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The Translational Drug Development Organization: A Paradigm Shift In Managing The Development Of A Compound From Laboratory To Market
While research and development costs in the pharmaceutical industry continue to increase, the number of new approved drugs is on a steady decline (Di Masi et al, 2003). In contradistinction to the rapid emergence of laboratory research and development tools, such as in vitro and in silico screening tools and new tools necessary to describe the affects of drug candidates within the complex biochemical pathways of intact, fully assembled living networks (Maguire et al, 2006), there have been few advances in the discovery and development of management tools necessary to bring a therapeutic candidate (e.g. a drug) from the laboratory into the clinic. The pharmaceutical industry has thus realized the need to develop innovative strategies and new management methodologies that will focus on the translational process, that is the process during which a therapeutic candidate is brought from the lab and into successful completion of Phase II proof of efficacy studies.
This translational process, with all of its inherent problems, has been blamed as a key contributor to the high failure rate of therapeutic candidates as they progress from the lab through the drug discovery and development process only to find a high probability of failure at Phase II proof of efficacy clinical trials. This failure occurs after years of study and millions of dollars spent on the scrapped potential therapeutic, with little or nothing to show for the huge investment. Often the developmental program for the candidate is dropped at this point, and the infrastructure is repositioned to work on another candidate, or the infrastructure is simply disassembled. The failure rate at Phase II proof of efficacy is 50%, and has doubled in the past decade (Dimasi et al, 2001). In contrast, the failure rate in Phase III clinical trials has remained flat for the last decade. Clearly there is a problem of great magnitude in bringing the candidate from the lab into the clinic, during the so-called translational process.
One such newly identified strategy and technology at the scientific level is systems biology and metabolomics. As science becomes more sophisticated and specialized, scientist learn more and more about less and less. That is, scientist tend to become more focused on a specific area because there is so much to learn in that one area, gaining great depth in that one area of focus at the expense of a breadth of knowledge across multiple disciplines. This is because science is burgeoning, and there is more to learn in any one specific area, and therefore it is more and more difficult for any one person to maintain a great breadth of knowledge across disciplines. Systems biology has been employed to view the drug candidate in the system where the various components of the system can be seen to interact, as opposed to individual components of the system where no interaction can be determined.
This phenomenon of specialization is readily apparent in the drug discovery and development process which has become a very complicated, long-term, and expensive process (Fitzgerald, 2005). Early in the discovery/development (DD) process, at the stage of lead candidate discovery and into non-clinical studies, biological bench scientist are mostly involved in the process and can readily communicate with one another. Likewise, late in the development stage, when Phase III clinical trial are well underway, the process mostly involves clinical scientist, and they can readily communicate with one another too. However, during the translational process, when the therapeutic candidate is being moved from the laboratory into the clinic for proof of efficacy studies, the process highly involves three different groups of scientists (discovery, regulatory, and clinical), with three different goals, three different languages, and for whom the communication and work flow between groups can be highly strained. For example, the goal of the discovery, laboratory groups is usually innovation, while the goal of the clinical team is usually speed and procedures. While both are critical scientific endeavors, the methods and terminology are very different and communication between the two can often be a monologue instead of a dialogue. This is an example of the common management problem called the “Silo Effect.”
Much has been said about this problem, and a number of attempts have been made to alleviate the problem, a few with resounding success. One such success has been the development of the translational drug development organization (TDDO). The TDDO is a contract research organization that is specialized to bring a therapeutic candidate from the laboratory to IND enablement, and into the clinic for successful proof of efficacy studies.
What is a TDDO and what does it do? The TDDO can be thought of as a type of CRO that is structured to focus on the translational process and can serve to meet all needs of the client during this portion of the DD process. The TDDO needs to have a special structure and skill set not normally associated with the traditional CRO. Yes, the TDDO must possess what the traditional CRO possesses, such as a management, regulatory, clinical, data management, and compliance and audit sections, but the TDDO requires more beyond these traditional disciplines found in the traditional CRO. The TDDO also requires a special, highly qualified Program Management branch that can oversee the translational process, understanding all aspects of the translational process, and thus facilitate communication and work flow between the three groups (discovery, regulatory, and clinical groups).
In order to bridge the three disciplines, the program management branch must be composed of highly qualified scientists that understand what has been previously done in the laboratory research program that will support bringing the candidate to IND enablement. They must also be able to assemble this information and communicate it to the appropriate groups within the regulatory circles, and then all of this information must be translated into the development of a clinical research plan that will successfully bring the candidate through Phase II proof of efficacy studies.
To move development of the therapeutic candidate expeditiously and to successful completion, the Program Managers of the TDDO must also be able to optimize the developmental program, and recognize any shortcomings in the translational process and be able to implement corrective strategies. For example, in developing the Phase I and II clinical trials, it may be evident that the clinical endpoints used to measure efficacy in Phase II will require a long and expensive study with little feedback until completion of the trial. If the trial fails at the point of Phase II, much time and money will have been spent to no useful means. Therefore, in order to have feedback about the success of the efficacy of the candidate before spending so much time and money through Phase II, it may very well be advantageous to perform a shorter trial and acquire the feedback more quickly and inexpensively. Thus, to have feedback on efficacy in the human trials, it may be recommended to conduct a Phase 0 or first in human, pilot study using biomarkers or other surrogate or non-surrogate endpoints that can be utilized to determine efficacy for purposes of internal decision making; this may involve a go-nogo decision or a decision about dosing strategies for example.
