Jay Udani article on clinical trial design

[Guest guest]

An article by Jay Udani, MD - on designing clinical trials (for supplements)

http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622

Clinical Trials: Will the Wrong Trial Design Make Your Dietary Supplement or

Functional Food an Unregistered Drug?

By Jay Udani<http://www.nutritionaloutlook.com/author/jay-udani> April 11, 2012

0<http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622#com\

ments> Comments

Designing clinical trials for natural health products, including dietary

supplements and functional foods, is a balancing act. It requires knowledge of

basic science, pathophysiology (the functional changes associated with a disease

or injury), good clinical practice (GCP), clinical medicine, regulatory affairs,

and even marketing. In order to maximize the likelihood of success, a good

clinical trial design will take all these into account.

If a study is successful, it can yield significant returns on investment for a

company. The payoffs of a successful study can include health claims

substantiation, use in scientific conference presentations, and publication in

peer-reviewed medical journals and company press releases-all resulting in

increased sales and distribution.

Alternatively, a poorly designed and/or executed study-regardless of whether the

study's results seemed to come out positive-can generate a series of

disappointments. Disappointments of a poor-quality study can range from a loss

of the investment made in the study, the presence of a negative study in your

regulatory file, or worse-a poorly designed or executed study can cause

regulatory agencies to categorize your dietary supplement or functional food as

an unregistered drug.

" Really? " you might say. An unregistered drug? How can that be? After all, you

have done the responsible thing by investing in a human clinical trial to prove

that your natural health product is in fact safe and efficacious.

However, as discussed ahead, what your study is designed to evaluate, and who

your study is performed on, can ultimately determine how regulators regard your

product.

What Regulatory Agencies Say

Let's look at how some regulatory bodies distinguish drug studies from

supplement studies.

First, what is the definition of a drug? According to FDA, a drug includes-among

other things- " articles intended for use in the diagnosis, cure, mitigation,

treatment, and prevention of disease... " Thus, if a clinical trial is performed

in which a product is tested to diagnose, cure, mitigate, treat, or prevent a

disease, FDA would classify the product as a drug.

FDA underlined this position in draft guidance published in October 2010, titled

" Investigational New Drug Applications (INDs)-Determining Whether Human Research

Studies Can Be Conducted without an IND. " In the draft guidance, the agency

stated that human studies must be conducted under an IND if the research

involves a drug, is a clinical investigation, and is not otherwise exempt from

the IND requirements. Thankfully, the draft guidance specifically exempts

dietary supplement clinical trials from IND requirements-as long as the dietary

supplement is being used to affect the structure and/or function of the body.

However, the guidance does specify that " whether an IND is needed for a clinical

investigation evaluating a dietary supplement is determined by the intent of the

clinical investigation [italics added]. "

Also, note that IND regulations apply to studies regardless of whether there is

commercial intent. This means that if a university performs a study on your

product (with or without your permission and/or involvement), the study requires

an IND if the study is designed to test the supplement's ability to diagnose,

cure, etc.

The bottom line is that even if you are very careful to follow DSHEA (Dietary

Supplement Health and Education Act) requirements by making no drug claims

whatsoever on your label and your website, your clinical trial design may in the

end determine whether or not your product is in fact considered a drug in FDA's

eyes.

Across the pond, the European Food Safety Authority (EFSA; Parma, Italy) also

draws differences between study designs for supplements and drugs. Specifically,

EFSA has stated that studies supporting non-drug products-e.g., dietary

supplements or functional food-that target a non-drug market should be performed

on a non-drug population. For instance, EFSA's July 2007 " Scientific and

Technical Guidance for the Preparation and Presentation of an Application for

Authorizations of a Health Claim (Revision 1) " states that health claim

applications must contain all scientific data (published and unpublished; data

in favor and not in favor). Notably, among the requirements is that the

" specific study group(s) in which the evidence was obtained is representative of

the target population for which the claim is intended. "

To date, EFSA has rejected many health claims applications. In reviewing the

rejection documents, it is clear that EFSA considers studies performed on

non-healthy, diseased subjects as not applicable to health claims for healthy

consumers of supplements and functional food.

