Background: ESBL-producing gram-negative bacilli are becoming increasingly common. Carbapenems are considered the treatment of choice for these infections, but they may in turn select for carbapenem-­resistant gram-negative bacilli.

The primary outcome was all-cause mortality at 30 days after randomization. The study was stopped early because of a significant mortality difference between the two groups (12.3% in the piperacillin/tazobactam group versus 3.7% in the meropenem group).

The overall mortality rate was lower than expected. The sickest patients may have been excluded because the treating physician needed to approve enrollment. Because of the necessity for empiric antibiotic therapy, there was substantial crossover in antibiotics between the groups, although this would have biased the study toward noninferiority.

Bottom line: For patients with ESBL E. coli or K. pneumoniae blood stream infections, treatment with piperacillin/tazobactam was inferior to meropenem for 30-day mortality.

Citation: Harris PNA et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: A randomized clinical trial. JAMA. 2018;320(10):984-94.

Dr. Gabriel is assistant professor of medicine and director of Preoperative Medicine and Medicine Consult Service in the division of hospital medicine at Mount Sinai Hospital, New York.

Background: ESBL-producing gram-negative bacilli are becoming increasingly common. Carbapenems are considered the treatment of choice for these infections, but they may in turn select for carbapenem-­resistant gram-negative bacilli.

The primary outcome was all-cause mortality at 30 days after randomization. The study was stopped early because of a significant mortality difference between the two groups (12.3% in the piperacillin/tazobactam group versus 3.7% in the meropenem group).

The overall mortality rate was lower than expected. The sickest patients may have been excluded because the treating physician needed to approve enrollment. Because of the necessity for empiric antibiotic therapy, there was substantial crossover in antibiotics between the groups, although this would have biased the study toward noninferiority.

Bottom line: For patients with ESBL E. coli or K. pneumoniae blood stream infections, treatment with piperacillin/tazobactam was inferior to meropenem for 30-day mortality.

Citation: Harris PNA et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: A randomized clinical trial. JAMA. 2018;320(10):984-94.

Dr. Gabriel is assistant professor of medicine and director of Preoperative Medicine and Medicine Consult Service in the division of hospital medicine at Mount Sinai Hospital, New York.

Background: ESBL-producing gram-negative bacilli are becoming increasingly common. Carbapenems are considered the treatment of choice for these infections, but they may in turn select for carbapenem-­resistant gram-negative bacilli.

The primary outcome was all-cause mortality at 30 days after randomization. The study was stopped early because of a significant mortality difference between the two groups (12.3% in the piperacillin/tazobactam group versus 3.7% in the meropenem group).

The overall mortality rate was lower than expected. The sickest patients may have been excluded because the treating physician needed to approve enrollment. Because of the necessity for empiric antibiotic therapy, there was substantial crossover in antibiotics between the groups, although this would have biased the study toward noninferiority.

Bottom line: For patients with ESBL E. coli or K. pneumoniae blood stream infections, treatment with piperacillin/tazobactam was inferior to meropenem for 30-day mortality.

Citation: Harris PNA et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: A randomized clinical trial. JAMA. 2018;320(10):984-94.

Dr. Gabriel is assistant professor of medicine and director of Preoperative Medicine and Medicine Consult Service in the division of hospital medicine at Mount Sinai Hospital, New York.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

As a first-year gastroenterology fellow, banding my first patient with a variceal bleed was an exciting – but also stress-provoking – event. What if I banded incorrectly and caused more bleeding? With a successful band, a patient’s hemorrhagic shock is now controlled, hemodynamics improved, and euphoria takes over. Now, in my third year of a gastroenterology fellowship but my first year of the American Gastroenterological Association (AGA) Editorial Fellowship, preparing to present the first manuscript that I handled to the Board of Editors at our weekly meeting has now induced the same excitement and need for the same level of dedication. Have I researched the foundational literature that this current manuscript was built on? What is the trajectory of this research and will this project be interesting to our readers and lead to breakthroughs in the field?

Gastroenterology is the premier flagship journal of the AGA and, in this Editorial Fellowship, I was selected to spend a fully immersive 1-year experience working on all aspects of this journal. In its second year of inception, I echo Dr. Eric Shah’s insight into the transformative and immersive nature of this fellowship.¹ In this role, I have made three developments, and each one has left me with a valuable lesson.

Mentorship

My first development was as a direct mentee under the leadership of the two editors in chief Richard Peek, MD, and Douglas Corley, MD, and associate editor John Inadomi, MD. In this role, I reviewed submitted manuscripts regarding outcome data of oncologic studies in the fields of colon, esophageal, and gastric cancer. I served as a reviewer for submitted manuscripts and discussed the impact, novelty, and decision for publication with the Board of Editors. In our weekly meetings, the associate editors discussed manuscripts that needed further review prior to acceptance, revision, or rejection. A few themes underpinned the discussion of these manuscripts:

• Is this science reproducible and is there scientific rigor for study design, validity, and analysis?
• How does this manuscript add to the current state of the literature?
• What is the trajectory of this research field?
• How will this manuscript lead to breakthroughs in this field?
• Are the advancements in this manuscript likely to lead to paradigm shifts in the field in its approach, design, or findings?

I also was fortunate to meet leaders in the field, including working daily in person with multiple members of the Board of Editors at Vanderbilt University Medical Center, Nashville, Tenn., as well as visiting professors, including Dr. Corley, Linda Rabeneck, MD, and T. Jake Liang, MD, who not only spoke on their scientific inquiries but also about their transitional path from gastroenterology fellows to pioneers in their respective fields. From these lessons, I have learned the scientific rigor of manuscript review for Gastroenterology and how to approach modern challenges in our field to directly improve patient care.
 

AGA’s commitment to early-career investigators

The Editorial Fellowship allowed me to expand a traditional third-year gastroenterology fellowship to dive deep into the intense path to get a manuscript published in Gastroenterology. Whereas 1 year prior, I had found dilating a complete esophageal stricture difficult, I now found myself learning to master clinical trial design, applying modern techniques of artificial intelligence, understanding organoid development, and navigating the impact of the microbiome. I was fortunate to be selected for Vanderbilt’s Master’s in Science in Clinical Investigation, which allowed me to apply my education not only to my own research but also to synergistically understand and deconstruct new submissions ranging from modern statistics with Bayesian modeling to analysis of large genetic data. All of this was built in the supportive framework of my mentoring committee.

As a fellow, I am inspired to see the multicenter, international collaboration to answer important questions in our field. Leveraging large databases and the expertise of multiple investigators, breakthroughs were made because of the collaborative nature of the science. This also was felt in the review process, where experts generously reviewed manuscripts to enhance the quality of the submission in order to advance knowledge in the field. Reading hundreds of these reviews this year has allowed me to refocus my current research studies and improve the way I write my current reviews. In the spirit of reproducible science and challenging the precision of study design, I was impressed by the time, effort, and dedication reviewers from our field spent to help improve the literature. Dr. Peek and Dr. Corley, our editors in chief, committed their time in discussing my innovations and critiques and displayed their level of interest in the opinions of early-career investigators and fostering the next generation of scientists and practitioners. In this lesson, I was invigorated by the depth of AGA opportunities for fellows and junior faculty in education, research, and involvement.
 

Self-reflection

Having the honor and privilege to review manuscripts upon submission also increased my critical view of my current practices. I now question the level of evidence for which current patient care practices are based, which allows me to better understand the research areas that need increased attention to improve the quality of our guidelines and evidence. For motivated fellows interested in a path of academic medicine, I would strongly advise applying for this prestigious fellowship. In no other training process could I have learned such a breadth of scientific skills and directly apply them to my patient care, my research, and my role as an educator. Furthermore, I was able to contribute to the reviewing and editing process, which allowed me to directly contribute to the field at an early stage of my career. In this final lesson, I exit this impactful Editorial Fellowship in self-reflection. I leave this fellowship humbled – by you – the reader who continues to learn to improve your patient care, the scientist as she works tirelessly to answer questions and contribute to the literature, the gastroenterology community for their willingness to teach and mentor fellows and early-career investigators and practitioners, and the patients who remind us that we all have a shared mission to advance scientific knowledge to improve patient care.

Dr. Naik is a gastroenterology fellow in the department of gastroenterology and hepatology at Vanderbilt University Medical Center in Nashville, Tenn.

Reference

1. Shah ED. Skills acquired during my 1-year AGA Editorial Fellowship. Gastroenterology. 2018;154(6):1563.

As a first-year gastroenterology fellow, banding my first patient with a variceal bleed was an exciting – but also stress-provoking – event. What if I banded incorrectly and caused more bleeding? With a successful band, a patient’s hemorrhagic shock is now controlled, hemodynamics improved, and euphoria takes over. Now, in my third year of a gastroenterology fellowship but my first year of the American Gastroenterological Association (AGA) Editorial Fellowship, preparing to present the first manuscript that I handled to the Board of Editors at our weekly meeting has now induced the same excitement and need for the same level of dedication. Have I researched the foundational literature that this current manuscript was built on? What is the trajectory of this research and will this project be interesting to our readers and lead to breakthroughs in the field?

Gastroenterology is the premier flagship journal of the AGA and, in this Editorial Fellowship, I was selected to spend a fully immersive 1-year experience working on all aspects of this journal. In its second year of inception, I echo Dr. Eric Shah’s insight into the transformative and immersive nature of this fellowship.¹ In this role, I have made three developments, and each one has left me with a valuable lesson.

Mentorship

My first development was as a direct mentee under the leadership of the two editors in chief Richard Peek, MD, and Douglas Corley, MD, and associate editor John Inadomi, MD. In this role, I reviewed submitted manuscripts regarding outcome data of oncologic studies in the fields of colon, esophageal, and gastric cancer. I served as a reviewer for submitted manuscripts and discussed the impact, novelty, and decision for publication with the Board of Editors. In our weekly meetings, the associate editors discussed manuscripts that needed further review prior to acceptance, revision, or rejection. A few themes underpinned the discussion of these manuscripts:

• Is this science reproducible and is there scientific rigor for study design, validity, and analysis?
• How does this manuscript add to the current state of the literature?
• What is the trajectory of this research field?
• How will this manuscript lead to breakthroughs in this field?
• Are the advancements in this manuscript likely to lead to paradigm shifts in the field in its approach, design, or findings?

