February 1, 2011 (Vol. 31, No. 3)

Rama Modali

Increased Use of High-Quality Biospecimens Set to Change Drug Development Practices

Even though the technology of biospecimens have been around for over 150 years, today they are still vastly underutilized in the life science community. With the decoding of the human genome and the rapid move to personalized medicine, the value of biospecimens will appreciate significantly.

In fact, the realization of personalized healthcare rests on the notion that vast libraries of vetted biomarkers and diagnostic tests will be widely available to effectively inform patient treatment. This is an outcome we take for granted, but we should not. The only way that it can be assured is through the use of high-quality biospecimens.

Unlike many other technologies in use today, biospecimens hold the predictive power to decode underlying mechanisms for major disease targets, while providing insight on how a compound will fair in clinical trials.

Rama Modali

Human Tissue Samples

Perhaps the greatest opportunity to benefit from biospecimens is in the preclinical assessment and optimization of drug development. With the cost of bringing a new drug to market at $1 billion, the ability to more confidently anticipate how a compound will fair in human trials is priceless.

Using human tissue samples in biomarker studies that demonstrate genetic expression or suppression of molecular targets can provide the necessary guidance in making critical go/no-go decisions for first-in-man trials. In fact, most big pharma and biotech companies are now on record in stating they will not pursue any new drugs without an associated biomarker or companion diagnostic.

Today, the bulk of preclinical drug development packages contains only animal-based experiments. The utility of in vivo xenograft models are undisputed, but complementing these studies with ex vivo experiments in either fresh or archived human samples can serve to validate findings and new mechanistic insights.

Targeted organ tissues should, at minimum, be screened for simple presence or absence of the drug target of interest. Better yet, studies that evaluate whether the target is expressed in off-target tissues will help researchers anticipate or avoid possible safety issues when the compound enters clinical trials. There is a strong possibility that these types of human-specific preclinical models’ efficacy and safety studies will be mandated by worldwide regulatory agencies in the future.

Furthermore, if the associated clinical annotation includes outcome/longitudinal/follow-up data from the patient, it’s possible to achieve clinical trial-like data for a fraction of the cost of an efficacy-driven Phase II trial. Such in vitro clinical trial experiments are excellent resources for drug developers of all size, particularly those with limited budgets.

Preclinical optimization studies with human material need not be confined to efficacy studies. Alternative drug delivery techniques or absorption studies are made possible by evaluating candidates in various tissue membranes of the alimentary, integumentary, or respiratory systems.

Biospecimen work is also transforming the clinical trial paradigm. For example, adaptive clinical trial designs assign patients to different drugs based on the individual molecular fingerprint of a patient’s tumor. This strategy allows clinical researchers to enrich trials with smaller numbers of patients identified as most likely to benefit from treatment from tumor tissue analysis.

The most visible application of biospecimens in personalized medicine is in the study and optimization of drugs already on the market, particularly in oncology. Molecular profiling of solid cancer tumors, from biopsied or excised tumors, is creating an entire new paradigm of diagnosing, choosing treatment options, and determining prognosis.

Today, the steady stream of molecular tests pouring forth from the industry rely on the validation from high-quality archived and prospectively procured biospecimens. Regulators are taking notice, too. Last July, for example, the FDA updated the labels of two monoclonal antibody drugs for the treatment of metastatic colorectal cancer (Vectibix by Amgen and Erbitux marketed by Bristol-Myers Squibb) to include information about genetic mutations in a gene called KRAS.

Other stakeholders are getting involved as well. Pharmacy benefit management companies like Medco and CVS are expanding their PGx testing for certain drugs, Medco going so far as to tie drug prescriptions to Dx test results.

Not All Biospecimens Are Created Equal

With the enhanced value proposition of biospecimen analysis, it should be noted that not all biospecimens are created equal. Biospecimen collection is a complex exercise in logistics.

The most important criterion for all biospecimens is quality. For example, when working with tissue samples, processing time is critical. Molecular changes take shape within minutes of surgical removal of a tumor. The gold standard for acceptable cold ischemia time—the time after a tissue blood supply has been cut off and captured in the appropriate preservative—is 15 to 30 minutes.

The best biospecimen providers not only track processing time data points but also offer strict quality control measures to gauge the impact of these times on specimen quality.

Another essential requirement is sufficient clinical annotation or associated data from the patient donor. Demographic data including age, sex, and race is standard. Information such as diet, exercise, and smoking and other lifestyle factors is also beneficial. Finally, extensive disease-specific criteria, as well as associated pathology reports for tissue samples are a must.

The most important requirement, however, for biospecimens is appropriate ethical standard compliance. Internal review board or ethical committee review of collection protocols focus on identity privacy, informed consent by donors, proper regulatory conformity with legal guidelines such as HIPAA, and more.

From target discovery and early lab studies to late-stage clinical trials and patient diagnosis, biospecimens will play an increasingly important role. In many ways they are positioned to be the linchpin to turning personalized medicine theory into practice.

Biospecimens are critical to each segment of the personalized medicine value chain.

Rama Modali ([email protected]) is president of BioServe.

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