Research Corner
Research study for patients with PDE or GA I
We are recruiting patients and families for the CHARLIE metabolism Project (CHAnging Rare disorder of LysINe metabolism). This is an international collaboration focused on developing novel therapies for patients with pyridoxine-dependent epilepsy (PDE) and glutaric aciduria type I (GA I). Both substrate reduction therapy (an upstream block of lysine metabolism) and gene replacement therapy will be trialed in model systems such as neuronal stem cells, mouse, and zebrafish models. The CHARLIE project is led by Professor Clara van Karnebeek at the University of Amsterdam UMC in the Netherlands.
Although this is a basic-research focused project, we also want to work closely with patients and families in order to describe the needs and wishes of families and to define goals of care that are essential to improve quality of life. This project (referred to as “patients in the lead”) is led by Hanna Dekker who is the director of the VKS (a Dutch patient support organization). https://www.stofwisselingsziekten.nl/
If you are interested in more information or in participating, please contact Dr. Curtis Coughlin II at the University of Colorado (Curtis.Coughlin@cuanschutz.edu, 303.724.3839)
We are recruiting patients and families for the CHARLIE metabolism Project (CHAnging Rare disorder of LysINe metabolism). This is an international collaboration focused on developing novel therapies for patients with pyridoxine-dependent epilepsy (PDE) and glutaric aciduria type I (GA I). Both substrate reduction therapy (an upstream block of lysine metabolism) and gene replacement therapy will be trialed in model systems such as neuronal stem cells, mouse, and zebrafish models. The CHARLIE project is led by Professor Clara van Karnebeek at the University of Amsterdam UMC in the Netherlands.
Although this is a basic-research focused project, we also want to work closely with patients and families in order to describe the needs and wishes of families and to define goals of care that are essential to improve quality of life. This project (referred to as “patients in the lead”) is led by Hanna Dekker who is the director of the VKS (a Dutch patient support organization). https://www.stofwisselingsziekten.nl/
If you are interested in more information or in participating, please contact Dr. Curtis Coughlin II at the University of Colorado (Curtis.Coughlin@cuanschutz.edu, 303.724.3839)
Dr. Karolina M. Stepien
Salford Royal NHS Foundation Trust
Manchester, ENG
karolina.stepien@nca.nhs.uk
Together with EHOD members, I work on an international collaborative research study aiming at identifying:
- pregnant females affected with Cobalamin Deficiency or Remethylation Disorder
- pregnant females where the fetus is affected with Cobalamin Deficiency or Remethylation Disorder
- to document clinical management throughout the pregnancy, with a focus on therapeutic options
- to review the safety data of betaine and hydroxycobalamin as therapies
- to review the acute and long-term clinical maternal and fetal outcomes
- to develop consensus guidelines on their management
If you are interested in participating, please contact Dr. Stepien at the email above.
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.
Interventional Clinical Research: What to know, what to ask, is it right for my family?
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). Last time we discussed observational clinical trials like registries and natural histories. Here we are focusing on clinical trials.
Clinical trials are interventional studies which are often designed to determine whether an intervention works. This is often a medication (or things like gene therapy). It can also be for a surgical device or technique. It may also be a new measurement technique. In research, the patient is often referred to as the subject so we will use that language from now on in our discussion
The “gold standard” type a trial is called a placebo controlled clinical trial. In this type of trial, the design is that the subject will either 1) receive the intervention (i.e. medication, intervention, etc.) or 2) a sham (i.e. a sugar pill or pretend intervention) and an outcome is measured. This way whether the intervention impacted the subject or whether it is just them thinking they got intervention (instead getting the sham treatment also known as placebo) helped the subject can be determined. It is well known that in some people, the sham or placebo can result in the measured outcome. It is amazing how powerful our brains can be. The whole idea of this type of study is to decrease bias and make sure something really works. As you can see in the placebo controlled study, the advantage is you may receive the intervention, the disadvantage is you may not. However, it does prove that an intervention works or not (and the FDA who approved interventions really likes these kind of studies).
