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Model based drug development - what is it good for?

LIFE SCIENCE TECHNICAL BULLETIN
MODEL BASED DRUG DEVELOPMENT – WHAT IS IT
GOOD FOR?
AUTHOR: JANET R WADE, PHD, SENIOR CONSULTANT, SGS EXPRIMO

The FDA ‘‘critical path'' document characterizes model-based drug development (MBDD) as the development and application of pharmaco-statistical models of drug efficacy and safety from preclinical and clinical data to improve both drug development knowledge management and decision-making (1), (2). A less formal description of MBDD would be the development and use of mathematical models to aid answer existing and future project team questions that arise during drug development. As an analogy, many of us probably played with Lego bricks during our childhood. We could make many different models out of those bricks, but we made what we wanted to make at that point in time. In MBDD, the Lego bricks represent pieces of information and the models they are used to create (castle, house, farm, etc.), depends on what is needed (a place to defend yourself from an attack, somewhere warm to sleep, somewhere to raise cows and chickens, respectively).
More seriously, MBDD brings data from many sources together and describes it (the biomedical situation) as a whole, thus maximizing the information and understanding that can be gained from the data. All of this is done to provide answers to questions. Some examples of the different types of models that may be built are listed below.
POPULATION PK MODELING
pharmacology study done to assess the Traditional statistical analysis of dose Population pharmacokinetic (PK) influence of renal impairment on the PK response usually involves an analysis models are frequently built during the of a compound. When appropriate, a of covariance (ANCOVA), followed by development of new medicines. The further study may look at the influence multiple pair-wise comparisons. These population PK model can bring together of metabolic status (such as poor and analyses are often unable to reconcile information from the single ascending extensive metabolizers of CYP2D6). the not infrequent occurrence in a dose (SAD) and multiple ascending dose While no pharmaceutical company would parallel group study when a lower dose (MAD) studies to provide an integrated attempt to study the combination of poor of a new compound gives rise to a description of the new medicines' renal function in poor metabolizers of better response than a higher dose. By pharmacokinetics. For example, such CYP2D6, these patients do infrequently analyzing the data using a single model, an approach has greater power to exist and their prescriber needs to decide the observed response disharmony characterize any non-linear PK situations what dose they should start treatment between the different dose groups can due to saturable absorption or elimination with. In this situation, the population be resolved. A simulated example is PK model could be used to propose a presented in the figure below (Figure reasonable starting dose and this model 1). The black line depicts the true dose Population PK models built using later predicted information could well be response curve; the red points and stage data often provide information included in the drug label.
vertical lines are a set of simulated about the influence of demographic possible point estimates with their or pathophysiological factors on the DOSE RESPONSE CHARACTERISATION
associated 95% confidence intervals pharmacokinetics of the compound, under the variability described by the in the target population. These Building models that describe dose- underlying model. If this was a real life models can also be used to predict response or dose-concentration- example, it would not be surprising if unstudied situations. An example of response relationships is one of the the project team decided that the 8 mg this is a frequently performed clinical more important MBDD activities.


clients (Roche), developed a comprehensive hepatitis C viral kinetic model that explainedcure (4). A representation of the disease part of the model is shown in Figure 2; the assorted different viral response profiles that the model can explain are shown in Figure 3. Representation of the extended HCV viral kinetic model. Infectious HCV virions (VI) infect target cells (T), creating productively infected hepatocytes (I). Uninfected hepatocytes (T) are produced at rate s and die at rate d. Infected hepatocytes die at rate δ. A density-dependentproliferationof hepatocytes (r) is assumed. Infectious (VI) and non-infectious (VNI) virions are LIFE SCIENCE TECHNICAL BULLETIN
produced at rate p and cleared at rate c. Peginterferon α-2a dose-dep2endently inhibits the production of new virions (ε), and ribavirin dose-dependently renders a fraction of newly produced virions non-infectious (ρ). SVR, defined as the status of having an undetectable viral load at 24 weeks after completion of treatment, is the primary clinical end point desired to be predicted in the treatment of hepatitis C. HCV, hepatitis C virus; SVR, sustained virologic response.
dose is the best dose to take forward first child is dosed. The model and the to Phase III. The model based analysis simulated virtual trials are part of an model, the observed response disharmony between the different dose groups can be resolved. A simul act atedually indicates that the 8 mg response example is presented in the figure below (Figure 1). The iterativ black lin e process to design the best depicts the true is higher than w dose response curv ould be e e; the red p xpected, purely oints and vertical lines ar possible st simulated possible point estimates with their associated 95% confidence intervals under udy. This aids the goal to the variability de due to the random v scribed by the underlyin g model. If t y that is his was a real life exampl collect sufficient dat a in the children not be surprising if the project team decided that the 8 mg dose is the best dose to take forward to Phase present in all clinical st III. The model based analysis udies.
actually indicates that the 8 mg response er the study question while is higher than would be expected, purely due to the random variability that is present in all clinical studies.
ensuring that no more children than necessary are included. The models can also be used to ensure that a minimal, yet sufficient, number of blood samples are taken.
