Drug Discovery Today Volume 00, Number 00 June 2014
EDITORIAL
editorial Majid Moridani
Sam Harirforoosh
Drug development and discovery: challenges and opportunities Introduction For every successful medicine finding its way to market, there are 5000 to 10,000 compounds that fail necessary tests [1]. It takes an estimated 8–12 years of intense research and approximately $1 billion for a new medicine to reach patients [2]. Over the last
several decades, there has been an enormous increase in spending on the development of new medicines; however, this has not been translated into the introduction of more medicines to market [3]. In fact, research and development efficiency, measured by the number of drugs introduced to market per billion dollar spent over the course of drug development, has shrunk, despite remarkable advances in the field of biomedical research [3,4]. The lack of productivity in drug develoment has been acknowledged by the US Food and Drug Administration (FDA). In 2004, the FDA started the Critical Path Initiative project to improve drug development by using modern technology and public–private partnerships [5]. In addition, the President’s Council of Advisors on Science and Technology published a report [6] and addressed the concerns and outlined several recommendations to achieve an important goal which was to double the number of new medicines within a 10–15 year time period [7]. To discuss the root cause of drug development inefficiency, a short course entitled ‘Drug Development and Discovery by FDA Standards’ was held in November 2013 at American Association of Pharmaceutical Scientists Annual Meeting in San Antonio. The course provided an overview of steps involved in pre-clinical and clinical research followed by regulatory aspects of drug development. Although the speakers from the FDA, industry, and academia covered a wide range of topics relevant to the process of drug development and discovery, the current communication discusses only the challenges faced by small pharmaceutical companies and academic scientists over the course of drug discovery and development.
Pre-discovery challenges The progress of any research depends on many factors including talent, cutting-edge technology, and more importantly the availability of funds for conducting research. The National Institutes of Health (NIH) is the key player in funding biomedical research in the United States [8]. Although increasing from $14 billion in 1998 to $27 billion in 2003, the NIH budget remained at the same level for five years. After receiving an additional $10.4 billion in 2009 as a part of the governmental stimulus plan, the agency faced a budget cut in 2013. In addition, the research dollar value has decreased over the last several years, after adjusting for inflation [9]. Altogether, budget cuts have pushed down the success rate for
www.drugdiscoverytoday.com 1 Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.06.003
DRUDIS 1431 1–3 EDITORIAL
Editorial
R01 grants from 32% in 2000 to 17% in 2013 [8] and decreased the number of funded grants, which can easily correspond to a 100% reduction in funding for some investigators whose salary depends completely on extramural funding [9]. Due to a recent NIH policy change, investigators are now allowed to submit the same idea as many times as they wish [10]. This may have positive implications in improving the chances of new investigators who do not have time to work on new ideas in the beginning of their career. The issue of lack of funding for young and even seasoned investigators can be addressed by a reduction in funding for the investigators who receive more than $1.5 million per year from the NIH [8]. Here, we propose this reduction to be adjusted at $300,000 a year with 1–2 year overlap of two funding grants, limited to $600,000 a year. The salaries of principal investigators should not be covered through research funding rather through salary agreement with academic institutions stemming from teaching and administrative duties. Such arrangements also improve the quality of research and infrastructure in a wider range of academic centers. Alternatively, grants should be awarded to universities which see research dollars as an opportunity to perform research rather than income opportunities. In most cases, the office of intellectual properties in universities is too slow and controlling. They should have a process in place to make a decision quickly if they wish to patent an idea. Alternatively they should release the intellectual property rights back to the principal investigator in a period of no longer than 3 months. This will make it possible for principal investigators to market their projects to pharmaceutical companies, large or small, at a lower or nominal fee so that their ideas have a chance to survive and thrive. Although ideas can be patented, but there is a long road to be travelled from idea to product. The patent should cover the right to the idea after a product is on the market. Perhaps a standard 5% fee for profit should be given to the idea holder to encourage the development of new ideas. Because there are many good ideas with preliminary data that are published which can never become a product or hold a patent under current patient law; the patent law should change so investors can work on old ideas to develop new products.