Healthy Study Subjects: Challenges

Thus, for natural products like dietary supplements and functional food, studies

should target non-diseased populations and non-drug endpoints. Statistically,

however, there are challenges in performing studies in a non-diseased, healthy

population. In healthy volunteers, the magnitude of a physiological change due

to an intervention is likely to be smaller than it would be in diseased

subjects-and as a result of a smaller effect, the likelihood of demonstrating a

statistically significant difference is diminished.

How do you reconcile these seemingly competing requirements? On one hand, the

natural products industry is being asked to perform clinical trials to

demonstrate effects supporting health claims. On the other hand, if a study

involves a diseased population or measures endpoints that are only relevant to

drug products, it automatically brands the study product as a drug.

What options remain to provide scientifically valid studies that support

scientific, regulatory, and consumer needs?

Clinical Trial Design Goals

To design the perfect study, it is always best to start with the end in mind.

This means you should start by specifically determining the following goals: 1)

scientific, 2) regulatory, and 3) marketing.

The scientific goals of a clinical study can include determination and

demonstration of efficacy and safety, understanding and validating the mechanism

of action, and understanding for whom the product works best.

The regulatory goals of a clinical study can include establishing substantiation

for your proprietary product, determining that the substantiation for your

finished product specifically stems from an active ingredient within your

formulation, and protecting your company from legal challenges (especially class

action lawsuits).

The consumer (marketing) benefits of a clinical trial can include press-worthy

events (scientific poster presentations, peer-reviewed publications) and

providing experts with specific documentation to reference in interviews

regarding your product.

Once the goals have been established, it's time to design the study.

The Udani Theory of Natural Health Product Clinical Trial Design

For the last decade, one of the challenges for Medicus Research has been

designing clinical trials that meet a sponsor's goals while keeping in mind a

moving regulatory target. Consulting counsel, regulators, scientists, and past

experience has led the company to develop a working theory on how to design

studies that meet all of these needs. It's called The Udani Theory of Natural

Health Product Clinical Trial Design. This theory has three components:

1. Identify a healthy or at-risk population

2. Apply a standardized stressor to overwhelm subjects' normal physiological

mechanisms

3. Measure objective endpoints that are functionally relevant to the

scientist, regulator, and consumer

When it comes to selecting a healthy, non-disease population, keep this in mind:

while studies for non-drug products may not include diseased populations,

non-drug studies can include an at-risk population. The rationale for

identifying an at-risk population rests in understanding that the meaning of

healthy is not strictly the absence of disease but rather is where an

individual's well-being sits somewhere on the spectrum between perfect health

and end-stage disease. Therefore, a subject who is not diseased but who has

pathophysiology representing a point on the journey toward the diagnosis of a

disease is one who can most likely benefit from a dietary supplement-and is

therefore the perfect subject for a clinical trial on natural health products.

The purpose of the second step, applying a standardized stressor, is to

overwhelm the subject's physiology toward the edge of control. Doing so provides

the opportunity for the dietary supplement to potentially have a greater impact

and demonstrate a statistically and/or clinically significant distinction when

compared to placebo.

The third step, measuring objective and functionally relevant endpoints, means

to select functional endpoints that have meaning to scientists (by being

clinically meaningful and familiar in medical settings), regulators (by staying

within the framework established by DSHEA and EFSA), and subjects (by being

understandable and relevant to their health).

Clinical Trial Design Example: Immune Health

The immune system is a complex orchestration of structure and function involving

several organs and cell types. Claims for immune health are equally complex. A

healthy immune system is one that is vigilant, responds appropriately to the

presence of an antigen, removes the antigen, and cleans up after it is done.

Healthy people are exposed to environmental antigens on a daily basis. We are

coughed and sneezed upon, and touch surfaces which contain potentially

infectious microorganisms. Normally, our immune system recognizes these

antigens, takes action to destroy them, and then returns to the quiescent phase,

waiting for the next antigen to appear.