Another example for using a pilot study is for the purpose of determining patient stratification. That is, which subjects are likely to respond to the treatment, and which subjects will show an adverse response to treatment? Predictions have been made for the selection of patients for targeted chemotherapy for the treatment of breast cancer (Pittman et al, 2001) and for chronic myeloid leukemia (Maguire et al, 2006).
And, if the Phase I and II clinical trials are to be long and expensive, another strategy frequently used in the TDDO is to employ adaptive trials. In this way, emerging data from the trial is quickly gathered and used to make modifications of the ongoing trial. A simple example of using adaptive trials is the modification of patient sample size as the trial proceeds. If the power of the statistical measure of efficacy is determined to be too strong because patients are responding to the therapeutic in a manner better than predicted, then the sample size of the trial can be adjusted downward, thus saving time and money to complete the trial. A multitude of strategies and adaptive procedures can be designed and implemented in the translational process, and only require that the TDDO be able to properly oversee the translational process with a fundamental understanding of the scientific, regulatory, clinical, and business issues at hand for developing the particular therapeutic candidate. Upon completion of bringing the therapeutic candidate through the translational process, with a successful completion of phase II efficacy studies, the development program is then transitioned to the CRO who will conduct the Phase III study. Because of the work performed by the TDDO, all efficacy, safety, and dosing issues will have been optimized and Phase III should be successfully completed in record time.
Who benefits from the TDDO? The obvious answer is, anyone who is bringing a therapeutic candidate from the laboratory into the clinic. Specific examples of who benefits are emerging, start-up companies without the infrastructure to conduct the steps required in the translational process themselves. Less obvious, perhaps, are angel groups and VC firms with portfolio companies or virtual companies. In the case of virtual companies, the TDDO can be particularly helpful in determining whether a therapeutic candidate is efficacious and safe before the company is actually built. In this case, if the compound fails, then time and money was not lost in building a company infrastructure based on a failed therapeutic. Rather the therapeutic was tested first using a streamlined, inexpensive approach by hiring the TDDO to perform the required translational studies. If the compound is efficacious and safe, then the company is built. If the therapeutic fails, there is no company to disassemble, costing time and money, and there was no company built in the first place, which also required time and money to build. And of course, traditional biotech and pharma companies with candidates moving from the lab to the clinic will require such services. While large pharma companies may have certain aspects of the TDDO infrastructure in place within their own company, they can integrate their own aspects of the CRO structure into that of the TDDO and allow the TDDO to best manage the translational process through the TDDO’s program management branch. These are but a few of the examples in which the TDDO can optimize the translational process of drug or therapeutic development for virtual, small, or large companies, leading to not only reduced time and costs for the successful development of a candidate, but also by optimizing the program to satisfy the business goals of the company too.
References:
Dimasi, JA (2001) Risks in new drug development: approval success rates for investigational drugs. Clin. Pharmacol. Ther. 69:297-307.
Fitzgerald G.A. (2005) Anticipating change in drug development: the merging era of translational medicine and therapeutics. Nature Reviews 4: 815-818.
Maguire, G. et al (2006) SiDMAP: A metabolomics approach to assess the effects of drug candidates on the dynamic properties of biochemical pathways. Exp. Opinion Drug Disc. 1:351-359.
Pittman, J. et al (2001) Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes. Proc Natl. Acad. Sci. USA 101: 8431-8436
About the Author
Dr. Maguire has spent over 20 years in research and development as a professor of neuroscience and ophthalmology at the UCSD School of Medicine where he was awarded an NIH Fogarty Fellowship and ran an NIH- and NSF-grant supported research laboratory. Dr. Maguire holds numerous patents for drugs and devices, has over 100 publications in the areas of neuroscience, ophthalmology, cancer, and pharmaceuticals, is a founder and director of two biotechnology companies and two non-profit life science organizations, and has led the implementation of several large BD contracts between biotech and big pharma companies. He serves on the Scientific Advisory Board of several health care companies and routinely lectures around the world on health care and pharmaceutical related issues. He is Co-Founder and CEO of A & G Skin Solutions,Inc. (www.agskinsolutions.com) and COO and a Principal of the RRI Group, Inc. (www.rriconsult.com), a pharmaceutical regulatory and managment company. Email:gregmaguire5@gmail.com
At what stage of life the self develoment is most rewarding?
Self development is viewed as best tool for advancement of individuals in life. There different ways and means of self development. In Indian context we pay our attention more in initial schooling with emphasis on internationally accepted human values which are termed as core values of our living and society. As we advanc we have different stages of self development – in management schools and institutions, professional achievements in qualifications and experience and then in the organised working of business, service and of other organisations at national and international levels. But at times the society demands keeping the basic human values invariably with not much emphasis on other values at large from people. If it is not so then why the people having acquired other achievements aren’t present everywhere in the exemplary top positions in the society. How the society be represented and with what returns to the type of individuals?
to me there are 2 stages in our life where self development is most rewarding. firstly, fag of teenage when wecomplete our education and start to live on our own without depending on our elders. Achievement acquired at this stage will be quite rewarding. Secondly, at old age when everybody disown the veterans of the family. its often heard that the oldparents are kicked out by shameless children.they are forced to retire their life at oldage home. self development at this stage will be quite rewarding as it will act as wheelchair to carry on the remaining days. the first is beginning of the life and the later is near end of life.
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