Why Drug Discovery Needs Your Tissues


WHY DRUG DISCOVERY NEEDS YOUR TISSUES
Interview in FUTURE PHARMACEUTICALS.
Edition 1, 2006
Olga Potapova, PhD, President and Scientific Director, Cureline,Inc. delves into the details of using human tissue for drug discovery.
Future Pharmaceuticals: What is the importance of human tissue and human tissue-derived bio-reagents in biomedical research and drug discovery?
Using human tissues at many stages of R&D process is essential. In early dis¬covery projects, you work with objects, animals, and tissue culture - all the substances modeling an ultimate target, a human, however not representing it well. In the next stage, translational research, you identify the link between new targets (or newfound links between targets) and humans. Here you definitely need to use the best-representing model of human disease in vitro: human tissue models (tissue specimens, 3D tissue models, etc.) The closer you get to clinical trials stage, the more important, specific, and extensive it is. There are extensive time and resources involved at this stage: You have to collect high-quality tissue specimens, obtain extensive linked clinical information, identify the best matching models for your project, and perform your experi¬ment asking the right questions with the right controls. Obtaining data with a correct question will allow you to develop the knowledge that may pout the clinical trial just with the right patient population and get your drug candidate approved sooner. Although the company is investing significant resources ear¬ly, it’ll save millions and earn substantial profits from selling the drug longer.

Are there direct savings directed from the use of human tissues?
Yes, lacking data that helps to select a right indication for target-specific clini¬cal trials, companies practice old-fashion ways of testing new drug candidates in major indications, including combinations with present medication and the trials could be very lengthy without much significance.

Do you find the value of the use of human tissue within the drug discovery escalates as you go from the pre-clinical to the early phase clinical trials?
In fact, the importance of using human tissues for research picks up somewhere in translational (also called exploratory) research stage. In discovery stage, scientists are looking for a particular biochemical, molecular event in a tube-based model. Then they are using in vitro and in vivo models for testing drug candidates' efficacy and safety. Extensive use of human cell lines at this step is helping to identify the best human models. Usually, around the same time human tissues are investigated for target expression and other related events. Early phase clinical trials are the most important part of R&D process where understanding the biology is paramount. Data developed from results obtained with human specimens are considered as a part of the decision where to go for testing a new drug in humans: will it be GIST or metastatic kidney cancer or some other indication? Then, in the clinical trial, use of biomarkers comes to play. During the first steps in clinical research, you need to learn if your drug is safe, is it really doing a predicted job, and if there is a certain patient sub-populations that may benefit from it the most.

What are some key strategies and technologies used for biomarker discovery and validation and their use in assessment of drug efficacy in vitro and in v/Vo disease models?
Like anywhere else in research, you model each experiment with a right question in mind using the available scientific and medical knowledge, secure proper controls, and utilize the most appropriate techniques. Normalizing for differences such as locations, variable personnel, and medical condition of patients is also important. Accurate data analysis helps develop valuable results. Personally, l would rather properly analyze fewer appropriate targets, spending less time and resources.

How difficult is it to create a completely custom set of proto-cols for these and what are the actual effects on the procurement process?
It’s a challenge. Every time you change the protocol or use a completely project-specific one, you need a project coordinator who understands the science behind this who is able to implement the correct procedure at each participating clinical site. It takes a lot of hands-on time to match such protocol with the correct facilities and make sure the custom-designed protocol is implemented in accordance with the customer's SOPs. Before organizing Cureline, l was a member of SUGEN preclinical team that started one of the first American biomarker programs attached to a real cancer drug development. This drug, SUTENT, was approved by the FDA in 2006, much earlier than anticipated, for two cancer indications. Developing biomarkers for SUTENT treatment helped me understand how to organize such projects. Now, at Cureline, we are making sure that all projects we are doing are scientifically-sound, ethically and legally approved, and properly consented.

Human tissue acquisition is not on/y highly valued in target validation, but specimens can be scarce and difficult to handle. What procurement protocols are in place for quality requirements?
During the site initiation we provide each procurement center with a set of SOPs and make sure regularly that all participating personnel is adequately trained and follows these procedures. After that we use a two-step procedure for controlling the qual¬ity. First, we request all arriving specimens have a morphology report from the site of the acquisition and then we validate those reports with the US board-certified medical pathologist. These data are entered into an inventory database. However, this procure is significantly increasing the cost of the human specimens, and many of our clients have requested to skip the second part in order to reduce the cost of the project. After all, most of the companies that have a pathologist on board are re-validating the specimens quality to make sure they use proper samples for their experiments. Cureline has a "quality guarantee" for every project and if our customer is not satisfied with the quality of the material we provided, it’s replaced for free.

How important are ethical standards in bioethics and human subject research?
It’s paramount. Especially for companies that, like Cureline, are working in tissue procurement internationally. Different countries have different issues and attitudes toward ethical issues in human research. After making sure that all our samples are suitable for commercial R&D in the customer's country (mostly the USA and EU), we have also to deal with all applicable laws and regulations of the country of tissue procurement plus to observe the internal institutional regulations as well. However, many topics that are under discussion in the USA are not involved into consideration somewhere else. For instance, in the US, people are afraid some undesired personal medical information could become available to insurance companies. This fact makes it very difficult to collect blood samples for DNA analysis. All samples Cureline have provided for such purposes to its customers are very safe to use for both sides: customers (samples are de-identified and not-traceable) and the patients (since they are located in other countries). Other major issue is that many human samples are collected internationally without properly consenting patients. We have worked on this matter for the past three years with the sites and customers to make sure that all our specimens are properly consented, and this is a work in progress all the time.

Attrition in the decision-making chain is sometimes attributed to a lack of range in specimen origin. What effect does the need for diversity have to the integrity of the specimens collected?
Five years ago, l asked that exact question to a clinical group. It’s well known that mutations do not happen with the same frequency in white, black, and Asian populations. In the modern age of targeted medicines, this might lead to variable efficacy and sensitivity to new drug candidates, and drug development industry is quickly becoming much more aware of this issue. Clinical trials are designed to address this question in mind in addition to previously-asked differences related to a fact that different cultures have different diets and smoking habits. We already have a few projects where we were asked to collect "racial origin balanced" pools of human specimens.
   Olga Potapova Ph.D. Executive Director (USA) Marketing and Client Relations, is a co-Founder of Cureline, Inc. and its President since 2003. Under her leadership Cureline has grown into a successful biomedical project management provider. Dr. Potapova has twelve years of academic (NIH) and industrial research experience in human genetics and oncology. Her previous position was with Pfizer, Inc., in exploratory drug development (SUGEN). She is an expert on leading edge molecular, histological and biochemical technologies, and is a recipient of numerous awards from the American Association for Cancer Research and NATO.