Kristin Brooks09.01.10
Accelerating Clinical Trials
AcPOC trials cut development time
Contract Pharma
Accelerating clinical development from research to marketing is a big priority drug developers. There have been many advances with the use of technology, such as electronic data capture (EDC), exploring statistics through adaptive trial designs, and now Accelerated Proof-of-Concept (AcPOC). Contract research organizations (CROs) providing clinical research services now encompass strategies and methodologies to help achieve various gains. We spoke with Graham Wood, Ph.D., president of Clinical Operations at Cetero Research about AcPOC and the advancements this model has made in clinical drug development.–KB
Contract Pharma: What’s the history of AcPOC trials?
Graham Wood: For years, clinical researchers have been looking at ways to speed early clinical development and reach go/no-go decisions faster. The FDA’s Critical Path Initiative, which started in 2004, gave a boost to these efforts by encouraging out-of-the-box thinking that is based on sound scientific rationale. At first, the shortening of early clinical development focused on Human Pharmacology (Phase I) studies. However, over the last few years, that focus has expanded to combine all of the early Human Pharmacology studies with Therapeutic Exploratory (Phase II) studies. This approach is known as an Accelerated Proof-of-Concept (AcPOC) study design.
The continued development of biomarkers and models that allow fast measurement of symptoms has also fueled the growth of the AcPOC design, as these factors are the key to attaining a measure of the proof-of-concept. A good example of this is in seasonal allergy studies where historically the trials had to be conducted during the allergy season and subjects assessed their own symptoms at home. A large number of patients are needed for this method because of the variability of the assessments. Now it’s possible to use Environmental Exposure Chambers (EECs) where the subjects can be exposed to the allergen in a carefully controlled environment at any time of year and patients’ symptoms or objective measures of the signs can be assessed by trained researchers. The greater flexibility in scheduling the studies, plus the reduced variability of the controlled environment, results in the need for fewer patients and makes it feasible to combine the Human Pharmacology studies with Therapeutic Exploratory studies conducted in the EEC. Similar benefits can be seen in many other study environments.
CP: Who benefits from these study designs?
GW: The AcPOC approach cutsin half the time it takes to go from first-in-human to proof-of-concept studies, so any organization looking to save time and money, while maintaining high standards of good clinical practice, can benefit. This approach can be used by any company that is developing a new therapy, whether the compound is a new chemical entity never before given to humans, a reformulation, or a new route of administration for an existing compound. If the compound requires a proof-of-concept study, then AcPOC designs can help.
CP: What therapeutic areas are AcPOC trials not appropriate for?
GW: We have conducted AcPOC trials across a large number of therapeutic areas, including potential treatments for allergy, diabetes, obesity, depression, dermatology and schizophrenia. However, while AcPOC designs are not limited to those indications, there are limitations. One of the key limiting factors is whether there is a biomarker or model that will quickly give an idea that the compound is working how it was designed. For example, if the only way to determine if a diabetes therapy is working is to administer the compound for four months and measure hemoglobin A1c levels, then it is not a therapeutic area amenable to an AcPOC study. However, since you can perform a glucose or insulin clamp study in diabetic patients, often with just one or a few doses given, AcPOC designs can be used extensively in diabetes research.
CP: What are some of the challenges associated with these trial designs?
GW: The first challenge is having the therapeutic and clinical pharmacology expertise to successfully design the studies. The AcPOC design will be different, not just for every therapeutic area, but for each target within the therapeutic area. An AcPOC design for an antihistamine being tested as an allergy treatment will be different than the AcPOC design for an inhaled steroid also being tested as an allergy treatment, since the two compounds act on different targets.
A second challenge is that the complexity of the designs requires the use of a clinic that has experience in both human pharmacology and therapeutic exploratory studies. There are many clinics that perform human pharmacology studies and many focused on bioequivalence or drug interaction studies. However, these clinics often do not have experience in recruiting patient populations, which is needed in many AcPOC designs. They may also lack experience in collecting efficacy measures. Alternatively, there are many clinics focused on therapeutic exploratory studies that have not completed many human pharmacology studies, where the compound is being given to humans for the first time. To maximize the savings and benefits of the AcPOC design, you need a clinic that has the right mix of experience.
CP: How does the protocol and the single format tie into various EDC systems?
