Category Archives: clincial trials

Metabolomics and Precision Medicine

Advancing Precision Medicine: Genomics, Metabolomics, and Clinical Trials

Monday, October 12 was the evening of an interesting talk at BIOCOM. Teresa Gallagher, founder of the San Diego Clinical Research Network (SDCRN) introduced the moderator of the event, Arnold Gelb, MD, Senior Medical Director at Halozyme. Rather than attempt to summarize all of the topics examined, the goal of this blog is to give a sampling of some of the areas discussed during the event.

Deterministic versus probabilistic genetics

The first speaker of the evening was Amalio Telenti, MD, PhD, Head of Genomics at Human Longevity, Inc. His talk touched on the ever-present nature vs. nurture debate. Do our genes determine a particular characteristic or merely influence the probability of developing that characteristic? In the world of whole genome sequencing, this can be described as deterministic versus probabilistic genetics.

In general, a deterministic trait would be something like Tay-Sachs Disease: if you have two copies of the gene for this condition, you have a better than 99% chance of developing the disease. A probabilistic trait is one with many genes that influence it, like height. Outside factors like disease and diet also affect how tall an individual grows. Hence, height is a probabilistic trait.

Telenti predicted that genomics will not revolutionize all aspects of medicine; but some medicine will be revolutionized profoundly; clinical trials will benefit the most. Genomics will be employed to stratify patient populations both before studies are commenced and after all the data is collected. Ideally genomics will be utilized to both determine who benefits from a drug and who should not take the drug.

Metabolomics combines genetics and environment

Steve Watkins, PhD, Chief Technology Officer of Metabolon spoke next. Metabolon specializes in metabolomics, offering comprehensive measurements of small molecules such as glucose, cholesterol, cortisol, and amino acids in a CLIA-certified lab.

Metabolites reflect the integration of genetic and environmental influences on an individual. Diseases can be prevented and diagnosed by checking on an individual’s metabolites. Response to disease treatment can be monitored by testing metabolites. Metabolomics is emerging as an effective tool in precision medicine.

Metabolomics integrates the effects of the environment with the effects of genetics

A person’s genome and environment affect their metabolome. Used with permission from Metabolon.

Watkins shared that Proceedings of the National Academy of Sciences recently published a study led by Baylor University’s Tom Caskey, MD. Caskey comprehensively tested the metbolites of many patients with no frank disease. Metabolon’s platform spotted underlying health issues not previously noticed in the patients’ genetic data.

For example, Patient 3905 had very high levels of sorbitol and fructose, but no clinically significant mutation was reported in their genome. Looking back at the genomic data for that individual, a mutation in the fructose pathway indicating “fructose intolerance” was discovered. This mutation had been overlooked previously. When discussing these results with the patient, the patient simply stated that fruit bothered him, so he refrained from eating it.

In the same study, Patient 3923 carried a gene for Xanthinuria type 1. He showed no symptoms of the disease such as kidney stones, suggesting the gene was not penetrant (or not expressed), leaving the patient symptom-free.

In conclusion, Watkins stated that metabolomics can be used in a number of ways:

1) By identifying pathways of interest for genetic assessment

2) By revealing non-penetrance of genes suspected of being deleterious

3) By enabling monitoring and understanding of metabolic conditions

Which drugs to use in cancer treatment?

The final speaker for the evening was Nicholas Schork, PhD Professor and Director of Human Biology at the J. Craig Venter Institute. He focused on emerging themes of design for precision medicine trials.

Schork presented several novel ideas. One was the idea of vetting algorithms for the treatment of cancers based on the mutations the cancers carry. Some hospitals already use this method, begging the question of who has the best algorithm for cancer treatment. As Schork points out, this has led to some interesting conversations with the FDA. He envisions clinical trials in the future for the evaluation of algorithms for cancer treatment with existing drugs, in direct contrast to the conventional clinical trial, usually designed to assess the effectiveness of a new drug.

In all, this was an exciting presentation of cutting-edge research and future directions in precision medicine.

