied on a supply chain that ended up delaying launch for over a year.  I know people at Boeing and they have good project managers and good communicators and they told their suppliers exactly what they needed, and problems still arose.  Ever after launch, unexpected issues with batteries grounded the jets again.  How much messier might a supply chain relationship be between biotech and pharma?  Can deadlines and milestones be guaranteed when we won’t know until Phase I if we’re dealing with the next best thing in air travel or a flaming battery?

All this is not to say it couldn’t work; just that I’m skeptical.  I agree the current method seems inefficient and difficult to make work in the current funding environment.  I just wonder if maybe there is a third way.  Now, if only Bill Clinton could get into drug development…

Greenhouse Gas Is Changing Ocean Ecosystems

 

This article originally appeared in Real Change in 2005.  I wrote it about one of my main concerns regarding climate change.   

 

The oceans have buffered the effects of man-made carbon dioxide in the atmosphere, but at a potential cost to the organisms living in the oceans’ upper layers. Scientists at the Pacific Marine Environmental Laboratory on Sand Point Way are part of an international team who discovered that half of the carbon dioxide produced by human industry has ended up in the oceans instead of remaining in the air. They reported their findings last year in the journal Science.

Their research represents the culmination of a 15-year effort to measure and interpret the role of the ocean in the global carbon cycle.

Over the past two centuries, although the amount of man-made carbon dioxide in the atmosphere has steadily increased, only about half of the expected increase was seen. Where the other half went was unknown.

These studies represent “the first time we’ve taken direct measurements to show that the oceans take up man-made carbon dioxide,” says Dr. Chris Sabine, one of the primary authors on the reports. Dr. Richard Feely, another of the lead authors, adds: “These numbers are used to constrain the global carbon cycle models. We need to have these constraints to know if the models are working properly.”

Building accurate models for the movement of carbon dioxide is of particular importance because carbon dioxide acts as a greenhouse gas. As the amount of carbon dioxide in the atmosphere increases, more of the heat from the sun is trapped near the earth’s surface, potentially leading to an increase in average temperatures around the world.

This research also demonstrated the effects of carbon dioxide uptake on the oceans themselves. “People seem to have very strong feelings about global warming,” says Sabine. “But whether you believe in global warming or not, we are adding huge amounts of carbon dioxide to the atmosphere, and that is measurably changing the chemistry of the oceans.”

Carbon dioxide’s potential to affect the environment was recognized over a century ago by the Swedish chemist Svante Arrhenius in 1896. Since then, scientists have struggled to accurately measure and model the global carbon cycle—the movement of carbon dioxide into and out of the many components of the environment such as the forests and the oceans, as well as the man-made inputs from burning fossil fuels, cutting down forests, and producing cement.

Carbon dioxide also deserves particular attention because it has an extremely long retention time in the atmosphere. Once it is released through a process like deforestation, it takes thousands of years for an ecosystem to re-absorb it.

The international team, a coalition between two consortia—the World Ocean Circulation Experiment (WOCE) and the Joint Global Ocean Flux Study (JGOFS)—measured carbon dioxide levels in ocean waters across the globe and at several depths. They compiled measurements demonstrated that the surface waters of the oceans show a net uptake of about 118 billion metric tons of carbon from the air over the past 200 years.

“The surprise was not that the carbon dioxide was there, but how much,” says Feely.

At the same time, the absorbed carbon dioxide is changing the chemistry of ocean waters and jeopardizing some inhabitants’ survival.

As carbon dioxide is absorbed by the upper layers of the ocean, it causes a drop in ocean pH. As this happens, “all organisms that form calcium carbonate shells and skeletons, from [some types of plankton] to the coral reefs—all of these species will have a harder time producing calcium carbonate,” says Feely.

Several studies under controlled laboratory conditions have demonstrated how, when ocean conditions change due to carbon dioxide uptake, marine organisms produce less shell or skeleton material. These experiments suggest the potential for large effects on marine ecosystems.

The actual pH changes are small; according to Sabine, the ocean surface pH has dropped about 0.1 pH unit.

