Proactive Use

Pharmaceutical and biotech companies continue to spend more on drug discovery and development, yet applications for new drug approvals remain flat. FDA reports that between 2006 and 2010, applications for new molecular entities remained at an average of 30.6 per year.¹ Approved drugs can take up to $2 billion and more than 10 years to develop. Yet, late stage failures are still common and a company may spend several years and hundreds of millions of dollars before it discovers the drug is ineffective or unsafe. Even a 10% improvement in predicting failures can save a company $100 million in development costs per drug.²

The FDA and the EMA both believe the use of predictive and evaluative tools, like biomarkers, will help "give product developers the information they need to make good decisions about which products to move forward in testing, which doses to test, and how to design clinical trials that will provide clear information about product benefit and safety." ³

During clinical development, biomarkers play a crucial role in assessing the safety and clinical efficacy of a drug. There is industry and regulatory consensus that the use of biomarkers may help facilitate the development of new types of clinical trials and produce better data faster, which, in turn, will help reduce clinical trial duration and costs. However, their application in clinical practice has been slowed by the following industry and regulatory challenges: sensitive technologies required to discover and validate biomarkers are expensive; intellectual property ownership; biomarkers can create complexities for clinical trials; some bio/pharmaceutical companies question the reliability of biomarkers in predicting drug candidates; and regulations require biomarkers to produce perfect detection with no false diagnosis.⁴

Why biomarkers? Because they work. Think about a clinical trial for a new diabetes drug without the biomarker Hemoglobin A1c. It would take years if the determined efficacy was dependent on the presence or absence of retinopathy or nephropathy—two of the major pathologies in diabetes. We now know the traditional therapeutic paradigm—"one drug fits all"—does not work in most instances. Using this approach in cancer chemotherapies leaves as many as 75% of the patients as non-responders to the drug. The new paradigm of personalized medicine—"the right drug, at the right dose, at the right time, for the right patient"—has shown great promise. But, it requires biomarkers. Biomarkers to predict, prognose, monitor, dose, and select.

Tamoxifen in the treatment of Estrogen Receptor positive (ER+) breast cancer can be a model for both paradigms. It was thought the drug would work in all women with ER+ breast cancer (the traditional paradigm), with the biomarker being the estrogen receptor. Early studies showed excellent results. However, there were a small number of clearly ER+ women who did not do well. Subsequently, a second biomarker was established that would stratify women with ER+ breast cancer—the gene CYP2D6 (a personalized medicine paradigm). Tamoxifen is a prodrug that must be metabolized into the active drug endoxifen. The ER+ women who did not respond were found to have a mutant CYP2D6 gene, and did not metabolize the tamoxifen to endoxifen.

In 2004, the FDA initiated the Critical Path Initiative which stressed the importance of biomarker development. Subsequently, the FDA's "Critical Path Opportunities Report" (March 2006) specifically stated: "The existence of a predictive efficacy biomarker in particular can revolutionize product development in a disease area." The FDA believes so strongly that biomarkers will continue to play an important role in drug development and therapy that in 2007 the National Cancer Institute's (NCI) Investigational Drug Steering Committee (IDSC) formed the Biomarkers Task Force to establish recommendations for investigators to use biomarkers in early clinical trials. Although biomarkers have been studied for years, the NCI believed they were under utilized and when used, often were inappropriate for the study or misused. Their conclusions and recommendations were approved by the IDSC in 2008 and published in 2010.⁵ The importance of biomarker studies in clinical trials was also recognized by the FDA, as shown by a number of guidelines for industry published in the same time frame.⁶

Recently, the FDA approved two drugs—crizotinib and vemurafenib—with specific "indications and usage" requirements that patients be tested for certain biomarkers (ALK and BRAFV600E, respectively). This requirement for biomarkers fell under the FDA guidance "In Vitro Companion Diagnostic Devices" (July 14, 2011), which discusses the use of a biomarker detected/measured by an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product. In developing these companion diagnostics during the early phase of drug development, the pharmaceutical companies were able to stratify their subjects and run smaller studies faster. The contemporaneous co-development of the drug and companion diagnostic and expedited FDA review saved between 12 and 18 months in the development time for vemurafenib. These two drugs were the first of many in which both the drug and a biomarker in vitro diagnostic device were simultaneously approved. In these cases the biomarkers were discovered during the bio-discovery phase, while in most cases biomarkers are discovered retrospectively. Over the past years, the FDA has required drug manufacturers to either "black box" or place warnings in their package inserts for numerous drugs based on adverse events that could have been identified by biomarkers (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm). This has cost the industry millions of dollars to retrofit products, and in some instances has resulted in litigation.

In conclusion, proactive discovery of biomarkers is good for patient care and safety, and good for everyone's bottom line in regards to savings in drug development, drug usage, and insurance reimbursement for the correct and appropriate use of these expensive drugs.

Steven Lobel, PhD, D-ABMLI, MBA, FACB, is Vice President, Global Lab Operations at PPD, e-mail: Steve.Lobel@ppdi.com.

References

1. FDA, "CDER New Drug Review: 2011 Update."

2. Boston Consulting Group, "A Revolution in R&D: How Genomics and Genetics will Affect Drug Development Costs and Times," PAREXEL's Pharmaceutical R&D Statistical Sourcebook, (2002/2003).

3. FDA, "Innovation or Stagnation: Critical Path Opportunities Report," (March 2006), http://1.usa.gov/b9Wg6z.

4. FDA, "Guidance for Industry: E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure, and Format of Qualification Submissions," (2011).

5. J. E. Dancey, , K. K. Dobbins, S. Groshen, et al., "Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents," Clin Cancer Res, 16, 1745-1755 (2010).

6. FDA, "Guidance for Industry: Qualification Process for Drug Development Tools," http://1.usa.gov/997GCf.