In order to design a study to support an immune-health claim, we applied The

Udani Theory as follows:

1. Identify a healthy population

a. Healthy volunteers were screened and enrolled for this study.

b. Any subjects with an underlying immune-system disorder were excluded.

2. Apply a standardized stressor

a. Wintertime community-based exposures to cold and flu viruses provide a

stressor that may potentially overwhelm the immune system of healthy volunteers.

During such an exposure, the natural (and self-limiting) immune-response

function is to increase the number of circulating immune cells and to increase

the function of these cells.

3. Measure objective endpoints that are functionally relevant to the

scientist, regulators, and the consumer

The progression of a viral prodrome (early virus signs or symptoms) to an upper

respiratory infection is the result of the failure of the immune system to

properly identify and overwhelm the antigen, leading to increased viral

replication and eventually the onset of the common cold. It is the natural

immune-response function that causes the viral prodrome.

In a clinical setting, it is very specifically the reduction of signs and

symptoms of the viral prodrome that is a surrogate marker for the appropriate

activation of the immune system, which is the primary endpoint.

a. To the scientist, these signs and symptoms are relevant, as they indicate the

presence of the activation of a physiologic process.

b. Regulators would not regard these as signs and symptoms of a disease; only of

a normal physiologic response.

c. The endpoint is meaningful to the consumer as well, as the average consumer

understands the feeling of a viral prodrome: feeling unwell.

Therefore, the dietary supplement structure/function claim " Helps support your

immune system " is measured by documenting the natural history of the

self-limiting process of the viral prodrome.

This is but one example of many therapeutic categories in which The Udani Theory

can be applied in order to design human clinical studies for non-diseased

populations. The natural health products industry is therefore presented with an

enormous opportunity by which it can firmly establish the efficacy and safety of

its products-while responsibly staying within regulatory parameters.

S. Kalman PhD, RD, FACN

Director, BD - Nutrition & Applied Clinical Trials

Miami Research Associates

6141 Sunset Drive - Suite 301

Miami, FL. 33143

Direct -

Office ext. 5109

Fax

Email: dkalman@...

Web: www.miamiresearch.com<www.mraclinicalresearch.com/>

Linked In: http://www.linkedin.com/in/douglaskalmanphdrd

[Guest guest]

How reliable is the information posted on the nutritional outlook website?

Green RD, LD, CDM

Clinical/Outpatient Dietitian

Gerald Champion Regional Medical Center

kgreen@...

________________________________

From: rd-usa [rd-usa ] On Behalf Of

Kalman [dkalman@...]

Sent: Thursday, April 12, 2012 12:52 PM

To: nutritionnews ; theissn ;

ACSMNutrition ; (rd-usa )

Subject: Jay Udani article on clinical trial design

An article by Jay Udani, MD - on designing clinical trials (for supplements)

http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622

Clinical Trials: Will the Wrong Trial Design Make Your Dietary Supplement or

Functional Food an Unregistered Drug?

By Jay Udani<http://www.nutritionaloutlook.com/author/jay-udani> April 11, 2012

0<http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622#com\

ments> Comments

Designing clinical trials for natural health products, including dietary

supplements and functional foods, is a balancing act. It requires knowledge of

basic science, pathophysiology (the functional changes associated with a disease

or injury), good clinical practice (GCP), clinical medicine, regulatory affairs,

and even marketing. In order to maximize the likelihood of success, a good

clinical trial design will take all these into account.

If a study is successful, it can yield significant returns on investment for a

company. The payoffs of a successful study can include health claims

substantiation, use in scientific conference presentations, and publication in

peer-reviewed medical journals and company press releases-all resulting in

increased sales and distribution.

Alternatively, a poorly designed and/or executed study-regardless of whether the

study's results seemed to come out positive-can generate a series of

disappointments. Disappointments of a poor-quality study can range from a loss

of the investment made in the study, the presence of a negative study in your

regulatory file, or worse-a poorly designed or executed study can cause

regulatory agencies to categorize your dietary supplement or functional food as

an unregistered drug.

