How Distributed R&D Could Spark Entrepreneurship in Biopharma

This piece originally appeared in the Timmerman Report.

Remember the patent cliff and the general lack of new and innovative medicines in the industry pipeline? That was the big story of the past decade in biopharma. It caused a lot of searching for the next best way to organize R&D to improve productivity. One doesn’t hear that quite as often today. There are more innovative drugs both recently approved and moving forward through the pipelines of several biopharma.

The conversation these days has shifted toward drug pricing, and how the public is going to pay for some of these new, exciting drugs (the answer, in some cases, is maybe it can’t).

I don’t think the industry out of the woods yet. One of the main reasons drug prices have become such an issue is because even though there are new, innovative drugs, there aren’t enough of them. At the same time many of the drugs being approved are incrementally better but nevertheless being priced at a premium. And good reporting has made the public more aware of how many of our existing drugs are rising in price on a yearly basis. Especially in a time of little inflation, prices of most goods have not been going up at nearly the rate of pharmaceuticals.

Biopharma sits in a tough place. Analyses suggest the cost of developing a new drug has generally been doubling every nine years, which may be a by-product of some combination of the complexity of biology, our inability to predict which drugs will work, and the “better than the Beatles” problem. The question then is how to overcome these issues and increase the efficiency of developing new, innovative drugs. Without some kind of change, the industry is looking at a very difficult future in which price hikes run headlong into the wall of payers who finally say enough. Then what? Continue reading

One way to improve clinical trial reporting: a Yelp-style rating system

This piece originally appeared in the Timmerman Report.

STAT recently published an in-depth report about the many research centers that don’t bother to publicly disclose the results of their clinical trials, even though they are required to do so. This follows on a New England Journal of Medicine article back in March that had a similar analysis of the lack of reporting and publication of clinical trial data to clinicaltrials.gov.

Most observers of biomedical research would agree that getting clinical trial data out about what happened in a trial is pretty important, whether the trial succeeded or failed. After all, biomedical translational research is most meaningful when done on human subjects and negative information can be quite informative and useful. Animal models are nice, but translation of results from animals to humans is a spotty proposition at best. We need to know what’s working, and what’s not, to know how to best allocate our research resources and how to treat patients.

The lack of reporting is an embarrassment for research. It’s also understandable, because so far the FDA hasn’t used its authority to punish anyone for delayed reporting. Nobody appears to have lost any research funding because they failed to post trial results in a timely manner. Universities told STAT their researchers were “too busy,” given other constraints on their time, to report their results. So what really seems to be going on is that reporting is prioritized below most other activities in clinical research.

It was interesting and eye-opening that industry fared better than academia in both the STAT story and the NEJM article with respect to how many studies have been reported. Having seen the industry process first-hand, I’d speculate that (at least for positive trials) there’s a much stronger incentive to get data out in public. Successful trial results can create buzz among clinicians and patients, revving up trial enrollment which can then help get a new drug on the market faster, and convince people to use it when it’s available. It may be that in academia the effort of getting trial results in the required format for clinicaltrials.gov is perceived as too much work, relative to the rewards. Academics are naturally going to spend more energy on directly rewarded activities like writing grant proposals and writing peer-reviewed scientific publications that help them win even more grants, promotions, and other accolades. Well okay. If this is the case, then figuring out new incentives may be key.

So what would work? Anyone who participates in a clinical trial is providing time, may be subject to risks and often is asked to provide samples that are biobanked to support future exploratory and translational research. It’s like when people donate to food banks. I’m pretty sure they mean that food to be eaten and not to sit on a shelf. These participants in clinical trials deserve to have their volunteerism rewarded.

This got me thinking about how to empower patients to get more of what they want. Patient-centered research is a buzzword these days, and for good reason. Patients have at times been an afterthought in the biomedical research enterprise. I thought of services like Yelp and Uber and Angie’s List and other peer-to-peer systems that allow users to get information, provide feedback and give ratings to specific providers. And I wondered: could this be a way to apply pressure to clinical trial researchers to improve their reporting? Continue reading

The immune system as a metaphor for the Turing Pharma mess

H/T to @DerekLowe for the initial metaphor of Turing as a virus, and to the many, many commenters and journalists who’ve covered this topic.

