Pharmacometrics 2020

Jogarao V. S. Gobburu, PhD

This special issue of the Journal of Clinical Pharmacology is dedicated to pharmacometrics, covering topics related to methodological research, application to decisions, standardization, PhRMA survey, and growth strategy. Inno vative methodological and technological advances in analyzing disease, drug, and trial data have equipped pharmacometricians with the know-how to influence high-level decisions, which in turn creates more pharmacometric opportunities. Pharmacometrics is revolutionizing drug development and regulatory decision making. To sustain the success and growth of this field, we need to up the ante. Strategic goals for pharmacometric groups

in industry, regulatory agencies, and academia are proposed in this report. These goals should be of significance to all stakeholders who have a vested interest in drug development and therapeutics. The future of pharmacometrics depends on how well we all can deliver on the strategic goals. Keywords: Clinical pharmacology; clinical trials; pharmaceutical research and development; regulatory/ scientific affairs; pharmacodynamics. Journal of Clinical Pharmacology, 2010;50:151S-157S 2010 The Author(s)

harmacometrics is the science of quantifying disease, drug, and trial characteristics with the goal of influencing drug development and regulatory and therapeutic decisions. Figure 1 depicts a macroscopic view of the evolution of pharmacometrics. The field started out (prior to 1960) with quantifying time courses of drug concentrations in biofluids (pharmacokinetics, or PK) from laboratory experiments.1 Scientists then developed methods to link drug exposures to steady-state pharmacologic res ponses (pharmacodynamics, or PD).2-4 The fusion of PK and clinical pharmacology principles was essential to develop innovative methods and tools to analyze data from clinical trials.5 In 1979, pharmacometric scientists adopted econometric and biometric methods (mixed-effects modeling) to quantify patterns in observational data, opening opportunities beyond the small homogeneous studies.6-8 In 1989, guidelines from the US Food and Drug Administration (FDA) (found on www.fda.gov) for the study of drugs likely to be used in elderly people called for
From the Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland. Submitted for publication May 24, 2010; revised version accepted June 4, 2010. Address for correspondence: Jogarao V. S. Gobburu, 10903 New Hampshire Avenue, Building 51, Rm 3186, Silver Spring, MD 20993-0002; e-mail: jogarao.gobburu@ fda.hhs.gov. DOI:10.1177/0091270010376977

pharmacokinetic screening, where sparse PK information is to be collected from registration trials to understand the sources of variability. Later, the FDA issued guidances for industry on population analyses in 1999 and on exposureres ponse relationships in 2003. By this time, labeling statements pertaining to intrinsic and extrinsic factors were being supported by pharmacometric analyses. More recent research efforts are focused on building quantitative disease and drug trial models.9-14 The importance and number of pharmacometricians have increased to an extent that a focused conference on pharmacometrics (called the American Conference of Pharmacometrics, ACoP) was created in 2008. ENTRepReNeURIAL SUccess During the late 1990s and early 2000s, 2 important developments defined the value of pharmacometrics. First, pharmacometric analyses started to influence drug approvals and drug development decisions. Second, the introduction of clinical trial simulations began to shift toward designing trials. Figure 2 shows a few selected case studies for which pharmacometric analyses played a critical role in decision making.15-22 Analyses for most of the case studies in Figure 2 were conducted by industry scientists, although some might have been prompted by the FDA. Pharmacometrics analyses began to be recognized as more efficient, compared with

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Figure 1. Brief history of pharmacometrics. The key milestones in the growth of this discipline are depicted.

