# Presentation: 162351

## Slide 1

## FDA Levothyroxine Workshop, May 23, 2005

**Introduction**
- Beth Brannan, Sandoz, Director, Regulatory
**Access to care, a provider’s perspective**
- Robert Richards, MD, Louisiana State University** **
**Levothyroxine Generic Approval June, 2004:  What changed? Healthcare cost impact of generic levothyroxine**
- Sally Schimelpfenig, Sandoz, Director, Marketing
**Technical issues relevant to bioequivalence study design, data analysis, and conclusions**
- Alfred Elvin, PhD, Sandoz, Director, Biopharmaceutics
**Clinical impact of generic levothyroxine**
- Bruce D. Weintraub, MD, Trophogen; COO and CSO, Trophogen, Inc
- 	    Former Chief, Molecular and Cellular Endocrinology Branch, NIH

## Sandoz Panel of Experts

**Bioequivalence and Pharmacodynamics**
**Dr. Leslie Benet, Pharm. D.,**
- 	University of California, San Francisco
**Dr. Sanford Bolton, Ph. D., **
- 	University of Arizona
**Clinical Endocrinology**
**Dr. Bruce D. Weintraub, M.D.**
- 	COO and CSO, Trophogen, Inc
- Former Chief, Molecular and Cellular Endocrinology Branch, NIH
**Dr. Tony Toft, M.D., **
- 	Consultant Physician, Royal Infirmary, Edinburgh
- Former President, Royal College of Physicians of Edinburgh
- Founding President, British Thyroid Association
- Physician to Her Majesty the Queen in Scotland
**Dr. Robert Richards, M.D.,**
- Louisiana State University Medical Center

## Dr. Robert Richards, M.D.Associate Professor of MedicineAssociate Director of the Diabetes ClinicDirector of the Fellowship Program in Endocrinology, Diabetes, and Metabolism

**History of my prescribing habits**
**Inherent TSH variability**
- Diurnal rhythm
- Pulsatile secretion
- Variances in methods among labs
**Patient compliance**
- TSH variability due to missed doses
- TSH levels are often slow to respond to thyroxine
**Clinical applications**
- TSH used in conjunction with f-T4 to monitor patient care
- Routine hypothyroidism
- Thyroid cancer
- Pregnancy

## Dr. Robert Richards, M.D.Associate Professor of MedicineAssociate Director of the Diabetes ClinicDirector of the Fellowship Program in Endocrinology, Diabetes, and Metabolism

**Generic substitution**
- Charity Hospital (New Orleans) and Earl K. Long Hospital (Baton Rouge) dispense only generic levothyroxine
- No clinical issues raised
- Choice of levothyroxine in state institutions is mandated by state contract
- No visibility to manufacturer name or change in manufacturer
**Position statements from ATA, ES, and AACE**

## Dr. Robert Richards, M.D.Associate Professor of MedicineAssociate Director of the Diabetes ClinicDirector of the Fellowship Program in Endocrinology, Diabetes, and Metabolism

**Generic Levothyroxine Affordability = Access**
**Patient well being** is the most important value and goal in all therapy.
**Persistency and compliance** are essential to successful therapy but a patient can achieve neither if they can’t afford their prescription.
**Generics are required for many patients to afford their therapy**, not everyone is employed, covered by insurance, or able to pay cash for a brand name levothyroxine.
**Generics offer the opportunity for more people to have access** to affordable healthcare by freeing up dollars otherwise spent on a brand-name label whose therapeutic value is no greater than any BE generic.
**Levothyroxine is **_**life-long therapy**_, the incremental savings generic pricing brings per prescription need to be multiplied by the **months of refill and **_**years**_** of therapy.**

## Approvals as of May 2004		IMS Market Share
Abbott Labs (Synthroid®)			62% 
Jones Pharmaceuticals (Levoxyl®)		28%
Stevens (Unithroid®)				2%
Forest Pharmaceuticals (Levothroid®)	6%
Vintage (Levolet®)				1%
Mylan (Generic TE* to Unithroid®)		1%
Alara (Levo-T®)				0%

Approvals June 2004 Onwards
Alara (Sandoz)	June:	TE to Synthroid and Levoxyl
Mylan  		June:	TE to Levoxyl 
				July:	TE to Synthroid  
Lannett  		June:	TE to Levoxyl 
				Dec: 	TE to Synthroid

 *TE:  Therapeutically Equivalent to the reference brand

**Abbott Labs (Synthroid®)****	****	****	****62% **
**Jones Pharmaceuticals (Levoxyl®)****	****	****28%**
**Stevens (Unithroid®)****	****	****	****	****2%**
**Forest Pharmaceuticals (Levothroid®)****	****6%**
**Vintage (Levolet®)****	****	****	****	****1%**
**Mylan (Generic TE* to Unithroid®)****	****	****1%**
**Alara (Levo-T®)****	****	****	****	****0%**
**Approvals June 2004 Onwards**
**Alara (Sandoz)****	****June:****	****TE to Synthroid and Levoxyl**
**Mylan  ****	****	****June:****	****TE to Levoxyl **
**	****	****	****	****July:****	****TE to Synthroid  **
**Lannett  ****	****	****June:****	****TE to Levoxyl **
**	****	****	****	****Dec: ****	****TE to Synthroid**
** *****TE:  Therapeutically Equivalent to the reference brand**

