The levothyroxine spectrum: Bioequivalence and cost considerations

Abstract

Levothyroxine, a critical medication for millions of Americans, has had a long and turbulent history. In the face of tougher FDA regulations and especially its reclassification as a "new drug" in 1997, manufacturers have struggled to carve out their niche in an expansive market. The principal concern of physicians, patients, endocrinologists, manufacturers, and FDA is levothyroxine's relative bioequivalence. Even after FDA classified several products as bioequivalent, a single brand name product still holds most of the market share, despite the fact that it is more costly. Current issues surrounding levothyroxine include: controversy about research, the number and types of recalls, the lack of a single reference-listed drug for comparison, and conflicting claims about the bioequivalence of various formulations. (Formulary. 2005;40:258–271.)

Hypothyroidism is the second most common endocrine disorder in the United States, second only to diabetes mellitus.¹ Hypothyroidism is a chronic condition requiring lifetime compliance with hormone replacement therapy. Furthermore, because of the importance and difficulty of maintaining consistent hormone levels, patients have traditionally been tied to specific titrated doses. Because hypothyroidism is a condition in which the thyroid gland no longer produces an adequate supply of thyroid hormones (predominantly T₄), a patient with untreated hypothyroidism may experience a variety of ill-effects, including weakness, skin changes, lethargy, slow speech, and cold sweats.

The total US market for the 2 leading levothyroxine products, Synthroid and Levoxyl, was $1.1 billion in 2003.² As such, it is imperative for clinicians and formulary decision-makers to understand the drug's complex history and current issues. Current issues surrounding levothyroxine include: controversy about research, the number and types of recalls, the lack of a single reference-listed drug for comparison, conflicting claims about the bio-equivalence of various formulations, and potential conflict of interest by medical specialty groups receiving financial support from drug manufacturers.

EARLY TREATMENT

Prior to the 1890s, there was no treatment for hypothyroidism. The first treatment, developed in 1894, involved the desiccated thyroid glands of cows. Essentially, this process involved removing the cow's thyroid gland, drying it, and grinding it into a powder. While this method was certainly a significant medical improvement (there was previously no treatment at all), it was far from perfect.

Modern synthesized thyroid medication relies on measuring the T₄ content of tablets to match a patient to the appropriate levothyroxine dose. This is a vast improvement over the original method of standardization, which relied on the iodine content of the product rather than its T₄ count. Because cows, like humans, produce different levels of thyroid hormone, there was no bioequivalence between different tablets, let alone different manufacturers. It was not until the 1960s that synthetic thyroid hormone replacement became the gold standard.

THE FIRST SYNTHETIC

In 1958, the first synthetic T₄ entered the market: Synthroid, originally manufactured by Flint Laboratories. Never receiving patent protection, Synthroid was distributed without major competition for approximately 40 years. Since its creation, the production and distribution of Synthroid has changed hands several times. By 1990, Flint Laboratories had been acquired by Boots Company, Inc. In 1995, Knoll Pharmaceuticals acquired the pharmaceutical branch of Boots and later that year, both became subsidiaries of BASF AG. Then in 2001, Abbott Laboratories acquired BASF AG and became the current distributor of Synthroid.

Synthroid was, and still is, the industry leader in terms of sales. Synthroid is the second most commonly prescribed drug in America and in 2004 had sales of $627 million.^3,4 Even through FDA has listed several other drugs as bioequivalent, including Unithroid, Levo-T, Levothyroxine, and Levoxyl (Table 1),^5,6 Synthroid has been able to maintain an extraordinarily high percentage of the market (82% of the market as of May 2005).³

Because Synthroid was similar to previously utilized natural thyroid drugs, it was "grandfathered" by FDA. This "grandfathering" occurred with products that were approved by FDA before the 1938 Food, Drug, and Cosmetic Act that required new drugs to pass safety and efficacy tests.

RECLASSIFICATION AS A 'NEW DRUG'

Levothyroxine products, while representing the primary medication option for the treatment of hypothyroidism, have had a history of bioequivalence and bioavailability problems. As a result of these problems, combined with concerns from patients and the health-care community, FDA declared levothyroxine a "new drug" on August 14, 1997.⁷ This meant that all current manufacturers of levothyroxine would be required to submit a New Drug Application (NDA), requiring extensive clinical studies, to FDA by August 14, 2000. FDA, realizing the medical necessity of levothyroxine, allowed manufacturers that were already distributing levothyroxine to continue to do so while working through the approval process. FDA also elucidated a scheduled phase-down procedure for any potential manufacturer unable to meet the NDA deadline or FDA standards of safety and efficacy. The phase-down process involved a mandated monthly reduction in sales for an unapproved product, with total distribution cessation by 2003.

