Jessica Bylander

Clinical studies in support of premarket approval applications should ideally be randomized and blinded, the Food and Drug Administration maintains in recent guidance.

The FDA issued draft guidance for sponsors and staff Aug. 15 to help researchers and manufacturers design better quality clinical trials for device submissions.

The draft guidance spells out different clinical study designs that may be appropriate to support device approval, including the advantages and disadvantages of each.

But the FDA emphasized randomized, blinded (or masked) trials above all else, as other study designs may provide less-robust evidence and introduce bias.

These study designs, however, are generally the most expensive to carry out and difficult to enroll.

The FDA’s guidance acknowledges these studies might not be practical, feasible, or even ethical in all cases. In those situations, the onus is on the sponsor to justify why an alternative study design was chosen and how it will adequately control bias, the draft guidance emphasizes.

Some in the medical community have been critical of the relatively small proportion of premarket approval (PMA) pivotal trials that are randomized, controlled studies.

The guidelines apply mainly to PMA device trials, but could also inform the design of clinical trials for 510(k) devices, the FDA suggests.

FDA Wants the Gold Standard

Pivotal studies are meant to determine whether a new device is reasonably safe and effective, and whether the probable benefits outweigh the potential risks.

The FDA is addressing what specific factors go into its risk-benefit determinations in separate draft guidance also issued Aug. 15.

Comparative studies generally provide a higher level of evidence than single-arm trials, the clinical trials draft guidance explains.

Comparative trials may be parallel design, in which comparisons are made between groups treated with different therapies; paired, in which each subject receives all of the interventions or tests at the same time, such as with a "split-face" test where each side of the face is treated with a different device; or crossover, in which each subject receives two or more interventions at different, predetermined time points.

These study designs may be randomized or nonrandomized, but randomized, double-blinded, controlled studies are preferred, the FDA maintains.

The FDA recommends the device be compared with an active control, such as another effective therapy; or a placebo control, such as an ineffective device used in conditions that mimic the investigational device as much as possible.

"Deviation from this study design is especially problematic in situations where there is a possible placebo effect," the guidance notes.

Masking Trials

The FDA also prefers that pivotal trials be masked, or blinded, meaning participants in the trial have limited knowledge as to which intervention they were assigned.

"If study participants are not masked, it is very difficult to assess the size of the resulting bias, and it can threaten the scientific validity of an otherwise solid study, even when a truly objective end point is used," the guidance states.

If the trial subjects and investigators cannot be masked, the FDA strongly recommends that independent, third-party evaluators of the study measurements or end points be denied knowledge of the intervention assignment.

"Even if it is inconvenient or difficult, FDA recommends that masking be considered and attempted, if at all possible," the guidance notes.

But a range of other study options are available to sponsors who cannot conduct the ideal trial, the guidance clarifies.

In any case, the FDA strongly recommends that sponsors consult with the agency about trial design in a pre-submission meeting.

The sponsor’s investigational device exemption application should include not only the details of the proposed study design and why it was chosen, but also an explanation of alternative study designs that were considered and why they were deemed "inappropriate, impractical, or not possible," the guidance states.

This coverage is provided courtesy of "The Gray Sheet." This news organization and "The Gray Sheet" are owned by Elsevier.

Clinical studies in support of premarket approval applications should ideally be randomized and blinded, the Food and Drug Administration maintains in recent guidance.

The FDA issued draft guidance for sponsors and staff Aug. 15 to help researchers and manufacturers design better quality clinical trials for device submissions.

The draft guidance spells out different clinical study designs that may be appropriate to support device approval, including the advantages and disadvantages of each.

But the FDA emphasized randomized, blinded (or masked) trials above all else, as other study designs may provide less-robust evidence and introduce bias.

These study designs, however, are generally the most expensive to carry out and difficult to enroll.

The FDA’s guidance acknowledges these studies might not be practical, feasible, or even ethical in all cases. In those situations, the onus is on the sponsor to justify why an alternative study design was chosen and how it will adequately control bias, the draft guidance emphasizes.

Some in the medical community have been critical of the relatively small proportion of premarket approval (PMA) pivotal trials that are randomized, controlled studies.

