Clifton J. Leaf, Lidia Schapira, MD

Oncology’s Deadly Caution

Editor’s Note: In researching The Truth in Small Doses: Why We’re Losing the War on Cancer — and How to Win It,[1] Clifton Leaf, Assistant Managing Editor at Fortune and a longtime student of the cancer community, interviewed more than 1000 cancer stakeholders over 9 years to assess oncology’s state of health in the United States. His conclusion, supported by extensive documentation, is that urgent intervention is required. In a recent interview for Medscape, Lidia Schapira, MD, Assistant Professor at Harvard Medical School, spoke to Mr. Leaf about his provocative ideas on how to get cancer research and practice off the critical list.

Dr. Schapira: In reading your book, I was struck by the way that you view oncology. How would you describe it, as a former patient and a student of the culture of oncology?

Mr. Leaf: Imagine that the cancer community is divided into 3 parts: academic research, drug development, and treatment. In the last of these — the practice of medicine — there is a profound sense of urgency. When you and other doctors see patients, there is an immediacy to your response and a very clear sense of the stakes, whatever action is taken. This urgency pervades the whole treatment process.

In academic research, we have what I would call a “deadly caution,” a phrase that I think captures the essence of academic science in oncology. It is a bureaucratic caution that is manifest through the grants review system in which truly new or radical or innovative ideas are squeegee-ed from the process.

On the drug development side, it is similar; we are pushed into “me-too” incrementalism. Much of the caution is sensible and necessary, but a lot of it isn’t. In the bureaucracy, in the paperwork, and in the choices that are made, we have erred on the wrong side.

Bureaucracy Takes Its Toll

Dr. Schapira: In reading your book, one almost has a sense of longing for cancer pioneers, such as Sidney Farber and Denis Burkitt, who were absolutely dedicated and brilliant cancer investigators. How can we make it possible for the current generation of passionate, brilliant cancer investigators to have a chance? What do we need to change?

Mr. Leaf: I want to make this clear, and I emphasize this in the book: We have an lot of absolutely dedicated and brilliant cancer investigators working today. I spent a decade interviewing people throughout the oncology field, and I don’t think there’s a smarter, more passionate, more humane group of people than those who are now engaged in the anticancer fight. But that said, we are driving many young, brilliant investigators out of cancer research, and we are at risk of losing a generation of cancer scientists if we don’t fix the culture and day-to-day systems that are driving them out.

On the research side, the grants review process, for example, is set up to utterly discourage young investigators. In 1980, new investigators got their first National Institutes of Health (NIH) Research Project Grant (R01), launching their independent research career, at an average age of 36, and 4 in 10 R01s went to people under the age of 40. Today, the average age for a first-time grant is 42, and barely 10% of these awards go to someone under 40.[1]

Investigators are forced to deal with so much nonsense

The grants application process, moreover, squeezes the lifeblood of creativity from the overwhelming majority of these projects, and forces highly trained investigators to spend half of their waking hours in mindless pursuit of these project awards, even though the NIH funds but 1 in 10. It’s an insane and destructive cycle. Instead, we need to free really bright, energetic, innovative people from the chore of trying to lay out their research projects in minute detail when we know that the truth of science is that these things evolve and change as new knowledge comes into play. Our first challenge is to rethink the system of grants review so that we are funding people, not projects.

On the clinical side, investigators are forced to deal with so much nonsense when they are putting together a trial — from having to get okays from dozens of institutional review boards, to filling out needless paperwork and ordering needless procedures, to creating limitations on the trial populations through inclusion and exclusion criteria — that it makes trials slow to recruit and slow to get off the ground, phenomenally (and often prohibitively) expensive, and ultimately uninformative if the trial populations don’t fairly represent the real patient populations for which the treatment is intended.

This cost has driven up the price of drugs — the price of medical innovation — to staggering heights, and it has encouraged those who can pay this admission price to pursue the least ambitious, least risky me-too agents that have the best chance of getting marketing approval. The entire process, as I write in my book, is driven by a paralyzing fear of risk, and the cost is a community-wide incrementalism that inures us to the very real danger of the fast-rising global cancer burden.

New Models Are Needed

Dr. Schapira: Do you have any thoughts about novel ways for funding science? How should the relationships among academic centers, government agencies, and pharmaceutical companies or biotech companies evolve?