I also was fortunate to meet leaders in the field, including working daily in person with multiple members of the Board of Editors at Vanderbilt University Medical Center, Nashville, Tenn., as well as visiting professors, including Dr. Corley, Linda Rabeneck, MD, and T. Jake Liang, MD, who not only spoke on their scientific inquiries but also about their transitional path from gastroenterology fellows to pioneers in their respective fields. From these lessons, I have learned the scientific rigor of manuscript review for Gastroenterology and how to approach modern challenges in our field to directly improve patient care.
 

AGA’s commitment to early-career investigators

The Editorial Fellowship allowed me to expand a traditional third-year gastroenterology fellowship to dive deep into the intense path to get a manuscript published in Gastroenterology. Whereas 1 year prior, I had found dilating a complete esophageal stricture difficult, I now found myself learning to master clinical trial design, applying modern techniques of artificial intelligence, understanding organoid development, and navigating the impact of the microbiome. I was fortunate to be selected for Vanderbilt’s Master’s in Science in Clinical Investigation, which allowed me to apply my education not only to my own research but also to synergistically understand and deconstruct new submissions ranging from modern statistics with Bayesian modeling to analysis of large genetic data. All of this was built in the supportive framework of my mentoring committee.

As a fellow, I am inspired to see the multicenter, international collaboration to answer important questions in our field. Leveraging large databases and the expertise of multiple investigators, breakthroughs were made because of the collaborative nature of the science. This also was felt in the review process, where experts generously reviewed manuscripts to enhance the quality of the submission in order to advance knowledge in the field. Reading hundreds of these reviews this year has allowed me to refocus my current research studies and improve the way I write my current reviews. In the spirit of reproducible science and challenging the precision of study design, I was impressed by the time, effort, and dedication reviewers from our field spent to help improve the literature. Dr. Peek and Dr. Corley, our editors in chief, committed their time in discussing my innovations and critiques and displayed their level of interest in the opinions of early-career investigators and fostering the next generation of scientists and practitioners. In this lesson, I was invigorated by the depth of AGA opportunities for fellows and junior faculty in education, research, and involvement.
 

Self-reflection

Having the honor and privilege to review manuscripts upon submission also increased my critical view of my current practices. I now question the level of evidence for which current patient care practices are based, which allows me to better understand the research areas that need increased attention to improve the quality of our guidelines and evidence. For motivated fellows interested in a path of academic medicine, I would strongly advise applying for this prestigious fellowship. In no other training process could I have learned such a breadth of scientific skills and directly apply them to my patient care, my research, and my role as an educator. Furthermore, I was able to contribute to the reviewing and editing process, which allowed me to directly contribute to the field at an early stage of my career. In this final lesson, I exit this impactful Editorial Fellowship in self-reflection. I leave this fellowship humbled – by you – the reader who continues to learn to improve your patient care, the scientist as she works tirelessly to answer questions and contribute to the literature, the gastroenterology community for their willingness to teach and mentor fellows and early-career investigators and practitioners, and the patients who remind us that we all have a shared mission to advance scientific knowledge to improve patient care.

Dr. Naik is a gastroenterology fellow in the department of gastroenterology and hepatology at Vanderbilt University Medical Center in Nashville, Tenn.

Reference

1. Shah ED. Skills acquired during my 1-year AGA Editorial Fellowship. Gastroenterology. 2018;154(6):1563.

As a first-year gastroenterology fellow, banding my first patient with a variceal bleed was an exciting – but also stress-provoking – event. What if I banded incorrectly and caused more bleeding? With a successful band, a patient’s hemorrhagic shock is now controlled, hemodynamics improved, and euphoria takes over. Now, in my third year of a gastroenterology fellowship but my first year of the American Gastroenterological Association (AGA) Editorial Fellowship, preparing to present the first manuscript that I handled to the Board of Editors at our weekly meeting has now induced the same excitement and need for the same level of dedication. Have I researched the foundational literature that this current manuscript was built on? What is the trajectory of this research and will this project be interesting to our readers and lead to breakthroughs in the field?

Gastroenterology is the premier flagship journal of the AGA and, in this Editorial Fellowship, I was selected to spend a fully immersive 1-year experience working on all aspects of this journal. In its second year of inception, I echo Dr. Eric Shah’s insight into the transformative and immersive nature of this fellowship.¹ In this role, I have made three developments, and each one has left me with a valuable lesson.

Mentorship

My first development was as a direct mentee under the leadership of the two editors in chief Richard Peek, MD, and Douglas Corley, MD, and associate editor John Inadomi, MD. In this role, I reviewed submitted manuscripts regarding outcome data of oncologic studies in the fields of colon, esophageal, and gastric cancer. I served as a reviewer for submitted manuscripts and discussed the impact, novelty, and decision for publication with the Board of Editors. In our weekly meetings, the associate editors discussed manuscripts that needed further review prior to acceptance, revision, or rejection. A few themes underpinned the discussion of these manuscripts:

• Is this science reproducible and is there scientific rigor for study design, validity, and analysis?
• How does this manuscript add to the current state of the literature?
• What is the trajectory of this research field?
• How will this manuscript lead to breakthroughs in this field?
• Are the advancements in this manuscript likely to lead to paradigm shifts in the field in its approach, design, or findings?

I also was fortunate to meet leaders in the field, including working daily in person with multiple members of the Board of Editors at Vanderbilt University Medical Center, Nashville, Tenn., as well as visiting professors, including Dr. Corley, Linda Rabeneck, MD, and T. Jake Liang, MD, who not only spoke on their scientific inquiries but also about their transitional path from gastroenterology fellows to pioneers in their respective fields. From these lessons, I have learned the scientific rigor of manuscript review for Gastroenterology and how to approach modern challenges in our field to directly improve patient care.
 

AGA’s commitment to early-career investigators

The Editorial Fellowship allowed me to expand a traditional third-year gastroenterology fellowship to dive deep into the intense path to get a manuscript published in Gastroenterology. Whereas 1 year prior, I had found dilating a complete esophageal stricture difficult, I now found myself learning to master clinical trial design, applying modern techniques of artificial intelligence, understanding organoid development, and navigating the impact of the microbiome. I was fortunate to be selected for Vanderbilt’s Master’s in Science in Clinical Investigation, which allowed me to apply my education not only to my own research but also to synergistically understand and deconstruct new submissions ranging from modern statistics with Bayesian modeling to analysis of large genetic data. All of this was built in the supportive framework of my mentoring committee.

As a fellow, I am inspired to see the multicenter, international collaboration to answer important questions in our field. Leveraging large databases and the expertise of multiple investigators, breakthroughs were made because of the collaborative nature of the science. This also was felt in the review process, where experts generously reviewed manuscripts to enhance the quality of the submission in order to advance knowledge in the field. Reading hundreds of these reviews this year has allowed me to refocus my current research studies and improve the way I write my current reviews. In the spirit of reproducible science and challenging the precision of study design, I was impressed by the time, effort, and dedication reviewers from our field spent to help improve the literature. Dr. Peek and Dr. Corley, our editors in chief, committed their time in discussing my innovations and critiques and displayed their level of interest in the opinions of early-career investigators and fostering the next generation of scientists and practitioners. In this lesson, I was invigorated by the depth of AGA opportunities for fellows and junior faculty in education, research, and involvement.
 

Self-reflection

Having the honor and privilege to review manuscripts upon submission also increased my critical view of my current practices. I now question the level of evidence for which current patient care practices are based, which allows me to better understand the research areas that need increased attention to improve the quality of our guidelines and evidence. For motivated fellows interested in a path of academic medicine, I would strongly advise applying for this prestigious fellowship. In no other training process could I have learned such a breadth of scientific skills and directly apply them to my patient care, my research, and my role as an educator. Furthermore, I was able to contribute to the reviewing and editing process, which allowed me to directly contribute to the field at an early stage of my career. In this final lesson, I exit this impactful Editorial Fellowship in self-reflection. I leave this fellowship humbled – by you – the reader who continues to learn to improve your patient care, the scientist as she works tirelessly to answer questions and contribute to the literature, the gastroenterology community for their willingness to teach and mentor fellows and early-career investigators and practitioners, and the patients who remind us that we all have a shared mission to advance scientific knowledge to improve patient care.

Dr. Naik is a gastroenterology fellow in the department of gastroenterology and hepatology at Vanderbilt University Medical Center in Nashville, Tenn.

Reference

1. Shah ED. Skills acquired during my 1-year AGA Editorial Fellowship. Gastroenterology. 2018;154(6):1563.

As medical professionals, you may have encountered patients with serious illnesses and asked yourself the following questions: What if I was in that situation? Where will my assets go when I die? What will happen to my loved ones, and will they be taken care of? Who would handle my affairs if I became ill? These important questions can only be addressed through effective estate planning.

Everyone needs an estate plan regardless of age, health, and financial or family situation. An effective estate plan provides for the orderly management and disposition of your assets upon your death. In addition, as medical professionals may appreciate, an effective estate plan appoints individuals to manage your financial affairs and make health care decisions for you in the event that you become physically or mentally incapacitated.

The most common estate planning tool is a will, which dictates how your assets pass at death. In addition, a will identifies the personal representative of your estate (that is, the person who will see that your assets pass in accordance with your wishes) and, in many states, identifies the guardian of any minor children. Although a court will make the ultimate determination of who is appointed as the guardian, courts typically give significant weight to the person named in a will.

If you die “intestate,” meaning that you died without a valid will, your assets will be distributed in accordance with your state’s intestacy statutes, and any interested person (as opposed to the individual of your choice) may be appointed as the personal representative of your estate. Therefore, to ensure that your property goes to the individuals of your choice and that your final affairs are handled by the person you trust, a will is essential.

