# Presentation: 134087

## Levothyroxine Therapeutic Equivalence  Workshop: Presentation Before the Food and Drug AdministrationMay 23, 2005

**John Leonard, MD**
**Vice President, Global Scientific & Medical Affairs**
**Abbott**

**Notes:**

Thank you.
I am John Leonard, VP of Medical and Scientific Affairs at Abbott.  We appreciate the opportunity to share some of our thoughts with the workshop here today. 
Abbott is the manufacturer of Synthroid, a widely prescribed levothyroxine product.  
I come to this workshop as a manufacturer, understanding what it means to produce a product.
I also come as a physician who is mindful of the conditions for which these products are used.  
I will discuss both perspectives and describe why we, and virtually the entire endocrine treatment community, believe that this workshop is not discussing dry Regulatory issues, but instead critically important medical questions.
These are medical questions that should be addressed very carefully before proceeding further down the path that assumes therapeutic equivalence and permits widespread switching of agents used in highly individualized therapy, regardless of who manufactures those agents.
Let’s review why this is so.

## What is the Role of Thyroid Hormone?

**Modulate metabolic and growth processes in the body**
- Part of a finely-tuned physiologic mechanism to maintain a tightly controlled homeostatic state
**Consequences of hypothyroidism, where thyroid hormone is low and TSH is elevated**
- Elevated cholesterol levels
- Atherosclerosis and myocardial infarction
- Decreased intellectual function in the children of women hypothyroid in early pregnancy
**Consequences of hyperthyroidism, where thyroid hormone is high and TSH is decreased**
- Osteoporosis in the elderly
- Atrial fibrillation and other arrhythmias

**Notes:**

The thyroid gland produces LT4, a hormone essential to life.

Because the thyroid produces an essential hormone, the body developed a finely tuned mechanism to assure that thyroid hormone is present in appropriate levels. These levels vary relatively little within a patient day-to-day.

When the thyroid is diseased, this delicate balance is disrupted.

Hypothyroidism manifests with well known effects illustrated here and ....

...Hyperthyroidism also causes many medical conditions, each highly prevalent. 

## What is the Primary Goal of Thyroid Hormone Replacement?

**Approximate the body’s finely-tuned thyroid hormone system**
- Individualized patient titration to optimal state
- Maintenance of optimized state by consistent, day-to-day thyroid hormone delivery
**Thyroid hormone must be dosed consistently to maintain normal thyroid hormone status in a narrow range**
- Multiple dose strengths, with increments as small as 12 mcg, are essential for optimal titration and therapy
- Clinicians titrate thyroid hormone to a constant dose
- Once a patient is euthyroid, ideally that regimen will remain unchanged
***Variability in thyroid hormone therapy ******must be minimized***

**Notes:**

What is the goal of thyroid hormone replacement therapy?
The doctor is attempting to replicate the finely tuned homeostatic state that is essential to human health.  
At best we can only approximate this goal.  
When a physician initiates thyroid hormone therapy, a titration process is carried out to achieve the appropriate dose.  
Doctors provide microgram doses to patients with dose increments differing by as little as 9 percent.  
These tiny dose increments are essential to good titration and are critical to achieving the optimized treatment regimen for each  patient.  
Clinical indicators, such as pulse and temperature, provide gross indications of improvement, but the titration is further informed by serum TSH levels, the body’s internal thermostat for detecting LT4 effects.
Ultimately physicians supplement clinical observation and biochemical tests with a highly discerning indicator of treatment success: asking a patient how he or she feels. 
And, once the patient feels well, great attention is placed on keeping the patient well by minimizing variations to the treatment regimen.

## Is There a Clinical Reason to Avoid Variability?

**Clinical community says: “yes”**
- Experts have testified that differences in bioavailability may be especially significant for at-risk populations:
- Geriatric patients, cancer patients, high-risk cardiovascular patients, and pregnant patients and their children
**FDA has said: “yes”**
- In 2001, FDA stated that a 9% difference refill-to-refill could result in “serious consequences” for thyroid patients.
- In July 2004, FDA assured manufacturers and the clinical community that its standards “will not allow products that differ by 9% or more in potency or bioavailability to be rated therapeutically equivalent.”