There is a variation in this type of study in which a known beneficial intervention is used instead of the sham and compared to that being tested intervention. In organic acidemias, there are only rare occasions in which this design method would be able to be used instead of a placebo controlled mostly because there are few known beneficial interventions.
Usually placebo-controlled or comparison of two interventions/therapies needs lots and lots of subjects to reach a statistical difference---the fancy math needed to show something works or not. As you can imagine this is hard in rare diseases, because, well they are rare---like organic acidemias. So sometimes, a subject can be their own control and so they receive or do not receive the intervention for some time and then for the next part of the study receive the opposite of the first part. Few subjects are needed and so more common in rare disease and this is an advantage. The disadvantage is it takes more time to do these studies as the subject since there are two parts.
Less useful, but sometimes the only option are intervention only studies. Sometimes having a sham section is unethical since the process of doing the sham procedure is too dangerous or the disorder is so lethal that if the intervention works it is lifesaving. Sometimes interventional only studies will use natural history data as their control group (sort of like a placebo group but without a group getting placebo). For this type of interventional clinical trial, good natural history studies (and registries) are essential---part of the goal of the OAA natural history registry with NORD is to help provide this data. This is why sometimes a company with an intervention may try to start a natural history---they are looking for their control group.
Now with every research study, risks and benefits are weighed. The goal is for the potential benefit to outweigh the risk of the trial. In trials which are thought to have little benefit to the individual participating then the trial must be very or no minimal risk. Clinical trials by definition introduce some risk---the intervention as well as sometimes the way to figure out it works because laboratory blood and urine collections introduce risk, as does biopsies, as do radiology interventions. It is important to examine the risks for any study you consider. It is also important to think about not just the procedure related risks, but risks like time commitment (okay maybe not a risk, but could be if it is more than your employer allows). Since time is an issue, some studies reimburse for time. Some reimburse for travel and food during the study.
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 about whether the research can be done with the goal to keep the subject safe. Consents are the legal document you sign in which you agree to participate and understand the risks and benefits. These are approved by the IRB/ethics board. Different IRBs and ethic boards may weigh the risks and benefits differently and so often different institutions who are participating in an interventional study will have slightly different consents if their boards are different. We will talk more about consents in a subsequent Research Corner.
So how do you decide whether a study is right for your family? Ask yourself whether you think the benefits outweigh the risks? You are the only one who can ultimately make this decision. To help you, you can talk to your metabolist or primary doctor. Talk to the researchers and ask questions about anything you do not understand. Evaluate the consent and what the design of the study.
Some questions you can use to evaluate a study include the following: Is there a placebo arm? Are you your own control with some placebo/standard of care compared to the intervention? Is it a comparison study looking at intervention compared to standard of care? How much is the time commitment? Will I need to travel and how often? Are the answers to these questions okay with my family? Also ask yourself, if the intervention works, what does this mean to me/my care, my family, to OAA community at large? In addition ask yourself, if the intervention does not work, what does this mean to me/my care, my family, to OAA community at large? What is the risk of dying or worsening and is this known? Am I okay with the risk of worsening, if there is a chance to get better? What chance of getting better am I or my family willing to take?
For some, the information about whether a particular intervention works or not, is enough for them to say, “this is a good thing”, and decide to participate. For others, this is not a motivation and their calculations are different. My hope is that you and your family participates in research at the level of your comfort. Only you and your family can balance the risks and benefits. As you know, we NEED you to help us take better care of you or your cares.
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). Last time we discussed observational clinical trials like registries and natural histories. Here we are focusing on clinical trials.