Pre-clinical challenges Technological advances, discovery of new biomarkers, and enhancement of pre-clinical procedures have improved the preclinical step in drug development. However, the lack of business and management skills is one major barrier in drug development for academic or industrial scientists. It is important to fund research projects proposed by scientists covering a wide range of expertise in chemistry, toxicology, and biomedical research who can tackle not only the basic research aspect of the project but also assist with drug development in planning and conducting toxicological and pharmacokinetics studies in animal model early in drug development stage in a Good Laboratory Practices (GLP) compliant environment. Nearly 100% of academic research laboratories of independent scientists are not GLP compliant; therefore, the data generated in these laboratories are not presentable to the FDA. The size of a research group can dictate how far they can progress in drug development and these research groups are not typically equipped to coordinate research for drug development. 2
Drug Discovery Today Volume 00, Number 00 June 2014
Our proposal is that a new category of research funds or grant mechanisms should be developed for academic scientists. When funded, all the research needs to be contracted with established contract research organizations (CROs). In such circumstances, the principal investigator’s responsibility should be to coordinate, communicate, and compile the data generated by established GLP compliant CROs. These principal investigators should have a very good understanding of the drug development business and have excellent managerial skills. Moreover, the principal investigators need to release their ideas and market or contract their ideas to investors who can invest in those ideas. Unfortunately, most scientists are too closely attached to their ideas. They need to see the value of product development not just ideas, and learn to market their ideas to small pharmaceutical companies who specialize in early stages of drug development. Thus giving their ideas a chance to live and thrive in a small pharmaceutical company that is constantly searching for new opportunities and has the ability to market and invest in their ideas.
Clinical challenges Without doubt, this step is the most expensive phase of any drug development process. Budget cuts have impacted clinical research as well as pre-clinical research. For instance, the NIH Clinical Center admitted fewer patients in 2013 [9]. As drug development is a lengthy process, hospitals need to subsidize research instead of looking to research dollars as revenue. They should have a moral responsibility to look beyond profits and use research as a marketing tool to recruit patients and attract health care dollars for research purposes rather than revenue. We also believe that the patent clock should start after a drug has gone through phase I clinical trial. This single change could create enormous opportunities for pharmaceutical industries to revisit some of their old projects and identify those drug candidates which may have a chance of becoming a product but had a short life span for patent protection. The key point should be product development not the newness of an idea. Other important questions include whether an old molecule can be taught a new trick and which drug candidate molecule should be selected for further investigation. This patent clock change will make it possible for investors to come forward with a plan to complete toxicology, pharmacokinetics, and efficacy studies in a GLP compliant environment within a reasonable time period and make a decision whether to move forward to phase I and II clinical trials.
Conclusion An increase in research dollars for pharmaceutical and toxicological studies in GLP compliant laboratory would improve the drug development process. Universities need to invest in making their research laboratories GLP compliant. A change in university policies is needed to fast track evaluation of projects for patent suitability or for releasing the intellectual properties back to investigators. Other changes include refocusing patent law on new product development, and changing the patent clock to start following phase I clinical trial completion. These two changes alone can create enormous opportunities for the development of new drug products. Most scientists are not familiar with the business and regulatory aspects of drug development; thus education and experience in these areas is very much needed. In addition, federal research
www.drugdiscoverytoday.com Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
DRUDIS 1431 1–3 Drug Discovery Today Volume 00, Number 00 June 2014
Disclosure statement No financial support was received in the writing of this paper. The authors have no conflicts of interest. References 1 FitzGerald, G.A. (2011) Re-engineering drug discovery and development. LDI Issue Brief 17, 1–4 2 Reitz, A.B. and Czupich, K.M. (2010) The challenge of drug discovery in the 21st century. Open Conf. Proc. J. 1, 45–53 3 Scannell, J.W. et al. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 11, 191–200 4 Munos, B. (2009) Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug Discov. 8, 959–968 5 Woodcock, J. and Woosley, R. (2008) The FDA critical path initiative and its influence on new drug development. Annu. Rev. Med. 59, 1–12
6 PCAST. (2012) Report To The President On Propelling Innovation In Drug Discovery, Development, and Evaluation. http://www.whitehouse.gov/sites/ default/files/microsites/ostp/pcast-fda-final.pdf 7 Morris, S.A. et al. (2013) The PCAST report: impact and implications for the pharmaceutical industry. Clin. Pharmacol. Ther. 94, 300–302 8 Couzin-Frankel, J. (2014) Chasing the money. Science 344, 24–25 9 Kuehn, B.M. (2014) Budget woes, sequester place researchers in a bind: young researchers hard hit. JAMA 311, 15–16 10 Kaiser, J. (2014) Biomedical funding, At NIH, two strikes policy is out. Science 344, 350
Majid Moridani* Medical College of Wisconsin, Department of Pathology, Milwaukee, WI 53226, United States Sam Harirforoosh Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, United States *Corresponding author: emails: [email protected] (M. Moridani), [email protected] (S. Harirforoosh).
www.drugdiscoverytoday.com 3 Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
Editorial
funding should be limited to no more than $300,000 per year for investigators. The key is that the grant agencies should spread the betting chips around rather than betting multiple times on a handful of ideas by limited number of scientists, as the current model has not been successful over the last few decades.