**Notes:**
Some degree of variability surrounds any treatment regimen for any medical condition.  
Minimizing that variability is always desirable, but particularly so when giving LT4.
Most drug regimens provide a chemical exogenous to the body, one that is not part of its homeostatic mechanism. Because they are extrinsic to the body, the body is forgiving of major variability.
Levothyroxine, in distinction to almost all other medicines, is a replicate of an agent that the body itself produces and is one of the pillars of the body’s homeostatic mechanisms. 
Clinical experts emphasize the importance of minimizing variability in LT4 therapy.  They recognize that additional variability is introduced by differences in bioavailability across different formulations of LT4.  These clinical experts and the societies that represent the vast majority of endocrinologists, urge avoiding any source of variability introduced unnecessarily into their treatment regimens.
They identify vulnerable patient populations as being at the highest risk for the consequences of over- or under-treatment. 
For many, the clinical consequences, when they occur, are profound and not reversible.
The FDA also recognized the importance of minimizing variability in treatment regimens.  
They required all makers of levothyroxine to submit NDAs.  
They determined that the NDA process would assure control of manufacturing variability, and this has been achieved as pointed out already. 
In 2001, they stated their intention to control refill-to-refill variability to 9 percent or less and then reiterated this target just last year. 
In July 2004, FDA assured manufacturers and the clinical community that its standards “will not allow products that differ by 9 percent or more in potency or bioavailability to be rated therapeutically equivalent.”
This target was set to reduce the medical consequences of introducing variability into these products.

## What Is the Clinical Consequence of Variability?

**Consequences of hypothyroidism, where thyroid hormone is low and TSH is elevated.**
- Elevated cholesterol levels
- Atherosclerosis and myocardial infarction
- Decreased intellectual function in the children of women hypothyroid in early pregnancy
**Consequences of hyperthyroidism, where thyroid hormone is high and TSH is decreased.**
- Osteoporosis in the elderly
- Atrial fibrillation and other arrhythmias

**Notes:**

The clinical consequences of missing the optimal, targeted state are profound, from either insufficient or excess LT4.

These consequences can present with disastrous medical outcomes.  After a child is born is the wrong time to realize that a mother had been under-treated with LT4 therapy during early pregnancy. The damage is done.

Likewise, osteoporosis discovered at the time of hip fracture, or afib discovered at the time of stroke or MI is the wrong time to identify that too much levothyroxine hormone was administered.  The damage is done.

## Levothyroxine Variability is Additive 

**Known and Managed**

**Levothyroxine Variability is Additive **

**Increasing****Variability**

**Notes:**
What are the sources of variability that doctors must overcome?  

How do doctors and patients contend with these sources of variability as they chart a course of treatment?

They recognize that LT4 variability is additive.  Each source of uncertainty in a treatment regimen is an element that must be accounted for and overcome by some strategy.

These sources of variability can be grouped into two categories.

The first are variabilities that we know and manage.  These are risks that doctors, patients, and manufacturers have identified and studied.  We have treatment strategies that are usually successful in overcoming these sources of variability.

The second category of variability is new and not understood.  Strategies to overcome this newly introduced variability have not been devised and tested.  We therefore must consider any approach to addressing this new source of variability at best hypothetical, and more strictly, unknown.

What are these sources of variability that doctors treating thyroid disorders must overcome?

## Sources of Variability:  Known and Managed

**Intra-product variability**

**Sources of Variability:  Known and Managed**

**Increasing****Variability**

**Notes:**

The set of known and managed sources of variability contain two main elements.

The first is intra-product variability...

...and the second consists of human factors.  

Each is inherent to treating any condition with any product regardless of the therapeutic intention.  

But, variability in patients receiving LT4 therapy is particularly consequential because LT4 is replacing an endogenous hormone essential to the body’s homeostasis unlike most drugs that are not replacements for hormones made by the body.  

## Source of Variability – Intra-product Variations

**Every product has inherent variability at release and over its shelf-life **
** **
**This variability is controlled and monitored**
- Formal FDA approval is now required for all LT4 products
- Good manufacturing practice and quality controls are in place to minimize intra-product variations
**These controls apply uniformly to all manufacturers and products**

**Notes:**
Intra-product variability is the first variability that we know and have devised strategies to manage.  FDA took action to assure that this source of variability was addressed via the manufacturing controls that come with NDAs.