Clinical trials are interventional studies which are often designed to determine whether an intervention works. This is often a medication (or things like gene therapy). It can also be for a surgical device or technique. It may also be a new measurement technique. In research, the patient is often referred to as the subject so we will use that language from now on in our discussion
The “gold standard” type a trial is called a placebo controlled clinical trial. In this type of trial, the design is that the subject will either 1) receive the intervention (i.e. medication, intervention, etc.) or 2) a sham (i.e. a sugar pill or pretend intervention) and an outcome is measured. This way whether the intervention impacted the subject or whether it is just them thinking they got intervention (instead getting the sham treatment also known as placebo) helped the subject can be determined. It is well known that in some people, the sham or placebo can result in the measured outcome. It is amazing how powerful our brains can be. The whole idea of this type of study is to decrease bias and make sure something really works. As you can see in the placebo controlled study, the advantage is you may receive the intervention, the disadvantage is you may not. However, it does prove that an intervention works or not (and the FDA who approved interventions really likes these kind of studies).
There is a variation in this type of study in which a known beneficial intervention is used instead of the sham and compared to that being tested intervention. In organic acidemias, there are only rare occasions in which this design method would be able to be used instead of a placebo controlled mostly because there are few known beneficial interventions.
Usually placebo-controlled or comparison of two interventions/therapies needs lots and lots of subjects to reach a statistical difference---the fancy math needed to show something works or not. As you can imagine this is hard in rare diseases, because, well they are rare---like organic acidemias. So sometimes, a subject can be their own control and so they receive or do not receive the intervention for some time and then for the next part of the study receive the opposite of the first part. Few subjects are needed and so more common in rare disease and this is an advantage. The disadvantage is it takes more time to do these studies as the subject since there are two parts.
Less useful, but sometimes the only option are intervention only studies. Sometimes having a sham section is unethical since the process of doing the sham procedure is too dangerous or the disorder is so lethal that if the intervention works it is lifesaving. Sometimes interventional only studies will use natural history data as their control group (sort of like a placebo group but without a group getting placebo). For this type of interventional clinical trial, good natural history studies (and registries) are essential---part of the goal of the OAA natural history registry with NORD is to help provide this data. This is why sometimes a company with an intervention may try to start a natural history---they are looking for their control group.
Now with every research study, risks and benefits are weighed. The goal is for the potential benefit to outweigh the risk of the trial. In trials which are thought to have little benefit to the individual participating then the trial must be very or no minimal risk. Clinical trials by definition introduce some risk---the intervention as well as sometimes the way to figure out it works because laboratory blood and urine collections introduce risk, as does biopsies, as do radiology interventions. It is important to examine the risks for any study you consider. It is also important to think about not just the procedure related risks, but risks like time commitment (okay maybe not a risk, but could be if it is more than your employer allows). Since time is an issue, some studies reimburse for time. Some reimburse for travel and food during the study.
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 about whether the research can be done with the goal to keep the subject safe. Consents are the legal document you sign in which you agree to participate and understand the risks and benefits. These are approved by the IRB/ethics board. Different IRBs and ethic boards may weigh the risks and benefits differently and so often different institutions who are participating in an interventional study will have slightly different consents if their boards are different. We will talk more about consents in a subsequent Research Corner.
So how do you decide whether a study is right for your family? Ask yourself whether you think the benefits outweigh the risks? You are the only one who can ultimately make this decision. To help you, you can talk to your metabolist or primary doctor. Talk to the researchers and ask questions about anything you do not understand. Evaluate the consent and what the design of the study.
Some questions you can use to evaluate a study include the following: Is there a placebo arm? Are you your own control with some placebo/standard of care compared to the intervention? Is it a comparison study looking at intervention compared to standard of care? How much is the time commitment? Will I need to travel and how often? Are the answers to these questions okay with my family? Also ask yourself, if the intervention works, what does this mean to me/my care, my family, to OAA community at large? In addition ask yourself, if the intervention does not work, what does this mean to me/my care, my family, to OAA community at large? What is the risk of dying or worsening and is this known? Am I okay with the risk of worsening, if there is a chance to get better? What chance of getting better am I or my family willing to take?
For some, the information about whether a particular intervention works or not, is enough for them to say, “this is a good thing”, and decide to participate. For others, this is not a motivation and their calculations are different. My hope is that you and your family participates in research at the level of your comfort. Only you and your family can balance the risks and benefits. As you know, we NEED you to help us take better care of you or your cares.