Treating Cancer in the Genomic Era

Revolutionizing Cancer Treatment

by DeeAnn Visk

We have all had “ah-ha” moments. I had one on October 15, 2013 listening to Dr. Razelle Kurzrock illustrate a new way of thinking about cancer and cancer drug development. Historically, cancers are categorized by the organ in which they originate. With the advent of genomic sequencing, cancers can now be grouped by the mutations they contain. Thinking about cancer in this way will revolutionize how this disease is treated therapeutically, researched in academia, targeted by drug companies, and conceptualized in clinical trial design.

This epiphany occurred at the recent meeting of the Southern California Chapter of Women In Bio at Janssen Labs, while listening to Dr. Kurzrock, one of three excellent speakers at the meeting.

Director of Clinical Trials, Moores Cancer Research Center

Dr. Razelle Kurzrock, Director, Center for Personalized Cancer Therapy

Dr. Kurzrock pointed out that, while the light microscope was invented in 1590, it is still used today to diagnose cancer. While current cancer therapies are not quite as ancient, treatment for many cancers has not changed for up to 20 years. This is shocking, given the enormous strides in technology that have occurred in the last two decades. Most importantly, we need to change the paradigm of thinking of cancer as an organ-centric disease. Molecular abnormalities in cancer are not associated with the cancer’s organ of origin. Hence, we should treat cancers based on their molecular profile, not on where they originated in the body.

Now that the genomic era is upon us…

we can analyze the molecular signature of each cancer. Clinical trials need to be redesigned to be mutation-centric, not drug-centric. Multiple genetic markers should be employed to diagnose and classify cancers.

Generally, clinicians are entrenched in their way of thinking, which presents an obstacle to this kind of fundamental change. To paraphrase Max Planck, science progresses one funeral at a time. Regrettably, medicine also seems to progress this way. Previous ways of thinking about cancer have become so ingrained that many are not even aware of their underlying assumptions.

The concept of classifying cancer by mutational profile will also impact cancer research. How many times have you heard of a laboratory studying breast cancer, or prostate cancer, or liver cancer? Several more times than you hear about a laboratory studying a particular mutation in a cancer biomarker like the epidermal growth factor receptor (EGFR), I’ll bet.

Further areas of inertia include applications for new drugs submitted to the Food and Drug Administration (FDA). No application for an investigational new drug study (IND) has ever been filed based on a treatment targeted at a mutation in a cancer (of any kind), rather than treatment of a cancer in a specific organ. This situation persists despite the fact that the FDA has indicated it would be open to INDs using this approach.

Need a new paradigm for treating cancers.

Hope for new cancer treatments–turning in a new direction.

I hope the idea of classifying cancers by the mutations that drive them, not the organ in which they originate, changes how cancers are treated. Dr. Kurzrock did an excellent job of articulating and advocating for these changes. Employing old-school approaches to cancer is so engrained that we are often unaware of these underlying assumptions. Rethinking cancer biology certainly has changed how I would respond to a loved one being diagnosed with cancer. I would seek out a forward-thinking doctor, willing to utilize this new paradigm from the onset, not waiting for last-ditch efforts once the cancer re-occurs.

Challenging the current methods for treatment, research, and drug development will not be easy, given with the institutional barriers that remain. Financial interests of the institutions involved will need to be realigned with this new paradigm. Either that or we need AIDS-activist-like protests to spur on this change in thinking. In the end, as with AIDS, it may be patient advocacy groups that can best bring about this change in thinking in the medical, pharmaceutical, research, and regulatory communities.

The views expressed here are solely those of DeeAnn Visk are not necessarily those of Women in Bio, AWIS-SD, Janssen Labs, NPR, or your local NPR station. A special thanks to Nurith Amitai for her especially helpful editing.

This article was previously published in the January/February 2014 edition of the Association for Women in Science San Diego Chapter Newsletter.

DeeAnn Visk, Ph.D., is a freelance science writer, editor, and blogger. Her passions include cell culture, molecular biology, genetics, and microscopy. DeeAnn lives in the San Diego, California area with her husband, two kids, and two spoiled hens. You are welcome to contact her at deeann.v@cox.net

Clinical Trials Improved by Leveraging Technology

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On November 25, 2013, the San Diego Clinical Research Network held a meeting at the Sanford Consortium for Regenerative Medicine, with a reception at Bella Vista Cafe. Three speakers talked about innovations in clinical trials. J. Summer Rogers, Chief Executive Officer of nPruv, Inc., a company which acts like a “match.com” to match up patients and clinical trials, moderated the event.