In many states, a revocable living trust can be equally beneficial. Like a will, a revocable living trust will dictate how your property passes at death and appoints a trustee to see that the property is distributed in accordance with your wishes. Revocable living trusts can be great tools for incapacity planning and, unlike a will, are not required to be recorded, so the trust agreement can remain private. The assets that are held in a revocable living trust also avoid the often lengthy and expensive probate process, which generally includes the preparation and filing of a petition to open the estate, an inventory identifying the assets of the estate, and an accounting that details all assets received and distributed, followed by the payment of fees based upon the value of the probate estate.

In many situations, leaving assets to young, disabled, or troubled children would result in catastrophic consequences, such as disqualification for government benefits, dissipation of assets for inappropriate uses, or attachment by creditors. Further, for wealthy individuals, outright distributions to spouses could lead to unnecessary estate tax. Wills and revocable trusts can protect against these issues by requiring that, at death, the decedent’s assets are held in further trust for these individuals.

There are various types of trusts that can help ensure that your assets are used for the benefit of your loved one while avoiding any unintended consequences, some of which include the following:

• Special needs trusts, which allow the trustee to use the trust funds for the benefit of the disabled beneficiary without disqualifying the beneficiary from important government benefits.
• Spendthrift trusts, which can protect the trust assets from claims of creditors or property division in a divorce action.
• Marital trusts, which can be used to reduce taxes and ensure that property will be distributed pursuant to your wishes upon the death of your spouse.
• Dynasty trusts, which can be used to protect assets for many generations and, in doing so, reduce the amount of federal and state transfer taxes.

Whether you use a will or revocable living trust, it is critical to coordinate the beneficiary designations of assets such as retirement accounts and life insurance policies, as well as any other account that passes by beneficiary designation. These beneficiary designations trump the provisions of your will and revocable living trust. Likewise, property owned jointly with another person as joint tenants with the right of survivorship, or with a spouse as tenants by the entirety, will pass directly to the joint owner and not pursuant to the terms of your will or revocable trust.

An effective estate plan involves not just planning for death, but also for your incapacity. A durable power of attorney allows you to select an agent or agents to manage your property during your lifetime. The power of attorney can become effective immediately so that the agent can act on your behalf upon execution of the document or the power of attorney can become effective only if and when you become incapacitated.

A durable power of attorney for health care (or advance health care directive) permits you to appoint an agent to make health care decisions on your behalf in the event that you cannot make your own decisions. In addition, should you become permanently unconscious or in a terminal condition, it permits you to appoint an agent who can withhold or withdraw life-sustaining treatment. With a living will, you can express in writing the circumstances under which you do or do not want artificial life-sustaining measures.

With respect to these powers of attorney, the persons that you appoint as your agents should be people that you trust. It is also important to have conversations with your designated agents to ensure that they understand their responsibilities and your wishes. Without these powers of attorney, in the event of your incapacitation, a court will appoint a guardian. The guardian may not be the person you would have appointed, and it will result in annual, and burdensome, court filings.

As busy medical professionals, it may be difficult to find time to develop an estate plan and you may believe that there is plenty of time to do it in the future. It is important to begin thinking about your estate-planning goals and to speak with an attorney to help develop and draft your estate-planning documents. If you already have estate-planning documents, it is important to review those documents periodically to ensure that your estate-planning objectives have remained the same and, if they have changed, to update your documents.

No one knows what the future will hold, so it is important to consult with a local attorney to establish or review your estate plan now. If you do, you will be comforted by the fact that you and your loved ones will be taken care of in accordance with your wishes if you are unable to do so in the future.
 

Mr. D’Emilio is a managing member and Mr. Riley is an associate at McCollom D’Emilio Smith Uebler, Wilmington, Del.

As medical professionals, you may have encountered patients with serious illnesses and asked yourself the following questions: What if I was in that situation? Where will my assets go when I die? What will happen to my loved ones, and will they be taken care of? Who would handle my affairs if I became ill? These important questions can only be addressed through effective estate planning.

Everyone needs an estate plan regardless of age, health, and financial or family situation. An effective estate plan provides for the orderly management and disposition of your assets upon your death. In addition, as medical professionals may appreciate, an effective estate plan appoints individuals to manage your financial affairs and make health care decisions for you in the event that you become physically or mentally incapacitated.

The most common estate planning tool is a will, which dictates how your assets pass at death. In addition, a will identifies the personal representative of your estate (that is, the person who will see that your assets pass in accordance with your wishes) and, in many states, identifies the guardian of any minor children. Although a court will make the ultimate determination of who is appointed as the guardian, courts typically give significant weight to the person named in a will.

If you die “intestate,” meaning that you died without a valid will, your assets will be distributed in accordance with your state’s intestacy statutes, and any interested person (as opposed to the individual of your choice) may be appointed as the personal representative of your estate. Therefore, to ensure that your property goes to the individuals of your choice and that your final affairs are handled by the person you trust, a will is essential.

In many states, a revocable living trust can be equally beneficial. Like a will, a revocable living trust will dictate how your property passes at death and appoints a trustee to see that the property is distributed in accordance with your wishes. Revocable living trusts can be great tools for incapacity planning and, unlike a will, are not required to be recorded, so the trust agreement can remain private. The assets that are held in a revocable living trust also avoid the often lengthy and expensive probate process, which generally includes the preparation and filing of a petition to open the estate, an inventory identifying the assets of the estate, and an accounting that details all assets received and distributed, followed by the payment of fees based upon the value of the probate estate.

In many situations, leaving assets to young, disabled, or troubled children would result in catastrophic consequences, such as disqualification for government benefits, dissipation of assets for inappropriate uses, or attachment by creditors. Further, for wealthy individuals, outright distributions to spouses could lead to unnecessary estate tax. Wills and revocable trusts can protect against these issues by requiring that, at death, the decedent’s assets are held in further trust for these individuals.

There are various types of trusts that can help ensure that your assets are used for the benefit of your loved one while avoiding any unintended consequences, some of which include the following:

• Special needs trusts, which allow the trustee to use the trust funds for the benefit of the disabled beneficiary without disqualifying the beneficiary from important government benefits.
• Spendthrift trusts, which can protect the trust assets from claims of creditors or property division in a divorce action.
• Marital trusts, which can be used to reduce taxes and ensure that property will be distributed pursuant to your wishes upon the death of your spouse.
• Dynasty trusts, which can be used to protect assets for many generations and, in doing so, reduce the amount of federal and state transfer taxes.

Whether you use a will or revocable living trust, it is critical to coordinate the beneficiary designations of assets such as retirement accounts and life insurance policies, as well as any other account that passes by beneficiary designation. These beneficiary designations trump the provisions of your will and revocable living trust. Likewise, property owned jointly with another person as joint tenants with the right of survivorship, or with a spouse as tenants by the entirety, will pass directly to the joint owner and not pursuant to the terms of your will or revocable trust.

An effective estate plan involves not just planning for death, but also for your incapacity. A durable power of attorney allows you to select an agent or agents to manage your property during your lifetime. The power of attorney can become effective immediately so that the agent can act on your behalf upon execution of the document or the power of attorney can become effective only if and when you become incapacitated.

A durable power of attorney for health care (or advance health care directive) permits you to appoint an agent to make health care decisions on your behalf in the event that you cannot make your own decisions. In addition, should you become permanently unconscious or in a terminal condition, it permits you to appoint an agent who can withhold or withdraw life-sustaining treatment. With a living will, you can express in writing the circumstances under which you do or do not want artificial life-sustaining measures.

With respect to these powers of attorney, the persons that you appoint as your agents should be people that you trust. It is also important to have conversations with your designated agents to ensure that they understand their responsibilities and your wishes. Without these powers of attorney, in the event of your incapacitation, a court will appoint a guardian. The guardian may not be the person you would have appointed, and it will result in annual, and burdensome, court filings.

As busy medical professionals, it may be difficult to find time to develop an estate plan and you may believe that there is plenty of time to do it in the future. It is important to begin thinking about your estate-planning goals and to speak with an attorney to help develop and draft your estate-planning documents. If you already have estate-planning documents, it is important to review those documents periodically to ensure that your estate-planning objectives have remained the same and, if they have changed, to update your documents.

No one knows what the future will hold, so it is important to consult with a local attorney to establish or review your estate plan now. If you do, you will be comforted by the fact that you and your loved ones will be taken care of in accordance with your wishes if you are unable to do so in the future.
 

Mr. D’Emilio is a managing member and Mr. Riley is an associate at McCollom D’Emilio Smith Uebler, Wilmington, Del.

As medical professionals, you may have encountered patients with serious illnesses and asked yourself the following questions: What if I was in that situation? Where will my assets go when I die? What will happen to my loved ones, and will they be taken care of? Who would handle my affairs if I became ill? These important questions can only be addressed through effective estate planning.

Everyone needs an estate plan regardless of age, health, and financial or family situation. An effective estate plan provides for the orderly management and disposition of your assets upon your death. In addition, as medical professionals may appreciate, an effective estate plan appoints individuals to manage your financial affairs and make health care decisions for you in the event that you become physically or mentally incapacitated.

The most common estate planning tool is a will, which dictates how your assets pass at death. In addition, a will identifies the personal representative of your estate (that is, the person who will see that your assets pass in accordance with your wishes) and, in many states, identifies the guardian of any minor children. Although a court will make the ultimate determination of who is appointed as the guardian, courts typically give significant weight to the person named in a will.

If you die “intestate,” meaning that you died without a valid will, your assets will be distributed in accordance with your state’s intestacy statutes, and any interested person (as opposed to the individual of your choice) may be appointed as the personal representative of your estate. Therefore, to ensure that your property goes to the individuals of your choice and that your final affairs are handled by the person you trust, a will is essential.

In many states, a revocable living trust can be equally beneficial. Like a will, a revocable living trust will dictate how your property passes at death and appoints a trustee to see that the property is distributed in accordance with your wishes. Revocable living trusts can be great tools for incapacity planning and, unlike a will, are not required to be recorded, so the trust agreement can remain private. The assets that are held in a revocable living trust also avoid the often lengthy and expensive probate process, which generally includes the preparation and filing of a petition to open the estate, an inventory identifying the assets of the estate, and an accounting that details all assets received and distributed, followed by the payment of fees based upon the value of the probate estate.

