Author Archive

No Test, No Drug

November 4, 2014

It is very difficult to select the appropriate therapy for a patient if you don’t know what disease you are treating. For the practicing physician, the patient’s presenting symptoms, history, physical examination, and radiological and biochemical evaluations typically establish the diagnosis by placing the disease in one of many accepted clinical diagnostic categories (phenotypes). The search for more clearly recognizable, homogeneous patient phenotypes has driven much of our early medical progress. Treating congestive heart failure, for example, is much more productive than trying to treat dropsy; a much older and imprecise collection of not-otherwise-specified edematous conditions.

Have we now arrived at the limit of utility of the descriptive phenotypic disease classification? I suggest that genotypic descriptions based on the root cause, or key molecular attribute, of the disease will rapidly replace phenotype-based disease classifications.  This can’t happen fast enough for those in drug discovery where a drug’s mechanism of action (increasingly derived from genetic considerations) must be matched with a recognized clinical indication.

The transition from phenotype-based to genotype-based indications will not be easy. It was not that long ago that we recognized that several distinctly different genetic alterations can lead to the same clinical phenotype. For example, patients with the same clinical presentation of cystic fibrosis are not expected to respond to a therapy such ivacaftor (Kalydeco, Vertex Pharmaceuticals) unless they have the appropriate CFTR mutations among the many CFTR mutations that cause cystic fibrosis.

We have discovered that patients with the same molecular basis of disease may have distinctly different phenotypes. This means that two patients with markedly different clinical presentations may be responsive to the same therapy specifically directed at their shared molecular basis of disease. While this has yet to be reduced to routine practice, recent discoveries are clearly taking us in this direction.

For example, Kevin Strauss and colleagues at the Clinic for Special Children (Human Molecular Genetics, July 2014) have identified a variant of KCNH7 (which encodes a potentially targetable ion channel) that strongly associates with bi-polar spectrum disorder. Especially noteworthy is their observation that patients with the KCNH7 variant do not present as a single psychiatric phenotype but rather with a variety of axis 1 major affective disorders.

But medical progress in this new era depends upon coordinated activity by multiple stakeholders. In this instance, psychiatrists must be comfortable with genetic classifications of disease and be sufficiently knowledgeable to order the correct drug for patients with similar phenotypes but differing genotypes. The drug developer must have established the safety and efficacy of a new drug in patients with the specific genetic alteration and also potentially have established the lack of efficacy in patients with similar phenotypes but lacking the genotype for which the drug was developed. A diagnostic company must have developed and validated a FDA approved genetic test. Finally, there must be a reimbursement scheme that recognizes the contributions of all of the above parties.

For this to become commonplace, the clinical molecular test (at least in a prototype form) will need to exist once one begins to look for the new chemical entity that will become a drug. This will also mean that we need to invest more in genetic epidemiology. The availability of the drug for the target and the test for the target will be essential in early development, especially if there is a plan to enrich for patients with appropriate particular genotype among those with a similar phenotype.

Does this mean that all new drugs in development need a companion diagnostic? Not just yet, though we may be getting there. There is plenty of disease biology for which a drug can be made but for which a test can’t be found, including in the field of immunotherapy. But even here the secrets that regulate immune response will be revealed and genotype testing will be a prerequisite for prescription writing in this field and in almost all indications.

These and other topics will be explored at the Harvard Personalized Medicine Conference in Boston on November 12-13.


The Personalized Medicine Conference is an annual two-day event co-hosted and presented by Partners HealthCare Personalized Medicine, Harvard Business School, and Harvard Medical School in association with the American Association for Cancer Research and Personalized Medicine Coalition.

For more information and to register for the 10th Annual Personalized Medicine Conference, please visit http://www.personalizedmedicineconference.org.

Strategies for Accelerating Progress in Personalized Medicine

November 5, 2013

Last year around this time, I wrote a blog aimed toward skeptics of personalized medicine, citing the progress we have made in lung cancer as just one example of how well this approach works for treating diseases. As I have reflected upon the advances we have made in areas like cancer and diabetes and how personalized medicine now seems to be the cornerstone for drug discovery and development for many pharmaceutical companies, it has become clear to me that there are still a number of areas for continued investment and focus.

What can we do to continue to grow the field of personalized medicine, find new and exciting therapies, and maintain the momentum we have seen over the past few years?

I believe that developing a personalized medicine strategy is the answer, but this is far from simple.

It begins by first appreciating that one needs to study the diversity inherent in diseases. When a new medicine is introduced in human clinical trials, for example, it is important to describe and understand the diversity of human responses to the medicine and to determine ways to identify those who will benefit the most from the medicine.

While we would ideally like to have such a clear scientific understanding of a disease that we can predict in advance who the likely benefiting patients are (which can be done in some instances), in most cases the personalization of a medicine comes from the observations made in clinical studies of diverse populations.