Mr. Leaf: We need lots of new models. Carl Nathan, MD, a microbiologist at Weill Cornell Medical College, has done some deep and creative thinking about the drug development question, particularly in regard to new antibiotics and vaccines — for which there is obviously critical need, but little financial incentive to entice for-profit companies.[2,3]

Depending on the specific requirement, one model might be a better fit than another. For example, when there’s some good evidence to suggest that an off-patent molecule or natural agent may be active against a specific disease, it may make sense to try what some have called a “pull” model of drug development.[4] In this model, a government body or even a well-funded charity essentially pays for early testing (or a share of it) or partners with a for-profit biotech or pharmaceutical company to pay for preclinical testing, or maybe phase 1 clinical trials. A model such as this might also be useful in funding the development of biomarker tests, which are expensive to vet and unlikely to offer a quick return on investment.

Another issue is the clinical trials we undertake. I think we have to start choosing trial designs that let us learn far more quickly about what’s working and what isn’t — whether that’s through adaptive trial designs, as Laura Esserman, Don Berry, and others are doing with the I-SPY 2 trial,[5] or through so-called “N of 1” studies.[6] The incredible individuality of patients — and the often striking intratumoral heterogeneity within those patients — makes it almost impossible to have a “big box” clinical trial that provides any real information. We need to try some new clinical trial models.

We also want to think about models that allow us to combine drugs earlier in the investigational stage. If we are talking about hitting multiple targets, we are going to have to combine targeted therapies — sometimes before their marketing approval — in order to see real effects. What we do now is serial testing: We will try a drug until we see resistance, and then we will try a second one that works on those resistance mechanisms, and then we will see new resistance mechanisms and so forth. What we need to do is combine investigational agents.

Again, we want to be careful about all of these new models. We don’t want to necessarily charge into the unknown full-steam. But we have to try something. The current system just doesn’t work.

Consensus: The System Is Not Working

Dr. Schapira: You have dynamic ideas for everything from funding to innovative cooperation and training, and even clinical trial design. What do you think is necessary for change to take place? Do we need to raise public awareness of these problems? Or would it be more productive to change the mindsets of physicians in positions of power or leadership?

Mr. Leaf: There are a lot of stakeholders in this effort: doctors, regulators, scientists, drug developers — and, of course, most important of all, patients and their families. These constituents all have something to contribute. And I believe that, in different ways and to different extents, each has come to a recognition that things aren’t working, or aren’t working as well as they should. For us to make meaningful progress in the issues we’ve discussed, we all have to be willing to have the systems that we’ve grown to know and dislike actually change.

Each one of these constituencies will probably go about that change in a different way. I think people within the academic community understand that the grants system is badly flawed. A lot of people in medical science are finding their careers and lives uncertain — so uncertain that a lot of very brilliant laboratory heads are concerned about whether they are going to lose their postdoctoral fellows. Some of them are paying their secretaries or their postdocs out of their own salaries. We can’t have a situation in which researchers are constantly looking over their shoulders, worrying, “Is my lab going to be around tomorrow?” We have got to change this whole system of institutional uncertainty.

Drug developers are going to have to realize, “We are spending more and more money and getting less and less bang for our buck. We can blame the FDA). We can blame academic science. We can blame anyone we want, but in the end we don’t have a very efficient model, so we have to start developing new models.” Maybe it will involve sharing precompetitive knowledge, as is done with such consortiums as Sematech in the semiconductor industry.

Regulators at the FDA acknowledge that we are still using tests for liver toxicity that are from the 1950s. We have to be willing to confront this head-on. We have got to rethink the clinical trials process. We have to rethink our rules on surrogate endpoints for trials. We have to remember what the aim of our multibillion-a-year enterprise of drug development is — to improve human lives — and to remember the stakes of our inaction or severe incrementalism. Lives are lost in the endless delay, just as they are in moving ahead with reckless speed.

Patients have to rethink their blind allegiance to the notion, “If we raise more money, we will solve this problem. If we only contribute more — if we have more pink ribbon races and wear more yellow bands — that somehow we are going to get there.”

We have to take action and look at the things that clearly don’t work. When we do that, we don’t need a 5-point plan or a massive bill from Congress. What we need is change from within that makes sense, the way any smart organization changes itself. I am very optimistic that we can do that.

Passion and Conference Calls Yield Success

Dr. Schapira: Can you name, perhaps, one organization that you think is taking sufficient steps or that actually has bought into this message that there needs to be a culture change?