The guidelines apply mainly to PMA device trials, but could also inform the design of clinical trials for 510(k) devices, the FDA suggests.

FDA Wants the Gold Standard

Pivotal studies are meant to determine whether a new device is reasonably safe and effective, and whether the probable benefits outweigh the potential risks.

The FDA is addressing what specific factors go into its risk-benefit determinations in separate draft guidance also issued Aug. 15.

Comparative studies generally provide a higher level of evidence than single-arm trials, the clinical trials draft guidance explains.

Comparative trials may be parallel design, in which comparisons are made between groups treated with different therapies; paired, in which each subject receives all of the interventions or tests at the same time, such as with a "split-face" test where each side of the face is treated with a different device; or crossover, in which each subject receives two or more interventions at different, predetermined time points.

These study designs may be randomized or nonrandomized, but randomized, double-blinded, controlled studies are preferred, the FDA maintains.

The FDA recommends the device be compared with an active control, such as another effective therapy; or a placebo control, such as an ineffective device used in conditions that mimic the investigational device as much as possible.

"Deviation from this study design is especially problematic in situations where there is a possible placebo effect," the guidance notes.

Masking Trials

The FDA also prefers that pivotal trials be masked, or blinded, meaning participants in the trial have limited knowledge as to which intervention they were assigned.

"If study participants are not masked, it is very difficult to assess the size of the resulting bias, and it can threaten the scientific validity of an otherwise solid study, even when a truly objective end point is used," the guidance states.

If the trial subjects and investigators cannot be masked, the FDA strongly recommends that independent, third-party evaluators of the study measurements or end points be denied knowledge of the intervention assignment.

"Even if it is inconvenient or difficult, FDA recommends that masking be considered and attempted, if at all possible," the guidance notes.

But a range of other study options are available to sponsors who cannot conduct the ideal trial, the guidance clarifies.

In any case, the FDA strongly recommends that sponsors consult with the agency about trial design in a pre-submission meeting.

The sponsor’s investigational device exemption application should include not only the details of the proposed study design and why it was chosen, but also an explanation of alternative study designs that were considered and why they were deemed "inappropriate, impractical, or not possible," the guidance states.

This coverage is provided courtesy of "The Gray Sheet." This news organization and "The Gray Sheet" are owned by Elsevier.

Clinical studies in support of premarket approval applications should ideally be randomized and blinded, the Food and Drug Administration maintains in recent guidance.

The FDA issued draft guidance for sponsors and staff Aug. 15 to help researchers and manufacturers design better quality clinical trials for device submissions.

The draft guidance spells out different clinical study designs that may be appropriate to support device approval, including the advantages and disadvantages of each.

But the FDA emphasized randomized, blinded (or masked) trials above all else, as other study designs may provide less-robust evidence and introduce bias.

These study designs, however, are generally the most expensive to carry out and difficult to enroll.

The FDA’s guidance acknowledges these studies might not be practical, feasible, or even ethical in all cases. In those situations, the onus is on the sponsor to justify why an alternative study design was chosen and how it will adequately control bias, the draft guidance emphasizes.

Some in the medical community have been critical of the relatively small proportion of premarket approval (PMA) pivotal trials that are randomized, controlled studies.

The guidelines apply mainly to PMA device trials, but could also inform the design of clinical trials for 510(k) devices, the FDA suggests.

FDA Wants the Gold Standard

Pivotal studies are meant to determine whether a new device is reasonably safe and effective, and whether the probable benefits outweigh the potential risks.

The FDA is addressing what specific factors go into its risk-benefit determinations in separate draft guidance also issued Aug. 15.

Comparative studies generally provide a higher level of evidence than single-arm trials, the clinical trials draft guidance explains.

Comparative trials may be parallel design, in which comparisons are made between groups treated with different therapies; paired, in which each subject receives all of the interventions or tests at the same time, such as with a "split-face" test where each side of the face is treated with a different device; or crossover, in which each subject receives two or more interventions at different, predetermined time points.

These study designs may be randomized or nonrandomized, but randomized, double-blinded, controlled studies are preferred, the FDA maintains.

The FDA recommends the device be compared with an active control, such as another effective therapy; or a placebo control, such as an ineffective device used in conditions that mimic the investigational device as much as possible.

