| While research and development costs in the | | | | information must be translated into the |
| pharmaceutical industry continue to increase, the | | | | development of a clinical research plan that will |
| number of new approved drugs is on a steady | | | | successfully bring the candidate through Phase II |
| decline (Di Masi et al, 2003). In contradistinction to | | | | proof of efficacy studies. |
| the rapid emergence of laboratory research and | | | | To move development of the therapeutic |
| development tools, such as in vitro and in silico | | | | candidate expeditiously and to successful |
| screening tools and new tools necessary to | | | | completion, the Program Managers of the TDDO |
| describe the affects of drug candidates within the | | | | must also be able to optimize the developmental |
| complex biochemical pathways of intact, fully | | | | program, and recognize any shortcomings in the |
| assembled living networks (Maguire et al, 2006), | | | | translational process and be able to implement |
| there have been few advances in the discovery | | | | corrective strategies. For example, in developing |
| and development of management tools necessary | | | | the Phase I and II clinical trials, it may be evident |
| to bring a therapeutic candidate (e.g. a | | | | that the clinical endpoints used to measure |
| drug) from the laboratory into the clinic. The | | | | efficacy in Phase II will require a long and |
| pharmaceutical industry has thus realized the need | | | | expensive study with little feedback until |
| to develop innovative strategies and new | | | | completion of the trial. If the trial fails at the point |
| management methodologies that will focus on the | | | | of Phase II, much time and money will have been |
| translational process, that is the process during | | | | spent to no useful means. Therefore, in order to |
| which a therapeutic candidate is brought from the | | | | have feedback about the success of the efficacy |
| lab and into successful completion of Phase II | | | | of the candidate before spending so much time |
| proof of efficacy studies. | | | | and money through Phase II, it may very well be |
| This translational process, with all of its inherent | | | | advantageous to perform a shorter trial and |
| problems, has been blamed as a key contributor | | | | acquire the feedback more quickly and |
| to the high failure rate of therapeutic candidates | | | | inexpensively. Thus, to have feedback on efficacy |
| as they progress from the lab through the drug | | | | in the human trials, it may be recommended to |
| discovery and development process only to find a | | | | conduct a Phase 0 or first in human, pilot study |
| high probability of failure at Phase II proof of | | | | using biomarkers or other surrogate or |
| efficacy clinical trials. This failure occurs after | | | | non-surrogate endpoints that can be utilized to |
| years of study and millions of dollars spent on the | | | | determine efficacy for purposes of internal |
| scrapped potential therapeutic, with little or nothing | | | | decision making; this may involve a go-nogo |
| to show for the huge investment. Often the | | | | decision or a decision about dosing strategies for |
| developmental program for the candidate is | | | | example. |
| dropped at this point, and the infrastructure is | | | | Another example for using a pilot study is for the |
| repositioned to work on another candidate, or | | | | purpose of determining patient stratification. That |
| the infrastructure is simply disassembled. The | | | | is, which subjects are likely to respond to the |
| failure rate at Phase II proof of efficacy is 50%, | | | | treatment, and which subjects will show an |
| and has doubled in the past decade (Dimasi et al, | | | | adverse response to treatment? Predictions have |
| 2001). In contrast, the failure rate in Phase III | | | | been made for the selection of patients for |
| clinical trials has remained flat for the last decade. | | | | targeted chemotherapy for the treatment of |
| Clearly there is a problem of great magnitude in | | | | breast cancer (Pittman et al, 2001) and for chronic |
| bringing the candidate from the lab into the clinic, | | | | myeloid leukemia (Maguire et al, 2006). |
| during the so-called translational process. | | | | And, if the Phase I and II clinical trials are to be |
| One such newly identified strategy and technology | | | | long and expensive, another strategy frequently |
| at the scientific level is systems biology | | | | used in the TDDO is to employ adaptive trials. In |
| and metabolomics. As science becomes more | | | | this way, emerging data from the trial is quickly |
| sophisticated and specialized, scientist learn more | | | | gathered and used to make modifications of the |
| and more about less and less. That is, scientist | | | | ongoing trial. A simple example of using adaptive |
| tend to become more focused on a specific area | | | | trials is the modification of patient sample size as |
| because there is so much to learn in that one | | | | the trial proceeds. If the power of the statistical |
| area, gaining great depth in that one area of | | | | measure of efficacy is determined to be too |
| focus at the expense of a breadth of knowledge | | | | strong because patients are responding to the |
| across multiple disciplines. This is because science | | | | therapeutic in a manner better than predicted, |
| is burgeoning, and there is more to learn in any | | | | then the sample size of the trial can be adjusted |
| one specific area, and therefore it is more and | | | | downward, thus saving time and money to |
| more difficult for any one person to maintain a | | | | complete the trial. A multitude of strategies and |
| great breadth of knowledge across disciplines. | | | | adaptive procedures can be designed and |
| Systems biology has been employed to view the | | | | implemented in the translational process, and only |
| drug candidate in the system where the various | | | | require that the TDDO be able to properly |
| components of the system can be seen to | | | | oversee the translational process with a |
| interact, as opposed to individual components of | | | | fundamental understanding of the scientific, |
| the system where no interaction can be | | | | regulatory, clinical, and business issues at hand for |
| determined. | | | | developing the particular therapeutic candidate. |
| This phenomenon of specialization is readily | | | | Upon completion of bringing the therapeutic |
| apparent in the drug discovery and development | | | | candidate through the translational process, with a |