conventional hypothesis testing, in that they enabled investigators to quantify the totality of information. Building on the initial success, about 250 new drug applications (NDAs) or biologic license applications (BLAs) with pharmacometric analyses have been submitted by the industry and reviewed by the FDA since 2000. Of these, 140 were submitted between 2005 and 2009, signifying an exponential increase in this type of work. More than 70% of the reviews influenced approval, and almost all of them affected labelingspecifically dose selection to balance benefit and risk (JY Lee, et al. Unpublished data, 2010) Pharmacometrics also influenced the approval of drugs against bioterrorism and for emergency preparedness. Approval of Levaquin (levofloxacin) dosing in pediatrics to treat anthrax exposure was primarily based on mechanistic modeling and simulation.23 Approval decisions previously were driven primarily by medical and statistical reviewers. Allowing model-based inferences (rooted in clinical pharmacology theory) to drive an approval decision is a game-changing achievement. The use of modeling and simulation for internal decisions by industry is not reflected by

these statistics. The PhRMA survey24 reports that 10 companies performed 115 modeling and simulation projects in 2008 alone. The survey also states that all companies are anticipating an increase in pharmacometric activity in the future. The introduction of clinical trial simulations to des ign trials (prospectively) created more opportunities for pharmacometricians. Clinical trial simulation of Cellcept (mycophenolate mofetil) is considered an early example of model-based trial design.25 Exp erience with NDA/BLA review identified weaknesses in drug development efficiency. In 2004, the FDA introduced a pilot end-of-phase 2A (EOP2A) meeting to provide pharmaceutical companies an opportunity for an early dialogue with the FDA on designing late-phase clinical trials.26 The first NDA with an EOP2A meeting during development to be submitted to the FDA is Firmagon (degarelix). The extensive modeling and simulation performed by the companys scientists aided in the dose and regimen selection for the registration trial. The studied dosing met the primary end point, and Firmagon is currently approved for treatment of patients with advanced prostate cancer.27 Several pharmacometrics groups in

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Figure 2. Selected case studies that highlight the value of pharmacometric analyses. These case studies aided in demonstrating the value of exposureresponse modeling and simulation in trial design and in drug approval and labeling. The symbols shown in the Drug column signify time and cost savings and improved product profile (better dose). The list is not meant to be exclusive.

the industry are now engaged early in development to guide trial design and go/no-go decisions. STRATeGIc 2020 GOALs Despite the success of pharmacometrics, there are sig nificant challenges to overcome. The strategic goals can be categorized into 2 broad areas: (1) enhanced efficiency of the current scope and (2) innovation to expand the future scope of pharmacometrics. Scope is defined here as the quantity and type of pharmacometric projects. These goals ustry, academia, and regulaare intended for ind tory agencies. The spe cific strategic goals of the

FDAs Division of Pharma cometrics are presented elsewhere.28 Enhancing Efficiency of Current Scope The SWOT (strengths, weaknesses, opportunities, threats) analysis29 suggests that lack of enough trained scientists, lack of motivation to share success stories, and lack of efficient tools are some of the important weaknesses. In Table I, a set of strategic goals are presented for consideration. Ardent commitment by each of us will dictate the level of accomplishment.

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GOBBURU Table I Proposed Strategic 2020 Goals for the Field of Pharmacometrics
Strategic 2020 Goals

Train 500 pharmacometricians Design 100% trials using advanced simulations Develop data and analysis standards for 15 indications Share 250 case studiesa
a. Of the 250 case studies, 25 should be presented at conferences where clinicians and investigators attend.