Mr. Leaf: I think I would have everyone in the cancer community study the Multiple Myeloma Research Foundation, led by Kathy Giusti. Kathy is a myeloma patient. She was diagnosed in 1996, and practically from that moment, she started to disrupt the culture. Part of that effort entailed getting patient groups together, but mostly it involved getting academics and drug developers to work in a collaborative fashion. She started an almost unheard-of consortium for drug development, and she started a biospecimen bank that should be the envy of the world. She has created a phenomenal patient resource to enroll patients in clinical trials and test new agents.

By getting people who wanted access to these things to get on a weekly conference call and agree to share X and Y, she has remade the world. The Multiple Myeloma Research Foundation is also proof positive that change can have a phenomenal effect on outcomes. What has happened in myeloma in the past 10 years is a sea change. I think that is a model for us to look at, for sure.

Dr. Schapira: It’s interesting that you picked a model in which the driving force is one person’s passion, a passion that is linked to her own survival. It is urgent, and it is personal. Can you think of an example of an organization or an academic institution where scientists are encouraged and nurtured in a way that serves as a positive model?

Mr. Leaf: I really like what Brian Druker is doing out at Oregon Health Sciences University (OHSU) Knight Cancer Institute.[7] Druker, of course, is one of the scientists and clinical leaders behind the development of imatinib mesylate (Gleevec®). Having been thrust into leadership at an organization outside the epicenter of cancer science, he is able to redevelop, to rethink, a culture. It is not 100% there yet, but I am encouraged by his energy for that undertaking.

I would say that probably the most extraordinary place is St. Jude Children’s Research Hospital in Memphis,[8] where they have a phenomenal culture built on collaboration and sharing, and they get everything into the public domain as quickly as possible.

Among universities there is frenzied competition — to get their share of grants, of intellectual property through patents, and of licensing dollars from their technology transfer. We have to remember that universities essentially are public trusts, and that we have to get back into that sense of the collaborative enterprise.

There, we have 3 very different models: the Multiple Myeloma Research Foundation, Oregon Health Sciences University, and St. Jude Children’s Research Hospital — all of which we can learn from.

There is some really great science out there, and we should be proud of the work that is being done. My criticisms in The Truth in Small Doses center on things that stop science from being done, that stop people from thinking great ideas and from sharing their great ideas. We have got probably more brain power in the cancer community and more will to solve this problem and more passion than in any other pursuit I can think of. How do we free these people to do what they were meant to do? That is our challenge, our collective challenge.

A Network of Minds Linked by Technology

Dr. Schapira: Perhaps we can use technology to better link research centers, even to the point of sharing patient data. Do you know of any organizations that are thinking about how we can allow science to progress by sharing resources?

Mr. Leaf: There is an effort led by investigators at the Arizona State University, including Anna Barker and George Church, who are working on an alliance — the National Biomarker Development Alliance[9] — that will collect and bank tumor specimens, network the information, and collaborate to find tools to uncover biomarkers.

What is most critical for exchange is not the content but rather the tools for disseminating, sharing, aggregating that content in a useful way. Look at how the Internet has transformed every part of our lives. The heart of the Internet isn’t some piece of electronic equipment. It is an agreement. It is an agreement on protocols. It is an agreement on conventions. It is an agreement on language. It is an agreement that everyone around the world adheres to, so that they can put information out into the public sphere and have it be accessible to all. Every great network, at its core, is simply an agreement among people to follow a certain set of rules, and from that you get critical mass.

I believe that we have to do that with the search for biomarkers and with the banking and networking of biospecimens, and with bioinformatics. I think we have to do that with clinical trial enrollment — making sure that patients have information about what treatments are out there, what treatments are truly effective (and in which populations), and what is coming down the pike.

There are an awful lot of things that we can learn from the noncancer community about agreement. In the cancer community, we have got to get out of the habit of having multiple names for everything, and multiple platforms for such things as microarrays that make it difficult (and sometimes impossible) to compare data from one study against another. We have to have agreements and conventions that make it easier for researchers to communicate with one another. That is a fundamental issue we have to resolve.

Dr. Schapira: You have made a huge contribution toward bringing these issues to the attention of the public. What has been the most meaningful aspect of writing the book?

Mr. Leaf: The most meaningful thing to me is the engagement from the people within the cancer community. This is a community that wants to heal itself. These are people who want to be able to do what they got into this business to do, which is to end the cancer burden or lessen it as much as human biology will permit. That is what they are here for. We may never defeat cancer. But this passion, this engagement of the community to get as close as we can to that goal — that is deeply moving to me.


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