" Really? " you might say. An unregistered drug? How can that be? After all, you

have done the responsible thing by investing in a human clinical trial to prove

that your natural health product is in fact safe and efficacious.

However, as discussed ahead, what your study is designed to evaluate, and who

your study is performed on, can ultimately determine how regulators regard your

product.

What Regulatory Agencies Say

Let's look at how some regulatory bodies distinguish drug studies from

supplement studies.

First, what is the definition of a drug? According to FDA, a drug includes-among

other things- " articles intended for use in the diagnosis, cure, mitigation,

treatment, and prevention of disease... " Thus, if a clinical trial is performed

in which a product is tested to diagnose, cure, mitigate, treat, or prevent a

disease, FDA would classify the product as a drug.

FDA underlined this position in draft guidance published in October 2010, titled

" Investigational New Drug Applications (INDs)-Determining Whether Human Research

Studies Can Be Conducted without an IND. " In the draft guidance, the agency

stated that human studies must be conducted under an IND if the research

involves a drug, is a clinical investigation, and is not otherwise exempt from

the IND requirements. Thankfully, the draft guidance specifically exempts

dietary supplement clinical trials from IND requirements-as long as the dietary

supplement is being used to affect the structure and/or function of the body.

However, the guidance does specify that " whether an IND is needed for a clinical

investigation evaluating a dietary supplement is determined by the intent of the

clinical investigation [italics added]. "

Also, note that IND regulations apply to studies regardless of whether there is

commercial intent. This means that if a university performs a study on your

product (with or without your permission and/or involvement), the study requires

an IND if the study is designed to test the supplement's ability to diagnose,

cure, etc.

The bottom line is that even if you are very careful to follow DSHEA (Dietary

Supplement Health and Education Act) requirements by making no drug claims

whatsoever on your label and your website, your clinical trial design may in the

end determine whether or not your product is in fact considered a drug in FDA's

eyes.

Across the pond, the European Food Safety Authority (EFSA; Parma, Italy) also

draws differences between study designs for supplements and drugs. Specifically,

EFSA has stated that studies supporting non-drug products-e.g., dietary

supplements or functional food-that target a non-drug market should be performed

on a non-drug population. For instance, EFSA's July 2007 " Scientific and

Technical Guidance for the Preparation and Presentation of an Application for

Authorizations of a Health Claim (Revision 1) " states that health claim

applications must contain all scientific data (published and unpublished; data

in favor and not in favor). Notably, among the requirements is that the

" specific study group(s) in which the evidence was obtained is representative of

the target population for which the claim is intended. "

To date, EFSA has rejected many health claims applications. In reviewing the

rejection documents, it is clear that EFSA considers studies performed on

non-healthy, diseased subjects as not applicable to health claims for healthy

consumers of supplements and functional food.

Healthy Study Subjects: Challenges

Thus, for natural products like dietary supplements and functional food, studies

should target non-diseased populations and non-drug endpoints. Statistically,

however, there are challenges in performing studies in a non-diseased, healthy

population. In healthy volunteers, the magnitude of a physiological change due

to an intervention is likely to be smaller than it would be in diseased

subjects-and as a result of a smaller effect, the likelihood of demonstrating a

statistically significant difference is diminished.

How do you reconcile these seemingly competing requirements? On one hand, the

natural products industry is being asked to perform clinical trials to

demonstrate effects supporting health claims. On the other hand, if a study

involves a diseased population or measures endpoints that are only relevant to

drug products, it automatically brands the study product as a drug.

What options remain to provide scientifically valid studies that support

scientific, regulatory, and consumer needs?

Clinical Trial Design Goals

To design the perfect study, it is always best to start with the end in mind.

This means you should start by specifically determining the following goals: 1)

scientific, 2) regulatory, and 3) marketing.