"Deviation from this study design is especially problematic in situations where there is a possible placebo effect," the guidance notes.

Masking Trials

The FDA also prefers that pivotal trials be masked, or blinded, meaning participants in the trial have limited knowledge as to which intervention they were assigned.

"If study participants are not masked, it is very difficult to assess the size of the resulting bias, and it can threaten the scientific validity of an otherwise solid study, even when a truly objective end point is used," the guidance states.

If the trial subjects and investigators cannot be masked, the FDA strongly recommends that independent, third-party evaluators of the study measurements or end points be denied knowledge of the intervention assignment.

"Even if it is inconvenient or difficult, FDA recommends that masking be considered and attempted, if at all possible," the guidance notes.

But a range of other study options are available to sponsors who cannot conduct the ideal trial, the guidance clarifies.

In any case, the FDA strongly recommends that sponsors consult with the agency about trial design in a pre-submission meeting.

The sponsor’s investigational device exemption application should include not only the details of the proposed study design and why it was chosen, but also an explanation of alternative study designs that were considered and why they were deemed "inappropriate, impractical, or not possible," the guidance states.

This coverage is provided courtesy of "The Gray Sheet." This news organization and "The Gray Sheet" are owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic’s Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration on Feb. 11. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product’s safety and efficacy data by FDA’s Radiological Devices advisory panel last September.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Hologic's Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product's safety and efficacy data by the FDA's Radiological Devices advisory panel last September.

Hologic's Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product's safety and efficacy data by the FDA's Radiological Devices advisory panel last September.

Hologic's Selenia Dimensions digital breast tomosynthesis system (Dimensions 3-D) is the first three-dimensional mammography system to reach the U.S. market following premarket approval by the Food and Drug Administration. The low-dose x-ray device provides both 2-D and 3-D images of the breast for breast cancer screening and diagnosis.

Conventional 2-D mammography systems have limitations caused by overlapping tissue in the breast that may hide lesions or cause benign areas to appear suspicious, the company explained. Clinical trials of Dimensions 3-D showed significant gains in specificity and other benefits, including improved lesion and margin visibility and the ability to accurately localize structures in the breast, the firm noted.

The approval follows endorsement of the product's safety and efficacy data by the FDA's Radiological Devices advisory panel last September.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should conduct randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks disproportionate to the risk of the disease itself, according to the panel.

New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity. The FDA asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the panel noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, the panel said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Additionally, the panel did not reach consensus on the appropriate length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

Prostate disease is the second leading form of cancer among men in the United States, with 192,000 cases expected to be diagnosed this year. It is also the second leading cause of cancer deaths. The disease generally affects men older than the age of 60 years.

Jessica Bylander is with “The Gray Sheet,” which like this newspaper, is published by Elsevier.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should conduct randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks disproportionate to the risk of the disease itself, according to the panel.

New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity. The FDA asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the panel noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, the panel said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Additionally, the panel did not reach consensus on the appropriate length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

Prostate disease is the second leading form of cancer among men in the United States, with 192,000 cases expected to be diagnosed this year. It is also the second leading cause of cancer deaths. The disease generally affects men older than the age of 60 years.

Jessica Bylander is with “The Gray Sheet,” which like this newspaper, is published by Elsevier.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should conduct randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks disproportionate to the risk of the disease itself, according to the panel.

New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity. The FDA asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the panel noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, the panel said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Additionally, the panel did not reach consensus on the appropriate length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

Prostate disease is the second leading form of cancer among men in the United States, with 192,000 cases expected to be diagnosed this year. It is also the second leading cause of cancer deaths. The disease generally affects men older than the age of 60 years.

Jessica Bylander is with “The Gray Sheet,” which like this newspaper, is published by Elsevier.

