Psychopharmacology The Role of Proof of Concept (POC) Studies in Drug Development Using the EVP-6124 POC Study as an Example SHELDON H. PRESKORN, MD
The goal of early proof of concept studies, typically involving a small number of subjects and more latitude in statistical requirements, is to provide evidence that a drug is likely to be successful in later stages of drug development. Although often not published, such studies allow drug developers to make “Go/No Go” decisions about proceeding with larger, more expensive studies. (Journal of
Psychiatric Practice 2014;20:59–60) KEY WORDS: drug development, proof of concept
In the last several years, a number of pharmaceutical companies have reduced or altogether stopped efforts to develop new psychiatric medications.1,2 The reasons are cost and the speculative nature of such development programs, due to the absence of substantive knowledge of the pathophysiology and pathoetiology underlying specific psychiatric illnesses. While some companies continue to develop psychiatric medications, they have put more emphasis on early phase IIa proof of concept (POC) studies to provide evidence that a molecule is likely to be successful in later stages of the drug development process (i.e., late phase II and large-scale phase III studies required for U.S. Food and Drug Administration [FDA] approval). Often, these early studies are not published but instead used only for internal “Go/No Go” decision-making (i.e., should more money be put into the development of either that molecule or its mechanism of action?). For this reason, clinicians often have little or no idea that such studies are commonly done nor about the nature of these studies. This information deficit is addressed in this issue of the journal by the publication of such a study, “Normalizing Effects of EVP-6124, an Alpha-7 Nicotinic Partial Agonist, on Event Related Potentials and Cognition: A Proof of Concept, Randomized Trial in Patients with Schizophrenia.”3 Figure 1 (reprinted from an earlier series of columns describing the transition from phase I to early phase II studies.4,5) will help the reader put this study and others like it in perspective. As shown in the figure, the
Journal of Psychiatric Practice Vol. 20, No. 1
drug development process is divided into “learn” and “confirm” phases. In the learn phase, the drug developer determines whether the drug is likely to be helpful to patients with a given condition to a clinically meaningful degree. These studies help define which, if any, patients are sufficiently helped and under what dosing conditions (e.g., dose and formulation). As noted above, most clinicians are only familiar with studies done in the confirm phase, because they are more often published and also form most of the basis for the indication section of the package insert. Studies in the confirm phase are typically large and multi-site, involving hundreds or even thousands of patients. Because these studies are expensive, they are not a cost-effective way to determine the optimal population or dose/formulation for a drug. The goal is to obtain that information in early phase II trials to increase the likelihood of success of later, large-scale studies, which have two main goals: 1. To determine whether the effect is sufficiently large to be detectable in a multi-site trial, and 2. To increase the number of patients exposed to the drug, to gain confidence that there are not a sizable number of outliers on the dose-response curves in terms of efficacy or safety/tolerability. For these reasons, early POC studies, such as the study presented in this issue,3 differ in several important ways from later large phase III studies: PRESKORN: University of Kansas School of Medicine-Wichita and Kansas University-Wichita Clinical Trials Unit. Copyright ©2014 Lippincott Williams & Wilkins Inc. Please send correspondence to: Sheldon H. Preskorn, MD, Kansas University-Wichita Clinical Trials Unit,1010 N. Kansas, Wichita KS 67214, [email protected] Over his career, Dr. Preskorn has worked with over 100 pharmaceutical companies in the United States and throughout the world. Over the past year, Dr. Preskorn has received grants/research support from or has served as a consultant, on the advisory board, or on the speakers bureau for the following: Abbott, Assurex Health, AstraZeneca, Eisai, Envivo, Impax Laboratories, Johnson & Johnson, Merck, National Institute of Mental Health, Naurex, Pfizer, Stanley Medical Research Institute, Sunovion, and Taisho. DOI: 10.1097/01.pra.0000442938.61575.c2
January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
59
Psychopharmacology Figure 1. “Learn and confirm” phases of drug development
Discovery
Preclinical Testing
Phase 0
Phase I
© Preskorn 2011
Phase II
“Learn”
Phase III
Phase IV*
“Confirm”
*Approval frequently contingent upon agreement with the regulatory agency (e.g., the U.S. Food and Drug Administration) to perform specific phase IV studies to confirm findings or provide additional data on specific issues (e.g., a drug-drug interaction) or in specific populations (e.g., children and adolescents)