Any medication has some inherent chemical variability.  It is precisely because of this that all medications, including LT4, carry expiration dating displayed on each batch of product.  This dating gives confidence that the variability of that product lies within a known range and is controlled by careful monitoring.  

Although tight limits surround release specifications for each LT4 product from any given manufacturer, differences of bioavailability across products result in a widening of the total range when all products are considered as a class.  

This is highly undesirable.

## Source of Variability – Human Factors

**Absorption of LT4 is affected by other drugs and food**
**Patient compliance patterns can add variability**
**These variabilities can be minimized by patient counseling**
**Initial individual titration to a euthyroid state accounts for and compensates for this variability**
**While these levels of variability complicate maintenance of thyroid status, they are well described and can be effectively managed**

**Notes:**

Human factors are the second category of known and managed sources of variability.
We know that, like any substance presented to the body, the absorption of LT4 can be influenced by food and other drugs.
We also know that patient compliance can vary person to person.  
We address these human factors directly by two important means, both at the level of the doctor and patient.
First, doctors engage and influence their patients directly via face-to-face encounters. Many opportunities exist for ongoing counseling to control these factors over time.
In addition to counseling is the titration process by which therapy is individualized.  
Individualized therapy is fundamental to overcoming the variability in a patient’s diet, concomitant medications, and compliance patterns.  
Because titration is carried out over weeks or months, it is an excellent tool to identify, integrate, and address the variability emanating from the human factors of any individual.  
This is how we have successfully carried out LT4 replacement therapy for years.

## Levothyroxine Variability is Additive

**Human Factors**

**Intra-product Variability**

**Levothyroxine Variability is Additive**

**Increasing****Variability**

**Notes:**
Variability is cumulative.  

Each additional source of variability in levothyroxine is another hurdle that the physician must overcome while attempting to establish the euthyroid state.

We have now introduced another source of variability into the treatment of thyroid disorders.  [CLICK]

It is a source of variability that is new and strategies to overcome that variability are untested and therefore their adequacy is unknown.  

This, I believe, constitutes a real but unnecessary risk for patients taking LT4 products.

This new risk is product switching based on assumed therapeutic equivalence.

While product switching for most products for which bioequivalence has been established is usually not an issue; it is far from certain that this applies to LT4.

## New and Unknown Source of Variability – Switching LT4 Products 

**FDA does not require that therapeutically equivalent products have identical bioavailability profiles **
**FDA has established statistical criteria to determine when two products can be used interchangeably**
**These criteria work well for most drugs, but this may not be appropriate for a narrow therapeutic index, endogenous hormone**
**These criteria, applied to LT4 products, deemed one product to be interchangeable that, on average, delivered 12.5% more LT4 than its reference**
**The additional variability is uncontrolled – patients and physicians are often unaware that a switch has occurred**

**Notes:**
What is the standard by which product switching is permitted?  When we term products interchangeable, what do we accept as close enough?
When products are deemed interchangeable, it is different from saying that they are identical.  
Products are deemed interchangeable when they are found to have bioavailability characteristics that lie within a pre-specified statistical range.  
We use statistical limits to say that products are “close enough to each other” to be considered interchangeable. 
The PK characteristics we examine must then have the extent of their variability lie within boundaries that are within 80-125% of the performance characteristics of the reference product.
This is a range used for many products over the years and it has served us well.  
However, it is usually a limit used for drugs that are exogenous to the body and that have little to no direct role in maintaining the body’s homeostatic state. 
A fundamental question is whether this set of boundaries is acceptable for endogenous hormones such as LT4.  Can we assume that one size fits all?  We heard that these boundaries are used, but we did not hear why they should apply to LT4.
This question is fundamental, not so much because it is a regulatory standard laid out years ago and applied to products not produced by the body, but because in the case of LT4 it is a medical question.  Have we established that the bioequivalence standards, implying therapeutic equivalence, for products like Prozac and penicillin apply to hormones the body itself makes?  Where are the data showing this?
This medical question has been explored only in a cursory fashion.  
In fact, we now know that, based on clinical testing, the bioavailability standards for LT4 products will lead to the approval of products that are known to vary by 12.5 percent. Is this appropriate for this class of medication?