The manufacturer of Synthroid (Knoll at that time) contested FDA's NDA ruling by submitting a citizens' petition.⁸ In addition, Forest continued to manufacture and market Levothroid without it being approved, prompting FDA to take a harsher stance.⁹ On August 7, 2003, FDA sent Forest a warning letter stating, "[FDA] investigators determined that you have failed to obtain an approved application and have made a deliberate decision not to follow the agency's gradual phase-down plan."⁹ The letter described various violations of "Good Manufacturing Practices" affecting the potency and safety of Levothroid. These initial problems, however, were just the tip of the iceberg.

LEVOTHYROXINE PROBLEMS

While it should not be forgotten that levothyroxine has unquestionably improved and saved the lives of millions of people over the course of its history, it has also been embroiled in multiple controversies surrounding its stability, formulation consistency, and perhaps most vehemently, its relative bioequivalence.

As the major thyroid medication in the United States, Synthroid has over recent years been the subject of much debate. In an effort to avoid the rigorous NDA process, which requires clinical trials for safety and efficacy, Knoll requested in 1997 that Synthroid be granted GRAS/E (Generally Recognized as Safe and Effective) standing by FDA. GRAS/E status is granted to drugs that have been marketed under previous FDA regulations that did not require clinical trials for safety and efficacy but because of the longevity of their use are not required to endure clinical trials. To gain GRAS/E standing, a drug must maintain the same level of scientific research as drugs undergoing complete modern FDA approval through medical literature, and expert scientists must attest to the drug's safety and efficacy. When a drug gains GRAS/E standing, the manufacturer/distributor does not have to perform costly clinical trials to prove safety and efficacy. On April 26, 2001, the Department of Health and Human Services (HHS) responded to Knoll's attempt to gain GRAS/E standing in response to FDA's reclassification of levothyroxine as a "new drug."

In response to Knoll's request, FDA concluded that "Synthroid cannot be generally recognized as safe and effective because it is of no fixed composition" and that "Synthroid has a history of problems."⁸ The former argument deals with FDA's findings that Synthroid could not be evaluated as safe and effective because "the composition... has been changed repeatedly." According to FDA, the production of Synthroid involved the use of a technique called overage. Due to levothyroxine's categorization as a drug with a narrow therapeutic index, it is crucial that each individual tablet contains the requisite, stated amount of active ingredient.

Because it is known that levothyroxine is susceptible to the loss of active ingredient over time, FDA contended that Knoll used the method of overage (adding more active ingredient in the production phase, anticipating its loss by the point of oral administration) that ranged over the course of Synthroid's production history.

Additionally, FDA claimed the following:

In addition to its claims that the composition of Synthroid had changed over its history, FDA also found a "history of problems" related to the drug. FDA cited the many recalls of Synthroid as a result of "subpotency" to be a primary concern and reason for GRAS/E refusal. According to FDA: "The firm [Knoll] had failed to identify the causes for the stability failures that resulted in the recall of 21 lots of Synthroid tablets in August 1989, 26 lots in February 1991, and 15 lots in June 1991. The firm had failed to identify the causes for the potency or content uniformity failure of 46 lots of Synthroid tablets manufactured from 1990 through 1992 that it destroyed."⁸

The FDA findings resulted in the refusal to grant GRAS/E standing to Synthroid. As a result, Knoll was forced to begin the NDA process and conduct clinical trials. It should be noted that the FDA response to Knoll's request, while implying that Synthroid had production problems, did not label Synthroid as a dangerous drug (in which case it would have been removed from the market), but simply required Knoll to undergo the same NDA process as its competitors. After much debate, the manufacturer of Synthroid acquiesced, filed an NDA, and received FDA approval in July 2002. While a major levothyroxine controversy, FDA's new NDA requirement was not the only levothyroxine issue.

ADDITIONAL NDA DEBATE

Another debate concerning FDA's decision to declare levothyroxine as a "new drug" has involved its determinations of which product/s would be designated as reference-listed drug/s. A reference-listed drug is a drug (according to active ingredient) identified by FDA "as the drug product upon which an applicant relies in seeking approval of its abbreviated application."¹⁰ Typically, the reference-listed drug is the first drug to be approved by FDA, to which all subsequent equivalent drugs must be compared. In the case of levothyroxine, the reference listing of the various approved drugs is important for establishing which drugs can be switched. Because Unithroid was the first drug to receive FDA approval, it also became the first reference-listed levothyroxine product.

A problem, however, arose from this original designation because subsequent manufacturers were more concerned with comparing their product, and subsequently receiving bioequivalent status, to Synthroid, the clear market leader. But Synthroid was not yet approved by FDA as a "new drug" when the initial decision regarding the reference-listed drug was made. The result of this problem, as explored later in this article, is that there are now multiple approved FDA levothyroxine products that are also reference-listed, resulting in confusion as to which levothyroxine products can be switched with each other.