The first speaker, Marcos Milla, Ph.D., Scientific Director and Fellow at Janssen, spoke from the pre-clinical research perspective about the search for drugs and patients by phenotypes. New thinking about entire systems within a cell versus a specific target, allows complex cellular systems as a whole to be targeted. Given the intricacies of problems with the immune system, this way of thinking will simplify a complex milieu.

Executing these experiments is the simple part. A more difficult question is interpreting them. One approach employs phenotypic read outs: proliferation, migration, contact, differentiation, and activation. These phenotypes can be read with automated systems, enabling high throughput screens. Next, gross readouts of cell behaviors must be correlated with molecular readouts to permit determination of structural activity relationships. To accomplish this, functional readouts need to be deconvoluted to concrete “hits”. Harnessing knowledge of the human interactome will facilitate this goal.

Clinical trials can target complex pathways in the human interactome.

An example of this workcan be found in the eicosanoid biosynthetic pathway. High throughput and high-sensitivity liquid chromatography mass spectroscopy is utilized to acquire data from three different phenotypically-normal, healthy patients exposed to prostaglandin inhibitors. All three displayed remarkably different profiles. Differences in these profiles suggest different drugs would be most effective for each patient.

One method to optimize these interactions is to bring together the wide variety of “-omics” (genomics, metabolomics, proteomics, etc.) to build a drug profile for each individual patient. This information could then be used to optimize individual treatments for specific patients.

The next speaker, Andreas Koester, M.D., Ph.D., VP Clinical Trial Innovation & External Alliances, Janssen, spoke about clinical trial innovations spawned by collaborations between large pharmaceutical companies, and a patient-centric approach to designing trials. As a leader in clinical trial operations, he offered a different perspective.

As a potential drug journeys through the research and development process, out of 10,000 compounds, 1 new drug will be approved by the FDA. Presently this process costs about 2 billion dollars and takes 10 years. How can we better spend our time and money?

A collage of words from Andreas Koester’s talk on improving clinical trials.

We need to change how we design clinical studies. Patients should be first in mind in designing trials. Collaboration between drug companies will streamline this process. TransCelerate BioPharma, Inc., a non-profit organization established by leading pharmaceutical companies to advance innovation and tackle inefficiencies in R&D, is an example of this. TransCelerate has developed guidelines for risk-based monitoring to reduce the cost of clinical trials, and established criteria for the qualifications and training of clinical research sites.

A Blue Button™ Initiative begun by the Veterans Administration to allow patients the opportunity to access and download their health records is being extended to clinical trials. Pfizer is piloting the use of Blue Button™ technology to enable participants in Pfizer trials to download their own electronic clinical data collected in the trial. Patients sign up after the study to get data results through a third party. Normally patients receive no information about the results of a clinical trial in which they participate. By allowing patients access to this information, patients are more engaged with the process.

Novartis is partnering with Walgreens to bring clinical trials to the patient. Ninety percent of all Americans live within three miles of a Walgreens pharmacy. No longer must patients interested in participating in clinical trials travel scores of miles to participate. Novartis is currently doing a novel trial, allowing study participants to have their follow-up visits at Walgreens rather than hospitals, in an attempt to run the trial more efficiently and scale more widely.

Recently, the FDA allowed a trial for a investigational new drug (IND) with a clinical trial protocol developed using crowdsourcing. The open innovation drug developer, Transparency Life Sciences, gained FDA clearance to proceed with a phase II trial of the antihypertensive drug lisinopril as adjunctive therapy in multiple sclerosis. This groundbreaking, crowdsourced protocol also eliminated most study visits by using telemonitoring to assess outcomes.

The final speaker of the evening, Steven Steinhubl, M.D., Director of Digital Medicine at Scripps Clinic and Scripps Translational Science Institute, spoke about using mobile health technologies (mHealth) to conduct patient-centered clinical trials. The change he advocates in clinical trials is to “move the mountain,” by bringing clinical trials to patients. Presently healthcare is designed around the physician and not the patient. Clinical trials are also designed around physician investigators.