In many situations, leaving assets to young, disabled, or troubled children would result in catastrophic consequences, such as disqualification for government benefits, dissipation of assets for inappropriate uses, or attachment by creditors. Further, for wealthy individuals, outright distributions to spouses could lead to unnecessary estate tax. Wills and revocable trusts can protect against these issues by requiring that, at death, the decedent’s assets are held in further trust for these individuals.

There are various types of trusts that can help ensure that your assets are used for the benefit of your loved one while avoiding any unintended consequences, some of which include the following:

• Special needs trusts, which allow the trustee to use the trust funds for the benefit of the disabled beneficiary without disqualifying the beneficiary from important government benefits.
• Spendthrift trusts, which can protect the trust assets from claims of creditors or property division in a divorce action.
• Marital trusts, which can be used to reduce taxes and ensure that property will be distributed pursuant to your wishes upon the death of your spouse.
• Dynasty trusts, which can be used to protect assets for many generations and, in doing so, reduce the amount of federal and state transfer taxes.

Whether you use a will or revocable living trust, it is critical to coordinate the beneficiary designations of assets such as retirement accounts and life insurance policies, as well as any other account that passes by beneficiary designation. These beneficiary designations trump the provisions of your will and revocable living trust. Likewise, property owned jointly with another person as joint tenants with the right of survivorship, or with a spouse as tenants by the entirety, will pass directly to the joint owner and not pursuant to the terms of your will or revocable trust.

An effective estate plan involves not just planning for death, but also for your incapacity. A durable power of attorney allows you to select an agent or agents to manage your property during your lifetime. The power of attorney can become effective immediately so that the agent can act on your behalf upon execution of the document or the power of attorney can become effective only if and when you become incapacitated.

A durable power of attorney for health care (or advance health care directive) permits you to appoint an agent to make health care decisions on your behalf in the event that you cannot make your own decisions. In addition, should you become permanently unconscious or in a terminal condition, it permits you to appoint an agent who can withhold or withdraw life-sustaining treatment. With a living will, you can express in writing the circumstances under which you do or do not want artificial life-sustaining measures.

With respect to these powers of attorney, the persons that you appoint as your agents should be people that you trust. It is also important to have conversations with your designated agents to ensure that they understand their responsibilities and your wishes. Without these powers of attorney, in the event of your incapacitation, a court will appoint a guardian. The guardian may not be the person you would have appointed, and it will result in annual, and burdensome, court filings.

As busy medical professionals, it may be difficult to find time to develop an estate plan and you may believe that there is plenty of time to do it in the future. It is important to begin thinking about your estate-planning goals and to speak with an attorney to help develop and draft your estate-planning documents. If you already have estate-planning documents, it is important to review those documents periodically to ensure that your estate-planning objectives have remained the same and, if they have changed, to update your documents.

No one knows what the future will hold, so it is important to consult with a local attorney to establish or review your estate plan now. If you do, you will be comforted by the fact that you and your loved ones will be taken care of in accordance with your wishes if you are unable to do so in the future.
 

Mr. D’Emilio is a managing member and Mr. Riley is an associate at McCollom D’Emilio Smith Uebler, Wilmington, Del.

Officials at the Food and Drug Administration have issued a safety alert regarding the use of fecal microbiota for transplantation (FMT) and the risk of serious adverse reactions because of transmission of multidrug-resistant organisms (MDROs).

According to the alert, which was issued on June 13, 2019, the agency became aware of two immunocompromised adult patients who received investigational FMT and developed infections caused by extended-spectrum beta-lactamase (EBSL)–producing Escherichia coli. One of the patients died.

“This is certainly a theoretical risk that we’ve known about,” Lea Ann Chen, MD, a gastroenterologist at New York University, said in an interview. “This announcement is important, because we probably don’t counsel patients specifically about this risk. We say there is a risk for transmission of infectious agents in general, but I think that probably very few counsel patients about a risk for transmission of MDROs.”

The donor stool and FMT used in the two patients were not tested for ESBL-producing gram-negative organisms prior to use. As a result of these serious adverse reactions, the FDA has determined that certain donor screening and stool testing protections are needed for any investigational use of FMT. On June 18, the agency released an additional statement, which stipulated that all Investigational New Drug (IND) holders must implement the following new requirements no later than July 15, 2019:

“1. Donor screening must include questions that specifically address risk factors for colonization with MDROs, and individuals at higher risk of colonization with MDROs must be excluded from donation. Examples of persons at higher risk for colonization with MDROs include:

a. Health care workers

b. Persons who have recently been hospitalized or discharged from long-term care facilities

c. Persons who regularly attend outpatient medical or surgical clinics

d. Persons who have recently engaged in medical tourism

2. FMT donor stool testing must include MDRO testing to exclude use of stool that tests positive for MDRO. The MDRO tests should at minimum include extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillin-resistant Staphylococcus aureus (MRSA). Culture of nasal or perirectal swabs is an acceptable alternative to stool testing for MRSA only. Bookend testing (no more than 60 days apart) before and after multiple stool donations is acceptable if stool samples are quarantined until the post-donation MDRO tests are confirmed negative.

3. All FMT products currently in storage for which the donor has not undergone screening and stool testing for MDROs as described above must be placed in quarantine until such time as the donor is confirmed to be not at increased risk of MDRO carriage and the FMT products have been tested and found negative. In the case of FMT products manufactured using pooled donations from a single donor, stored samples of the individual donations prior to pooling must be tested before the FMT products can be administered to subjects.

4.The informed consent process for subjects being treated with FMT product under your IND going forward should describe the risks of MDRO transmission and invasive infection as well as the measures implemented for donor screening and stool testing.”

On June 14, the American Gastroenterological Association sent a communication about the FDA alert to its members, which stated that the AGA “is committed to advancing applications of the gut microbiome. Our top priority is ensuring patient safety from microbiome-based therapeutics, such as FMT. Through the AGA FMT National Registry, AGA is working with physicians and patients to track FMT usage, patient outcomes and adverse events. Associated with the registry is a biorepository of donor and patient stool samples, which will allow further investigation of unexpected events such as those described in FDA’s safety alert.”

Dr. Chen, who received the AGA Research Foundation’s 2016 Research Scholar Award for her work on the gut microbiome and inflammatory bowel disease, pointed out that FMT has also been studied as a way to prevent colonization and infection with certain drug resistant organisms, such as VRE.

“Therefore, it’s not that FMT is ‘bad;’ we just have to be more diligent about optimizing the safety of the procedure by screening for of multidrug-resistant organisms,” she said. “We also need to study the use of FMT more, so that we can fully understand the risks associated with the procedure. It’s an important and potentially lifesaving procedure for some, but it’s important that everyone go into the procedure understanding fully what the risks and benefits are.”

Suspected adverse events related to the administration of FMT products can be reported to the FDA at 1-800-332-1088 or via MedWatch.

dbrunk@mdedge.com

Officials at the Food and Drug Administration have issued a safety alert regarding the use of fecal microbiota for transplantation (FMT) and the risk of serious adverse reactions because of transmission of multidrug-resistant organisms (MDROs).

According to the alert, which was issued on June 13, 2019, the agency became aware of two immunocompromised adult patients who received investigational FMT and developed infections caused by extended-spectrum beta-lactamase (EBSL)–producing Escherichia coli. One of the patients died.

“This is certainly a theoretical risk that we’ve known about,” Lea Ann Chen, MD, a gastroenterologist at New York University, said in an interview. “This announcement is important, because we probably don’t counsel patients specifically about this risk. We say there is a risk for transmission of infectious agents in general, but I think that probably very few counsel patients about a risk for transmission of MDROs.”

The donor stool and FMT used in the two patients were not tested for ESBL-producing gram-negative organisms prior to use. As a result of these serious adverse reactions, the FDA has determined that certain donor screening and stool testing protections are needed for any investigational use of FMT. On June 18, the agency released an additional statement, which stipulated that all Investigational New Drug (IND) holders must implement the following new requirements no later than July 15, 2019:

“1. Donor screening must include questions that specifically address risk factors for colonization with MDROs, and individuals at higher risk of colonization with MDROs must be excluded from donation. Examples of persons at higher risk for colonization with MDROs include:

a. Health care workers

b. Persons who have recently been hospitalized or discharged from long-term care facilities

c. Persons who regularly attend outpatient medical or surgical clinics

d. Persons who have recently engaged in medical tourism

2. FMT donor stool testing must include MDRO testing to exclude use of stool that tests positive for MDRO. The MDRO tests should at minimum include extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillin-resistant Staphylococcus aureus (MRSA). Culture of nasal or perirectal swabs is an acceptable alternative to stool testing for MRSA only. Bookend testing (no more than 60 days apart) before and after multiple stool donations is acceptable if stool samples are quarantined until the post-donation MDRO tests are confirmed negative.

3. All FMT products currently in storage for which the donor has not undergone screening and stool testing for MDROs as described above must be placed in quarantine until such time as the donor is confirmed to be not at increased risk of MDRO carriage and the FMT products have been tested and found negative. In the case of FMT products manufactured using pooled donations from a single donor, stored samples of the individual donations prior to pooling must be tested before the FMT products can be administered to subjects.

4.The informed consent process for subjects being treated with FMT product under your IND going forward should describe the risks of MDRO transmission and invasive infection as well as the measures implemented for donor screening and stool testing.”

On June 14, the American Gastroenterological Association sent a communication about the FDA alert to its members, which stated that the AGA “is committed to advancing applications of the gut microbiome. Our top priority is ensuring patient safety from microbiome-based therapeutics, such as FMT. Through the AGA FMT National Registry, AGA is working with physicians and patients to track FMT usage, patient outcomes and adverse events. Associated with the registry is a biorepository of donor and patient stool samples, which will allow further investigation of unexpected events such as those described in FDA’s safety alert.”

Dr. Chen, who received the AGA Research Foundation’s 2016 Research Scholar Award for her work on the gut microbiome and inflammatory bowel disease, pointed out that FMT has also been studied as a way to prevent colonization and infection with certain drug resistant organisms, such as VRE.