A few weeks ago when Turing Pharmaceuticals’ plan to jack up the price of Daraprim by 5000% hit the news, I found myself glued to Twitter and other journalistic sources as each day brought a new wave of insults, reactions, condemnations, harangues, plans and concessions. I’ve frankly never seen any piece of biopharma industry news evoke this kind of response. When even U.S. Presidential candidates—well, the Democratic ones, anyway—are compelled to offer their takes and plans for reform, it seems that something fundamental may have changed.1

The question is, what should the biopharma industry take away from this? While a few CEOs such as Biogen Idec’s George Scangos and Novartis’ Joseph Jimenez have spoken out against the price hike, and both PhRMA and BIO have taken actions to repudiate Turing Pharma’s actions, there are still demands that biopharma come out with a clearer, more unified position—or risk being labeled as hypocritical. But that doesn’t seem to be happening. Just recently Ian Read, the CEO of Pfizer, told Evercore ISI that he wasn’t worried about Democratic presidential candidate Hillary Clinton’s proposals to control drug prices. Not the most conciliatory or self-aware comment to make, especially for a CEO who went on the record last year saying Biopharma has a reputation problem. So how to influence the industry to take this problem seriously?

Behavioral economics tells us that framing can be a key component influencing decision making. Among other things, a framing approach makes choices and consequences as real as possible to people through the use of analogy and filters. So I thought to myself, we all work in biology. Maybe a biological analogy might help drive home what’s at stake. And given that immuno-oncology is so hot these days it makes plasma look cool, I thought an immune related frame might be helpful. So let me present the recent pricing fiasco through the lens of the immune system.2

An extended analogy between an immune system response and the reaction to Turing Pharma
Immune system element Analog in the recent Turing Pharma debate
Priming antigens Recent discussions about the price of Sovaldi, and several other new drugs in indications like Hepatitis C, cardiovascular disease, and oncology primed the public to discussions of drug prices. Also, the Affordable Care Act’s influence on employer-provided health plans has led to rising out of pocket costs and therefore higher visibility for prices for medications.
Subthreshold immune response The lack of response to earlier instances of companies hiking the prices of generic drugs for companies like Questcor, Valeant and URL Pharma.
Virulent, triggering pathogenic infection Turing Pharmaceuticals raising the price of Daraprim by 5000%.
Immunization adjuvant Turing CEO Martin Shkreli’s amazingly annoying and provocative internet persona and behavior.
Innate immune response Social media and other responses to the price increase. Phrases like “drug price hikes,” “vulnerable populations,” and “maximizing shareholder value” that serve as pattern recognition motifs that trigger a speedy response like a macrophage engulfing a Staphylococcus bacterium.
Adaptive immune response The various regulatory plans being proposed–price caps, single payer negotiations, transparency initiatives, etc.–to stem drug price increases long-term.
Commensal bacteria Biopharma

 

The response to Turing Pharma didn’t come out of nowhere; there had already been several different factors that led the public to be primed for an affront like the Turing Pharma price hike. Over the last few years several high profile, high priced drugs have entered the market and raised real fears about the affordability of new medicines for conditions like Hepatitis C and high cholesterol that affect a substantial proportion of the US population. In addition, the Cadillac tax and other requirements of the Affordable Care Act appear to be leading to higher out-of-pocket expenses for patients (which is a feature, not a bug), further sensitizing them to drug prices. These developments have created social sensitivity to drug price changes, just as exposure to potential antigens primes the immune system for a stronger later response.

So why didn’t earlier, similar actions by other biopharma companies raise the same response? I think there are two main factors: first, randomness. We live in a world where a multitude of stimuli are clamoring for our attention. In that kind of environment there’s only enough oxygen for a few things to rise to wide-spread attention. I suspect the earlier price increases, some of which were in scale similar to what Turing did, just didn’t break the surface tension of the internet. Which brings me to the other factor: Turing’s CEO.