## Relative Bioavailability of Levothyroxine Sodium Products

**1.00**

- 0.80

- 0.84

- 0.88

- 0.92

- 0.96

- 1.04

- 1.08

- 1.12

- 1.16

- 1.20

- 1.24

**Notes:**
This variability is not a theoretical concern, it is a reality.
Consider the case of four levothyroxine products.  
We will treat Synthroid as a reference product and compare relative bioavailability of other products considered seamlessly interchangeable.  The bottom axis shows the relative bioavailabilities, but it can also be considered practically as Synthroid microgram dose equivalents. 
If a dose of Synthroid is found to have relative bioavailability of one, we record that as such.   [CLICK]
A recently approved version of levothyroxine was found to have a relative bioavailability of 1.03 compared to Synthroid.  [CLICK]
Another 1.09      [CLICK]
And another 1.125. [CLICK]  Around these point estimates there is a range of variability as indicated here     [CLICK]
There is no inherent issue with any one of these agents by themselves because patients will be titrated to their targeted level on an individual basis, so long as patients remain on the agent on which they were titrated.
But what has not been tested is whether patients can safely move from one product to another.  Imagine if a patient were titrated to a 100 microgram dose of Synthroid...
...and was then switched to the Sandoz product. It is as if the patient is now receiving 112 micrograms of Synthroid instead of the 100 microgram dose to which she was titrated. This is a form of variability that the physician did not anticipate and, thus, did not address via titration.  
It is a form of variability introduced unbeknownst to the doctor. 
When this much variation is allowed for a hormone, what is a doctor to do? Should he read each product’s NDA or ANDA to compensate?
As you can see, we have traded the intra-product concerns we have heard about from FDA for the unknown, uncontrolled, inter-product concerns.

## Simulation of Effect of Switching LT4 Source

**Prior to switch, virtually all patients are controlled with TSH values between 0.4 to 4.0  **

**Notes:**

What might be the consequences when many patients are switched from the agent on which they were initially titrated?

This analysis illustrates such an example.  
A simulated population of 200 patients is titrated to TSH levels between 0.4 and 4.0, typical targets.

Note that when TSH levels fall due to high LT4 levels, a hyperthyroid state is achieved as denoted by the red line.  

There are no abrupt cut offs, but the likelihood of afib and other manifestations of hyperthyroidism climb as one moves further below the red line.

As TSH levels rise due to low LT4, the manifestations of hypothyroidism increase, especially as one moves increasingly beyond the green line.

## Simulation of Effect of Switching LT4 Source

**Prior to switch, virtually all patients are controlled with TSH values between 0.4 to 4.0**
**  **
**With the switch to new product with relative bioavailability of 1.125, the median patient still remains euthyroid**

**Notes:**

If one introduces a switch of LT4 preparations varying by 12.5 percent, as can happen based on approved products, the population responds to the more bioavailable formulation by reducing the median TSH levels.

The median patient lies within the desired TSH boundaries.  

But, half of all the patients will lie above this median value and the other half will lie below it.  

## Simulation of Effect of Switching LT4 Source

**Notes:**
It is clear that the median levels do not tell the whole story.

We retain the median patient as before, but now we also cull out the most extreme 10 percent of patient TSH levels. 

Under these conditions we have taken patients who were within our targeted boundaries at the outset and have pushed them unwittingly into  values well outside of our targets.  

These patients, if presenting to a medical clinic, would likely have their LT4 doses reduced in response to their low TSH levels.

In this case, products were clearly not seamlessly interchangeable. 

And especially worrisome is that the prescribing physician may not even know that a switch took place after the prescription was written.  

Remember that in this example, we are talking about one in 10 patients who if switched would become hyperthyroid.  And recall about 13 million Americans take LT4 products. 

## What Consequences Could Result from Unknown Hyperthyroidism?

**Yearly incidences of atrial fibrillation (AF)**
- Euthyroid 1% per year
- Mild hyperthyroid 1.6% per year

**Cumulative incidence of atrial fibrillation among Framingham Study subjects ********60 years of age, stratified by serum TSH levels at baseline.**

**Notes:**

The prior example is the result of a simulated switch of LT4 and its consequences on TSH levels.  

