Research Corner
Natural Histories and Registries:
the good, the bad and the oiy.
Kimberly A Chapman, MD, PhD
Children’s National Rare Disease Institute, Washington D.C.
kchapman@childrensnational.org
Children’s National Rare Disease Institute, Washington D.C.
kchapman@childrensnational.org
So you are thinking in enrolling yourself or your care into a research study, thank you for helping us
understand your family’s disorder. We are going to start a new section to the newsletter to talk about
research.
Let’s start with what research is. It is a system or process in which the goal is to better understand
something in the world around us. We divide research into clinical (that which affects the patient
directly) and basic (that which studies fundamental processes, e.g. studying the Kreb’s cycle or how
cells talk to each other). Today we are going to talk about a subset of clinical research. As part of this
discussion, we are going to examine the expected benefits and risks from this subset of clinical
research--observational studies.
The two big, most basic categories of clinical research, basically research that which is designed to
understand the natural course of a disorder (observational) and that which tries to impact that natural
course (interventional). Sometimes, the research protocol tries to do both, especially if little is known
about a particular disorder or if a disorder is generally lethal to almost all with the disorder.
So from this point forward, we are going to ignore issues of interventional studies—these are clinical
trials in which an intervention, like a medication or a device is tested to see if it works better than
current practice and address these at a future date, and focus on observational studies.
Observation studies have several flavors, the shallow, the medium and the deep evaluations. In
general, observational studies collect information about an individual (like an individual with an
organic acidemia and their family). They can collect information at one particular time in many
individuals or can follow an individual or cohort of individuals over time. The best designed studies to
gather natural history—what happens in the disorder with current interventions over time---follows
individuals through time, but these can take a long time so some studies are designed to look at many
individuals who are at different points in their disorder at one moment in time and makes assumptions
about impact of time on the disorders. Either of these studies can be shallow, medium or deep in
terms of how much information they gather.
A study which is designed to take a shallow look at a disorder looks for the most basic facts (i.e.
disorder, genotype, current health) and often is fairly short in length (and so can take less time to
complete the initial forms). This can gather information once or over time from the same individuals.
The benefit from this study is that it can provide a “google earth” view of the disorder and takes little
time from each participant to gather the information (like minutes). The problem is it is a shallow
look at the disorder and so rare complications or occurrences are unlikely to be identified.
A study which is more in depth (a deep information study) tries to examine every possible thing about
a disorder and collects a lot of data on each participant often over the course of days. Often times this
type of study also gathers biological specimens (i.e. laboratory, biopsy, etc.) and radiological data (i.e.
X-ray, MRIs, etc.). Dr. Venditti’s natural history studies (for MMA and PA) at NIH are an example of
this type of study. Again individual participants can be studied over time (like Dr. Venditti’s studies) or
deeply once. This is like getting a magnifying glass out on a walk through the neighborhood and
studying as much as possible as closely as possible. You learn lots about lots of things but it takes lots
of time and produces much data. The benefits with these studies is rare occurrences or small changes
are more likely to be identified. The disadvantage is it takes lots of time from the participant and is
very expensive for the researcher.
The type of study which sits between these two in the continuum of studies is the medium study. It is
like the view one has walking down the street in one’s neighborhood, some detail (the designs on the
houses), but not lots of specifics (no idea how many ants on the sidewalk). Our natural history
registry with NORD is an example of this type of study. It does not gather as much information as the
deep study, but more than a shallow study. It tries to gather enough information that common rare
occurrences can be identified, but has less time commitment (more measured in an hours).
Each of these observation studies have some risks. Consent to participate in research of this type
should include a list of the risks identified and possible mitigations for these risk.
Privacy and confidentiality are two of the biggest risks with observational studies. Those observational
studies which include laboratory and radiology as a component also have risk associated with these
procedures.
Some common privacy risks in these types of studies include 1) how safe are my data and will
someone outside the study be able to see them and identify that it belongs to me, 2) can I be
identified by my data and how are my data being protected? Data here can mean your name, your
address, connecting the disorder to you, your health history, your date of birth, etc. You can
understand why these privacy issues could be concerning and why you as a participant (or your care)
should be aware of this risk.