Jessica Bylander is with “The Gray Sheet.” This publication and “The Gray Sheet” are published by Elsevier.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should include randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks that are disproportionate to the risk of the disease itself, according to the FDA. New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity, the FDA noted. It asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the FDA noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, panel members said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Nor did the panel reach consensus on the length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion when it met on Dec. 11, 2009.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

Jessica Bylander is with “The Gray Sheet.” This publication and “The Gray Sheet” are published by Elsevier.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should include randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks that are disproportionate to the risk of the disease itself, according to the FDA. New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity, the FDA noted. It asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the FDA noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, panel members said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Nor did the panel reach consensus on the length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion when it met on Dec. 11, 2009.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

Jessica Bylander is with “The Gray Sheet.” This publication and “The Gray Sheet” are published by Elsevier.

GAITHERSBURG, MD. — Developers of targeted prostate cancer treatments should include randomized clinical trials with “watchful waiting” as a control, according to the Food and Drug Administration's Gastroenterology and Urology Devices Panel.

Active surveillance may be an appropriate control for studies of whole-gland therapies that treat or remove the entire prostate, as well as for studies of targeted therapies in which only the known cancerous regions are treated (focal treatments); however, the panel reached consensus only on the focal-treatment study controls.

The primary end point for active surveillance studies would measure the impact of therapy on disease progression. Because prostate cancer progresses so slowly, survival rates are not a feasible end point, the panel said.

“A win in the active surveillance arm is not needing treatment, and a win in the treatment arm is [cancer] not recurring after treatment,” said panel member Dr. Peter Scardino of Memorial Sloan-Kettering Cancer Center in New York.

There is a growing interest in developing new, minimally invasive device therapies, as current treatments may pose risks that are disproportionate to the risk of the disease itself, according to the FDA. New treatment methods include high-intensity focused ultrasound, radiofrequency ablation, lasers, microwave devices, and photodynamic therapy.

Current prostate cancer treatments rely on the radical, whole-gland approach in which the entire prostate is removed or irradiated, and they are associated with significant morbidity, the FDA noted. It asked the panel whether nonrandomized study designs for new prostate cancer treatments could be considered, and to identify appropriate control groups, patient selection criteria, and effectiveness end points.

The panel agreed that randomized trials were necessary, despite the many challenges of conducting them, and that outcomes from focal treatments, at least, should be compared with outcomes from a watchful-waiting (or active surveillance) approach.

Few randomized studies comparing different prostate cancer treatment modalities have been completed, the FDA noted. The Southwest Oncology Group study of prostatectomy vs. external-beam radiation treatment, for example, was terminated after enrolling only 6 of 1,000 planned subjects.

According to Dr. Scardino, it would be easier to enroll patients in a trial with an active surveillance control. He pointed to non-U.S. randomized studies that were successfully completed by using an active surveillance control.

Quality of life measurements and complication rates are also important, panel members said, but they disagreed on which data elements to collect and whether quality of life should be a primary or secondary end point. Nor did the panel reach consensus on the length of follow-up for randomized studies.

Janine Morris, acting director of the Division of Reproductive, Abdominal, and Radiological Devices in the FDA's Center for Devices and Radiological Health, said that although the panel was able to answer the FDA's most important questions, she was disappointed that there was not time for further discussion when it met on Dec. 11, 2009.

“We will have to address this in another format,” such as another advisory panel meeting, a public workshop, or a meeting with industry stakeholders, she said in an interview. “We have unanswered questions.”

GAITHERSBURG, MD. — Jessica Bylander is a reporter for The Gray Sheet. This newspaper and The Gray Sheet are published by Elsevier. Catherine Hackett contributed to this report.

Randomized clinical trials are needed to allow blood filtration devices to be labeled for heart failure treatment, a Food and Drug Administration advisory panel said.

The trials should include 1-year patient follow-up to demonstrate the safety and efficacy of blood filtration to treat acute decompensated heart failure by removing excess body fluid, the FDA's gastroenterology and urology devices panel recommended.

Primary end points should include safety, quality of life, and rehospitalization, while mortality should be a secondary end point, the advisory panel recommended.

Ultrafiltration is a promising new treatment for the disease, most likely as a second-line therapy, panel chair Dr. Clyde Yancy, medical director of the Baylor Heart and Vascular Institute at Baylor University in Dallas, said at the meeting. However, “we need more data; we need new data; we need prospective data for any device to get a heart failure label. We're not there yet,” he said.