**2 competitors with meaningful share, brand products not interchangeable with each other.         **

**What changed in the levothyroxine market with therapeutic equivalence approval?**

**+  3 competitors to each of the 2 leading innovator products.**

**Unithroid is a Registered Trademark of Jerome Stevens Pharmaceuticals, Inc.****Synthroid is Registered Trademark of Knoll Pharmaceutical Company****Levoxyl is a Registered Trademark of Jones Pharma**

**Levolet is a Registered Trademark of Vintage Pharmaceuticals, Inc.****Levo-T is a Registered Trademark of Alara**

## Prescription Savings Through Generic Pricing

**Prescription Savings Through Generic Pricing**

**Estimated healthcare savings **
**in the Levothyroxine segment as a result of BE generic launch**
**~$145 million**
**June 2004-March 2005**

- Net Sales data calculated using IMS Sales Data
- Units are from IMS NPA

**Estimated Annual Total Sales**
**~$1 billion**

**Estimated Annual Total Units**
**~4 billion**

## Technical Details of Bioequivalence:  A Manufacturer’s Challenge Met

- Every current generically marketed levothyroxine product has been approved and rated by FDA as therapeutically equivalent (AB-rated) according to FDA's expert guidance.
- No authenticated data exists on *any* FDA-approved, therapeutically equivalent levothyroxine product demonstrating any difference in safety and efficacy profile between the approved AB-rated drug and its reference listed counterpart(s).
- The 3 levothyroxine products approved as AB-rated are pharmaceutically equivalent to the reference listed products.
- The 3 levothyroxine products approved as AB-rated are bioequivalent to the reference listed products.

## Technical Details of Bioequivalence:  A Manufacturer’s Challenge Met

**Levothyroxine Characteristics**
- Highly soluble
- 100% dissolved in less than 30 minutes
- Simple formulations
**Potency difference in the Sandoz studies **
- RLDs and Sandoz products in bioequivalence studies differed less than 5%

## Technical Details of Bioequivalence:  A Manufacturer’s Challenge Met

- FDA levothyroxine guidance accounts for endogenous plasma T4 variability through a baseline correction method which provides an appropriate statistical basis for FDA to define levothyroxine bioequivalence.
- Based on Sandoz’ (Alara) sNDA submissions the FDA determined:
- Sandoz levothyroxine is _**pharmaceutically**_ _**equivalent**_ to the reference listed products.
- Sandoz levothyroxine is** **_**bioequivalent**__ _to the reference listed products.
- Consequently, Sandoz levothyroxine is _**therapeutically equivalent**_ (AB-rated) to both reference listed products.

## Dr. Bruce D. Weintraub, M.D.COO and CSO, Trophogen, IncFormer Chief, Molecular and Cellular Endocrinology Branch, NIH

**Although TSH is usually a sensitive measure of thyroid function it is an indirect measure and has limitations.**
- Many limits to TSH utility are already recognized by clinicians
- Non-thyroid illness
- Central (pituitary or hypothalamic ) hypothyroidism
-  Psychotropic drugs
- Heterophilic antibodies
- Hypothyroidism associated with these conditions is successfully controlled using T4 or freeT4 monitoring in place of TSH.
- TSH is an invalid drug bioequivalence measure as a result of intra-patient variations (within each individual patient) that preclude accurate or meaningful statistical analysis of drug presence across a test population.
**T4 or free T4 is the direct and accurately measured analyte and is the most meaningful chemical measure of drug absorption and bioequivalence using conventional FDA standards .**
- Selection of a clinical measure to test bioequivalence must meet statistical thresholds of consistency and control.

## Dr. Bruce D. Weintraub, M.D.COO and CSO, Trophogen, IncFormer Chief, Molecular and Cellular Endocrinology Branch, NIH

**Levothyroxine is an effective 60-year old therapy**:
- easily soluble and easy to measure
- demonstrated technical capability/feasibility to manufacture
- appropriately compared in BE studies according to FDA standards
- Current standards of care call for routine lab value monitoring (TSH with or without T4 or free T4) at least once or twice yearly. Such monitoring provides adequate safeguards to prevent * chronic* *over/under* *treatment *and greatly mitigates any threat of long-term health risks from exogenously-induced hyper-or hypo-thyroidism.
- Consensus views of thyroidologists relating to the clinical significance of so-called “subclinical” hypo- or hyperthyroidism ( decreased or increased TSH with normal T4 or free T4) are associated with TSH values well above or below the normal range for periods of many years or decades;such extreme TSH values for such long periods would not be encountered in patients switched to generics and receiving recommended monitoring.Thus, there is no convincing evidence for claims of such a narrow therapeutic range for thyroxine therapy and, in any case, such claims would have to take into account the **duration of such therapy.**

## Dr. Bruce D. Weintraub, M.D.COO and CSO, Trophogen, IncFormer Chief, Molecular and Cellular Endocrinology Branch, NIH

**Since launch of levothyroxine in June 2004 through April 28, 2005, Sandoz reports the following Adverse Event data**:

| Tablets Released  | ~1,300,000,000 |
| --- | --- |
| Prescriptions @ 30 tablets each  | ~43,000,000 |
| Adverse Events Reported  | 68 |
| Serious Events  | 0 |