Biomarkers: One Step Closer to Bureaucracy and This is a Good Thing (No, Really)

The FDA issued its recommendations on August 10, 2011 for biomarker approval. As expected, the FDA wants to find a clear standard for biomarker approval but also indicates that it will be hard to identify consistent and clear standards. This may seem a bit discouraging. The committee—going by the oh-so-jaunty title of Efficacy Working Group of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use—does want to establish guidelines that will result in standardized structure for genomic biomarker submission. The committee acknowledged that its recommendations are based on its experiences with previous submissions. Much of the its previous experience in this area is either with a single biomarker or a large scale assay used as a product-marketing application. In other words, the FDA has the best intentions but no significant clarity on the best unified approach to submissions going forward. It is clear, however, that the FDA has faith in the utility of biomarkers (as yet largely untapped) to add substantially to the drug development process from discovery to post-marketing. This is an improvement over the not-so-distant days of having to fight the FDA to consider biomarker data. So, what’s next?

The heart of the matter is how to prove the value of biomarkers throughout the pipeline-from discovery through treatment of targeted populations. There is hope. Earlier this week, Roche and partner Daichii Sankyo received early FDA approval (2 months ahead of PDUFA date) for Zelboraf to be used for the treatment of metastatic melanoma. Zelboraf targets the mutated BRAF gene and has a companion diagnostic, which was approved simultaneously. In clinical trials, Zelboraf was shown to reduce the risk of death by 64%.  By any measure, this is significant – especially in the cancer world. The success in the clinic, which led to early approval, represents a substantive step forward in personalizing treatment for certain cancers. Biomarkers played a role here—particularly the biomarker that indicates mutations in the BRAF gene. Zelbroaf, though sales are estimated to perhaps be a bit lighter than for BMS’s Yervoy, is expected to be a blockbuster. (Analyst and industry consensus for total peak revenues for Yervoy is just over US$1billion, while early consensus for Zelboraf point to US$735 million by 2015. Potential peak revenues could be as high as US 1.5 billion but there is not yet a consensus.) Its companion test will sell for US$150. On a side note, the companies plan to explore whether these two compounds work well together.

Biomarkers remain a bit of a dark horse as far as smooth approval processes goes, but there is progress being made. Biomarkers are being used as an Alzheimer’s early detection tool, for ovarian and prostate cancer and many other disease areas. Researchers and companies already know what the FDA just stated…..  it is not a walk in the park to come up with “consistent standards” that will add structure but still be flexible enough for specific characteristics of the biomarkers in each submission.    

As in nearly everything else to do with biotech, research and even bureaucracy—patience and perseverance will be the key. These recommendations, despite focus on data format and a structure checklist, are a step forward in this evolving situation.

Prostate Cancer and the Single Biomarker

As per my last post, biomarkers have a key role to play in biotechnology and medicine. It is also becoming clear that more than one biomarker in a diagnostic test is better, or a combination of biomarkers may be even better. There is always room for tweaks and improvements, as diagnostic tests are as much an art (and a lot of luck) as science.  Take the case of prostate cancer­­. Prostate-specific antigen (PSA) has become an accepted, if not foolproof, biomarker for testing for prostate cancer. Using a scale and environmental factors (patient’s family history, age etc.), doctors use PSA to help determine if the cancer warrants more aggressive treatment. However, PSA is not perfect. There is a risk of false positives—perhaps too many for comfort. These false results have led to unnecessary biopsies and other costly, invasive treatments and tests. Despite its less than perfect track record, PSA is still a useful tool on the whole. 

There is clearly a need for more biomarkers to work in tandem with PSA or on their own.   Prostate cancer is the leading cause of cancer for men in the United States, with 223,000 new cases reported a year, according the Centers for Disease Control. (This is based on 2007 statistics which are the most recent numbers available, according to both the American Cancer Society and the Centers for Disease Control.) At the moment, however, we are using a similar “throw the spaghetti on the wall” approach for everyone.  

There are several new biomarkers on the horizon for prostate cancer. Most are still in the early stages but some are moving along from academia into validation. For example, PCA3 is a gene that is over-expressed in prostate cancer cells and was identified by a group of researchers at Johns Hopkins in June of this year. Since PCA3 is only detected when there is prostate cancer in the body, it is currently thought that a urine test is all that will be necessary to detect its presence.Yesterday, a group of researchers from the University of Cleveland and Harvard University published a study in the British Journal of Cancer.  The group has discovered a biomarker, GSTP1, which boosts the efficacy of the PSA test. GSTP1 is more sensitive in detecting the difference between benign prostate troubles and prostate cancer than PSA. Like PCA3, it can be identified via a urine or blood test.

 Public and private companies also continue to make headway in this area. Some are still in early stages, some in the key validation phase. Tests that run the gamut—using one or two biomarkers to full assay panels with many markers—are expected to launch in 2012 and 2013.These tests are hoping to go one step better than “just” PSA. (For a brief sampling, read this.)

It is clear that biomarkers, in prostate and other cancers will continue to move along.

As investors, scientists and doctors, we are impatient to see the promise of biomarkers pay-off. Now, the possibility of a growing light in the tunnel—and one that is not attached to a speeding freight train fueled by wasted R&D dollars—is here.