In vaccination, there’s a continual effort to find new adjuvants. These are substances one adds to a vaccine to really jack up the immune response. Martin Shkreli’s behavior served as a kind of adjuvant, exacerbating the effect of the initial insult of Turing’s pricing change. And that led to the initial, wild, Internet-wide response.

The concept of social shaming was recently examined in Jon Ronson’s book “So you’ve been publicly shamed.” Among the many things the Internet has enabled has been the ability to rapidly pivot on perceived malfeasants and nail them to the wall with a response not unlike that big rolling stone ball that almost squashes Indiana Jones at the opening of “Raiders of the Lost Ark.” Once a negative event does enter the attention economy, vituperation is swift and merciless. However, this innate immune response predictably fades over time. The real, lingering effect is the adaptive immune system of society—regulatory policy, which we see being proposed and debated as the US Presidential election cycle proceeds. The adaptive immune system has memory for certain pathogens, and remains ready to strike them down at a moment’s notice, and society also has a memory for certain acts it wants to remain constantly vigilant against, through laws and regulations.

So the lesson I hope biopharma takes from this extended analogy is the following: it’s too late to keep on doing the same things and hope no one notices. The system’s primed now and already starting to develop its long-term defenses. You’ll note I liken biopharma to commensal bacteria. I do think the industry serves a vital, important, useful role in helping society, just as our commensal microorganisms perform a host of beneficial functions for us. But as these kinds of rent-seeking behaviors proliferate—and not just on the side of generic drugs—the system as a whole will begin treating biopharma as more of a pathogen than a friend and the results could be very unpredictable. After all, the immune response doesn’t think about long-term consequences for the whole; it operates quickly and locally, often with unforeseen consequences. When excessively agitated by certain stimuli, the immune system can enter a chronic state of autoimmunity, creating long-lasting pain and fatigue.

The biopharma industry is blessed with the gifts of intelligence and foresight, and can take actions to head off a more stringent adaptive response from society by being more transparent and ramping down its most immunogenic actions—namely, pricing drugs to the limit of what the market will bear rather than based on a reasoned consideration of innovation and value. Because the alternative, as Robert Nelson of Arch Ventures laid out so starkly in Forbes, could be a crushing of all the good things biopharma can do in the rush to punish for the sins of a few.

 

1Maybe. The internet is notorious for its short attention span. Still, Bernie Sanders already had been calling out for reform on drug prices, so it may well be that this is a controversy that won’t get swept away by the next noisy thing. And, it must be said that at least one Republican candidate did respond to Turing’s price hike. Donald Trump, the candidate with the most experience as a provocateur, felt compelled to call Martin Shkreli a “spoiled brat.”

2I’m not an immunologist by training—I’m a geneticist. But I’ve been working with immunologists for the last seven years, which I think qualifies me to make broad, overly generalized and not entirely accurate analogies for the sake of a good story hook.

The short sword doesn’t fall far from the weapons rack

And now for something completely different.  Regular programming will resume shortly.

I’m sitting in my living room on a Saturday night and I’m listening to my son tell me about Pathfinder.  Pathfinder is one of the most recent iterations of the Dungeons and Dragons franchise, and is described in many heavy, rather expensive books that lay out all the rules, characters, classes, spells, monsters, treasures, and other things that make up this flavor of fantasy role-playing.

“I’m going to be a sorcerer,” he’s telling me, “and since I’m also going to be Dungeon Master, I’m going to make a rule that any character who wants to have more than one class and wants to be a sorcerer for one of them has to start out as a sorcerer.  Because otherwise it doesn’t make sense.”

Believe it or not, the phrase “doesn’t make sense” has probably been uttered more often in the context of fantasy role-playing games than in all the articles about the government shutdown combined.  This is because D&D is all about internal consistency, about creating a world, about figuring out why orcs are so grumpy, why gnomes are without doubt the best character race, why only magic swords glow and not magic maces.  This is also because D&D is played, largely, by geeks who love to argue about esoteric things.

As my son continues telling me his theory about how the initial appearance of a sorcerer’s powers would have to occur before a character starts adventuring, I find I’m only half listening.  And that’s because I’m remembering back to when I started playing D&D, when I was his age, growing up in Hawaii. Continue reading

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