| process which has become a very complicated, | | | | successful completion of phase II efficacy studies, |
| long-term, and expensive process (Fitzgerald, | | | | the development program is then transitioned to |
| 2005). Early in the discovery/development (DD) | | | | the CRO who will conduct the Phase III study. |
| process, at the stage of lead candidate discovery | | | | Because of the work performed by the TDDO, all |
| and into non-clinical studies, biological bench | | | | efficacy, safety, and dosing issues will have been |
| scientist are mostly involved in the process and | | | | optimized and Phase III should be successfully |
| can readily communicate with one another. | | | | completed in record time. |
| Likewise, late in the development stage, when | | | | Who benefits from the TDDO? The obvious |
| Phase III clinical trial are well underway, the | | | | answer is, anyone who is bringing a therapeutic |
| process mostly involves clinical scientist, and they | | | | candidate from the laboratory into the clinic. |
| can readily communicate with one another too. | | | | Specific examples of who benefits are emerging, |
| However, during the translational process, when | | | | start-up companies without the infrastructure to |
| the therapeutic candidate is being moved from | | | | conduct the steps required in the translational |
| the laboratory into the clinic for proof of efficacy | | | | process themselves. Less obvious, perhaps, are |
| studies, the process highly involves three different | | | | angel groups and VC firms with portfolio |
| groups of scientists (discovery, regulatory, and | | | | companies or virtual companies. In the case of |
| clinical), with three different goals, three different | | | | virtual companies, the TDDO can be particularly |
| languages, and for whom the communication and | | | | helpful in determining whether a therapeutic |
| work flow between groups can be highly | | | | candidate is efficacious and safe before the |
| strained. For example, the goal of the discovery, | | | | company is actually built. In this case, if the |
| laboratory groups is usually innovation, while the | | | | compound fails, then time and money was not |
| goal of the clinical team is usually speed and | | | | lost in building a company infrastructure based on |
| procedures. While both are critical scientific | | | | a failed therapeutic. Rather the therapeutic was |
| endeavors, the methods and terminology are | | | | tested first using a streamlined, inexpensive |
| very different and communication between the | | | | approach by hiring the TDDO to perform the |
| two can often be a monologue instead of a | | | | required translational studies. If the compound is |
| dialogue. This is an example of the common | | | | efficacious and safe, then the company is built. If |
| management problem called the "Silo Effect." | | | | the therapeutic fails, there is no company to |
| Much has been said about this problem, and a | | | | disassemble, costing time and money, and there |
| number of attempts have been made to alleviate | | | | was no company built in the first place, which also |
| the problem, a few with resounding success. One | | | | required time and money to build. And of course, |
| such success has been the development of the | | | | traditional biotech and pharma companies with |
| translational drug development organization | | | | candidates moving from the lab to the clinic will |
| (TDDO). The TDDO is a contract research | | | | require such services. While large pharma |
| organization that is specialized to bring a | | | | companies may have certain aspects of the |
| therapeutic candidate from the laboratory to IND | | | | TDDO infrastructure in place within their own |
| enablement, and into the clinic for successful proof | | | | company, they can integrate their own aspects |
| of efficacy studies. | | | | of the CRO structure into that of the TDDO and |
| What is a TDDO and what does it do? The | | | | allow the TDDO to best manage the translational |
| TDDO can be thought of as a type of CRO | | | | process through the TDDO’s program |
| that is structured to focus on the translational | | | | management branch. These are but a few of the |
| process and can serve to meet all needs of the | | | | examples in which the TDDO can optimize the |
| client during this portion of the DD process. The | | | | translational process of drug or therapeutic |
| TDDO needs to have a special structure and skill | | | | development for virtual, small, or large companies, |
| set not normally associated with the traditional | | | | leading to not only reduced time and costs for |
| CRO. Yes, the TDDO must possess what the | | | | the successful development of a candidate, but |
| traditional CRO possesses, such as a | | | | also by optimizing the program to satisfy the |
| management, regulatory, clinical, data | | | | business goals of the company too. |
| management, and compliance and audit sections, | | | | References: |
| but the TDDO requires more beyond these | | | | Dimasi, JA (2001) Risks in new drug development: |
| traditional disciplines found in the traditional CRO. | | | | approval success rates for investigational drugs. |
| The TDDO also requires a special, highly qualified | | | | Clin. Pharmacol. Ther. 69:297-307. |
| Program Management branch that can oversee | | | | Fitzgerald G.A. (2005) Anticipating change in drug |
| the translational process, understanding all aspects | | | | development: the merging era of translational |
| of the translational process, and thus facilitate | | | | medicine and therapeutics. Nature Reviews 4: |
| communication and work flow between the three | | | | 815-818. |
| groups (discovery, regulatory, and clinical groups). | | | | Maguire, G. et al (2006) SiDMAP: A metabolomics |
| In order to bridge the three disciplines, the | | | | approach to assess the effects of drug |
| program management branch must be composed | | | | candidates on the dynamic properties of |
| of highly qualified scientists that understand what | | | | biochemical pathways. Exp. Opinion Drug Disc. |
| has been previously done in the laboratory | | | | 1:351-359. |
| research program that will support bringing the | | | | Pittman, J. et al (2001) Integrated modeling of |
| candidate to IND enablement. They must also be | | | | clinical and gene expression information for |
| able to assemble this information and | | | | personalized prediction of disease outcomes. Proc |
| communicate it to the appropriate groups within | | | | Natl. Acad. Sci. |
| the regulatory circles, and then all of this | | | | |