GW: One critical component in performing AcPOC studies is having a method of quickly compiling the safety data so decisions can be made about the safety of the compound before proceeding to the needed dose. In a standard single ascending dose study, it is not difficult to compile the safety information quickly between cohorts. However, the volume of data increases substantially when the single ascending dose and multiple ascending dose cohorts are dosing at the same time. EDC systems, such as the electronic case report form (eCRF) system we use, allow the sponsor and the principal investigator to have online access to the data as it is entered. Also, since there are many logic checks performed as the data is entered into the eCRF, the data they have to review is cleaner compared to working off of paper CRFs.
CP: What services do you provide associated with AcPOC?
GW: Cetero Research is an early phase CRO with more than 25 years of experience in conducting human pharmacology and therapeutic exploratory studies. We have designed many AcPOC studies across a number of therapeutic areas, conducted the clinical portion, performed the data management, analyzed the bioanalytical and clinical laboratory samples, ran the biostatistics, as well as prepared the final clinical study report. Our approach is managed by experienced project managers who ensure that all of the parts of the studies flow together seamlessly. We have conducted AcPOC studies in a number of therapeutic areas, including allergy, diabetes, obesity, depression, dermatology and schizophrenia.
CP: What are some other study designs currently being explored in an effort to accelerate clinical trials?
GW: Using biomarkers in early studies is another way to accelerate clinical trials. In addition, adaptive trials are used in early and later development as they can allow for the halting of treatment arms based on futility or efficacy. There is also a strong focus on translational research, which looks at how to best model disorders in preclinical studies so that they resemble what is seen in the clinic. As a result, these studies have a greater relevance and can help determine go/no-go decisions. Many of these approaches, particularly the use of biomarkers, can be used in conjunction with the AcPOC study design to further leverage the significant time and cost savings of this model and accelerate the drug development process.
CP: Does AcPOC work with adaptive trial designs? Can the two study design models be combined?
GW: Yes, AcPOC study designs can work with adaptive trial designs. In fact, even when they are not part of an AcPOC design, the majority of first-in-human studies are adaptive since the upper dose levels given to participants are adapted based on the data from the lower dose levels. However, AcPOC designs can also be used with the more advanced adaptive studies that have preliminary analyses and predetermined criteria for discontinuing due to futility or efficacy. These types of adaptive designs can be built into the proof-of-concept portion of the AcPOC design and allow for further savings in time and money.
Kristin Brooks is associate editor at Contract Pharma. She can be reached at kbrooks@rodpub.com.
AcPOC trials cut development time
Contract Pharma
Accelerating clinical development from research to marketing is a big priority drug developers. There have been many advances with the use of technology, such as electronic data capture (EDC), exploring statistics through adaptive trial designs, and now Accelerated Proof-of-Concept (AcPOC). Contract research organizations (CROs) providing clinical research services now encompass strategies and methodologies to help achieve various gains. We spoke with Graham Wood, Ph.D., president of Clinical Operations at Cetero Research about AcPOC and the advancements this model has made in clinical drug development.–KB
Contract Pharma: What’s the history of AcPOC trials?
Graham Wood: For years, clinical researchers have been looking at ways to speed early clinical development and reach go/no-go decisions faster. The FDA’s Critical Path Initiative, which started in 2004, gave a boost to these efforts by encouraging out-of-the-box thinking that is based on sound scientific rationale. At first, the shortening of early clinical development focused on Human Pharmacology (Phase I) studies. However, over the last few years, that focus has expanded to combine all of the early Human Pharmacology studies with Therapeutic Exploratory (Phase II) studies. This approach is known as an Accelerated Proof-of-Concept (AcPOC) study design.
The continued development of biomarkers and models that allow fast measurement of symptoms has also fueled the growth of the AcPOC design, as these factors are the key to attaining a measure of the proof-of-concept. A good example of this is in seasonal allergy studies where historically the trials had to be conducted during the allergy season and subjects assessed their own symptoms at home. A large number of patients are needed for this method because of the variability of the assessments. Now it’s possible to use Environmental Exposure Chambers (EECs) where the subjects can be exposed to the allergen in a carefully controlled environment at any time of year and patients’ symptoms or objective measures of the signs can be assessed by trained researchers. The greater flexibility in scheduling the studies, plus the reduced variability of the controlled environment, results in the need for fewer patients and makes it feasible to combine the Human Pharmacology studies with Therapeutic Exploratory studies conducted in the EEC. Similar benefits can be seen in many other study environments.
CP: Who benefits from these study designs?