CONTROVERSY OVER RESEARCH

In 1987, Flint Laboratories (distributor of Synthroid at the time) commissioned a study at the University of California, San Francisco (UCSF).¹¹ The study, headed by Dr Betty Dong, compared 4 different levothyroxine products (2 brand name products, Synthroid and Levoxyl; and 2 generics, both manufactured by Pharmaceutical Basics). Prior to the study, both the makers of Synthroid and the team headed by Dr Dong believed that the results would demonstrate that Synthroid was the superior levothyroxine medication and that other levothyroxine medications were not bioequivalent.¹¹

By 1990, the study had been completed by the researchers at UCSF and Flint Laboratories had become the Boots Company. The study found "no significant differences between the 4 products." Consequently, Boots began to pressure Dr Dong not to publish the study, claiming that it was faulty even though it had previously approved the study methods.¹¹ Initially backed by the university, Dr Dong did not back down to the corporate pressure and submitted the manuscript to the Journal of the American Medical Association (JAMA); the manuscript was peer-reviewed and accepted for publication. The Boots Company, however, not to be defeated, informed Dr Dong and the university that due to the nondisclosure agreement that was signed by Dr Dong prior to the study, the manuscript could not be published without written consent from Boots. Under increasing legal pressure, the university informed Dr Dong that it would not support her and her team in legal proceedings that could result if the manuscript were published. As a result, Dr Dong retracted the manuscript shortly before it was to be published.¹²

Five years later, while the study was still unpublished, Boots (now merged with Knoll) enlisted the help of a team employed by Knoll to conduct another study. This study, entitled "Limitations of levothyroxine bioequivalence evaluation: Analysis of an attempted study," using the same data from the 1990 study, resulted in different conclusions. This study was published in the American Journal of Therapeutics, even though the original study by Dr Dong's team had not yet been published. Upon publication of this retaliatory study, and under increasing pressure from FDA, Boots/Knoll ended up releasing the original manuscript, which was finally published in 1997 after having been completed 7 years earlier.¹³

In addition to finding that there was no difference between various levothyroxine products, Dr Dong and her team concluded that consumers, by switching to cheaper brand and generic versions of levothyroxine, could save as much as $356 million per year (in 1990 dollars). As a result of the research controversy, a class-action suit was filed against Knoll in 1996 (and its parent company BASF), which was settled in 2000 at a cost to the company of $138 million.¹⁴

A HISTORY OF RECALLS

Often times, recalls can be expected for a drug product with a narrow therapeutic index (NTI) such as levothyroxine. However, the number of recalls associated with levothyroxine is concerning. Subpotency, more than any other single factor, has historically been responsible for levothyroxine recalls. FDA, upon reclassifying levothyroxine as a "new drug," recognized the continuing number of recalls as evidence of the need to review all levothyroxine drug products. For example, between 1990 and 1997, there were 10 recalls of levothyroxine, equating to 150 lots and 100 million tablets.¹⁵ The information presented in Table 2 details levothyroxine recalls over the years.¹⁶

THE PROBLEM OF BIOEQUIVALENCE

Perhaps the most controversial and pertinent current issue concerning levothyroxine relates to its bioequivalence. Bioequivalence, as defined by FDA (21 CFR 320.1) is: "The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." It is well-known and accepted by medical experts that levothyroxine has a narrow therapeutic index.

Because of the importance of titrating doses to the patient's specific thyroid condition, physicians treating thyroid conditions and the manufacturers of the most widely used medications have long discouraged switching medications during treatment. There is no doubt, among the patient, medical, and research communities, that exhaustively studying and critiquing bioequivalence measures and examining the relative bioequivalence between various brand-name and generic medications is paramount to effective treatment of hypothyroidism.

BIOEQUIVALENCE STUDIES

Study conducted at UCSF by Dr Dong et al. As previously mentioned, the first major study examining the relative bioequivalence between brand and generic levothyroxine products was commissioned by Flint Laboratories (subsequently Boots/Knoll) in 1987 at UCSF. The study, entitled "Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism" found that "the 4 generic and brand-name preparations in [the] study are bioequivalent by current FDA criteria."¹³

This original levothyroxine bioequivalence study, carried out from 1988–1990, was a single-blind, randomized, 4-way crossover trial. The medications studied were Synthroid, Levoxyl, and 2 equivalent generic levothyroxine products manufactured by Pharmaceutical Basics, Inc. A total of 57 initial candidates were screened, resulting in a final subject sample of 24 patients with hypothyroidism who were "clinically and chemically euthyroid... for a minimum of 3 months before study entry." Each subject went through a random cycle of the 4 medications at 6-week intervals with no lapse between medications. For example, a subject (who was blinded to the name of the medication) might take Levoxyl for 6 weeks, a generic for 6 weeks, Synthroid for 6 weeks, and another generic for 6 weeks. Each subject was tested for complete thyroid functioning every 3 weeks during the study. The study concluded that all of the drugs were interchangeable because "the AUCs for all pairs of drugs were within the +/–25% bioequivalence criterion for total triiodothyonine in 91% to 100% of patients" and "no subjects discontinued therapy because of adverse effects."