The viral kinetic model characterizes the complexity and diversity of clinically observed HCV viral kinetics in patients with hepatitis C virus infection treated with peginterferon α-2a, alone or in cFigure 3: ombination The viral kinetic model c with ribavirin, and links thharacteriz e kinetics es the to clinical outcome. This is achieved by the implementation of a viral-eradication cure boundary and incorporation of left- MBDD IN VIRAL INFECTION
censored data, larcomple gely exclxit u y and div analysi y of clinically obser s in earlier studies, in ved a simultaneous analysis of a wide spectrum of HCV viral kinetics in patients with hepatitis C peginterferon α-2a ±ribavirin treatment regimens in 2,100 patients. EVR, early The models that can be built vary from virologic response; HCV, hepatitis C virus; LLOQ, lower limit of quantification; RVR, rapid virologicresponse.
virus infection treated with peginterferon δ-2a, reasonably straight forward (population alone or in combination with ribavirin, and links PK) to very complex. An example of a the kinetics to clinical outcome. This is achieved The true dose response is shown in black and the observed change from placebo by the implementation of a viral-eradication cure (with 95% CI) is shown in red.
complex model is one that describes Figure 1: The true dose response is shown in boundary and incorporation of left-censored data, If the (virtual in this blaccase) project tea k and the obserm ed c take the 8 mg dose forward to hange from placebo (with the underlying disease process and largely excluded from analysis in earlier studies, they could face a nasty disappointment later on. The MBDD approach of build 95% CI) is shown in red. then integrates it with a PK-biomark to describe dose response, performed alongside traditional statistical multiple testing in a simultaneous analysis of a wide spectrum of procedures where each dose level is compared to placebo, helps the project t clinical endpoint model. Suc peginterferon δ-2a ±ribavirin treatment regimens an informed choice about which dose(s) to study in Phase III. MBDD model building thus helps to maximize the probabilit If the (virt y of trial success. ual in this case) project has enormous potential to support drug in 2,100 patients. EVR, early virologic response; HCV, hepatitis C virus; LLOQ, lower limit of MBDD in paediatrics team did take the 8 mg dose forward development decisions. SGS Exprimo's Used in paediatrics, MBDD mitigates the practical and ethical constraints present when to Phase III, they could face a nasty quantification; RVR, rapid virologic response. performing studies in children. A MBDD approach allows for less data to be c Managing Director Eric Snoec fewer subjects which is helpful since the underlying variability across the age disappointment later on. The MBDD with other Exprimo colleagues and to 18 years can be far more considerable than the variability observed in adults. Further, The developed viral kinetic model while reasonable assumpti approacons can be made about scaling adult h of building models to describe pharmone of our clients (R oche), developed provided a framework for mechanistic parameters into children using well defined size and maturation factors, scaling biomarker or clinical endpoint responses is fra dose response, perf ught with questions. Imp ormed alongside lementina comprehensiv e hepatitis C viral exploration of treatment outcome and approach allows the influence of the assumptions made to be tested by running virtual traditional statistical multiple testing clinical trials before the first child is dosed. The model and the simulated virtua kinetic model that e xplained cure ( ). A facilitated evaluation of alternative part of an iterative process to design the best possible study. This aids the goal to collect procedures where each dose level is sufficient data in the children to answer the study question while ensuring tharepresent ation of the disease part of the chronic hepatitis C treatment options; children than necessary are included. The models can also be used to ens compared to placebo, helps the project minimal, yet sufficient, number of blood samples are taken.
wn in Figure 2; the assorted the ultimate aim was to develop and test team make an informed choice about clients (Roche), dif dev ferent viral response profiles that the eloped a comprehensive hepatitis C viral kinetic model th h or personalizing treatments MBDD in viral infectionThe models that can be whic built vary from re h dose(s) to st asonably straight forw udy in Phase III. assorted differe model can e nt viral response xplain are sho e disease part of profiles that the wn in Figure 3. the model is shown in F in the disease. The disease part of the very complex. An example of a complex model is one that describes the underlying MBDD model building thus helps to model can explain are shown in Figure disease process and then integrates it with a PK-biomarker-clinic . l endpoint model. Such model is drug independent (Figure 2) a model has enormous potential to support drug development decisions. SGS Exprimo's maximize the probability of trial success. Managing Director Eric Snoeck, together with other Exprimo colleagues and one of our and can be applied to different or new compounds being developed to treat MBDD IN PAEDIATRICS
Used in paediatrics, MBDD mitigates the practical and ethical constraints present when performing studies in children. A MBDD approach allows for less data to be collected in fewer subjects which is helpful since the Representation of the extended HCV viral kinetic model. Infectious HCV virions (VI) infect target cells (T), creating productively infected hepatocytes (I). Uninfected hepatocytes (T) are produced at r Figure 2: R ate s and die epresent at rate d. ation of the e Infected hepato xtended HCV underlying variability across the age cytes die at rate δ. A density-dependent proliferationof hepproduced at rate viral kinetic model. Inf atocytes (r) is assumed.