Train 500 Pharmacometricians There are several challenges to obtain training in the field of pharmacometrics. US educational institutions produce about 75000 statisticians and an equal number of medical doctors per year. Of course, only a portion of these graduates elect to work in the pharmaceutical sector. The number of pharmacometricians trained in the United States is probably about 5 per year, primarily because of 2 reasons: (1) the number of training institutions is limited, and (2) pharmacometric research is not well supported by federal research grants. Even if these challenges are addressed, pharmacometric training will need to differ from a typical graduate curriculum. Training can be considered with 3 different specialty tracks, as described below. All 3 tracks will need the same core pharmacometric expertise. Core expertise. The goal of gaining core expertise is to allow scientists to perform pharmacometric analysis independently. Pharmacometricians will have to master several fundamental PK, clinical pharmacology, and statistical concepts and develop the tools to implement these concepts. Most universities are self-sufficient in providing this type of training. Such modelers will need to have reasonable understanding of statistical concepts ranging from mixedeffects modeling to clinical trial design. Technical track. Scientists can elect to develop indepth skills and knowledge of mechanistic, semimechanistic, or empirical modeling. Advanced technical training might involve more statistical courses and project work pertaining to, for example, analysis of discrete data and Bayesian theory. Most universities can provide this type of training. Graduates of the technical track will play a key role in developing standards for analysis. Disease track. In addition to acquiring core expertise, pharmacometricians must have advanced know ledge 154SJ Clin Pharmacol 2010;50:151S-157S

of a particular disease area. As the influence of pharmacometrics expands, the need for specialization in different diseases both during drug development and in the clinical setting increases. For example, designing the next depression trial will require not only modeling (technical) skills but also understanding the clinical setting. Disease track training requires that the scientist undertakes medical or pharmacology courses. A PharmD program with clinical specialization along with the core course work in pharmacometrics would comprise such training. Graduates of the disease track will play a key role in therapeutic (eg, dose) decisions. Drug development track. In addition to gaining core expertise, pharmacometricians must have adv anced knowledge of drug developmentspecifically how decisions are made. Such training is only possible if academic institutions collaborate with industry and regulatory agencies. Reviewing literature and attending lectures on drug development will not suffice. Scientists will need to apply pharmacometric approaches to influence real-world decisions. For example, using exposureresponse analysis as evidence of effectiveness requires skills beyond technical skills. It requires (1) understanding of what comprises evidence of effectiveness, (2) knowledge about the organization responsible for making the final decisions, and (3) an effective strategy (consisting of judgment and skills in communication and negotiation) to influence the decision. Graduates of the drug development track will play a key role in bringing more business to the group. There is an urgent need for scientists with this training. To increase training opportunities, we need financing and expertise. Industry should be the major source of sustained financial support. Unless more internal work is generated by industry, our academic research cannot be fully supported for training future scientists and methodological innovation. Industry and academia could benefit from investing in development of detailed disease and drug trial models using data from early experiments or trials. Data from unsuccessful programs are seldom rigorously analyzed to learn and apply the lessons to future programs. Academic researchers should be given access to such data for building disease and drug trial models, which in turn can be used to guide industry decisions. There may be merit in forming an academic consortium, for example, to develop tools for a specific set of diseases that are active in terms of development. Professional societies and regulatory agencies can contribute financially, but only nominally. Both regulatory agencies