The biggest driver of cost for clinical trials is Phase III testing. Ninety percent of the cost is associated with this step. Mobile health technologies can allow us to do studies more efficiently, and reduce costs. However, there are cultural and regulatory barriers to implementing mobile health technologies into clinical trials.

translational medicine uses clinical trials to move ideas

Translational medicine employs clinical trials to move ideas from research to the bedside.

Another area needing change is the average lag time between a definitive clinical trial and changing the majority of clinical practice. Currently it is 17 years. Although 17 years is unacceptable, from a historical standpoint we are improving rather dramatically. For example, it took 264 years for vitamin C use (via citrus fruits) on ships to prevent scurvy to become common practice after a definitive study.

During discussion, the panel agreed that the device and pharma industry need to be integrated from invention through clinical trials. Perverse financial incentives for reimbursement on devices encourages the creation of a new device to accompany every new test. This needs to be fixed. Ironically, medicine is the only industry where more technology increases costs.

The human microbiome: a new approach to treating non-infectious diseases

The fault lies not in our genes, but in our microbiome

Conceptualizing humans as an organism, the microbes living within and on our bodies are often neglected. A recent trend in academia has been the research into the wide variety of micro-organisms living within and upon humans. Overlooked until recently, differences in the human microbiome are implicated in many disease states from auto-immune disorders to obesity. Some day is may be possible to lose a few pounds just by consuming the right mix of bacteria to colonizes your gut!

plaque--bacteria in the mouth microbiome

Many different bacteria from the mouth microbiome

Given the advent of low-cost, high-throughput sequencing and the relatively smaller genomes of micro-organisms, a plethora of studies have been done comparing microbiomes of healthy and sick patients. First academia must answer the chicken-or-the-egg-question: do people have these diseases because of the combination of bacteria they have (or don’t have) or does having the condition lead to the combination of bacteria? Does the microbiome of a sick patient arise from having a specific microbiome or does being sick lead to the presence of the specific microbiome?

To test this question, sickened laboratory animals have been inoculated with the microbiome of healthy animals. Generally, the answers point to the idea that the right combination of microbes can alleviate the symptoms of a disease. The list of non-infectious diseases (allergies, asthma, diabetes, and obesity) that have been effectively treated by reconstituting the microbiome in laboratory animals is growing. While academic research on this area is booming, what practical progress has been made on this front?

Compare the number of clinical trials using fecal transplants (46) to those using a cell therapy (29,268). Clearly there is much room for growth in the practical application of the human biome to disease states.

Additionally, these initial clinical studies are looking only at the microbiome of the lower gut. This leaves many areas of the human anatomy unstudied. What about the skin, upper gastrointestinal tract, hair, eyes, nose and other mucus membranes? While academia is well on the way to working on these issues, little has yet been seen in the way of practical application of this as evidenced by the lack of clinical trials.

Risk-based clinical trial monitoring

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Increasing efficiency in clinical trials

While it sounds intimidating, risk based management is simply applying common sense in a systematic way. Defining, evaluating, and managing risk is easily accomplished by using a documented approach to evaluate the risks. Which needs closer monitoring: a simple clinical trial in the United States at a reputable site previously used with much success or a complex trial in Zimbabwe at a location never utilized before?

Obviously, the trial with the greater unknowns is higher risk.

risk management for the FDA clinical trial

Evaluating risk to monitor clinical trials

Recently, the FDA came out with guidelines on risk-based management for clinical trials. “The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most important aspects of study conduct and reporting.”

What this means is merely commonsense in monitoring of clinical trials based on which ones have a higher risk of problems.

Another factor to consider beyond experience with a site and the complexity of the trial are the patient outcomes. Will your trial involve life and death situations?

Quantifying this can be done using a matrix of categories such as geographical location of the study, Good Clinical Practice compliance (GCP), and the relationship of the sponsor with the investigator.

Understanding these concepts is crucial to increase efficiency and decrease costs of clinical trials. As with any change in a regulatory environment, the industry is grappling with how to implement it. Pilot programs explore the implementation and thousands are waiting anxiously for “the answer”. The challenge is that the answer—as with everything within clinical research—is that it depends.

Laurie Halloran’s presentation on this and other topics in clinical trials made them easy to grasp. She presented at the San Diego Clinical Research Network meeting last week Tuesday at the Sheppard Mullin law firm.