The scientific goals of a clinical study can include determination and

demonstration of efficacy and safety, understanding and validating the mechanism

of action, and understanding for whom the product works best.

The regulatory goals of a clinical study can include establishing substantiation

for your proprietary product, determining that the substantiation for your

finished product specifically stems from an active ingredient within your

formulation, and protecting your company from legal challenges (especially class

action lawsuits).

The consumer (marketing) benefits of a clinical trial can include press-worthy

events (scientific poster presentations, peer-reviewed publications) and

providing experts with specific documentation to reference in interviews

regarding your product.

Once the goals have been established, it's time to design the study.

The Udani Theory of Natural Health Product Clinical Trial Design

For the last decade, one of the challenges for Medicus Research has been

designing clinical trials that meet a sponsor's goals while keeping in mind a

moving regulatory target. Consulting counsel, regulators, scientists, and past

experience has led the company to develop a working theory on how to design

studies that meet all of these needs. It's called The Udani Theory of Natural

Health Product Clinical Trial Design. This theory has three components:

1. Identify a healthy or at-risk population

2. Apply a standardized stressor to overwhelm subjects' normal physiological

mechanisms

3. Measure objective endpoints that are functionally relevant to the scientist,

regulator, and consumer

When it comes to selecting a healthy, non-disease population, keep this in mind:

while studies for non-drug products may not include diseased populations,

non-drug studies can include an at-risk population. The rationale for

identifying an at-risk population rests in understanding that the meaning of

healthy is not strictly the absence of disease but rather is where an

individual's well-being sits somewhere on the spectrum between perfect health

and end-stage disease. Therefore, a subject who is not diseased but who has

pathophysiology representing a point on the journey toward the diagnosis of a

disease is one who can most likely benefit from a dietary supplement-and is

therefore the perfect subject for a clinical trial on natural health products.

The purpose of the second step, applying a standardized stressor, is to

overwhelm the subject's physiology toward the edge of control. Doing so provides

the opportunity for the dietary supplement to potentially have a greater impact

and demonstrate a statistically and/or clinically significant distinction when

compared to placebo.

The third step, measuring objective and functionally relevant endpoints, means

to select functional endpoints that have meaning to scientists (by being

clinically meaningful and familiar in medical settings), regulators (by staying

within the framework established by DSHEA and EFSA), and subjects (by being

understandable and relevant to their health).

Clinical Trial Design Example: Immune Health

The immune system is a complex orchestration of structure and function involving

several organs and cell types. Claims for immune health are equally complex. A

healthy immune system is one that is vigilant, responds appropriately to the

presence of an antigen, removes the antigen, and cleans up after it is done.

Healthy people are exposed to environmental antigens on a daily basis. We are

coughed and sneezed upon, and touch surfaces which contain potentially

infectious microorganisms. Normally, our immune system recognizes these

antigens, takes action to destroy them, and then returns to the quiescent phase,

waiting for the next antigen to appear.

In order to design a study to support an immune-health claim, we applied The

Udani Theory as follows:

1. Identify a healthy population

a. Healthy volunteers were screened and enrolled for this study.

b. Any subjects with an underlying immune-system disorder were excluded.

2. Apply a standardized stressor

a. Wintertime community-based exposures to cold and flu viruses provide a

stressor that may potentially overwhelm the immune system of healthy volunteers.

During such an exposure, the natural (and self-limiting) immune-response

function is to increase the number of circulating immune cells and to increase

the function of these cells.

3. Measure objective endpoints that are functionally relevant to the scientist,

regulators, and the consumer

The progression of a viral prodrome (early virus signs or symptoms) to an upper

respiratory infection is the result of the failure of the immune system to

properly identify and overwhelm the antigen, leading to increased viral

replication and eventually the onset of the common cold. It is the natural

immune-response function that causes the viral prodrome.