GW: The AcPOC approach cutsin half the time it takes to go from first-in-human to proof-of-concept studies, so any organization looking to save time and money, while maintaining high standards of good clinical practice, can benefit. This approach can be used by any company that is developing a new therapy, whether the compound is a new chemical entity never before given to humans, a reformulation, or a new route of administration for an existing compound. If the compound requires a proof-of-concept study, then AcPOC designs can help.
CP: What therapeutic areas are AcPOC trials not appropriate for?
GW: We have conducted AcPOC trials across a large number of therapeutic areas, including potential treatments for allergy, diabetes, obesity, depression, dermatology and schizophrenia. However, while AcPOC designs are not limited to those indications, there are limitations. One of the key limiting factors is whether there is a biomarker or model that will quickly give an idea that the compound is working how it was designed. For example, if the only way to determine if a diabetes therapy is working is to administer the compound for four months and measure hemoglobin A1c levels, then it is not a therapeutic area amenable to an AcPOC study. However, since you can perform a glucose or insulin clamp study in diabetic patients, often with just one or a few doses given, AcPOC designs can be used extensively in diabetes research.
CP: What are some of the challenges associated with these trial designs?
GW: The first challenge is having the therapeutic and clinical pharmacology expertise to successfully design the studies. The AcPOC design will be different, not just for every therapeutic area, but for each target within the therapeutic area. An AcPOC design for an antihistamine being tested as an allergy treatment will be different than the AcPOC design for an inhaled steroid also being tested as an allergy treatment, since the two compounds act on different targets.
A second challenge is that the complexity of the designs requires the use of a clinic that has experience in both human pharmacology and therapeutic exploratory studies. There are many clinics that perform human pharmacology studies and many focused on bioequivalence or drug interaction studies. However, these clinics often do not have experience in recruiting patient populations, which is needed in many AcPOC designs. They may also lack experience in collecting efficacy measures. Alternatively, there are many clinics focused on therapeutic exploratory studies that have not completed many human pharmacology studies, where the compound is being given to humans for the first time. To maximize the savings and benefits of the AcPOC design, you need a clinic that has the right mix of experience.
CP: How does the protocol and the single format tie into various EDC systems?
GW: One critical component in performing AcPOC studies is having a method of quickly compiling the safety data so decisions can be made about the safety of the compound before proceeding to the needed dose. In a standard single ascending dose study, it is not difficult to compile the safety information quickly between cohorts. However, the volume of data increases substantially when the single ascending dose and multiple ascending dose cohorts are dosing at the same time. EDC systems, such as the electronic case report form (eCRF) system we use, allow the sponsor and the principal investigator to have online access to the data as it is entered. Also, since there are many logic checks performed as the data is entered into the eCRF, the data they have to review is cleaner compared to working off of paper CRFs.
CP: What services do you provide associated with AcPOC?
GW: Cetero Research is an early phase CRO with more than 25 years of experience in conducting human pharmacology and therapeutic exploratory studies. We have designed many AcPOC studies across a number of therapeutic areas, conducted the clinical portion, performed the data management, analyzed the bioanalytical and clinical laboratory samples, ran the biostatistics, as well as prepared the final clinical study report. Our approach is managed by experienced project managers who ensure that all of the parts of the studies flow together seamlessly. We have conducted AcPOC studies in a number of therapeutic areas, including allergy, diabetes, obesity, depression, dermatology and schizophrenia.
CP: What are some other study designs currently being explored in an effort to accelerate clinical trials?
GW: Using biomarkers in early studies is another way to accelerate clinical trials. In addition, adaptive trials are used in early and later development as they can allow for the halting of treatment arms based on futility or efficacy. There is also a strong focus on translational research, which looks at how to best model disorders in preclinical studies so that they resemble what is seen in the clinic. As a result, these studies have a greater relevance and can help determine go/no-go decisions. Many of these approaches, particularly the use of biomarkers, can be used in conjunction with the AcPOC study design to further leverage the significant time and cost savings of this model and accelerate the drug development process.
CP: Does AcPOC work with adaptive trial designs? Can the two study design models be combined?
GW: Yes, AcPOC study designs can work with adaptive trial designs. In fact, even when they are not part of an AcPOC design, the majority of first-in-human studies are adaptive since the upper dose levels given to participants are adapted based on the data from the lower dose levels. However, AcPOC designs can also be used with the more advanced adaptive studies that have preliminary analyses and predetermined criteria for discontinuing due to futility or efficacy. These types of adaptive designs can be built into the proof-of-concept portion of the AcPOC design and allow for further savings in time and money.
Kristin Brooks is associate editor at Contract Pharma. She can be reached at kbrooks@rodpub.com.