EDITORIAL
EDITORIAL
editorial Majid Moridani
Sam Harirforoosh
Drug development and discovery: challenges and opportunities Introduction For every successful medicine finding its way to market, there are 5000 to 10,000 compounds that fail necessary tests [1]. It takes an estimated 8–12 years of intense research and approximately $1 billion for a new medicine to reach patients [2]. Over the last
several decades, there has been an enormous increase in spending on the development of new medicines; however, this has not been translated into the introduction of more medicines to market [3]. In fact, research and development efficiency, measured by the number of drugs introduced to market per billion dollar spent over the course of drug development, has shrunk, despite remarkable advances in the field of biomedical research [3,4]. The lack of productivity in drug develoment has been acknowledged by the US Food and Drug Administration (FDA). In 2004, the FDA started the Critical Path Initiative project to improve drug development by using modern technology and public–private partnerships [5]. In addition, the President’s Council of Advisors on Science and Technology published a report [6] and addressed the concerns and outlined several recommendations to achieve an important goal which was to double the number of new medicines within a 10–15 year time period [7]. To discuss the root cause of drug development inefficiency, a short course entitled ‘Drug Development and Discovery by FDA Standards’ was held in November 2013 at American Association of Pharmaceutical Scientists Annual Meeting in San Antonio. The course provided an overview of steps involved in pre-clinical and clinical research followed by regulatory aspects of drug development. Although the speakers from the FDA, industry, and academia covered a wide range of topics relevant to the process of drug development and discovery, the current communication discusses only the challenges faced by small pharmaceutical companies and academic scientists over the course of drug discovery and development.
Pre-discovery challenges The progress of any research depends on many factors including talent, cutting-edge technology, and more importantly the availability of funds for conducting research. The National Institutes of Health (NIH) is the key player in funding biomedical research in the United States [8]. Although increasing from $14 billion in 1998 to $27 billion in 2003, the NIH budget remained at the same level for five years. After receiving an additional $10.4 billion in 2009 as a part of the governmental stimulus plan, the agency faced a budget cut in 2013. In addition, the research dollar value has decreased over the last several years, after adjusting for inflation [9]. Altogether, budget cuts have pushed down the success rate for
www.drugdiscoverytoday.com 1 Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.06.003
DRUDIS 1431 1–3 EDITORIAL
Editorial
R01 grants from 32% in 2000 to 17% in 2013 [8] and decreased the number of funded grants, which can easily correspond to a 100% reduction in funding for some investigators whose salary depends completely on extramural funding [9]. Due to a recent NIH policy change, investigators are now allowed to submit the same idea as many times as they wish [10]. This may have positive implications in improving the chances of new investigators who do not have time to work on new ideas in the beginning of their career. The issue of lack of funding for young and even seasoned investigators can be addressed by a reduction in funding for the investigators who receive more than $1.5 million per year from the NIH [8]. Here, we propose this reduction to be adjusted at $300,000 a year with 1–2 year overlap of two funding grants, limited to $600,000 a year. The salaries of principal investigators should not be covered through research funding rather through salary agreement with academic institutions stemming from teaching and administrative duties. Such arrangements also improve the quality of research and infrastructure in a wider range of academic centers. Alternatively, grants should be awarded to universities which see research dollars as an opportunity to perform research rather than income opportunities. In most cases, the office of intellectual properties in universities is too slow and controlling. They should have a process in place to make a decision quickly if they wish to patent an idea. Alternatively they should release the intellectual property rights back to the principal investigator in a period of no longer than 3 months. This will make it possible for principal investigators to market their projects to pharmaceutical companies, large or small, at a lower or nominal fee so that their ideas have a chance to survive and thrive. Although ideas can be patented, but there is a long road to be travelled from idea to product. The patent should cover the right to the idea after a product is on the market. Perhaps a standard 5% fee for profit should be given to the idea holder to encourage the development of new ideas. Because there are many good ideas with preliminary data that are published which can never become a product or hold a patent under current patient law; the patent law should change so investors can work on old ideas to develop new products.