In a clinical setting, it is very specifically the reduction of signs and

symptoms of the viral prodrome that is a surrogate marker for the appropriate

activation of the immune system, which is the primary endpoint.

a. To the scientist, these signs and symptoms are relevant, as they indicate the

presence of the activation of a physiologic process.

b. Regulators would not regard these as signs and symptoms of a disease; only of

a normal physiologic response.

c. The endpoint is meaningful to the consumer as well, as the average consumer

understands the feeling of a viral prodrome: feeling unwell.

Therefore, the dietary supplement structure/function claim " Helps support your

immune system " is measured by documenting the natural history of the

self-limiting process of the viral prodrome.

This is but one example of many therapeutic categories in which The Udani Theory

can be applied in order to design human clinical studies for non-diseased

populations. The natural health products industry is therefore presented with an

enormous opportunity by which it can firmly establish the efficacy and safety of

its products-while responsibly staying within regulatory parameters.

S. Kalman PhD, RD, FACN

Director, BD - Nutrition & Applied Clinical Trials

Miami Research Associates

6141 Sunset Drive - Suite 301

Miami, FL. 33143

Direct -

Office ext. 5109

Fax

Email:

dkalman@...<mailto:dkalman%40miamiresearch.com><mailto:dkalman@mia\

miresearch.com<mailto:dkalman%40miamiresearch.com>>

Web: www.miamiresearch.com<www.mraclinicalresearch.com/>

Linked In: http://www.linkedin.com/in/douglaskalmanphdrd

[Guest guest]

How reliable is the information posted on the nutritional outlook website?

Green RD, LD, CDM

Clinical/Outpatient Dietitian

Gerald Champion Regional Medical Center

kgreen@...

________________________________

From: rd-usa [rd-usa ] On Behalf Of

Kalman [dkalman@...]

Sent: Thursday, April 12, 2012 12:52 PM

To: nutritionnews ; theissn ;

ACSMNutrition ; (rd-usa )

Subject: Jay Udani article on clinical trial design

An article by Jay Udani, MD - on designing clinical trials (for supplements)

http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622

Clinical Trials: Will the Wrong Trial Design Make Your Dietary Supplement or

Functional Food an Unregistered Drug?

By Jay Udani<http://www.nutritionaloutlook.com/author/jay-udani> April 11, 2012

0<http://www.nutritionaloutlook.com/article/designing-clinical-trials-4-9622#com\

ments> Comments

Designing clinical trials for natural health products, including dietary

supplements and functional foods, is a balancing act. It requires knowledge of

basic science, pathophysiology (the functional changes associated with a disease

or injury), good clinical practice (GCP), clinical medicine, regulatory affairs,

and even marketing. In order to maximize the likelihood of success, a good

clinical trial design will take all these into account.

If a study is successful, it can yield significant returns on investment for a

company. The payoffs of a successful study can include health claims

substantiation, use in scientific conference presentations, and publication in

peer-reviewed medical journals and company press releases-all resulting in

increased sales and distribution.

Alternatively, a poorly designed and/or executed study-regardless of whether the

study's results seemed to come out positive-can generate a series of

disappointments. Disappointments of a poor-quality study can range from a loss

of the investment made in the study, the presence of a negative study in your

regulatory file, or worse-a poorly designed or executed study can cause

regulatory agencies to categorize your dietary supplement or functional food as

an unregistered drug.

" Really? " you might say. An unregistered drug? How can that be? After all, you

have done the responsible thing by investing in a human clinical trial to prove

that your natural health product is in fact safe and efficacious.

However, as discussed ahead, what your study is designed to evaluate, and who

your study is performed on, can ultimately determine how regulators regard your

product.

What Regulatory Agencies Say

Let's look at how some regulatory bodies distinguish drug studies from

supplement studies.

First, what is the definition of a drug? According to FDA, a drug includes-among

other things- " articles intended for use in the diagnosis, cure, mitigation,

treatment, and prevention of disease... " Thus, if a clinical trial is performed

in which a product is tested to diagnose, cure, mitigate, treat, or prevent a

disease, FDA would classify the product as a drug.