“If anyone’s ever had a fish tank, you know pH is very important to control,” says Sabine. “If you let pH get out of control, all the fish will die.”

While the changes in the oceans’ chemistry should not be that extreme, many of the species that may be affected by reduced pH are at the bottom of the food chain. Changes in these populations could therefore have far-reaching effects.

Feely sees greater problems in the future, given predictions that the amount of carbon dioxide in the atmosphere will likely more than double to 700 to 800 parts per million by the end of the century if changes are not made.

“You would see very significant changes to surface ocean chemistry,” he says.

Some policy makers appear to have noticed. Senator John McCain invited Feely to testify before the Senate Committee on Commerce, Science and Transportation in September of 2004. Sabine described the senators as “very interested” but was unsure about the policy impact the testimony would have.

Feely believes there is a need to decide what to do about man-made carbon dioxide emissions as soon as possible. Carbon dioxide will remain in the atmosphere for millennia, even with a decrease in man-made emissions. “What we do over the next hundred years will affect man over the next several thousand.”

Some thoughts in response to an article on why drug development is so hard

This comment was originally posted in response to an article by David Shaywitz at Forbes.  http://www.forbes.com/sites/davidshaywitz/2013/05/10/whats-holding-back-cures-our-collective-ignorance-and-no-not-a-pharma-conspiracy/  I hope to eventually expand on these ideas in a later piece.

Thanks for the interesting take on the pharmaceutical industry and the problems of finding truly new and innovative drugs. The reasons you put forward are, I think, a large part of the problem. Biology is hard and we’re discovering just how hard it really is. Just as an example, something like ENCODE comes out and one learns about the vast amount of transcription going on in the genome across the many different cell types profiled, and one realizes there is no clear way to make sense of all of it, or even really know how much of it actually means something and how much of it is noise. As other examples of how hard it can be, some of the other commentors have pointed out the inherent unpredictability of biology, including the lack of translation from in vivo, controlled results in a dish to organismal biology, and also the complexity of a system with billions of moving parts.

While I’m still optimistic about Systems Biology approaches, I don’t have much faith in top down engineering models employing circuit diagrams and differential equations. Systems level measurements have shown how much variability there is among individuals in things like transcripts, proteins, metabolic rate, etc. And yet at the same time organisms generally function despite undergoing what amounts to a complete rewiring every generation due to genetic recombination and gamete fusion. It may be that a better understanding might come from study not of the specifics but of the generalities of systems that allow them to remain stable despite the diversity of all the parts. Trying to comprehend how evolution has solved the problem of balancing stability with variation.

Another aspect of the problem facing pharma today I think has to do with being victims of our own success. Many of the biological approaches of the last century, including the phenotypic screening mentioned earlier, helped illuminate many of the major pathways and a lot of the key regulators in human biology. That wave of information helped inform the highly successful drugs developed in the 80s and 90s. However, once you have a decent drug, it’s difficult to go one better. Improving on a statin is hard. Anything obvious, with a big effect on biology (and, it must be noted, big side effects) has probably already been found.

I’m reminded of the metaphor of the adaptive landscape from evolutionary biology. The concept is that a given phenotype of a species occupies some position on a landscape consisting of peaks and valleys, with peaks representing local maxima for fitness, and valleys representing poor fitness. In evolution, favorable mutations allow some phenotypes to move up the side of a peak, approaching ideal fitness. I sometimes think of drugs today as occupying a similar fitness landscape with peaks representing diseases and many of our existing drugs positioned near their respective therapeutic peaks. Once you start moving up a given peak, it’s progressively harder to make a change that will move you closer to the top as opposed to sideways or backwards. So you get Zaltrap and Avastin.

The way out is to change the landscape itself. To stretch a tortured analogy further, your comment, David, about possible new therapeutic modalities could be likened to the development of the first feathered, gliding dinosaur. Suddenly the adaptive landscape changes, shuffling the peaks and valleys so that they can now be exploited in different ways. Maybe a radically different kind of drug, like siRNAs once were thought to be, could completely revamp the drug development space. Fundamental insights into biology might do the same.

Disclaimer: all opinions are my own and do not necessarily reflect those of Novo Nordisk.