Most reputable registries and natural history studies tell you how and where your information is stored
and protected as part of the consent. They are aware of the concern. In fact, the European Union
has just required much more strict privacy rules for any registry or natural history study which has
anyone who is lives in the EU or storage in the EU (it is called the General Data Protection
Regulations, if you want to look at them).
Despite the risks which can be associated with observational research, there is much that has and to
be learned by these studies. None of this discussion is to dissuade you from participating, it is merely
to help you make an informed choice.
As a research scientist who takes care of patients, I NEED you to help us take better care of
individuals with Organic Acidemias. As you know, many fundamental questions about these disorders
still exist. We do not know the natural history of these disorders well. We do not have adequate
medications and interventions. We cannot tell you whether you or your care is going to be severe or
mild, have a decompensation in the next 2 weeks or not, or develop a particular complication. This is
not to say that we are not getting better, but more information is necessary. Thanks for all the help
you provide to us.
understand your family’s disorder. We are going to start a new section to the newsletter to talk about
research.
Let’s start with what research is. It is a system or process in which the goal is to better understand
something in the world around us. We divide research into clinical (that which affects the patient
directly) and basic (that which studies fundamental processes, e.g. studying the Kreb’s cycle or how
cells talk to each other). Today we are going to talk about a subset of clinical research. As part of this
discussion, we are going to examine the expected benefits and risks from this subset of clinical
research--observational studies.
The two big, most basic categories of clinical research, basically research that which is designed to
understand the natural course of a disorder (observational) and that which tries to impact that natural
course (interventional). Sometimes, the research protocol tries to do both, especially if little is known
about a particular disorder or if a disorder is generally lethal to almost all with the disorder.
So from this point forward, we are going to ignore issues of interventional studies—these are clinical
trials in which an intervention, like a medication or a device is tested to see if it works better than
current practice and address these at a future date, and focus on observational studies.
Observation studies have several flavors, the shallow, the medium and the deep evaluations. In
general, observational studies collect information about an individual (like an individual with an
organic acidemia and their family). They can collect information at one particular time in many
individuals or can follow an individual or cohort of individuals over time. The best designed studies to
gather natural history—what happens in the disorder with current interventions over time---follows
individuals through time, but these can take a long time so some studies are designed to look at many
individuals who are at different points in their disorder at one moment in time and makes assumptions
about impact of time on the disorders. Either of these studies can be shallow, medium or deep in
terms of how much information they gather.
A study which is designed to take a shallow look at a disorder looks for the most basic facts (i.e.
disorder, genotype, current health) and often is fairly short in length (and so can take less time to
complete the initial forms). This can gather information once or over time from the same individuals.
The benefit from this study is that it can provide a “google earth” view of the disorder and takes little
time from each participant to gather the information (like minutes). The problem is it is a shallow
look at the disorder and so rare complications or occurrences are unlikely to be identified.
A study which is more in depth (a deep information study) tries to examine every possible thing about
a disorder and collects a lot of data on each participant often over the course of days. Often times this
type of study also gathers biological specimens (i.e. laboratory, biopsy, etc.) and radiological data (i.e.
X-ray, MRIs, etc.). Dr. Venditti’s natural history studies (for MMA and PA) at NIH are an example of
this type of study. Again individual participants can be studied over time (like Dr. Venditti’s studies) or
deeply once. This is like getting a magnifying glass out on a walk through the neighborhood and
studying as much as possible as closely as possible. You learn lots about lots of things but it takes lots
of time and produces much data. The benefits with these studies is rare occurrences or small changes
are more likely to be identified. The disadvantage is it takes lots of time from the participant and is
very expensive for the researcher.