FDA underlined this position in draft guidance published in October 2010, titled

" Investigational New Drug Applications (INDs)-Determining Whether Human Research

Studies Can Be Conducted without an IND. " In the draft guidance, the agency

stated that human studies must be conducted under an IND if the research

involves a drug, is a clinical investigation, and is not otherwise exempt from

the IND requirements. Thankfully, the draft guidance specifically exempts

dietary supplement clinical trials from IND requirements-as long as the dietary

supplement is being used to affect the structure and/or function of the body.

However, the guidance does specify that " whether an IND is needed for a clinical

investigation evaluating a dietary supplement is determined by the intent of the

clinical investigation [italics added]. "

Also, note that IND regulations apply to studies regardless of whether there is

commercial intent. This means that if a university performs a study on your

product (with or without your permission and/or involvement), the study requires

an IND if the study is designed to test the supplement's ability to diagnose,

cure, etc.

The bottom line is that even if you are very careful to follow DSHEA (Dietary

Supplement Health and Education Act) requirements by making no drug claims

whatsoever on your label and your website, your clinical trial design may in the

end determine whether or not your product is in fact considered a drug in FDA's

eyes.

Across the pond, the European Food Safety Authority (EFSA; Parma, Italy) also

draws differences between study designs for supplements and drugs. Specifically,

EFSA has stated that studies supporting non-drug products-e.g., dietary

supplements or functional food-that target a non-drug market should be performed

on a non-drug population. For instance, EFSA's July 2007 " Scientific and

Technical Guidance for the Preparation and Presentation of an Application for

Authorizations of a Health Claim (Revision 1) " states that health claim

applications must contain all scientific data (published and unpublished; data

in favor and not in favor). Notably, among the requirements is that the

" specific study group(s) in which the evidence was obtained is representative of

the target population for which the claim is intended. "

To date, EFSA has rejected many health claims applications. In reviewing the

rejection documents, it is clear that EFSA considers studies performed on

non-healthy, diseased subjects as not applicable to health claims for healthy

consumers of supplements and functional food.

Healthy Study Subjects: Challenges

Thus, for natural products like dietary supplements and functional food, studies

should target non-diseased populations and non-drug endpoints. Statistically,

however, there are challenges in performing studies in a non-diseased, healthy

population. In healthy volunteers, the magnitude of a physiological change due

to an intervention is likely to be smaller than it would be in diseased

subjects-and as a result of a smaller effect, the likelihood of demonstrating a

statistically significant difference is diminished.

How do you reconcile these seemingly competing requirements? On one hand, the

natural products industry is being asked to perform clinical trials to

demonstrate effects supporting health claims. On the other hand, if a study

involves a diseased population or measures endpoints that are only relevant to

drug products, it automatically brands the study product as a drug.

What options remain to provide scientifically valid studies that support

scientific, regulatory, and consumer needs?

Clinical Trial Design Goals

To design the perfect study, it is always best to start with the end in mind.

This means you should start by specifically determining the following goals: 1)

scientific, 2) regulatory, and 3) marketing.

The scientific goals of a clinical study can include determination and

demonstration of efficacy and safety, understanding and validating the mechanism

of action, and understanding for whom the product works best.

The regulatory goals of a clinical study can include establishing substantiation

for your proprietary product, determining that the substantiation for your

finished product specifically stems from an active ingredient within your

formulation, and protecting your company from legal challenges (especially class

action lawsuits).

The consumer (marketing) benefits of a clinical trial can include press-worthy

events (scientific poster presentations, peer-reviewed publications) and

providing experts with specific documentation to reference in interviews

regarding your product.

Once the goals have been established, it's time to design the study.

