Why Do Genomic Cancer Diagnostics Cost So Much?

After reading the introduction to this PLoS ONE article, I started to wonder why there are there several published microarray expression profiles for cancer progression yet relatively few microarray-based diagnostics used in a clinical setting. Although this PLoS ONE paper focuses on analysis of ovarian cancer (and mentions the lack of a clinical microarray diagnostic for ovarian cancer), the paper also cites the current use of a breast cancer diagnostic called MammaPrint.

After reading the wikipedia entry on MammaPrint, I was surprised to learn that it took 5 years for the diagnostic to reach the market following the initial publication showing that the expression profiles for a set of 70 genes could successfully predict the cancer progression. This information is important because more aggressive treatments early in cancer progression may be able to help cancer patients who would otherwise have a high mortality rate (as predicted by their gene expression profile). I was also surprised to learn the high price of both MammaPrint and its competitor Oncotype DX. Although I do not think I can provide a complete answer to why these prices are so high, I would like to take a moment to first demonstrate that the price of these tests far exceeds the cost to conduct the test and then discuss how I think these costs can be offset by decreasing the amount of time and effort that it takes to bring a medical diagnostic tool to the market.

Based upon their wikipedia entries, the MammaPrint diagnostic costs $4,200 and the Oncotype DX test costs $3,978. To give you an idea about how much it actually costs to carry out this test, it costs $350 for a full service microarray analysis (including labor and data analysis) of an Agilent Whole Human Genome Microarray for on-campus customers at the UT-Southwestern Micoarray facility. This is comparable to the cost of most of the microarray facilites that I have worked with, and Agilent produces high quality microarrays. Now, most laboratory kits have a warning that they are “intended for research purposes only,” and this is probably true for the human Agilent array. However, I think this warning is mostly to avoid litigation and not due to a severe lack of technical accuracy, and I expect the actual cost for a clinical microarray test to be in the hundreds (not thousands) of dollars. I’m sure that this high cost is the product of a combination of factors, such as research costs, legal costs, patent law, and the US healthcare system. However, I’m going to focus on ways to potentially cut research costs because that is the area that I know most about.

Now, I want to make clear that the initial publication of a potential diagnostic test is not sufficient to prove the widespread effectiveness of that test. For example, the microarray test for ovarian cancer in the PLoS ONE article had substantially better predictive power on the training dataset than when applied to a new dataset. Therefore, I want to make clear that I do think follow-up studies were necessary to prove the effectiveness of MammaPrint.  However, I still don’t think it should have taken 5 years to test the effectiveness of this diagnostic and I think effectiveness can be determined without as much government regulation.

Before MammaPrint could be put into widespread use, it had to gain FDA approval. This required multiple verification studies, and this is the crucial event that defines the 5 year gap between initial publication and availability on the free market. First off, I don’t think FDA approval should be necessary for diagnostics. I do think physicians need some way to quickly access the effectiveness of a medical diagnostic and/or therapeutic, but I think there are more better ways to determine the effectiveness of a given treatment. For example, a relatively recently posted TED talk by Jamie Heywood discusses how his start-up Patients Like Me, developed by three MIT engineers, can diagnose medical treatments more quickly and effectively than clinical trails. This website analyses a database of information provided by patients, and therapeutic effectiveness can be assessed immediately based upon currently available data. In the very least, I think this company could be an excellent model for a more formal system using data from physicians that does not carry all the restrictions of a clinical trail. These changes should decrease the cost of medical care because companies claim that these price markups are necessary to recoup the costs of research and development, and a more streamlined process for accessing the effectiveness of treatments will decrease research costs.

Democratizing Scientific Research

Today, I came across a very interesting blog post by Christina Agapakis (via a GenomeWeb article). This post focuses on efforts to "democratize scientific research.” For the most part, the article discusses a post on another blog and the efforts by a group called DIYbio, which stands for “do-it-yourself biology.” She also emphasizes the need to make formal changes in the way institutions conduct scientific research, and I particularly liked some of her suggestions for improvement:

"What if there were more opportunities for high-paying technical jobs in science for people without advanced degrees? What if there were more biotech vocational programs to learn the skills you would need to work in these jobs? What if it were easier and cheaper for groups of scientists and engineers everywhere to turn ideas and hypotheses into technology and knowledge? What if there were real ways for knowledge to become power for that kid living in South Central LA?"