The type of study which sits between these two in the continuum of studies is the medium study. It is
like the view one has walking down the street in one’s neighborhood, some detail (the designs on the
houses), but not lots of specifics (no idea how many ants on the sidewalk). Our natural history
registry with NORD is an example of this type of study. It does not gather as much information as the
deep study, but more than a shallow study. It tries to gather enough information that common rare
occurrences can be identified, but has less time commitment (more measured in an hours).
Each of these observation studies have some risks. Consent to participate in research of this type
should include a list of the risks identified and possible mitigations for these risk.
Privacy and confidentiality are two of the biggest risks with observational studies. Those observational
studies which include laboratory and radiology as a component also have risk associated with these
procedures.
Some common privacy risks in these types of studies include 1) how safe are my data and will
someone outside the study be able to see them and identify that it belongs to me, 2) can I be
identified by my data and how are my data being protected? Data here can mean your name, your
address, connecting the disorder to you, your health history, your date of birth, etc. You can
understand why these privacy issues could be concerning and why you as a participant (or your care)
should be aware of this risk.
Most reputable registries and natural history studies tell you how and where your information is stored
and protected as part of the consent. They are aware of the concern. In fact, the European Union
has just required much more strict privacy rules for any registry or natural history study which has
anyone who is lives in the EU or storage in the EU (it is called the General Data Protection
Regulations, if you want to look at them).
Despite the risks which can be associated with observational research, there is much that has and to
be learned by these studies. None of this discussion is to dissuade you from participating, it is merely
to help you make an informed choice.
As a research scientist who takes care of patients, I NEED you to help us take better care of
individuals with Organic Acidemias. As you know, many fundamental questions about these disorders
still exist. We do not know the natural history of these disorders well. We do not have adequate
medications and interventions. We cannot tell you whether you or your care is going to be severe or
mild, have a decompensation in the next 2 weeks or not, or develop a particular complication. This is
not to say that we are not getting better, but more information is necessary. Thanks for all the help
you provide to us.
Consents: Why do I care?
So, you are thinking in enrolling yourself or your care into a research study? Thank you for considering to help us understand your family’s disorder and search for treatments.
As we discussed last time, research is a process to understand the world in which we live. The most simplistic divisions include very basic research (i.e. the search to understand fundamental processes) and clinical research (most simplistically divided to observational and clinical trials). We have discussed observational clinical trials like registries and natural histories and interventional studies. Here we are focusing on consent.
So, let us talk about consents and here we are focusing on research consent. However, it is important to remember that you also sign consents every time you agree to be treated at the doctor and for any surgical-like procedures. Some of the same issues are applicable to research consents as to “permission to treat” consents. For example, if you need to have your appendix out, you sign a consent for the surgeon to take your appendix out which should list the risks of the surgery (like bleeding, infection, allergic reactions to medications, and yes even death) and the benefits of surgery (having a bad appendix out prevents its rupture, etc.). In the same way, when you participate in research, you also required to sign a consent to participate which reviews the risks and benefits of the study. Unlike a “permission to treat” consent which you are unlikely to refuse, you have the right to not participate in any research study and should not feel obligated in any way. We as researchers are very happy when you participate since it helps us learn more about your disorder, but never feel as though you are obligated to participate because it is your doctor who is asking. If you feel you have to participate because you feel it is right for you, your care or your family, then feel free to participate.
Research consents usually include 1) what is the intervention, procedure, or study, 2) what are the risks in participating and how are the risks mitigated, 3) what are the benefits of participating, and 4) your/your care’s signature and the date signed. You should be allowed to study the consent and ask any questions you wish about the study. Most consents list how to withdraw your consent and who do you contact if you think you have been harmed. They also review the responsibilities of the researchers and the participant.
To help with designing the consents and to determine if the risk and benefits are as balanced as possible, researchers have to present their research plans for interventional clinical trials (and any clinical trial for that matter) to their institutional review board (IRB for short) or ethics board (usually name in Europe). The IRB or ethics board makes a decision with the goal to keep the subject safe and consents are approved by the IRB/ethics board. IRB/ethic boards often have lay members from the community as evaluators of the proposals in addition to researchers unrelated to the research, physicians, research design experts, statisticians and legal experts. Many universities and medical centers have their own IRBs and often are looking for lay members to help, but it can be a big-time commitment, if you happen to be interested.