Firm epidemiological observations have established the association of depressed TSH levels and atrial fibrillation.  

In these data more than 2000 members of the original Framingham study cohort were followed to determine the incidence of afib and its relationship to baseline TSH levels during a 10-year period.

The Framingham data indicate that with slightly low levels of TSH, as indicated by the green line, the relative risk of afib over time is about 1.6 relative to people with normal TSH levels.  

At lower levels of TSH, the relative risk climbs substantially with the risk estimated to be 3.1 times that for normals.  
It is obvious that maintaining TSH levels close to normal is an important public health objective.

## Can We Quantify the Risk?

**Yearly incidences of atrial fibrillation (AF)**
- Euthyroid 1% per year
- Mild hyperthyroid 1.6% per year
**For 1,000,000 patients undergoing the switch, an excess of 1,200 AF would be expected over 1 year  **

**Cumulative incidence of atrial fibrillation among Framingham Study subjects ********60 years of age, stratified by serum TSH levels at baseline.**

**Notes:**

We can apply this information to our test group in which we introduced a simulated switch of products with a relative bioavailability differing by a factor of 1.12.

By anticipating the changes to TSH, we expect that for every 1 million patient years of switching, there will be in excess of 1200 cases of new afib.   
Just as with afib, one would expect to have additional cases of MI and the other well known consequences of hyperthyroidism. 

## If Switching Between LT4 Products is Unsafe, Where are the Data Showing Side Effects?

**These side effects are highly prevalent**
- Atrial fibrillation affects 2.2 million Americans
- 160,000 new cases of atrial fibrillation annually
- Of Americans >60 years of age, 1 in 200 will have new onset atrial fibrillation annually
- Annual incidence of acute myocardial infarction is 865,000
**Against these high background incidences for AEs, additional cases are not evident**

**Notes:**

One question raised by statistics such as these is where are all of the projected adverse events?

The answer to this question is straightforward.  The conditions associated with both hypo- and hyperthyroidism are highly prevalent in the United States.

Over two million people have afib in the United States and about 160,000 new cases occur annually.

With a background incidence this high, the incremental incidence of afib will easily be overwhelmed by the vast number of cases already present.

These thousands of new cases will only be an increase of about 2 percent in the overall incidence or less than 1 percent in the overall prevalence.  These rates will only be observed by careful observation, but the tools now in place are unlikely to suffice. Because doctors do not know a switch has occurred, they will not link an AE to the switch.

This is also true for the incidences of MI, osteoporosis and other manifestations of inappropriate thyroid hormone treatment caused by switching. 

## Patient Health is Paramount  

**What amount of variability is consistent with seamless substitution?**
**How should the methodology account for the unique clinical need of this endogenous hormone?**
**What is the appropriate variability for populations at risk?**
- Infants and children
- Thyroid cancer patients
- Elderly with heart disease
**Why introduce another source of variability into LT4 therapy, which is used by 1 in 19 Americans?**

***Is the additional variability, introduced from switching ******LT4 products, worth the risk to patients?***

**Notes:**
We all believe that patient health and safety is the paramount goal.
But, as we pursue that goal, we must confront some questions.
Do we really know what variability among products truly allows for seamless interchangeability?
What data assure us that criteria that apply to standard drugs are equally applicable to this endogenous hormone?
Do we really have appropriate tools in our hands to determine the correct relative bioavailability of these products?  As it is, we now do studies in healthy volunteers with intact thyroid glands.  This seems like an obvious problem as the thyroid gland in these healthy volunteers works to minimize variations among test agents by its own powerful homeostatic properties.
Do we really understand the relationship of variability to the underlying risks in different patient populations such as children, cancer patients, and the elderly with heart disease?
Why introduce yet another source of variability into this huge patient population?  In a setting in which more than 13 million people, one out of every 19 Americans, receive LT4 products, what appear to be small differences become big numbers.
So...what have we gained?
If we do not yet really have good tools to determine bioequivalence, if small differences matter, if treatment standards are not well developed to address the newly introduced variability, and if the clinical experts all point to this as a medical issue, this all reduces to a simple question:
Is the additional variability, introduced from switching LT4 products, worth the risk to patients?  
Thank you.