The panel agreed that there is a need for new heart failure treatments, but “you do need comparative data” in order to put the therapy “in the context of available strategies,” said panelist Dr. Jeffrey Borer, chief of cardiovascular medicine at the State University of New York's Downstate Medical Center in Brooklyn.

Fluid overload is a symptom of a variety of conditions, the FDA noted, including acute or chronic heart failure, kidney failure, and liver failure.

The agency has cleared several devices and accessories to achieve fluid removal through blood ultrafiltration, a process that removes excess water and solutes from a patient's blood. But the FDA has not yet reviewed such products for disease- or population-specific indications.

Ultrafiltration products—including dialysis systems and components—generally are cleared for marketing as class II devices, supported by technical data, bench studies, and the occasional clinical trial, according to the FDA.

However, the agency asked the panel to define what level of clinical evidence would be necessary to allow heart failure labeling for ultrafiltration devices, having noted an increase in research and promotion of ultrafiltration for treating the condition.

The largest trial to date on the treatment is the Ultrafiltration vs. IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, reported in 2006. It showed greater weight and fluid loss and reduced rehospitalizations with ultrafiltration, compared with treatment with loop diuretics, but not greater symptom relief.

There currently is no standard for the amount of fluid removal necessary to achieve positive outcomes for the various conditions, even with diuretic drugs, which are the current standard of care for medical management of fluid overload.

The panel agreed that the use of ultrafiltration as an adjunct or alternative heart failure therapy is not supported by evidence, but that its use as a tool to treat fluid overload in an inpatient setting is reasonable once standard medical care options are exhausted. The panel emphasized that there are no data from randomized controlled studies demonstrating ultrafiltration is safe and effective for first-line therapy in the treatment of heart failure.

Continuous renal replacement therapy and conventional dialysis systems that can perform ultrafiltration are available from several manufacturers. Only one system has been cleared as an isolated ultrafiltration system—CHF Solutions' Aquadex Flexflow. Isolated ultrafiltration systems are simpler and more portable, though less versatile, the FDA noted.

Unlike the other products, however, Aquadex is indicated for treating fluid overload in patients who have failed diuretic therapy.

GAITHERSBURG, MD. — Jessica Bylander is a reporter for The Gray Sheet. This newspaper and The Gray Sheet are published by Elsevier. Catherine Hackett contributed to this report.

Randomized clinical trials are needed to allow blood filtration devices to be labeled for heart failure treatment, a Food and Drug Administration advisory panel said.

The trials should include 1-year patient follow-up to demonstrate the safety and efficacy of blood filtration to treat acute decompensated heart failure by removing excess body fluid, the FDA's gastroenterology and urology devices panel recommended.

Primary end points should include safety, quality of life, and rehospitalization, while mortality should be a secondary end point, the advisory panel recommended.

Ultrafiltration is a promising new treatment for the disease, most likely as a second-line therapy, panel chair Dr. Clyde Yancy, medical director of the Baylor Heart and Vascular Institute at Baylor University in Dallas, said at the meeting. However, “we need more data; we need new data; we need prospective data for any device to get a heart failure label. We're not there yet,” he said.

The panel agreed that there is a need for new heart failure treatments, but “you do need comparative data” in order to put the therapy “in the context of available strategies,” said panelist Dr. Jeffrey Borer, chief of cardiovascular medicine at the State University of New York's Downstate Medical Center in Brooklyn.

Fluid overload is a symptom of a variety of conditions, the FDA noted, including acute or chronic heart failure, kidney failure, and liver failure.

The agency has cleared several devices and accessories to achieve fluid removal through blood ultrafiltration, a process that removes excess water and solutes from a patient's blood. But the FDA has not yet reviewed such products for disease- or population-specific indications.

Ultrafiltration products—including dialysis systems and components—generally are cleared for marketing as class II devices, supported by technical data, bench studies, and the occasional clinical trial, according to the FDA.

However, the agency asked the panel to define what level of clinical evidence would be necessary to allow heart failure labeling for ultrafiltration devices, having noted an increase in research and promotion of ultrafiltration for treating the condition.

The largest trial to date on the treatment is the Ultrafiltration vs. IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, reported in 2006. It showed greater weight and fluid loss and reduced rehospitalizations with ultrafiltration, compared with treatment with loop diuretics, but not greater symptom relief.