p and cleared at rate cectious HCV virions (VI) Infectious (VI) and non-infectious (VNI) virions are range of 0 to 18 years can be far more . Peginterferon α-2a dose-dependently inhibits the production of new inf ions ( arget cells (T), creating productiv ε), and ribavirin dose-dependently ren ely ders a fraction of newly produced considerable than the variability obser non-infectious (ρ). SVR, defined as the status of having an undetectable viral load at 24 weeks after comp inf leti ected hepatocytes (I). Uninf on of treatment, is the primary c ected hepatocytes linical end point desired to be predicted in the in adults. Further, while reasonable treatment of hepa (T) are produced at rate s and die at rate d. titis C. HCV, hepatitis C virus; SVR, sustained virologic response.
assumptions can be made about scaling Infected hepatocytes die at rate δ. A density-dependent proliferationof hepatocytes (r) is adult pharmacokinetic parameters into assumed. Infectious (VI) and non-infectious (VNI) children using well defined size and virions are produced at rate p and cleared at rate maturation factors, scaling biomarker or c. Peginterferon δ-2a dose-dependently inhibits clinical endpoint responses is fraught the production of new virions (δ), and ribavirin with questions. Implementing a MBDD dose-dependently renders a fraction of newly produced virions non-infectious (δ). SVR, defined approach allows the influence of the as the status of having an undetectable viral load assumptions made to be tested by at 24 weeks after completion of treatment, is the running virtual clinical trials before the primary clinical end point desired to be predicted in the treatment of hepatitis C. HCV, hepatitis C virus; SVR, sustained virologic response. The viral kinetic model characterizes the complexity and diversity of clinically observed HCV viral kinetics in patients with hepatitis C virus infection treated with peginterferon α-2a, alone or in combination with ribavirin, and links the kinetics to clinical outcome. This is achieved by the implementation of a viral-eradication cure boundary and incorporation of left-censored data, largely excluded from analysis in earlier studies, in a simultaneous analysis of a wide spectrum of peginterferon α-2a ±ribavirin treatment regimens in 2,100 patients. EVR, early virologic response; HCV, hepatitis C virus; LLOQ, lower limit of quantification; RVR, rapid virologicresponse.
LIFE SCIENCE TECHNICAL BULLETIN
The MBDD activities performed by SGS Exprimo efficiently aid in bringing the 1. Kola I & Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. right dose of new, safe, and effective Drug Discov. 2004; 3:711–715.
medicines to the patients who need them. We at SGS Exprimo are extremely 2. US Department of Health and Human Services, Food and Drug Administration. proud of our track record—we have Innovation or stagnation? Challenge and opportunity on the critical path to new performed over 300 MBDD projects, medical products (2004). Accessed 12 Oct 2013.
all delivered on time and to the highest 3. Jonsson EN, Wade JR, Karlsson MO. 2000. Nonlinearity Detection: Advantages of scientific standards. Global feedback Nonlinear Mixed-Effects Modeling. AAPS Pharmsci; 2000; 2(3); article 32. received from regulatory assessors who 4. Snoeck E, Chanu P, Lavielle M, Jacqmin P, Jonsson EN, Jorga K, Goggin T, Grippo J, read the reports of our MBDD analyses Jumbe NL, Frey N. A comprehensive hepatitis C viral kinetic model explaining cure. has been consistently good and always Clin. Pharmacol. Ther. 2010; 87(6): 706-713.
supported clients drug development decision at the right time.
In conclusion, the answer to the question ‘What is MBDD good for?' is ‘Better drug development decisions, made at the right time!'. ABOUT SGS
SGS Life Science Services is a leading ISO guidelines and directives and local can also count on SGS's large database contract service organization providing regulatory bodies. For optimized early of investigators and key opinion leaders clinical research, analytical development, phase clinical trials, SGS features sample with therapeutic expertise in Infectious biologics characterization, biosafety, tracking for safety lab data interfaced Disease & HIV/HCV, Vaccines, Oncology and quality control testing. Delivering with Oracle for PK samples, full and Respiratory. Clients benefit from the solutions for bio-pharmaceutical eSource clinic automation (EDC), a GMP favorable regulatory environment in the companies, SGS provides Phase I-IV pharmacy for on-site formulation, and a two countries with very short phase I clinical trial management services Biosafety Level 2 quarantine facility.
trial approval.
encompassing clinical project SGS has a wealth of expertise in: First- SGS also offers GMP/GLP contract management and monitoring, data In-Human studies, QT/QTc prolongation, laboratory services that include analytical management, biostatistics, and radio-labeled 14C ADME & PET scan chemistry, microbiology, stability regulatory consultancy. SGS's clinical unit trials, viral challenge testing, biosimilars, studies, bioanalysis, virology, and protein located in Antwerp, Belgium has a total and complex PK/PD studies. For a of 92 beds, and has successfully met qualitative and faster patient recruitment the standards of the US FDA, GCP, ICH, across Americas and Europe, clients To receive future articles on current trends and regulatory updates, subscribe to SGS' Life Science Ne Read more about SGS'.
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