The Udani Theory of Natural Health Product Clinical Trial Design

For the last decade, one of the challenges for Medicus Research has been

designing clinical trials that meet a sponsor's goals while keeping in mind a

moving regulatory target. Consulting counsel, regulators, scientists, and past

experience has led the company to develop a working theory on how to design

studies that meet all of these needs. It's called The Udani Theory of Natural

Health Product Clinical Trial Design. This theory has three components:

1. Identify a healthy or at-risk population

2. Apply a standardized stressor to overwhelm subjects' normal physiological

mechanisms

3. Measure objective endpoints that are functionally relevant to the scientist,

regulator, and consumer

When it comes to selecting a healthy, non-disease population, keep this in mind:

while studies for non-drug products may not include diseased populations,

non-drug studies can include an at-risk population. The rationale for

identifying an at-risk population rests in understanding that the meaning of

healthy is not strictly the absence of disease but rather is where an

individual's well-being sits somewhere on the spectrum between perfect health

and end-stage disease. Therefore, a subject who is not diseased but who has

pathophysiology representing a point on the journey toward the diagnosis of a

disease is one who can most likely benefit from a dietary supplement-and is

therefore the perfect subject for a clinical trial on natural health products.

The purpose of the second step, applying a standardized stressor, is to

overwhelm the subject's physiology toward the edge of control. Doing so provides

the opportunity for the dietary supplement to potentially have a greater impact

and demonstrate a statistically and/or clinically significant distinction when

compared to placebo.

The third step, measuring objective and functionally relevant endpoints, means

to select functional endpoints that have meaning to scientists (by being

clinically meaningful and familiar in medical settings), regulators (by staying

within the framework established by DSHEA and EFSA), and subjects (by being

understandable and relevant to their health).

Clinical Trial Design Example: Immune Health

The immune system is a complex orchestration of structure and function involving

several organs and cell types. Claims for immune health are equally complex. A

healthy immune system is one that is vigilant, responds appropriately to the

presence of an antigen, removes the antigen, and cleans up after it is done.

Healthy people are exposed to environmental antigens on a daily basis. We are

coughed and sneezed upon, and touch surfaces which contain potentially

infectious microorganisms. Normally, our immune system recognizes these

antigens, takes action to destroy them, and then returns to the quiescent phase,

waiting for the next antigen to appear.

In order to design a study to support an immune-health claim, we applied The

Udani Theory as follows:

1. Identify a healthy population

a. Healthy volunteers were screened and enrolled for this study.

b. Any subjects with an underlying immune-system disorder were excluded.

2. Apply a standardized stressor

a. Wintertime community-based exposures to cold and flu viruses provide a

stressor that may potentially overwhelm the immune system of healthy volunteers.

During such an exposure, the natural (and self-limiting) immune-response

function is to increase the number of circulating immune cells and to increase

the function of these cells.

3. Measure objective endpoints that are functionally relevant to the scientist,

regulators, and the consumer

The progression of a viral prodrome (early virus signs or symptoms) to an upper

respiratory infection is the result of the failure of the immune system to

properly identify and overwhelm the antigen, leading to increased viral

replication and eventually the onset of the common cold. It is the natural

immune-response function that causes the viral prodrome.

In a clinical setting, it is very specifically the reduction of signs and

symptoms of the viral prodrome that is a surrogate marker for the appropriate

activation of the immune system, which is the primary endpoint.

a. To the scientist, these signs and symptoms are relevant, as they indicate the

presence of the activation of a physiologic process.

b. Regulators would not regard these as signs and symptoms of a disease; only of

a normal physiologic response.

c. The endpoint is meaningful to the consumer as well, as the average consumer

understands the feeling of a viral prodrome: feeling unwell.

Therefore, the dietary supplement structure/function claim " Helps support your

immune system " is measured by documenting the natural history of the

self-limiting process of the viral prodrome.

This is but one example of many therapeutic categories in which The Udani Theory

can be applied in order to design human clinical studies for non-diseased

populations. The natural health products industry is therefore presented with an

enormous opportunity by which it can firmly establish the efficacy and safety of

its products-while responsibly staying within regulatory parameters.

S. Kalman PhD, RD, FACN

Director, BD - Nutrition & Applied Clinical Trials

Miami Research Associates

6141 Sunset Drive - Suite 301

Miami, FL. 33143

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Office ext. 5109

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Email:

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