PHARMACOMETRICS 2020 and industry can play a major role in training drug development track scientists. Design 100% Trials Using Advanced Simulations One of the challenges is that pharmacometric work is not considered critical path in terms of managing drug development. That is, pharmacometricians are not routinely considered part of the decision-making team with respect to trial design and analysis. All trials are designed using sample size simulations. Published reports have shown that pharmacometricbased simulations allow more informed decisions. The conventional simulations help determine the sample size given a projected drug effect and variability. In this case, the goal is not optimization. However, pharmacometric-based simulations provide the basis for the projected drug effect and, more important, strategies on how to maximize the success rate. The low productivity of pharmaceutical research and development (50%) in the late phases attests to the inefficiency of the conventional app roach to designing trials. On the contrary, from the success stories published by the industry and the FDA, investment in pharmacometrics has high returns and low risks. We should strive to design all clinical trials using pharmacometric approaches by 2020. The PhRMA survey of 10 companies with pharmacometrics groups indicates that senior leadership recognizes modeling and simulation to increase the chance of trial and regulatory filing success. Develop Data and Analysis Standards for 15 Indications More projects will entail more routine work, which calls for standardization and automation to improve productivity (ie, more quality reports per unit of time). Anecdotal evidence indicates that time constraints often limit the extent of pharmacometric involvement in the industry. Most often, the initial analysis of late-phase clinical trials for a given indication will be identical. The subsequent analysis could be tailored for each drug. Having consensual standards for data analysis and reporting automates most parts of the pharmacometric analysis, leaving more think time, and decreases uncertainty regarding decision making. Standardization also improves consistency within and across organizations. Scientists from other disciplines will gain more comfort reviewing results presented in the same format for a given type of problem. For example, Tornoe et al30 describe the data and analysis
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standards for a thorough QT study.31 Such standards render regulatory review more predictable. Additionally, the analysis time is reduced with the automated QT knowledge management system. The Coalition Against Major Diseases (CAMD) initiative aims to bring several companies together not only to share data but also to develop standards for data and disease models. The FDAs Antiviral Information Management System (AIMS) uses data and analysis standards for automating modeling and simulation of anti-HCV trials.32 A related and important requirement for improved efficiency is the availability of efficient tools to create and manage knowledge. Currently, analysis data sets and results are saved as flat files as opposed to a database that allows cross-trial analysis. The software programs used to format, model, and simulate data and to process and archive results are completely different. Development of more integrated software is critical to industrialize pharmacometric projects. Share 250 Case Studies Despite the increasing number of projects, organizations have not been sharing the success (or failure) stories of pharmacometrics. The number of publications is not commensurate with the number of pharmacometric projects reported in the PhRMA survey. There could be several reasons for this discrepancy, the most important being the organizations policy with respect to publications. Most scientific journals do not publish articles with blinded drug names. Yet sharing the success stories with respect to decision making is one of the most critical steps required for expanding our field. Knowing the name and the specifics of the drug is not necessary to appreciate the drug development problem and the pharmacometric-based solution. Organizations such as the American Conference on Pharmacometrics (ACoP), American Society for Clinical Pharmacology and Therapeutics (ASCPT), American Association for Pharmaceutical Scientists (AAPS), and American College of Clinical Pharmacology (ACCP) should join forces in creating a free-for-all webbased resource to share success stories with fewer constraints. An obvious advantage of such a centralized resource is streamlining the impact metrics. Exemplary case studies should be presented at clinical conferences such as the American Heart Association and American Society for Clinical Oncology. Reaching out to nonpharmacometricians will catalyze the growth of our opportunities.

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Figure 3. The external drivers and the potential opportunities for pharmacometrics and related fields (eg, informatics, statistics) in the future.

Innovation to Expand Future Scope A myriad of external factors will dictate the scope of our business. Figure 3 presents some of the key drivers. An increase in consumers and patients expectations will emerge as a major source of opportunities. An important opportunity would be in health technology assessment or comparative effectiveness. The United Kingdom already has an established infrastructure, NICE,33 to assess good value for money by weighing up the cost and benefits of treatments. Other opportunities, according to Figure 3, include increasing the use of systems biology models in discovery to identify new targets, tailoring indications for targeted populations, integrating evidence from global clinical trials, and conducting more efficient safety assessments. These opportunities call for collaboration across multiple disciplines to develop rational methods. 156SJ Clin Pharmacol 2010;50:151S-157S

CONcLUdING ReMARKs The field of pharmacometrics has come a long way with respect to its size and achievements. The hard work of numerous dedicated scientists in various organizations has come to fruition. Demand is increasing in quantity and complexity. However, the supply is trailing this high demand, in both quantity and efficiency. The current report proposes the top strategic goals that we can aspire to achieve by year 2020. The success depends on our commitment to accomplishing these goals.
The author wishes to thank Drs. Carl Peck, Steven Shafer, Donald Stanski, Robert Powell, Marc Pfister, Raj Madabushi, Pravin Jadhav, Hao Zhu, Christine Garnett for helpful comments on the manuscript. Financial disclosure: The articles in this supplement are sponsored by the American Conference on Pharmacometrics.

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