“Therefore, it’s not that FMT is ‘bad;’ we just have to be more diligent about optimizing the safety of the procedure by screening for of multidrug-resistant organisms,” she said. “We also need to study the use of FMT more, so that we can fully understand the risks associated with the procedure. It’s an important and potentially lifesaving procedure for some, but it’s important that everyone go into the procedure understanding fully what the risks and benefits are.”

Suspected adverse events related to the administration of FMT products can be reported to the FDA at 1-800-332-1088 or via MedWatch.

dbrunk@mdedge.com

Officials at the Food and Drug Administration have issued a safety alert regarding the use of fecal microbiota for transplantation (FMT) and the risk of serious adverse reactions because of transmission of multidrug-resistant organisms (MDROs).

According to the alert, which was issued on June 13, 2019, the agency became aware of two immunocompromised adult patients who received investigational FMT and developed infections caused by extended-spectrum beta-lactamase (EBSL)–producing Escherichia coli. One of the patients died.

“This is certainly a theoretical risk that we’ve known about,” Lea Ann Chen, MD, a gastroenterologist at New York University, said in an interview. “This announcement is important, because we probably don’t counsel patients specifically about this risk. We say there is a risk for transmission of infectious agents in general, but I think that probably very few counsel patients about a risk for transmission of MDROs.”

The donor stool and FMT used in the two patients were not tested for ESBL-producing gram-negative organisms prior to use. As a result of these serious adverse reactions, the FDA has determined that certain donor screening and stool testing protections are needed for any investigational use of FMT. On June 18, the agency released an additional statement, which stipulated that all Investigational New Drug (IND) holders must implement the following new requirements no later than July 15, 2019:

“1. Donor screening must include questions that specifically address risk factors for colonization with MDROs, and individuals at higher risk of colonization with MDROs must be excluded from donation. Examples of persons at higher risk for colonization with MDROs include:

a. Health care workers

b. Persons who have recently been hospitalized or discharged from long-term care facilities

c. Persons who regularly attend outpatient medical or surgical clinics

d. Persons who have recently engaged in medical tourism

2. FMT donor stool testing must include MDRO testing to exclude use of stool that tests positive for MDRO. The MDRO tests should at minimum include extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillin-resistant Staphylococcus aureus (MRSA). Culture of nasal or perirectal swabs is an acceptable alternative to stool testing for MRSA only. Bookend testing (no more than 60 days apart) before and after multiple stool donations is acceptable if stool samples are quarantined until the post-donation MDRO tests are confirmed negative.

3. All FMT products currently in storage for which the donor has not undergone screening and stool testing for MDROs as described above must be placed in quarantine until such time as the donor is confirmed to be not at increased risk of MDRO carriage and the FMT products have been tested and found negative. In the case of FMT products manufactured using pooled donations from a single donor, stored samples of the individual donations prior to pooling must be tested before the FMT products can be administered to subjects.

4.The informed consent process for subjects being treated with FMT product under your IND going forward should describe the risks of MDRO transmission and invasive infection as well as the measures implemented for donor screening and stool testing.”

On June 14, the American Gastroenterological Association sent a communication about the FDA alert to its members, which stated that the AGA “is committed to advancing applications of the gut microbiome. Our top priority is ensuring patient safety from microbiome-based therapeutics, such as FMT. Through the AGA FMT National Registry, AGA is working with physicians and patients to track FMT usage, patient outcomes and adverse events. Associated with the registry is a biorepository of donor and patient stool samples, which will allow further investigation of unexpected events such as those described in FDA’s safety alert.”

Dr. Chen, who received the AGA Research Foundation’s 2016 Research Scholar Award for her work on the gut microbiome and inflammatory bowel disease, pointed out that FMT has also been studied as a way to prevent colonization and infection with certain drug resistant organisms, such as VRE.

“Therefore, it’s not that FMT is ‘bad;’ we just have to be more diligent about optimizing the safety of the procedure by screening for of multidrug-resistant organisms,” she said. “We also need to study the use of FMT more, so that we can fully understand the risks associated with the procedure. It’s an important and potentially lifesaving procedure for some, but it’s important that everyone go into the procedure understanding fully what the risks and benefits are.”

Suspected adverse events related to the administration of FMT products can be reported to the FDA at 1-800-332-1088 or via MedWatch.

dbrunk@mdedge.com

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

Every guideline and lecture on suicide risk assessment includes the message: “Do not use suicide contracts.” Yet, as forensic psychiatrists, we continue to see medical records that rely solely on the patient verbalizing, agreeing, or signing that they will be safe, in order to justify medical decision-making. A recent case we reviewed involving a grossly psychotic male spotlighted the meaninglessness of suicide contracts. In an attempt to understand the impulse by clinicians to use suicide contracts, we decided to review the topic.

Suicide risk assessment is a confusing and poorly explained skill in our field. Suicide risk assessment tools are well-intended. They are meant to identify and stratify risk, and help guide medical decision-making. Popular tools are startlingly different. How can two scales represent adequate psychiatric knowledge yet be completely different? SADPERSONS¹ is widely used and still considered standard of care yet has nothing in common with the Columbia–Suicide Severity Rating Scale (CSSRS).²

For those of us working in forensic settings, we are aghast that neither assessment is modified for use in correctional settings or accounts for essential risk factors of suicide in jails and prisons (placement in solitary, significant charges, homeless, etc.) Yet, they are widely used in jails and prisons across the country. This can be extrapolated to all of us who work with specific populations yet are asked to follow generic scales by administrators.

In reviewing the literature, we are surprised to see the lack of acknowledgment that many tools used in suicide risk assessment have little to no evidence. Despite their numerous appearances in medical records that we review, we are not aware of existing evidence for asking patients whether patients are suicidal on an hourly basis, for psychotropic treatment other than lithium and clozapine (Clozaril), and for safety plans that involve telling the patient to call 911. Of even greater concern, suicide risk assessments themselves may have limited value because of a lack of evidence as suggested by large study findings. It may surprise some to learn that the National Institute for Health and Care Excellence (NICE) in the United Kingdom includes the following statement in its guidelines: “Do not use risk assessment tools and scales to predict future suicide or repetition of self-harm.”³

In 2017, Carter et al.⁴ reviewed 70 studies using suicide risk scales to stratify patients in higher-risk groups for self-harm or suicide, during a follow-up period. The study reviewed biological tests such as the dexamethasone suppression test and 5-hydroxyindoleacetic acid; as well as psychological scales, including Buglass & Horton, SADPERSONS, the Beck Hopelessness Scale, the Beck’s Depression Inventory, Manchester Self Harm Rule, and the Edinburgh Risk Rating Scale. Their conclusion was clear: “No individual predictive instrument or pooled subgroups of instruments were able to classify patients as being at high risk of suicidal behavior with a level of accuracy suitable to be used to allocate treatment.”

Despite the bad reputation, one must admit that suicide contracts intuitively feel right. Just as we ask patients whether they believe they will stay sober in the future, or ask patients if they will be compliant with their psychotropics, asking them if they feel that they can maintain safety seems relevant. Reading through the literature, one can even find articles promoting this approach. In 2011, researchers simply asked 147 patients in psychiatric hospitals considered to be high risk for suicide whether they would engage in self-harm in the following weeks. They followed those patients for 15 weeks after their discharge for acts of self-harm. They concluded that “self-perceptions of risk seem to perform as well as the best [standardized assessment tools] the field has to offer” for the prediction of self-harm^.5 We are unconvinced that juries would find suicide contracts irrelevant despite the lack of evidence. American society values individual autonomy and self-decision making. Patients telling their clinicians, “I will be OK” is relevant to suicide risk assessment. One can argue that the problem is not with the suicide contract itself, but with its blind use as a marker of safety.

The standard of care dictates that we try to assess suicide risk using evidence-based techniques. To the providers who see merit in asking patients whether they will be able to maintain their safety, we empathize with this impulse despite the lack of evidence. We do not ask those providers to stop but to supplement suicide contracts with more evidence-based tools that could lessen their liability. This will contribute in our shared effort to minimize suicide.

We acknowledge that the evidence of any assessment is limited and might miss a greater point in this entire discussion: Why are new iterations of suicide risk assessments not an improvement on the prior ones but a competing theory? New assessments emphasizing different facets of suicidal thinking do not include key demographic factors, while older tools do not include more recent understanding, such as the importance of hopelessness. From a provider’s perspective, the debate appears to be a battle of trends, theories, and acronyms rather than comprehensive analysis of the latest evidence. We, therefore, are concerned by “suicide experts” who advocate for any one assessment as the only gold standard and give false hopes about its efficacy.

As suicide rates continue to climb across the country, one wonders what we, as psychiatrists, are trying to achieve. Promises of zero suicides by hospitals,⁶ academic institutions,⁷ and even governments⁸ are well-meaning but possibly misleading to families and patients. Psychiatry should advocate within the standard of care for reasonable attempts at suicide risk assessment, including demographic factors (see SADPERSONS), as well as examination of the actual suicidality (see the CSSRS). Our professional organizations should clarify expectations for clinicians while also clarifying the limitations of our current knowledge base.
 

References

1. Patterson WM et al. Evaluation of suicidal patients: the SADPERSONS scale. Psychosomatics. 1983 Apr;24[4]:343-5, 348-9.

2. Posner K et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77.

3. Kendall T et al. Longer term management of self harm: summary of NICE guidance. BMJ. 2011;343. doi: 10.1136/bmj.d7073.

4. Carter G et al. Predicting suicidal behaviors using clinical instruments: systematic review and meta-analysis of positive predictive values for risk scales. Br J Psychiatry. 2017 Jun;210(6):387-95.

5. Peterson J et al. If you want to know, consider asking: How likely is it that patients will hurt themselves in the future? Psychol Assess. 2011 Sep;23(3):626-34.

5. Byrne JM et al. Implementation and impact of the central district of California’s suicide prevention program for crime defendants. Federal Probation. 2012 Jun;76(1):3-13.

6. “R.I.’s Butler Hospital sets ‘zero suicide’ goal for patients”/audio. Providence Journal. May 15, 2018.

7. “NIMH funds 3 ‘zero suicide’ grants.” National Institute of Mental Health. Sep 16, 2016.

8. Rothschild N. “Is it possible to eliminate suicide?” Atlantic. Jun 5, 2015.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Rao is a San Diego–based board-certified psychiatrist with expertise in forensic psychiatry, correctional psychiatry, telepsychiatry, and inpatient psychiatry.

Every guideline and lecture on suicide risk assessment includes the message: “Do not use suicide contracts.” Yet, as forensic psychiatrists, we continue to see medical records that rely solely on the patient verbalizing, agreeing, or signing that they will be safe, in order to justify medical decision-making. A recent case we reviewed involving a grossly psychotic male spotlighted the meaninglessness of suicide contracts. In an attempt to understand the impulse by clinicians to use suicide contracts, we decided to review the topic.

Suicide risk assessment is a confusing and poorly explained skill in our field. Suicide risk assessment tools are well-intended. They are meant to identify and stratify risk, and help guide medical decision-making. Popular tools are startlingly different. How can two scales represent adequate psychiatric knowledge yet be completely different? SADPERSONS¹ is widely used and still considered standard of care yet has nothing in common with the Columbia–Suicide Severity Rating Scale (CSSRS).²

For those of us working in forensic settings, we are aghast that neither assessment is modified for use in correctional settings or accounts for essential risk factors of suicide in jails and prisons (placement in solitary, significant charges, homeless, etc.) Yet, they are widely used in jails and prisons across the country. This can be extrapolated to all of us who work with specific populations yet are asked to follow generic scales by administrators.

In reviewing the literature, we are surprised to see the lack of acknowledgment that many tools used in suicide risk assessment have little to no evidence. Despite their numerous appearances in medical records that we review, we are not aware of existing evidence for asking patients whether patients are suicidal on an hourly basis, for psychotropic treatment other than lithium and clozapine (Clozaril), and for safety plans that involve telling the patient to call 911. Of even greater concern, suicide risk assessments themselves may have limited value because of a lack of evidence as suggested by large study findings. It may surprise some to learn that the National Institute for Health and Care Excellence (NICE) in the United Kingdom includes the following statement in its guidelines: “Do not use risk assessment tools and scales to predict future suicide or repetition of self-harm.”³

In 2017, Carter et al.⁴ reviewed 70 studies using suicide risk scales to stratify patients in higher-risk groups for self-harm or suicide, during a follow-up period. The study reviewed biological tests such as the dexamethasone suppression test and 5-hydroxyindoleacetic acid; as well as psychological scales, including Buglass & Horton, SADPERSONS, the Beck Hopelessness Scale, the Beck’s Depression Inventory, Manchester Self Harm Rule, and the Edinburgh Risk Rating Scale. Their conclusion was clear: “No individual predictive instrument or pooled subgroups of instruments were able to classify patients as being at high risk of suicidal behavior with a level of accuracy suitable to be used to allocate treatment.”

Despite the bad reputation, one must admit that suicide contracts intuitively feel right. Just as we ask patients whether they believe they will stay sober in the future, or ask patients if they will be compliant with their psychotropics, asking them if they feel that they can maintain safety seems relevant. Reading through the literature, one can even find articles promoting this approach. In 2011, researchers simply asked 147 patients in psychiatric hospitals considered to be high risk for suicide whether they would engage in self-harm in the following weeks. They followed those patients for 15 weeks after their discharge for acts of self-harm. They concluded that “self-perceptions of risk seem to perform as well as the best [standardized assessment tools] the field has to offer” for the prediction of self-harm^.5 We are unconvinced that juries would find suicide contracts irrelevant despite the lack of evidence. American society values individual autonomy and self-decision making. Patients telling their clinicians, “I will be OK” is relevant to suicide risk assessment. One can argue that the problem is not with the suicide contract itself, but with its blind use as a marker of safety.

The standard of care dictates that we try to assess suicide risk using evidence-based techniques. To the providers who see merit in asking patients whether they will be able to maintain their safety, we empathize with this impulse despite the lack of evidence. We do not ask those providers to stop but to supplement suicide contracts with more evidence-based tools that could lessen their liability. This will contribute in our shared effort to minimize suicide.

We acknowledge that the evidence of any assessment is limited and might miss a greater point in this entire discussion: Why are new iterations of suicide risk assessments not an improvement on the prior ones but a competing theory? New assessments emphasizing different facets of suicidal thinking do not include key demographic factors, while older tools do not include more recent understanding, such as the importance of hopelessness. From a provider’s perspective, the debate appears to be a battle of trends, theories, and acronyms rather than comprehensive analysis of the latest evidence. We, therefore, are concerned by “suicide experts” who advocate for any one assessment as the only gold standard and give false hopes about its efficacy.

As suicide rates continue to climb across the country, one wonders what we, as psychiatrists, are trying to achieve. Promises of zero suicides by hospitals,⁶ academic institutions,⁷ and even governments⁸ are well-meaning but possibly misleading to families and patients. Psychiatry should advocate within the standard of care for reasonable attempts at suicide risk assessment, including demographic factors (see SADPERSONS), as well as examination of the actual suicidality (see the CSSRS). Our professional organizations should clarify expectations for clinicians while also clarifying the limitations of our current knowledge base.
 

References

1. Patterson WM et al. Evaluation of suicidal patients: the SADPERSONS scale. Psychosomatics. 1983 Apr;24[4]:343-5, 348-9.

2. Posner K et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77.

3. Kendall T et al. Longer term management of self harm: summary of NICE guidance. BMJ. 2011;343. doi: 10.1136/bmj.d7073.

4. Carter G et al. Predicting suicidal behaviors using clinical instruments: systematic review and meta-analysis of positive predictive values for risk scales. Br J Psychiatry. 2017 Jun;210(6):387-95.

5. Peterson J et al. If you want to know, consider asking: How likely is it that patients will hurt themselves in the future? Psychol Assess. 2011 Sep;23(3):626-34.

5. Byrne JM et al. Implementation and impact of the central district of California’s suicide prevention program for crime defendants. Federal Probation. 2012 Jun;76(1):3-13.

6. “R.I.’s Butler Hospital sets ‘zero suicide’ goal for patients”/audio. Providence Journal. May 15, 2018.

7. “NIMH funds 3 ‘zero suicide’ grants.” National Institute of Mental Health. Sep 16, 2016.

8. Rothschild N. “Is it possible to eliminate suicide?” Atlantic. Jun 5, 2015.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Rao is a San Diego–based board-certified psychiatrist with expertise in forensic psychiatry, correctional psychiatry, telepsychiatry, and inpatient psychiatry.

Every guideline and lecture on suicide risk assessment includes the message: “Do not use suicide contracts.” Yet, as forensic psychiatrists, we continue to see medical records that rely solely on the patient verbalizing, agreeing, or signing that they will be safe, in order to justify medical decision-making. A recent case we reviewed involving a grossly psychotic male spotlighted the meaninglessness of suicide contracts. In an attempt to understand the impulse by clinicians to use suicide contracts, we decided to review the topic.

Suicide risk assessment is a confusing and poorly explained skill in our field. Suicide risk assessment tools are well-intended. They are meant to identify and stratify risk, and help guide medical decision-making. Popular tools are startlingly different. How can two scales represent adequate psychiatric knowledge yet be completely different? SADPERSONS¹ is widely used and still considered standard of care yet has nothing in common with the Columbia–Suicide Severity Rating Scale (CSSRS).²

For those of us working in forensic settings, we are aghast that neither assessment is modified for use in correctional settings or accounts for essential risk factors of suicide in jails and prisons (placement in solitary, significant charges, homeless, etc.) Yet, they are widely used in jails and prisons across the country. This can be extrapolated to all of us who work with specific populations yet are asked to follow generic scales by administrators.

In reviewing the literature, we are surprised to see the lack of acknowledgment that many tools used in suicide risk assessment have little to no evidence. Despite their numerous appearances in medical records that we review, we are not aware of existing evidence for asking patients whether patients are suicidal on an hourly basis, for psychotropic treatment other than lithium and clozapine (Clozaril), and for safety plans that involve telling the patient to call 911. Of even greater concern, suicide risk assessments themselves may have limited value because of a lack of evidence as suggested by large study findings. It may surprise some to learn that the National Institute for Health and Care Excellence (NICE) in the United Kingdom includes the following statement in its guidelines: “Do not use risk assessment tools and scales to predict future suicide or repetition of self-harm.”³

In 2017, Carter et al.⁴ reviewed 70 studies using suicide risk scales to stratify patients in higher-risk groups for self-harm or suicide, during a follow-up period. The study reviewed biological tests such as the dexamethasone suppression test and 5-hydroxyindoleacetic acid; as well as psychological scales, including Buglass & Horton, SADPERSONS, the Beck Hopelessness Scale, the Beck’s Depression Inventory, Manchester Self Harm Rule, and the Edinburgh Risk Rating Scale. Their conclusion was clear: “No individual predictive instrument or pooled subgroups of instruments were able to classify patients as being at high risk of suicidal behavior with a level of accuracy suitable to be used to allocate treatment.”

Despite the bad reputation, one must admit that suicide contracts intuitively feel right. Just as we ask patients whether they believe they will stay sober in the future, or ask patients if they will be compliant with their psychotropics, asking them if they feel that they can maintain safety seems relevant. Reading through the literature, one can even find articles promoting this approach. In 2011, researchers simply asked 147 patients in psychiatric hospitals considered to be high risk for suicide whether they would engage in self-harm in the following weeks. They followed those patients for 15 weeks after their discharge for acts of self-harm. They concluded that “self-perceptions of risk seem to perform as well as the best [standardized assessment tools] the field has to offer” for the prediction of self-harm^.5 We are unconvinced that juries would find suicide contracts irrelevant despite the lack of evidence. American society values individual autonomy and self-decision making. Patients telling their clinicians, “I will be OK” is relevant to suicide risk assessment. One can argue that the problem is not with the suicide contract itself, but with its blind use as a marker of safety.

The standard of care dictates that we try to assess suicide risk using evidence-based techniques. To the providers who see merit in asking patients whether they will be able to maintain their safety, we empathize with this impulse despite the lack of evidence. We do not ask those providers to stop but to supplement suicide contracts with more evidence-based tools that could lessen their liability. This will contribute in our shared effort to minimize suicide.

We acknowledge that the evidence of any assessment is limited and might miss a greater point in this entire discussion: Why are new iterations of suicide risk assessments not an improvement on the prior ones but a competing theory? New assessments emphasizing different facets of suicidal thinking do not include key demographic factors, while older tools do not include more recent understanding, such as the importance of hopelessness. From a provider’s perspective, the debate appears to be a battle of trends, theories, and acronyms rather than comprehensive analysis of the latest evidence. We, therefore, are concerned by “suicide experts” who advocate for any one assessment as the only gold standard and give false hopes about its efficacy.

As suicide rates continue to climb across the country, one wonders what we, as psychiatrists, are trying to achieve. Promises of zero suicides by hospitals,⁶ academic institutions,⁷ and even governments⁸ are well-meaning but possibly misleading to families and patients. Psychiatry should advocate within the standard of care for reasonable attempts at suicide risk assessment, including demographic factors (see SADPERSONS), as well as examination of the actual suicidality (see the CSSRS). Our professional organizations should clarify expectations for clinicians while also clarifying the limitations of our current knowledge base.
 

References

1. Patterson WM et al. Evaluation of suicidal patients: the SADPERSONS scale. Psychosomatics. 1983 Apr;24[4]:343-5, 348-9.

2. Posner K et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77.

3. Kendall T et al. Longer term management of self harm: summary of NICE guidance. BMJ. 2011;343. doi: 10.1136/bmj.d7073.

4. Carter G et al. Predicting suicidal behaviors using clinical instruments: systematic review and meta-analysis of positive predictive values for risk scales. Br J Psychiatry. 2017 Jun;210(6):387-95.

5. Peterson J et al. If you want to know, consider asking: How likely is it that patients will hurt themselves in the future? Psychol Assess. 2011 Sep;23(3):626-34.

5. Byrne JM et al. Implementation and impact of the central district of California’s suicide prevention program for crime defendants. Federal Probation. 2012 Jun;76(1):3-13.

6. “R.I.’s Butler Hospital sets ‘zero suicide’ goal for patients”/audio. Providence Journal. May 15, 2018.

7. “NIMH funds 3 ‘zero suicide’ grants.” National Institute of Mental Health. Sep 16, 2016.

8. Rothschild N. “Is it possible to eliminate suicide?” Atlantic. Jun 5, 2015.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Rao is a San Diego–based board-certified psychiatrist with expertise in forensic psychiatry, correctional psychiatry, telepsychiatry, and inpatient psychiatry.

GAITHERSBURG, MD. – There was sufficient evidence of a late mortality signal seen at 2-5 years post procedurally for paclitaxel-eluting stents and coated balloons to warrant a label change for the devices, the Food and Drug Administration’s Circulatory System Devices Panel unanimously agreed after 2 days of deliberation.

Wikimedia Commons/FitzColinGerald/Creative Commons License

That signal was brought to light in a meta-analysis published last December by Konstantinos Katsanos, MD, of Patras University Hospital, Rion, Greece, and colleagues (J Am Heart Assoc. 2018;7:e011245). Although there were concerns about the quality of the industry data used in the study, the caliber of the analysis itself and the subsequent data presented by the FDA to the panel were deemed sufficient to recommend a warning of concern to patients and providers.

Much of the new data from industry and large database registries presented to the panel, which was chaired by Richard A. Lange, MD, indicated a lessening to no evidence of the mortality effect. But this evidence was deemed insufficient to counter the evidence of the randomized controlled trials individually and collectively as presented in the Katsanos meta-analysis and subsequent information presented by the FDA that examined various parameters in a variety of sensitivity analyses that confirmed the late mortality signal. There was also concern that the industry and the registry analyses presented were not peer reviewed.

However, the panel also determined that it would be inappropriate to pull the devices from the market and from general use for several reasons.

One key reason was that, according to the panel, there was no mechanistic cause apparent for the late mortality. In addition, no convincing dose-response data could be teased from the preclinical and clinical trials studied because of their variability of devices, application methods, and lack of appropriate tissue analysis across studies.

In responding to FDA requests on a variety of concerns, the panel reiterated that there was a credible mortality signal, but that they could not be confident about the magnitude and whether it was caused by the paclitaxel treatment or some factor in the design or conduct of the studies. In addition, the panel members felt that they could neither confirm nor eliminate a class effect, given the fact that the information was based on a meta-analysis and thus none of the included devices could safely be removed from consideration.

They suggested that further safety information should be obtained, potentially by assessing and perhaps altering data collection in 29 ongoing studies over the next 5 years or so in more than 10,000 patients.

In addition, several of the panel members felt that additional animal studies might be performed including the use of older rat models; and using animal models that mimicked the kind of comorbidities present in the treated population, such as diabetes and atherosclerosis. They suggested cross-company industry cooperation with the FDA on these models, including looking at drug interactions and mimicking the dose application of stents/balloons.

Both the FDA representative and the panel were especially concerned with the benefit/risk profile.

The recommendation to still market the devices with a label warning was warranted, according to many members of the panel. They pointed to the clear benefits in quality of life and the lowered need for revascularization despite the evidence of the mortality signal, which, while statistically significant, could not be pinned town with regard to mechanisms or specific causes of death.

Overall, there was a concern that there should be a dialogue between patients and their doctors to discuss clear short-term benefits with unknown long-term risk, and that the label should support this by clearly mentioning the mortality signal that was found, although there was no attempt to develop exact wording.

Panel member Joaquin E. Cigarroa, MD, head of cardiovascular medicine at Oregon Health & Science University, Portland, suggested with regard to labeling that a statement “that ‘there may be’ – not ‘there is’ – a late mortality signal, should be included.”

Panel member John C. Somberg, MD, program director of clinical research and bioinformatics at Rush University in Lake Bluff, Ill., stated: “The label should say something like, ‘when looking at a meta-analysis that combined all studies with stents and balloons that carried paclitaxel, there may be a late mortality, which must be balanced against an early and sustained benefit in terms of pain on walking and potential loss of circulation to your extremity.’ ”

Other panel members thought that the meta-analysis should not be privileged and that somehow the totality of the evidence should somehow be distilled down into the label, including the evidence against the signal.

“We’re meeting because of a signal, of a concern – an honest, well-meaning concern – of increased mortality. And my opinion is that the patients need to be informed of it,” said Dr. Lange, president, Texas Tech University, El Paso.

Some members of the panel felt that it may not be justifiable to use these devices in patients with low intrinsic risk and low recurrence risk, and the whole spectrum of patients may need to be considered in further studies to figure out the subgroups that have more benefits and more risks, and also to consider how to mitigate risks in patients who receive the device, whether through medical therapy or lifestyle modification.

In particular, Frank W. LoGerfo, MD, the William V. McDermott Distinguished Professor of Surgery at Harvard Medical School, Boston, stated: “Interventions for claudication should be extremely rare. It rarely progresses, and the pain should be worked through by exercise with low risk of limb loss.” He added that intervention with these devices “takes away options. Trading life for something that is not limb-threatening is something we should not be considering.”

There was no firm consensus on whether new randomized trials should be done, although they were of course the ideal solution. Kevin E. Kip, PhD, Distinguished USF Health Professor at the University of South Florida, Tampa, and others argued that, whether new trials were necessary or not, to deal with the safety question in a timely fashion, existing trials have to capture as much of the missing data as possible, and carry out follow-up out further.

FDA representative Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at the Center for Devices and Radiological Health, indicated that those things might not be easily be accomplished due to regulatory constraints and the financial costs, and that to do so there would be need for community effort among stakeholders, including collaborative efforts with existing prospective registries such as that run by the Vascular Quality Initiative.

One overall conclusion by both the FDA and panel members was that the quality of these and other such studies going forward must improve, by standardizing definitions and data forms to make studies more uniform across the industry. They reemphasized the need to work with the registries to get common data included, and to incorporate of insurance provider and Social Security death data as much as possible to help alleviate the lost follow-up problem.

mlesney@mdedge.com

SOURCE: Webcasts of the complete 2 days of the FDA panel meeting are available online.

GAITHERSBURG, MD. – There was sufficient evidence of a late mortality signal seen at 2-5 years post procedurally for paclitaxel-eluting stents and coated balloons to warrant a label change for the devices, the Food and Drug Administration’s Circulatory System Devices Panel unanimously agreed after 2 days of deliberation.

Wikimedia Commons/FitzColinGerald/Creative Commons License

That signal was brought to light in a meta-analysis published last December by Konstantinos Katsanos, MD, of Patras University Hospital, Rion, Greece, and colleagues (J Am Heart Assoc. 2018;7:e011245). Although there were concerns about the quality of the industry data used in the study, the caliber of the analysis itself and the subsequent data presented by the FDA to the panel were deemed sufficient to recommend a warning of concern to patients and providers.

Much of the new data from industry and large database registries presented to the panel, which was chaired by Richard A. Lange, MD, indicated a lessening to no evidence of the mortality effect. But this evidence was deemed insufficient to counter the evidence of the randomized controlled trials individually and collectively as presented in the Katsanos meta-analysis and subsequent information presented by the FDA that examined various parameters in a variety of sensitivity analyses that confirmed the late mortality signal. There was also concern that the industry and the registry analyses presented were not peer reviewed.

However, the panel also determined that it would be inappropriate to pull the devices from the market and from general use for several reasons.

One key reason was that, according to the panel, there was no mechanistic cause apparent for the late mortality. In addition, no convincing dose-response data could be teased from the preclinical and clinical trials studied because of their variability of devices, application methods, and lack of appropriate tissue analysis across studies.

In responding to FDA requests on a variety of concerns, the panel reiterated that there was a credible mortality signal, but that they could not be confident about the magnitude and whether it was caused by the paclitaxel treatment or some factor in the design or conduct of the studies. In addition, the panel members felt that they could neither confirm nor eliminate a class effect, given the fact that the information was based on a meta-analysis and thus none of the included devices could safely be removed from consideration.

They suggested that further safety information should be obtained, potentially by assessing and perhaps altering data collection in 29 ongoing studies over the next 5 years or so in more than 10,000 patients.

In addition, several of the panel members felt that additional animal studies might be performed including the use of older rat models; and using animal models that mimicked the kind of comorbidities present in the treated population, such as diabetes and atherosclerosis. They suggested cross-company industry cooperation with the FDA on these models, including looking at drug interactions and mimicking the dose application of stents/balloons.

Both the FDA representative and the panel were especially concerned with the benefit/risk profile.

The recommendation to still market the devices with a label warning was warranted, according to many members of the panel. They pointed to the clear benefits in quality of life and the lowered need for revascularization despite the evidence of the mortality signal, which, while statistically significant, could not be pinned town with regard to mechanisms or specific causes of death.

Overall, there was a concern that there should be a dialogue between patients and their doctors to discuss clear short-term benefits with unknown long-term risk, and that the label should support this by clearly mentioning the mortality signal that was found, although there was no attempt to develop exact wording.

Panel member Joaquin E. Cigarroa, MD, head of cardiovascular medicine at Oregon Health & Science University, Portland, suggested with regard to labeling that a statement “that ‘there may be’ – not ‘there is’ – a late mortality signal, should be included.”

Panel member John C. Somberg, MD, program director of clinical research and bioinformatics at Rush University in Lake Bluff, Ill., stated: “The label should say something like, ‘when looking at a meta-analysis that combined all studies with stents and balloons that carried paclitaxel, there may be a late mortality, which must be balanced against an early and sustained benefit in terms of pain on walking and potential loss of circulation to your extremity.’ ”

Other panel members thought that the meta-analysis should not be privileged and that somehow the totality of the evidence should somehow be distilled down into the label, including the evidence against the signal.

“We’re meeting because of a signal, of a concern – an honest, well-meaning concern – of increased mortality. And my opinion is that the patients need to be informed of it,” said Dr. Lange, president, Texas Tech University, El Paso.

Some members of the panel felt that it may not be justifiable to use these devices in patients with low intrinsic risk and low recurrence risk, and the whole spectrum of patients may need to be considered in further studies to figure out the subgroups that have more benefits and more risks, and also to consider how to mitigate risks in patients who receive the device, whether through medical therapy or lifestyle modification.

In particular, Frank W. LoGerfo, MD, the William V. McDermott Distinguished Professor of Surgery at Harvard Medical School, Boston, stated: “Interventions for claudication should be extremely rare. It rarely progresses, and the pain should be worked through by exercise with low risk of limb loss.” He added that intervention with these devices “takes away options. Trading life for something that is not limb-threatening is something we should not be considering.”

There was no firm consensus on whether new randomized trials should be done, although they were of course the ideal solution. Kevin E. Kip, PhD, Distinguished USF Health Professor at the University of South Florida, Tampa, and others argued that, whether new trials were necessary or not, to deal with the safety question in a timely fashion, existing trials have to capture as much of the missing data as possible, and carry out follow-up out further.

FDA representative Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at the Center for Devices and Radiological Health, indicated that those things might not be easily be accomplished due to regulatory constraints and the financial costs, and that to do so there would be need for community effort among stakeholders, including collaborative efforts with existing prospective registries such as that run by the Vascular Quality Initiative.

One overall conclusion by both the FDA and panel members was that the quality of these and other such studies going forward must improve, by standardizing definitions and data forms to make studies more uniform across the industry. They reemphasized the need to work with the registries to get common data included, and to incorporate of insurance provider and Social Security death data as much as possible to help alleviate the lost follow-up problem.

mlesney@mdedge.com

SOURCE: Webcasts of the complete 2 days of the FDA panel meeting are available online.

GAITHERSBURG, MD. – There was sufficient evidence of a late mortality signal seen at 2-5 years post procedurally for paclitaxel-eluting stents and coated balloons to warrant a label change for the devices, the Food and Drug Administration’s Circulatory System Devices Panel unanimously agreed after 2 days of deliberation.

Wikimedia Commons/FitzColinGerald/Creative Commons License

That signal was brought to light in a meta-analysis published last December by Konstantinos Katsanos, MD, of Patras University Hospital, Rion, Greece, and colleagues (J Am Heart Assoc. 2018;7:e011245). Although there were concerns about the quality of the industry data used in the study, the caliber of the analysis itself and the subsequent data presented by the FDA to the panel were deemed sufficient to recommend a warning of concern to patients and providers.

Much of the new data from industry and large database registries presented to the panel, which was chaired by Richard A. Lange, MD, indicated a lessening to no evidence of the mortality effect. But this evidence was deemed insufficient to counter the evidence of the randomized controlled trials individually and collectively as presented in the Katsanos meta-analysis and subsequent information presented by the FDA that examined various parameters in a variety of sensitivity analyses that confirmed the late mortality signal. There was also concern that the industry and the registry analyses presented were not peer reviewed.

However, the panel also determined that it would be inappropriate to pull the devices from the market and from general use for several reasons.

One key reason was that, according to the panel, there was no mechanistic cause apparent for the late mortality. In addition, no convincing dose-response data could be teased from the preclinical and clinical trials studied because of their variability of devices, application methods, and lack of appropriate tissue analysis across studies.

In responding to FDA requests on a variety of concerns, the panel reiterated that there was a credible mortality signal, but that they could not be confident about the magnitude and whether it was caused by the paclitaxel treatment or some factor in the design or conduct of the studies. In addition, the panel members felt that they could neither confirm nor eliminate a class effect, given the fact that the information was based on a meta-analysis and thus none of the included devices could safely be removed from consideration.

They suggested that further safety information should be obtained, potentially by assessing and perhaps altering data collection in 29 ongoing studies over the next 5 years or so in more than 10,000 patients.

In addition, several of the panel members felt that additional animal studies might be performed including the use of older rat models; and using animal models that mimicked the kind of comorbidities present in the treated population, such as diabetes and atherosclerosis. They suggested cross-company industry cooperation with the FDA on these models, including looking at drug interactions and mimicking the dose application of stents/balloons.

Both the FDA representative and the panel were especially concerned with the benefit/risk profile.

The recommendation to still market the devices with a label warning was warranted, according to many members of the panel. They pointed to the clear benefits in quality of life and the lowered need for revascularization despite the evidence of the mortality signal, which, while statistically significant, could not be pinned town with regard to mechanisms or specific causes of death.

Overall, there was a concern that there should be a dialogue between patients and their doctors to discuss clear short-term benefits with unknown long-term risk, and that the label should support this by clearly mentioning the mortality signal that was found, although there was no attempt to develop exact wording.

Panel member Joaquin E. Cigarroa, MD, head of cardiovascular medicine at Oregon Health & Science University, Portland, suggested with regard to labeling that a statement “that ‘there may be’ – not ‘there is’ – a late mortality signal, should be included.”

Panel member John C. Somberg, MD, program director of clinical research and bioinformatics at Rush University in Lake Bluff, Ill., stated: “The label should say something like, ‘when looking at a meta-analysis that combined all studies with stents and balloons that carried paclitaxel, there may be a late mortality, which must be balanced against an early and sustained benefit in terms of pain on walking and potential loss of circulation to your extremity.’ ”

Other panel members thought that the meta-analysis should not be privileged and that somehow the totality of the evidence should somehow be distilled down into the label, including the evidence against the signal.

“We’re meeting because of a signal, of a concern – an honest, well-meaning concern – of increased mortality. And my opinion is that the patients need to be informed of it,” said Dr. Lange, president, Texas Tech University, El Paso.

Some members of the panel felt that it may not be justifiable to use these devices in patients with low intrinsic risk and low recurrence risk, and the whole spectrum of patients may need to be considered in further studies to figure out the subgroups that have more benefits and more risks, and also to consider how to mitigate risks in patients who receive the device, whether through medical therapy or lifestyle modification.

In particular, Frank W. LoGerfo, MD, the William V. McDermott Distinguished Professor of Surgery at Harvard Medical School, Boston, stated: “Interventions for claudication should be extremely rare. It rarely progresses, and the pain should be worked through by exercise with low risk of limb loss.” He added that intervention with these devices “takes away options. Trading life for something that is not limb-threatening is something we should not be considering.”

There was no firm consensus on whether new randomized trials should be done, although they were of course the ideal solution. Kevin E. Kip, PhD, Distinguished USF Health Professor at the University of South Florida, Tampa, and others argued that, whether new trials were necessary or not, to deal with the safety question in a timely fashion, existing trials have to capture as much of the missing data as possible, and carry out follow-up out further.

FDA representative Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at the Center for Devices and Radiological Health, indicated that those things might not be easily be accomplished due to regulatory constraints and the financial costs, and that to do so there would be need for community effort among stakeholders, including collaborative efforts with existing prospective registries such as that run by the Vascular Quality Initiative.

One overall conclusion by both the FDA and panel members was that the quality of these and other such studies going forward must improve, by standardizing definitions and data forms to make studies more uniform across the industry. They reemphasized the need to work with the registries to get common data included, and to incorporate of insurance provider and Social Security death data as much as possible to help alleviate the lost follow-up problem.

mlesney@mdedge.com

SOURCE: Webcasts of the complete 2 days of the FDA panel meeting are available online.

MADRID – Pending 2019 revisions to the EULAR recommendations for managing rheumatoid arthritis may be most notable for two discussed changes that were tabled: No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.

Mitchel L. Zoler/MDedge News

“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.

Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.

The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).

Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.

Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.

The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.

One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.

The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.

Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.

mzoler@mdedge.com

MADRID – Pending 2019 revisions to the EULAR recommendations for managing rheumatoid arthritis may be most notable for two discussed changes that were tabled: No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.

Mitchel L. Zoler/MDedge News

“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.

Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.

The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).

Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.

Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.

The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.

One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.

The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.

Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.

mzoler@mdedge.com

MADRID – Pending 2019 revisions to the EULAR recommendations for managing rheumatoid arthritis may be most notable for two discussed changes that were tabled: No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.

Mitchel L. Zoler/MDedge News

“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.

Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.

The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).

Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.

Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.

The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.

One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.

The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.

Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.

mzoler@mdedge.com