1. POC studies involve smaller numbers of subjects and hence more latitude in statistical requirements. For studies in the confirm phase (i.e., late phase II and phase III studies), the statistical requirement is a p value ⭐ 0.05 (i.e., the result would have occurred by chance in only 1 of 20 studies). In contrast, the p value in early POC studies may be 0.1. The goal of the POC study is to provide the drug developers with data to make their own internal decisions, rather than to comply with FDA regulatory guidance for approval. Since the sample size is small, the effect size has to be large to achieve statistical significance. 2. More sensitive and parametric measures, such as the event-related potentials and computerized test batteries in the EVP-6124 study, are commonly used in POC studies. 3. Subjects may be treated as inpatients for the duration of the study, as was the case in the EVP-6124 POC study. That may be done for a number of reasons, including ensuring the safety of subjects, decreasing the likelihood of extraneous factors (e.g., nonadherence, illicit substance use) affecting the results, and permitting more intensive measurements than would be possible in an outpatient setting. For example, consider the extensive eventrelated potentials and computerized measurements and the continuous 28-day cardiac monitoring of subjects in the EVP-6124 study. 4. Given their intensive nature, POC studies can provide data on numerous issues in addition to the primary questions about safety, tolerability, and early proof of efficacy. For example, the EVP-6124 POC study also provided data on whether EVP6124 was affected by or affects several commonly used atypical antipsychotics. The outcome of the POC study of EVP-6124 presented in this issue was positive, which led to a Go decision—i.e., the sponsor took the drug forward into
60
January 2014
a larger phase II study. That study was also positive, and hence, the drug is now in later phase III studies. To summarize, the goal of the drug development process is to reduce uncertainty about a drug’s effect and to provide adequate data to make a regulatory decision about the approvability of the drug: Does its efficacy in a specific condition outweigh its risk of causing safety or tolerability problems? If there are safety and/or tolerability issues, can those risks be minimized by proper labeling of the drug (e.g., by providing precautions or warnings about its use in special populations)? The goal of this column was to provide the practitioner with more context about POC studies, such as the EVP 6124 study published in this issue, as an example of the careful, stepwise nature of the drug development process. It is that process that eventually allows prescribers to have access to new drugs and to be able to prescribe them safely and effectively to their patients.
References 1.
2.
3.
4.
5.
Insell T. Who will develop the next generation of medications for mental illness? Rockville, MD: National Institute of Mental Health Director’s Blog; March 30, 2010 (available at http://www.nimh.nih.gov/about/director/2010/who-willdevelop-the-next-generation-of-medications-for-mental-illness.shtml, accessed November 1, 2013). Nierenberg AA. The perfect storm: CNS drug development in trouble. CNS Spectr 2010;15:282–3 (available at www.cnsspectrums.com/aspx/article_pf.aspx?articleid=2625, accessed November 1, 2013). Preskorn SH, Gawryl M, Dgetluck N, et al. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: A proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract 2014;20:12–24. Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches. Part I. J Psychiatr Pract 2011;17:200–3. Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches. Part II. J Psychiatr Pract 2011;17:277–84.
Journal of Psychiatric Practice Vol. 20, No. 1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The goal of early proof of concept studies, typically involving a small number of subjects and more latitude in statistical requirements, is to provide evidence that a drug is likely to be successful in later stages of drug development. Although often not published, such studies allow drug developers to make “Go/No Go” decisions about proceeding with larger, more expensive studies. (Journal of
Psychiatric Practice 2014;20:59–60) KEY WORDS: drug development, proof of concept
In the last several years, a number of pharmaceutical companies have reduced or altogether stopped efforts to develop new psychiatric medications.1,2 The reasons are cost and the speculative nature of such development programs, due to the absence of substantive knowledge of the pathophysiology and pathoetiology underlying specific psychiatric illnesses. While some companies continue to develop psychiatric medications, they have put more emphasis on early phase IIa proof of concept (POC) studies to provide evidence that a molecule is likely to be successful in later stages of the drug development process (i.e., late phase II and large-scale phase III studies required for U.S. Food and Drug Administration [FDA] approval). Often, these early studies are not published but instead used only for internal “Go/No Go” decision-making (i.e., should more money be put into the development of either that molecule or its mechanism of action?). For this reason, clinicians often have little or no idea that such studies are commonly done nor about the nature of these studies. This information deficit is addressed in this issue of the journal by the publication of such a study, “Normalizing Effects of EVP-6124, an Alpha-7 Nicotinic Partial Agonist, on Event Related Potentials and Cognition: A Proof of Concept, Randomized Trial in Patients with Schizophrenia.”3 Figure 1 (reprinted from an earlier series of columns describing the transition from phase I to early phase II studies.4,5) will help the reader put this study and others like it in perspective. As shown in the figure, the
Journal of Psychiatric Practice Vol. 20, No. 1