Pre-clinical challenges Technological advances, discovery of new biomarkers, and enhancement of pre-clinical procedures have improved the preclinical step in drug development. However, the lack of business and management skills is one major barrier in drug development for academic or industrial scientists. It is important to fund research projects proposed by scientists covering a wide range of expertise in chemistry, toxicology, and biomedical research who can tackle not only the basic research aspect of the project but also assist with drug development in planning and conducting toxicological and pharmacokinetics studies in animal model early in drug development stage in a Good Laboratory Practices (GLP) compliant environment. Nearly 100% of academic research laboratories of independent scientists are not GLP compliant; therefore, the data generated in these laboratories are not presentable to the FDA. The size of a research group can dictate how far they can progress in drug development and these research groups are not typically equipped to coordinate research for drug development. 2
Drug Discovery Today Volume 00, Number 00 June 2014
Our proposal is that a new category of research funds or grant mechanisms should be developed for academic scientists. When funded, all the research needs to be contracted with established contract research organizations (CROs). In such circumstances, the principal investigator’s responsibility should be to coordinate, communicate, and compile the data generated by established GLP compliant CROs. These principal investigators should have a very good understanding of the drug development business and have excellent managerial skills. Moreover, the principal investigators need to release their ideas and market or contract their ideas to investors who can invest in those ideas. Unfortunately, most scientists are too closely attached to their ideas. They need to see the value of product development not just ideas, and learn to market their ideas to small pharmaceutical companies who specialize in early stages of drug development. Thus giving their ideas a chance to live and thrive in a small pharmaceutical company that is constantly searching for new opportunities and has the ability to market and invest in their ideas.
Clinical challenges Without doubt, this step is the most expensive phase of any drug development process. Budget cuts have impacted clinical research as well as pre-clinical research. For instance, the NIH Clinical Center admitted fewer patients in 2013 [9]. As drug development is a lengthy process, hospitals need to subsidize research instead of looking to research dollars as revenue. They should have a moral responsibility to look beyond profits and use research as a marketing tool to recruit patients and attract health care dollars for research purposes rather than revenue. We also believe that the patent clock should start after a drug has gone through phase I clinical trial. This single change could create enormous opportunities for pharmaceutical industries to revisit some of their old projects and identify those drug candidates which may have a chance of becoming a product but had a short life span for patent protection. The key point should be product development not the newness of an idea. Other important questions include whether an old molecule can be taught a new trick and which drug candidate molecule should be selected for further investigation. This patent clock change will make it possible for investors to come forward with a plan to complete toxicology, pharmacokinetics, and efficacy studies in a GLP compliant environment within a reasonable time period and make a decision whether to move forward to phase I and II clinical trials.
Conclusion An increase in research dollars for pharmaceutical and toxicological studies in GLP compliant laboratory would improve the drug development process. Universities need to invest in making their research laboratories GLP compliant. A change in university policies is needed to fast track evaluation of projects for patent suitability or for releasing the intellectual properties back to investigators. Other changes include refocusing patent law on new product development, and changing the patent clock to start following phase I clinical trial completion. These two changes alone can create enormous opportunities for the development of new drug products. Most scientists are not familiar with the business and regulatory aspects of drug development; thus education and experience in these areas is very much needed. In addition, federal research
www.drugdiscoverytoday.com Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
DRUDIS 1431 1–3 Drug Discovery Today Volume 00, Number 00 June 2014
Disclosure statement No financial support was received in the writing of this paper. The authors have no conflicts of interest. References 1 FitzGerald, G.A. (2011) Re-engineering drug discovery and development. LDI Issue Brief 17, 1–4 2 Reitz, A.B. and Czupich, K.M. (2010) The challenge of drug discovery in the 21st century. Open Conf. Proc. J. 1, 45–53 3 Scannell, J.W. et al. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 11, 191–200 4 Munos, B. (2009) Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug Discov. 8, 959–968 5 Woodcock, J. and Woosley, R. (2008) The FDA critical path initiative and its influence on new drug development. Annu. Rev. Med. 59, 1–12
6 PCAST. (2012) Report To The President On Propelling Innovation In Drug Discovery, Development, and Evaluation. http://www.whitehouse.gov/sites/ default/files/microsites/ostp/pcast-fda-final.pdf 7 Morris, S.A. et al. (2013) The PCAST report: impact and implications for the pharmaceutical industry. Clin. Pharmacol. Ther. 94, 300–302 8 Couzin-Frankel, J. (2014) Chasing the money. Science 344, 24–25 9 Kuehn, B.M. (2014) Budget woes, sequester place researchers in a bind: young researchers hard hit. JAMA 311, 15–16 10 Kaiser, J. (2014) Biomedical funding, At NIH, two strikes policy is out. Science 344, 350
Majid Moridani* Medical College of Wisconsin, Department of Pathology, Milwaukee, WI 53226, United States Sam Harirforoosh Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, United States *Corresponding author: emails: [email protected] (M. Moridani), [email protected] (S. Harirforoosh).
www.drugdiscoverytoday.com 3 Please cite this article in press as: Moridani, M. Drug development and discovery: challenges and opportunities, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.06.003
Editorial
funding should be limited to no more than $300,000 per year for investigators. The key is that the grant agencies should spread the betting chips around rather than betting multiple times on a handful of ideas by limited number of scientists, as the current model has not been successful over the last few decades.
EDITORIAL