There currently is no standard for the amount of fluid removal necessary to achieve positive outcomes for the various conditions, even with diuretic drugs, which are the current standard of care for medical management of fluid overload.

The panel agreed that the use of ultrafiltration as an adjunct or alternative heart failure therapy is not supported by evidence, but that its use as a tool to treat fluid overload in an inpatient setting is reasonable once standard medical care options are exhausted. The panel emphasized that there are no data from randomized controlled studies demonstrating ultrafiltration is safe and effective for first-line therapy in the treatment of heart failure.

Continuous renal replacement therapy and conventional dialysis systems that can perform ultrafiltration are available from several manufacturers. Only one system has been cleared as an isolated ultrafiltration system—CHF Solutions' Aquadex Flexflow. Isolated ultrafiltration systems are simpler and more portable, though less versatile, the FDA noted.

Unlike the other products, however, Aquadex is indicated for treating fluid overload in patients who have failed diuretic therapy.

GAITHERSBURG, MD. — Jessica Bylander is a reporter for The Gray Sheet. This newspaper and The Gray Sheet are published by Elsevier. Catherine Hackett contributed to this report.

Randomized clinical trials are needed to allow blood filtration devices to be labeled for heart failure treatment, a Food and Drug Administration advisory panel said.

The trials should include 1-year patient follow-up to demonstrate the safety and efficacy of blood filtration to treat acute decompensated heart failure by removing excess body fluid, the FDA's gastroenterology and urology devices panel recommended.

Primary end points should include safety, quality of life, and rehospitalization, while mortality should be a secondary end point, the advisory panel recommended.

Ultrafiltration is a promising new treatment for the disease, most likely as a second-line therapy, panel chair Dr. Clyde Yancy, medical director of the Baylor Heart and Vascular Institute at Baylor University in Dallas, said at the meeting. However, “we need more data; we need new data; we need prospective data for any device to get a heart failure label. We're not there yet,” he said.

The panel agreed that there is a need for new heart failure treatments, but “you do need comparative data” in order to put the therapy “in the context of available strategies,” said panelist Dr. Jeffrey Borer, chief of cardiovascular medicine at the State University of New York's Downstate Medical Center in Brooklyn.

Fluid overload is a symptom of a variety of conditions, the FDA noted, including acute or chronic heart failure, kidney failure, and liver failure.

The agency has cleared several devices and accessories to achieve fluid removal through blood ultrafiltration, a process that removes excess water and solutes from a patient's blood. But the FDA has not yet reviewed such products for disease- or population-specific indications.

Ultrafiltration products—including dialysis systems and components—generally are cleared for marketing as class II devices, supported by technical data, bench studies, and the occasional clinical trial, according to the FDA.

However, the agency asked the panel to define what level of clinical evidence would be necessary to allow heart failure labeling for ultrafiltration devices, having noted an increase in research and promotion of ultrafiltration for treating the condition.

The largest trial to date on the treatment is the Ultrafiltration vs. IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, reported in 2006. It showed greater weight and fluid loss and reduced rehospitalizations with ultrafiltration, compared with treatment with loop diuretics, but not greater symptom relief.

There currently is no standard for the amount of fluid removal necessary to achieve positive outcomes for the various conditions, even with diuretic drugs, which are the current standard of care for medical management of fluid overload.

The panel agreed that the use of ultrafiltration as an adjunct or alternative heart failure therapy is not supported by evidence, but that its use as a tool to treat fluid overload in an inpatient setting is reasonable once standard medical care options are exhausted. The panel emphasized that there are no data from randomized controlled studies demonstrating ultrafiltration is safe and effective for first-line therapy in the treatment of heart failure.

Continuous renal replacement therapy and conventional dialysis systems that can perform ultrafiltration are available from several manufacturers. Only one system has been cleared as an isolated ultrafiltration system—CHF Solutions' Aquadex Flexflow. Isolated ultrafiltration systems are simpler and more portable, though less versatile, the FDA noted.

Unlike the other products, however, Aquadex is indicated for treating fluid overload in patients who have failed diuretic therapy.