The goals of consents are to protect you as the participant (and to some extent the investigator and their institution) and to make sure you understand the risks (and benefits) of a particular research study. To “sign” a consent, an individual must be of legal age (in the US usually 18 years), be able to understand the consent, be able to understand the risks and benefits and able to agree the consent. In most cases, children ages 12-17 years should agree to the study as well, this is called “assent” and in many cases they also “sign” the assent. It is “sign” since some are physically unable to actually “sign” (for example a movement disorder making it impossible to physically sign), they may make a mark or have someone else put their signature with some other protections in place. Let us say that your care cannot understand all the implications of a particular study, is over 18 years, and you have their power of attorney for medical decisions, then you as their guardian signs the consent. If they can understand some and are capable of agreeing, we get their assent.
Thank you again for considering research.
As we discussed last time, research is a process to understand the world in which we live. The most simplistic divisions include very basic research (i.e. the search to understand fundamental processes) and clinical research (most simplistically divided to observational and clinical trials). We have discussed observational clinical trials like registries and natural histories and interventional studies. Here we are focusing on consent.
So, let us talk about consents and here we are focusing on research consent. However, it is important to remember that you also sign consents every time you agree to be treated at the doctor and for any surgical-like procedures. Some of the same issues are applicable to research consents as to “permission to treat” consents. For example, if you need to have your appendix out, you sign a consent for the surgeon to take your appendix out which should list the risks of the surgery (like bleeding, infection, allergic reactions to medications, and yes even death) and the benefits of surgery (having a bad appendix out prevents its rupture, etc.). In the same way, when you participate in research, you also required to sign a consent to participate which reviews the risks and benefits of the study. Unlike a “permission to treat” consent which you are unlikely to refuse, you have the right to not participate in any research study and should not feel obligated in any way. We as researchers are very happy when you participate since it helps us learn more about your disorder, but never feel as though you are obligated to participate because it is your doctor who is asking. If you feel you have to participate because you feel it is right for you, your care or your family, then feel free to participate.
Research consents usually include 1) what is the intervention, procedure, or study, 2) what are the risks in participating and how are the risks mitigated, 3) what are the benefits of participating, and 4) your/your care’s signature and the date signed. You should be allowed to study the consent and ask any questions you wish about the study. Most consents list how to withdraw your consent and who do you contact if you think you have been harmed. They also review the responsibilities of the researchers and the participant.
To help with designing the consents and to determine if the risk and benefits are as balanced as possible, researchers have to present their research plans for interventional clinical trials (and any clinical trial for that matter) to their institutional review board (IRB for short) or ethics board (usually name in Europe). The IRB or ethics board makes a decision with the goal to keep the subject safe and consents are approved by the IRB/ethics board. IRB/ethic boards often have lay members from the community as evaluators of the proposals in addition to researchers unrelated to the research, physicians, research design experts, statisticians and legal experts. Many universities and medical centers have their own IRBs and often are looking for lay members to help, but it can be a big-time commitment, if you happen to be interested.
The goals of consents are to protect you as the participant (and to some extent the investigator and their institution) and to make sure you understand the risks (and benefits) of a particular research study. To “sign” a consent, an individual must be of legal age (in the US usually 18 years), be able to understand the consent, be able to understand the risks and benefits and able to agree the consent. In most cases, children ages 12-17 years should agree to the study as well, this is called “assent” and in many cases they also “sign” the assent. It is “sign” since some are physically unable to actually “sign” (for example a movement disorder making it impossible to physically sign), they may make a mark or have someone else put their signature with some other protections in place. Let us say that your care cannot understand all the implications of a particular study, is over 18 years, and you have their power of attorney for medical decisions, then you as their guardian signs the consent. If they can understand some and are capable of agreeing, we get their assent.
Thank you again for considering research.