drug development process is divided into “learn” and “confirm” phases. In the learn phase, the drug developer determines whether the drug is likely to be helpful to patients with a given condition to a clinically meaningful degree. These studies help define which, if any, patients are sufficiently helped and under what dosing conditions (e.g., dose and formulation). As noted above, most clinicians are only familiar with studies done in the confirm phase, because they are more often published and also form most of the basis for the indication section of the package insert. Studies in the confirm phase are typically large and multi-site, involving hundreds or even thousands of patients. Because these studies are expensive, they are not a cost-effective way to determine the optimal population or dose/formulation for a drug. The goal is to obtain that information in early phase II trials to increase the likelihood of success of later, large-scale studies, which have two main goals: 1. To determine whether the effect is sufficiently large to be detectable in a multi-site trial, and 2. To increase the number of patients exposed to the drug, to gain confidence that there are not a sizable number of outliers on the dose-response curves in terms of efficacy or safety/tolerability. For these reasons, early POC studies, such as the study presented in this issue,3 differ in several important ways from later large phase III studies: PRESKORN: University of Kansas School of Medicine-Wichita and Kansas University-Wichita Clinical Trials Unit. Copyright ©2014 Lippincott Williams & Wilkins Inc. Please send correspondence to: Sheldon H. Preskorn, MD, Kansas University-Wichita Clinical Trials Unit,1010 N. Kansas, Wichita KS 67214, [email protected] Over his career, Dr. Preskorn has worked with over 100 pharmaceutical companies in the United States and throughout the world. Over the past year, Dr. Preskorn has received grants/research support from or has served as a consultant, on the advisory board, or on the speakers bureau for the following: Abbott, Assurex Health, AstraZeneca, Eisai, Envivo, Impax Laboratories, Johnson & Johnson, Merck, National Institute of Mental Health, Naurex, Pfizer, Stanley Medical Research Institute, Sunovion, and Taisho. DOI: 10.1097/01.pra.0000442938.61575.c2
January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
59
Psychopharmacology Figure 1. “Learn and confirm” phases of drug development
Discovery
Preclinical Testing
Phase 0
Phase I
© Preskorn 2011
Phase II
“Learn”
Phase III
Phase IV*
“Confirm”
*Approval frequently contingent upon agreement with the regulatory agency (e.g., the U.S. Food and Drug Administration) to perform specific phase IV studies to confirm findings or provide additional data on specific issues (e.g., a drug-drug interaction) or in specific populations (e.g., children and adolescents)
1. POC studies involve smaller numbers of subjects and hence more latitude in statistical requirements. For studies in the confirm phase (i.e., late phase II and phase III studies), the statistical requirement is a p value ⭐ 0.05 (i.e., the result would have occurred by chance in only 1 of 20 studies). In contrast, the p value in early POC studies may be 0.1. The goal of the POC study is to provide the drug developers with data to make their own internal decisions, rather than to comply with FDA regulatory guidance for approval. Since the sample size is small, the effect size has to be large to achieve statistical significance. 2. More sensitive and parametric measures, such as the event-related potentials and computerized test batteries in the EVP-6124 study, are commonly used in POC studies. 3. Subjects may be treated as inpatients for the duration of the study, as was the case in the EVP-6124 POC study. That may be done for a number of reasons, including ensuring the safety of subjects, decreasing the likelihood of extraneous factors (e.g., nonadherence, illicit substance use) affecting the results, and permitting more intensive measurements than would be possible in an outpatient setting. For example, consider the extensive eventrelated potentials and computerized measurements and the continuous 28-day cardiac monitoring of subjects in the EVP-6124 study. 4. Given their intensive nature, POC studies can provide data on numerous issues in addition to the primary questions about safety, tolerability, and early proof of efficacy. For example, the EVP-6124 POC study also provided data on whether EVP6124 was affected by or affects several commonly used atypical antipsychotics. The outcome of the POC study of EVP-6124 presented in this issue was positive, which led to a Go decision—i.e., the sponsor took the drug forward into
60
January 2014
a larger phase II study. That study was also positive, and hence, the drug is now in later phase III studies. To summarize, the goal of the drug development process is to reduce uncertainty about a drug’s effect and to provide adequate data to make a regulatory decision about the approvability of the drug: Does its efficacy in a specific condition outweigh its risk of causing safety or tolerability problems? If there are safety and/or tolerability issues, can those risks be minimized by proper labeling of the drug (e.g., by providing precautions or warnings about its use in special populations)? The goal of this column was to provide the practitioner with more context about POC studies, such as the EVP 6124 study published in this issue, as an example of the careful, stepwise nature of the drug development process. It is that process that eventually allows prescribers to have access to new drugs and to be able to prescribe them safely and effectively to their patients.
References 1.
2.
3.
4.
5.
Insell T. Who will develop the next generation of medications for mental illness? Rockville, MD: National Institute of Mental Health Director’s Blog; March 30, 2010 (available at http://www.nimh.nih.gov/about/director/2010/who-willdevelop-the-next-generation-of-medications-for-mental-illness.shtml, accessed November 1, 2013). Nierenberg AA. The perfect storm: CNS drug development in trouble. CNS Spectr 2010;15:282–3 (available at www.cnsspectrums.com/aspx/article_pf.aspx?articleid=2625, accessed November 1, 2013). Preskorn SH, Gawryl M, Dgetluck N, et al. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: A proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract 2014;20:12–24. Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches. Part I. J Psychiatr Pract 2011;17:200–3. Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches. Part II. J Psychiatr Pract 2011;17:277–84.
Journal of Psychiatric Practice Vol. 20, No. 1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