In regard to the issues brought up directly in her post, I think Christina is a little too harsh on DIYbio. I do agree that the organization's efforts are probably not sufficient to help intelligent individuals “[living] in a community plagued by violence and poverty” reach their full potential, and it is probably reasonable to assume that most of the participants are “white, middle class, and primarily male.” However, I think DIYbio positively contributes to the production of new ideas and products that would not otherwise be feasible. To be fair, Christina does say that DIYbio has helped promote “scientific participation and enthusiasm” and could be a useful model for developing programs for underprivileged individuals, but her opinions about DIYbio are mostly negative. She also claims that DIYbio perpetuates “the myth of the Victorian Gentleman Scientist,” who “[pursues] a 'pure' science not because of an interest in money and free of any state control but because of a deep curiosity with the power of the natural world.” I certainly agree that the Gentleman Scientist is an undesirable model for scientists that is unlikely to produce practical research and does not provide a reasonable venue for research for anyone without prior financial security. However, I honestly didn’t get that vibe from reading over the DIYbio website, although I should admit that my knowledge is limited because I hadn't heard of DIYbio before today.

In general, I am a big supporter of anything that removes politics from scientific research because I think personal and professional bias compromises the objective judgment that is so critical to good science. I think this requires fair assessment of scientific progress that emphasizes the impact of a specific result (and the effectiveness of the methods to achieve that result) and limits the role of authority as much as possible. For example, I think it would help if the peer-review process for scientific journals was a double blind process. Currently, the reviewers know the author names and institutional affiliations, but the authors do not usually know the identity of their reviewers. I know some exceptions to the latter case but not the former case (please correct my ignorance if you know of some examples). Of course, this would not be a perfect solution. Some reviewers may be able to recognize the work done by established scientists due to biological systems and methods employed in previous publications, and well-connected scientists will probably be friends with some reviewers and can give them a heads up that they have submitted an article for peer review. This is slightly tangential to the topic of DIYbio, but my ideas are relevant to the broad concept of "democratizing” scientific research by formal changes in institutional policies.

There is also a very interesting (and long) response to Christina’s post that does a good job discussing how “[it] is entirely possible to develop high level expertise outside of the formal system” and also noting that certain avenues of research (like “programming and electronics’) are much more feasible for the everyday scientist than research in biology or chemistry. Materials for biological research can be harder to acquire and more prone to regulation. For certain types of biological research, such as biomedical research, it is also relatively difficult to bring therapeutics to the market without a formal research position, in part due to the need to run clinical trails and gain FDA approval. The author of the comment specifically mentions over-regulation. I agree that some regulation is definitely unnecessary and hinders scientific progress (for example, I personally think the FDA should only limit the use of drugs due to toxicity without also considering effectiveness, and instead allow physicians to decide on the own if the treatment is effective and superior to alternative methods), but I do think that there is some rationale for not allowing everyone access to stuff like anthrax.

In short, I think informal biology research is a good thing that can benefit society (as acknowledged in Christina’s concluding paragraph), and I also think it would also benefit society to employ formal institutional changes to encourage individuals from varied backgrounds to conduct scientific research.

Who should be responsible for genetic counseling?

Today, I read a GenomeWeb article regarding a debate on whether Myriad Genetics’ BRCA test (BRACAnalysis) should be interpreted by primary care physicians or genetic counselors. Myriad claims that primary care physicians can and should interpret the test results, but critics claim this can result in inaccurate interpretation of test results.

Certain mutations in BRCA1 or BRCA2 genes can lead to an increased risk of developing breast and/or ovarian cancer. I am trying to keep track of notes about BRCA risk here, and prevalence of high risk cancer genes here.  So, I welcome input from others, and I have modified some of the content in this paragraph since the original post.

At least one survey from Medco indicates “most [doctors] believe that personal genomic information can be useful in their care for patients and help them make treatment decisions [but] the majority said they do not know enough about such tests.” In contrast, a different survey reports that “community-based physicians appeared to be successful incorporating BRCA1/2 testing into their practices.” However, a majority of these doctors utilized the assistance of some sort of genetics expert when making decisions about patient care. Myriad also emphasizes the paucity of genetic counselors, but critics have pointed out that Myriad fails to inform doctors that telephone-based genetic counseling is available and, in fact, required by certain insurance companies such as United Healthcare and Aetna.

I do think patients should be given the option of talking to a genetic counselor, and I think most physicians would benefit from at least informally discussing the details of a specific genetic test with a genetics expert. In general, patients should always seek out second opinions if they do not feel comfortable with their physician’s advice, and I would also advocate that patients conduct some independent research. For example, the National Cancer Institute provides a lot of useful information on BRCA1/2.

More than 10 years after the original post, I think some of my impressions have changed.  However, I still believe that changes in medical training and public education about the role that genetic counselors can play in making medical decisions is important. I also still hope that legal intervention may not be necessary to improve the interpretation of medical diagnostics.

Change Log:

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4/23/2021 - add links to newer posts with notes about estimating BRCA risk / prevalence (since I think the numbers in the original post might have given the wrong impression).

Also, change concluding paragraph, which originally included this link, where I think I down-played the importance of oversight (and I myself have certainly been submitting FDA MedWatch reports for multiple more recent genomic results).