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December 28, 2007

Biomarkers and Adaptive clinical trials

I had previously proposed more widespread use of biomarkers for improved healthcare and medical research. I have now discovered the work that is already underway to realize that vision. The vision is to greatly shorten the time it takes to find and prove that a new drug or medical procedure is effective and to approve it for use and to personalize treatment and be able to model and monitor the effectiveness of treatment in real time.

A 41 page powerpoint presentation on using biomarkers to shorten clinical trials. Clinical trials for new drugs take 7 to 12 years and cost between $800 million to $1.7 billion. Clinical trials can take up to 15-18 years. 90% of new drugs fail during clinical trials because of toxicity or ADME issues. (ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion)

Biomarkers can increase productivity by identifying potential failures early, saving both time and cost. Most new drugs “fail late”, after huge investment. Biomarkers can aid in early decision making on whether to drop a drug from consideration or to move it through trials. Biomarkers can help fail 90% of the drugs that wil not succeed early.


Survey of current and planned usage of biomarkers


Identification of biomarkers take a lot of science and effort

FDA Definitions: FDA Definitions:
Probable and Validated Biomarkers Probable and Validated Biomarkers

-A probable biomarker …has well established performance characteristics for which there is a scientific framework or body of evidence thatappears to elucidateits physiological, toxicological, pharmacological or clinical significance

-A validated biomarker …has well established performance characteristics for which there is wide spread agreementin the scientific and medical community about its physiological, toxicological, pharmacological or clinical significance



Current Drug Timeline & Trial Format
Pre-clinical 2-5 years
•Retrospective and/or pilot
Phase 1 6 months
•Safety
Phase 2 1-2 years
•Dose setting
Phase 3 1-5 years
•Efficacy
Phase 4 2-10 years
•Post approval additions

The shortest time to go through Phase 2 through phase 4 is about 4 years.


Benefits of adaptive clinical trials


Examples of using biomarkers in past clinical trials


Tools for adaptive clinical trials



Many drugs fail because they are toxic at the doses required for optimum efficacy

-Often, this does not become evident until after phase 3 studies, and can even arise post-release

-Biomarkers may potentially:
•predict toxicity in early trials
•monitor toxicity in later trials
•help avoid toxicity in the clinic

The value of biomarkers in clinical research and in the drug development process is becoming increasingly more crucial. The old concept of a single marker for a given indication has been replaced with the new “panel”paradigm. As these biomarker panels increase in complexity, so does the effort involved in their evaluation. Decision Biomarkers has developed a system to simplify this process with the incorporation of array multiplexing, microfluidics, assay automation, and on-board data analysis


FURTHER READING
A related topic is the development an inexpensive microfluidics chip which could lead to earlier cancer detection and treatment



When blood flows through a new microfluidics device, designed by researchers at Massachusetts General Hospital, cancer cells (one cell shown in yellow) in the blood stick to microscopic posts lining the chip (shown in blue). Detecting these cells could aid with cancer monitoring and treatment.
Credit: Massachusetts General Hospital BioMEMS Resource Center

Malignant tumors continually shed cancer cells into the bloodstream, and these cells can spread the disease to other tissues. This process, known as metastasis, is the deadliest aspect of cancer: it is the culprit in nine out of ten cancer deaths. But the circulating tumor cells are so rare--with a concentration of onlyone in a billion cells in the bloodstream--that scientists haven't been able to detect them easily or accurately enough to be clinically useful. Now Mehmet Toner, a bioengineer at MGH and Harvard Medical School, and his colleagues have designed a microfluidics device that can analyze whole blood in large enough volumes to detect these scarce cells.

"I think this device is going to turn the field of metastasis upside down," says Toner, who led the work. "It finds the circulating tumor cells that end up killing people." He adds that the sensitivity of the test is "high enough for clinical applications."

The device consists of a business-card-size silicon chip dotted with 80,000 microscopic posts. Each post is coated with a molecule that binds to a specific protein found on most cells originating from solid tumors, such as breast, lung, or prostate cancer. As blood flows through the chip, tumor cells stick to the posts.

Initial tests show that the device is highly sensitive. An analysis of blood samples from 68 patients with five types of cancer detected cancer cells in all but one sample, according to findings published today in the journal Nature. Researchers also found that changes in the number of circulating cancer cells accurately reflected changes in the size of patients' tumors during treatment. Oncologists often use tumor size as a measure of how well a treatment is working, with the goal of shrinking the tumor.

Such blood tests could ultimately prove to be an inexpensive and noninvasive complement to the CT scans and tissue biopsies that oncologists traditionally use to characterize tumors. For example, regular blood tests assessing tumor cell count might be used to determine if a particular treatment is effective. That might allow "the treatment regimen to be modified much earlier than if physicians had to rely solely on changes in tumor size," says Jonathan Uhr, a scientist at the University of Texas Southwestern Medical Center, in Dallas, who wrote a commentary accompanying the paper in Nature.

Toner likens the circulating tumor cell count to viral loads in HIV, which doctors use to assess how effective antiviral drugs are. "If we're going to turn cancer into a chronic disease, we need to monitor the patient accordingly," he says.

Researchers can also examine the cells captured on the chip for molecular markers that suggest a more aggressive form of cancer or a tumor that will respond to specific cancer drugs. The researchers ultimately hope to use the chip to analyze genetic changes in the tumor, which might signal the need to change treatments.

The ability to monitor changes in the levels of circulating tumor cells might also reshape physicians' view of cancer. For example, a preliminary study of patients with prostate cancer showed that a subset of people diagnosed as having localized cancer actually had circulating tumor cells. "It may be that cancer needs to be defined more molecularly than morphologically," says Toner
. [so instead of the currently broadly defined stages of cancer there could be more detailed modeling of the molecular progression.]

A powerpoint of the FDA's critical path initiative

Adaptive Clinical Trials Are Steppingstone toward Personalized Medicine.

At the 2006 Conference on Adaptive Trial Design, FDA Deputy Commissioner for Medical and Scientific Affairs Scott Gottlieb emphasized how important it is to pursue alternatives to the traditional, highly empiric statistical approach to conducting clinical trials, by designing ones that can be adapted.


How Technology is Accelerating Adaptive Clinical Trials.

The journal of drug discovery and development

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