In contrast to basic laboratory research, where experimental designs seek to minimize variation, the “noise” in clinical trials can actually provide us with important clues to help form the basis of a personalized medicine. Well-designed studies, therefore, should study both the variation of the response as well as the scientific basis for that variation. When done well this can uncover biologic marker that become diagnostic agents for patient selection.

In addition to designing more clinical trials with these two aspects included, I would propose that those of us working in the field of personalized medicine should continue to support efforts that:

  • Fund basic research on the biologic basis of disease. Personalized medicine is based on fundamental scientific discoveries. Without these, there will be no improvement in our understanding of disease.
  • Fund research in diagnostic testing. Companion diagnostics can be useful tools to help healthcare providers and their patients make more informed treatment decisions.
  • Educate physicians and other healthcare providers about personalized medicine. Patients in specialized populations that may respond to a good therapy for their subgroup need to have access to the appropriate tests. This means making sure that those who can order the tests and use them as a part of standard care are aware that these tests and potential therapies exist.
  • Reimburse for diagnostic testing. Personalized medicine drugs will not have any benefit if they are not used and a healthcare provider won’t know to use a potentially life-saving drug unless the correct diagnostic tests have been performed.

Together, we can maintain and even accelerate the progress we have already made in delivering the right drug to the right patient at the right dose, every time.

_____________________________________________________________________

Join Dr. Stephen Eck on November 6, 2013 at the 9th Annual Personalized Medicine Conference hosted by Partners HealthCare Center for Personalized Genetic Medicine, Harvard Medical School, and Harvard Business School. 

View Dr. Eck’s video interview “Personalized Medicine: How Progress Happens” online at the Personalized Medicine Coalition.

Less May Be More

November 12, 2012

Personalized Medicine has come to be strongly associated with drug-diagnostic combinations (companion diagnostics).  While this is a very important aspect of personalized medicine, it is not the goal.  The goal of personalized medicine is to find the best possible care for each individual patient so as to maximize the likelihood of the individual achieving his/her personal life goals.  While this may seem obvious, this principle has become increasingly harder to identify in every day medical care.

A variety of different motivations has encouraged the healthcare enterprise to view illnesses, or even everyday complaints as the opportunity – if not obligation – to do something for the patient.  The better approach is to ask: What is the best thing one can do for a patient, including the possibility of doing nothing?

As we develop better drug-diagnostic combinations, this will become increasingly apparent.  Soon we will have the ability (through use of precise molecular diagnostics) to know with reasonable certainty whether there is little or no benefit for a particular individual to pursue a therapy which had historically been the standard of care.

But, are we truly ready to forgo a potential therapy even if such a decision is based on strong scientific data?  Or, will we continue to use a therapy on the off chance it might work?  Our desire to do something has to include the possibility that the best treatment might be no therapy, based on the risks to the patient, the likely benefits, and the life goals of the individual.  In the end, patients want their healthcare providers to help them make the best choice and personalized medicine can be a strong tool to do that.  This will provide the largest benefit for patients as they avoid the risks that come with all therapies when no benefit is realistically to be had.

Dr. Stephen Eck will be moderating a panel discussion on Wednesday, November 28, 2012 at the 8th Annual Personalized Medicine Conference in Boston, Massachusetts.  Join the discussion at #PMConf. 

Still Skeptical about Personalized Medicine?

October 29, 2012

Over a century ago Sir William Osler, M.D., stated: “Variability is the law of life and as no two faces are the same, so no two bodies are alike and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.” Despite our deep and long-standing understanding of the heterogeneity of disease and the variations in response to treatment, we are slow to adopt the notion that despite its complexity, the heterogeneity of human illness is decipherable. Skepticisms that we can actually deliver on the promise of personalized medicine is understandable, since converting such variables as severity of illness, uncertain vulnerability to side effects, co-morbid conditions and our cultural environment, to name a few, to precise algorithms for care seem daunting.

So, why has it taken so long for medical science to unravel this heterogeneity and why should we be optimistic that personalized medicine will happen? In part, our current views stems from where we have previously focused our attention. “Bergkrankheit “(mountain sickness) was known in the 14th century as an affliction of metal ore miners in Europe. By the 20th century we knew this as lung cancer and attributed it to a variety of environmental exposures. In this century, we have further refined our description of this disease to specific aberrations in molecular pathways, which if not entirely causative, account for much of the disease biology.

By contrast, medicinal chemistry as a science started much later than clinical medicine and is now closing the gap between knowing precisely what causes an illness to precisely what to do about it to improve the outcome for individual patients. No doubt we have a long way to go, but the current pace of personalized medicines suggests that it is becoming everyday reality for many lung cancer patients.

Join Dr. Stephen Eck on November 28, 2012, when he moderates a panel discussion at the 8th Annual Personalized Medicine Conference hosted by Partners HealthCare Center for Personalized Genetic Medicine, Harvard Medical School, and Harvard Business School. 


%d bloggers like this: