Rules for performing research with children

 

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

There is a long history of government attempts to promote research and development for the benefit of society. Sometimes government succeeds and sometimes not. For instance, when the U.S. federal government funded scientific research in the 1960s, it sought to increase the common good by promulgating those discoveries. The government insisted that all federally funded research be in the public domain. The funding produced a spectacular number of technological advancements that have enriched society. However, a decade later, the government concluded that too many good research ideas were never developed into beneficial products because without the ability to patent the results, the costs and risks of product development were not profitable for industry. By the late 1970s, new laws were enacted to enable universities and their faculty to patent the results of government-funded research and share in any wealth created.

Pharmaceutical research in the 1970s and 1980s was mostly performed on men in order to reduce the risk of giving treatments of unknown safety to pregnant women. The unintended consequence was that the new drugs frequently were less effective for women. This was particularly true for cardiac medications for which lifestyle risk factors differed between the sexes.

Similarly, children were often excluded from research because of the unknown risks of new drugs on growing bodies and brains. Children were also seen as a vulnerable population for whom informed consent was problematic. The result of these well-intentioned restrictions was the creation of new products that did not have pediatric dosing recommendations, pediatric safety assessments, or approval for pediatric indications. To remediate these deficiencies, in 1997 and 2007 the FDA offered a 6-month extension on patent protection as motivation for companies to develop those pediatric recommendations. Alas, those laws were primarily used to extend the profitability of blockbuster products rather than truly benefit children.

Over the past 4 decades, pediatric ethicists proposed and refined rules to govern research on children. The Common Rule used by institutional review boards (IRBs) to protect human research subjects was expanded with guidelines covering children. The new draft guidance is the latest iteration of this effort. Nothing in the 14 pages of draft regulation appears revolutionary to me. The ideas are tweaks, based on theory and experience, of principles agreed upon 30 years ago. Finding the optimal social moral contract involves some empirical assessment of praxis and effectiveness.

I am loathe to summarize this new document, which itself is a summary of a vast body of literature, that supports the Code of Federal Regulations Title 21 Part 50 and 45 CFR Part 46. The draft document is well organized and I recommend it as an excellent primer for the area of pediatric research ethics if the subject is new to you. I also recommend it as required reading for anyone serving on an IRB.

IRBs usually review and approve any research on people. Generally, the selection of people for research should be done equitably. However, children should not be enrolled unless it is necessary to answer an important question relevant to children. For the past 2 decades, there has been an emphasis on obtaining the assent of the child as well as informed consent by the parents.

An important determination is whether the research is likely to help that particular child or whether it is aimed at advancing general knowledge. If there is no prospect of direct benefit, research is still permissible but more restricted for safety and comfort reasons. Next is determining whether the research carries only minimal risk or a minor increase over minimal risk. The draft defines and provides anchor examples of these situations. For instance, oral placebos and single blood draws are typically minimal risk. Multiple injections and blood draws over a year fall into the second category. One MRI is minimal risk but a minor increase in risk if it involves sedation or contrast.

 

I strongly support the ideals expressed in these guidelines. They represent the best blend of intentions and practical experience. They will become the law of the land. In ethics, there is merit in striving to do things properly, orderly, and enforceably.

The cynic in me sees two weaknesses in the stated approach. First, the volume of harm to children occurring during organized clinical research is extremely small. The greater harms come from off-label use, nonsystematic research, and the ignorance resulting from a lack of research. Second, my observation in all endeavors of morality is, “Raise the bar high enough and people walk under it.”

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.

 

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

There is a long history of government attempts to promote research and development for the benefit of society. Sometimes government succeeds and sometimes not. For instance, when the U.S. federal government funded scientific research in the 1960s, it sought to increase the common good by promulgating those discoveries. The government insisted that all federally funded research be in the public domain. The funding produced a spectacular number of technological advancements that have enriched society. However, a decade later, the government concluded that too many good research ideas were never developed into beneficial products because without the ability to patent the results, the costs and risks of product development were not profitable for industry. By the late 1970s, new laws were enacted to enable universities and their faculty to patent the results of government-funded research and share in any wealth created.

Pharmaceutical research in the 1970s and 1980s was mostly performed on men in order to reduce the risk of giving treatments of unknown safety to pregnant women. The unintended consequence was that the new drugs frequently were less effective for women. This was particularly true for cardiac medications for which lifestyle risk factors differed between the sexes.

Similarly, children were often excluded from research because of the unknown risks of new drugs on growing bodies and brains. Children were also seen as a vulnerable population for whom informed consent was problematic. The result of these well-intentioned restrictions was the creation of new products that did not have pediatric dosing recommendations, pediatric safety assessments, or approval for pediatric indications. To remediate these deficiencies, in 1997 and 2007 the FDA offered a 6-month extension on patent protection as motivation for companies to develop those pediatric recommendations. Alas, those laws were primarily used to extend the profitability of blockbuster products rather than truly benefit children.

Over the past 4 decades, pediatric ethicists proposed and refined rules to govern research on children. The Common Rule used by institutional review boards (IRBs) to protect human research subjects was expanded with guidelines covering children. The new draft guidance is the latest iteration of this effort. Nothing in the 14 pages of draft regulation appears revolutionary to me. The ideas are tweaks, based on theory and experience, of principles agreed upon 30 years ago. Finding the optimal social moral contract involves some empirical assessment of praxis and effectiveness.

I am loathe to summarize this new document, which itself is a summary of a vast body of literature, that supports the Code of Federal Regulations Title 21 Part 50 and 45 CFR Part 46. The draft document is well organized and I recommend it as an excellent primer for the area of pediatric research ethics if the subject is new to you. I also recommend it as required reading for anyone serving on an IRB.

IRBs usually review and approve any research on people. Generally, the selection of people for research should be done equitably. However, children should not be enrolled unless it is necessary to answer an important question relevant to children. For the past 2 decades, there has been an emphasis on obtaining the assent of the child as well as informed consent by the parents.

An important determination is whether the research is likely to help that particular child or whether it is aimed at advancing general knowledge. If there is no prospect of direct benefit, research is still permissible but more restricted for safety and comfort reasons. Next is determining whether the research carries only minimal risk or a minor increase over minimal risk. The draft defines and provides anchor examples of these situations. For instance, oral placebos and single blood draws are typically minimal risk. Multiple injections and blood draws over a year fall into the second category. One MRI is minimal risk but a minor increase in risk if it involves sedation or contrast.

 

I strongly support the ideals expressed in these guidelines. They represent the best blend of intentions and practical experience. They will become the law of the land. In ethics, there is merit in striving to do things properly, orderly, and enforceably.

The cynic in me sees two weaknesses in the stated approach. First, the volume of harm to children occurring during organized clinical research is extremely small. The greater harms come from off-label use, nonsystematic research, and the ignorance resulting from a lack of research. Second, my observation in all endeavors of morality is, “Raise the bar high enough and people walk under it.”

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.

 

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

There is a long history of government attempts to promote research and development for the benefit of society. Sometimes government succeeds and sometimes not. For instance, when the U.S. federal government funded scientific research in the 1960s, it sought to increase the common good by promulgating those discoveries. The government insisted that all federally funded research be in the public domain. The funding produced a spectacular number of technological advancements that have enriched society. However, a decade later, the government concluded that too many good research ideas were never developed into beneficial products because without the ability to patent the results, the costs and risks of product development were not profitable for industry. By the late 1970s, new laws were enacted to enable universities and their faculty to patent the results of government-funded research and share in any wealth created.

Pharmaceutical research in the 1970s and 1980s was mostly performed on men in order to reduce the risk of giving treatments of unknown safety to pregnant women. The unintended consequence was that the new drugs frequently were less effective for women. This was particularly true for cardiac medications for which lifestyle risk factors differed between the sexes.

Similarly, children were often excluded from research because of the unknown risks of new drugs on growing bodies and brains. Children were also seen as a vulnerable population for whom informed consent was problematic. The result of these well-intentioned restrictions was the creation of new products that did not have pediatric dosing recommendations, pediatric safety assessments, or approval for pediatric indications. To remediate these deficiencies, in 1997 and 2007 the FDA offered a 6-month extension on patent protection as motivation for companies to develop those pediatric recommendations. Alas, those laws were primarily used to extend the profitability of blockbuster products rather than truly benefit children.

Over the past 4 decades, pediatric ethicists proposed and refined rules to govern research on children. The Common Rule used by institutional review boards (IRBs) to protect human research subjects was expanded with guidelines covering children. The new draft guidance is the latest iteration of this effort. Nothing in the 14 pages of draft regulation appears revolutionary to me. The ideas are tweaks, based on theory and experience, of principles agreed upon 30 years ago. Finding the optimal social moral contract involves some empirical assessment of praxis and effectiveness.

I am loathe to summarize this new document, which itself is a summary of a vast body of literature, that supports the Code of Federal Regulations Title 21 Part 50 and 45 CFR Part 46. The draft document is well organized and I recommend it as an excellent primer for the area of pediatric research ethics if the subject is new to you. I also recommend it as required reading for anyone serving on an IRB.

IRBs usually review and approve any research on people. Generally, the selection of people for research should be done equitably. However, children should not be enrolled unless it is necessary to answer an important question relevant to children. For the past 2 decades, there has been an emphasis on obtaining the assent of the child as well as informed consent by the parents.

An important determination is whether the research is likely to help that particular child or whether it is aimed at advancing general knowledge. If there is no prospect of direct benefit, research is still permissible but more restricted for safety and comfort reasons. Next is determining whether the research carries only minimal risk or a minor increase over minimal risk. The draft defines and provides anchor examples of these situations. For instance, oral placebos and single blood draws are typically minimal risk. Multiple injections and blood draws over a year fall into the second category. One MRI is minimal risk but a minor increase in risk if it involves sedation or contrast.

 

I strongly support the ideals expressed in these guidelines. They represent the best blend of intentions and practical experience. They will become the law of the land. In ethics, there is merit in striving to do things properly, orderly, and enforceably.

The cynic in me sees two weaknesses in the stated approach. First, the volume of harm to children occurring during organized clinical research is extremely small. The greater harms come from off-label use, nonsystematic research, and the ignorance resulting from a lack of research. Second, my observation in all endeavors of morality is, “Raise the bar high enough and people walk under it.”

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.