Monday, January 26, 2015

President Obama's Precision Medicine Initiative: Counter-arguments

In his 2015 State of the Union Address, President Obama launched his new Precision Medicine Initiative to “bring us closer to curing diseases like cancer and diabetes -- and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” The initiative will be described in greater detail in the administration's budget proposal, but the following are widely assumed to be true: 1) requested funding will be in the hundreds of millions of dollars; 2) budgeted items will received considerable bipartisan support in congress; 3) the initiative will be championed by scientific and regulatory agencies of government (e.g., NIH and FDA) and by the pharmacy industry; and 4) the goals of the initiative will be similar to the goals of earlier legislation (The Genomics and Personalized Medicine Act) co-sponspored by President Obama when he was a Senator.

This blog lists six reasons why I am very skeptical of this initiative. Before I start, I'd like to clarify that I am a huge fan of President Obama. I believe he is the greatest U.S. president since FDR, and I will be eternally grateful for all that he has done for this country and for the world. Also, I am a great believer in the importance of genomics research. Hence, when I criticize this initiative, so early in the game, I do so with a great deal of ambivalence.

Nonetheless, here are my counter-arguments to the Precision Medicine Initiative.

1. Genomics research, this past decade, has taught us that genetics is a lot more complex than we had imagined. Human traits (e.g., height, weight), common diseases (e.g., diabetes, obesity, heart disease, and cancer), may involve hundreds of gene variants, non-coding regulatory sequences, competing epigenomic influences, and so on. Extrapolating from what we know about the complexity of gene expression, it seems that we are a very long way from understanding how disease genes are controlled. If we don't know how disease genes are controlled, then, with a few exceptions [see point 3], we can't practice genomic-based medicine.

2. It has long been promised that gene sequencing will lead, rapidly, to important advances in personalized medicine (also known as pharmacogenomics, and most recently renamed “precision medicine”). As it happens, simply knowing a sequence of nucleotides has not proven to be particularly helpful for understanding diseases that involve hundreds of genes, and an unspecified number of poorly characterized regulatory modifiers. Hence, personalized medicine, has not appreciably reduced the burden of morbidity and mortality produced by common diseases [see point 3].

3. Most of genomics-based medical progress has come in the realm of rare diseases and rare subsets of common diseases. As a generalization, rare diseases tend to be caused by single gene errors, while common diseases are caused by environmental agents (e.g., infections, toxins, carcinogens) or by multi-gene errors, or by some combination of the environment and multiple genes. The reason for this genetic dichotomy between rare diseases and common diseases is discussed, in depth, in my recently published book Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases. So yes, there are examples wherein abnormalities of one gene can account for a specific disease, but this phenomenon applies exclusively to rare diseases, to rare variants of common diseases, and to a few common genetic disorders associated with a relatively benign clinical course. In aggregate, single gene disorders account for a miniscule portion of the life-threatening disease burden in the U.S. and the world.

As an aside, I am an advocate for funding research into the genetics of rare diseases. It is the premise of my book that we have been astoundingly successful in rare disease research, and that treatments developed for the rare diseases are applicable to the common diseases [because rare and common diseases use the same cellular pathways]. Hence, a good way to conquer the common diseases is to steer the NIH research budget towards funding rare disease research.

4. It is conceivable that genomic tests will prove useful, notwithstanding the aforementioned complexities in gene controls. How so? It could be that a common disease is driven by a particular biological pathway that is dominated by one particular protein. If that protein were blocked [or stimulated in the case of an inhibitor protein], then it would be great to have a test for the pathway, or its dominant protein, or for gene variants that influence the activity of the expressed protein. Hence, precision medicine would apply in these instances. Nonetheless, the approach to precision medicine has been focused on looking for sequence variations, and I don't believe that sequence variations are bringing us much closer to finding the key proteins that drive the cellular pathways that account for common diseases. Again, the best way of finding key pathways operative in common diseases is to study the rare diseases [further explained in my book].

5. Clinical practice, based on candidate molecular tests requires lots of clinical trials and huge outcomes databases (i.e., validation data). Clinical trials are hugely expensive, and can require more than a decade to accrue patients, collect and analyze the data, and draw conclusions. Experience suggests that in most cases, the final conclusions are disappointing. Population databases, also hugely expensive, pose problems related to patient confidentiality and privacy, accuracy of data, analytic methodology, and validity of the conclusions drawn from the data. At present, we are nowhere near having the kinds of databases that we will need to confirm the value of new molecular tests.

Historically, the molecular biomarker field has been an embarrassment for the clinical research community. There have been a few successful exceptions (e.g., herceptin), but for the most part, biomarkers have been a bust. Should we really have much faith in the future of precision biomarkers, when history suggests that the odds of success are low?

6. Do we have any trustworthy authorities who can objectively claim that precision medicine is a good idea? Let's look at who's backing funding for the precision medicine initiative.

First, there's congress. Many of the members of congress, perhaps the majority, do not believe in global warming, or evolution, or the benefit of vaccinations. An appreciable number of congressmen believe that the earth is 5,000 years old, that pollution is not harmful, and that there's good evidence indicating that the end times are close at hand. Does anyone seriously believe that Congress can distinguish good science from bad science?

Of course, big pharma loves precision medicine because it generates expensive new tests and treatments that will be paid by insurers, no matter how great the cost or how small the benefit.

Then there is the matter of the federal agencies that fund or conduct science. It is the responsibility of the leaders of federal agencies to be responsive to Congress. If legislators need to justify, to their constituents, a new research initiative, then legislators will simply ask their agency heads to invent a credible scientific justification.
The question that never seems to be discussed is, “Is this the best way to improve the health of the nation, or are there alternative research initiatives that would give us a better outcome?”

- Ⓒ 2015 Jules J. Berman

tags: rare disease, orphan disease, personalized medicine, individualized medicine, genetic testing, gene testing, molecular diagnostics, biomarkers, pharmacogenetics, pharmacogenomics, future of medicine, state of the union address, funding initiative, NIH, FDA, big pharma, lobbyists, lobbying, scientific politics, scientific ethics, disease genetics, common diseases, complex diseases, rare variants, gene variants, whole genome sequencing