'Limitations of levothyroxine study.' In 1995, a study also commissioned by Boots/Knoll, was conducted by Mayor et al entitled "Limitations of levothyroxine bioequivalence evaluation: Analysis of an attempted study."¹⁷ This study, essentially a rebuttal of Dr Dong's 1990 study, analyzed the same data but reached different conclusions.

According to the report, the results could not be verified because the study was conducted "without baseline correction and normalization for tablet potency differences." The authors asserted that because various levothyroxine medications differ in bioavailability, comparison studies without baseline corrections are faulty.

In addition, the report stated: "These flaws included evaluation of a heterogeneous population of hypothyroid patients with variable residual thyroid function, failure to achieve steady-state serum thyroid hormone levels, use of levothyroxine preparations with variable and unmatched potency, calculations based on a response variable that requires linear pharmacokinetics, and the application of bioequivalence criteria when required assumptions have not been met."¹⁷

LEVOTHYROXINE, BIOEQUIVALENCE, AND FDA

Since the inception of FDA's NDA requirement in 1997, a host of levothyroxine products have been approved. Importantly, FDA has strict standards regarding the bioequivalency of drugs marketed for the same condition. According to FDA guidelines, "for 2 orally administered drug products to be bioequivalent, the active drug ingredient or active moiety in the test product should exhibit the same range and extent of absorption as the reference drug product."¹⁸

In order to gain a bioequivalent rating from FDA, each manufacturer must conduct tests and submit data to unquestionably prove its product's interchangeability. The tests and data required must result in no less than a 90% confidence interval for each of the required pharmacokinetic parameters (C_max and AUC).¹⁸

As a result of increasing concern regarding FDA's bioequivalence measures pertaining to drugs with a narrow therapeutic index, FDA addressed the issue in 1998 in a general letter from the Associate Commissioner for Health Affairs. The letter stated, "For both brand-name and generic drugs, FDA works with pharmaceutical companies to assure that all drugs marketed in the US meet specifications for identity, strength, quality, purity and potency."¹⁹ In addition, "the FDA requires many rigorous tests and procedures to assure that the drug is interchangeable." The letter concluded by informing healthcare practitioners that FDA "does not recommend that any additional tests need to be performed by the healthcare provider when a switch occurs from a brand-name drug product to a generic equivalent drug product, from a generic equivalent to a brand-name product, or from one generic drug product to another when both are deemed equivalent."

In summary, FDA's ratings for drug product bioequivalence can be taken in good faith as FDA represents the most objective mediator in the interchangeability debate and maintains strict standards for bioequivalence measurement. In addition, FDA has the discretion to remove a drug from the market at any time. With this in mind, turning back to the specific case of levothyroxine, a discussion follows of FDA's rating system and its current approved levothyroxine products.

CURRENT FDA RATINGS

In order to inform manufacturers, consumers, and healthcare practitioners of approved drugs and bioequivalence status, FDA maintains the publication "Approved Drug Products with Therapeutic Equivalence Evaluations" ("Orange Book"), which lists all approved drugs and their bio-equivalence status.⁵ The listing provides easily accessible approval information. In addition to listing currently approved drugs categorized by active ingredient, proprietary name, applicant holder, etc, each drug product is assigned a therapeutic equivalence (TE) code.

The following is a brief description of the codes assigned to levo-thyroxine products:

Levothyroxine products approved by FDA have been assigned AB1, AB2, AB3, and BX codes. FDA maintains that only drug products with the same TE code can be considered interchangeable. Importantly, the TE code is not a reflection of product safety and efficacy, but only of its relationship to other drugs with the same active ingredient. In the case of levothyroxine, because there are 6 reference-listed products, each manufacturer must submit individualized bioequivalence data compared to each reference-listed drug in order to gain bioequivalence approval for that drug.

BATCH-TO-BATCH CONCERNS

An often overlooked primary concern of FDA regarding levothyroxine products is the bioequivalence between different batches of the same product made by the same manufacturer. In a recent presentation made by FDA concerning levothyroxine bioequivalence, it was noted that there were "case reports in the literature suggesting that therapeutic failures had occurred when patients received a refill of the same product for which they had been previously stable" and "of 58 case reports of therapeutic failure received by the agency, from 1987–1994, nearly half occurred when patients received a refill of a product on which they had been stable for years."¹⁵

One of the major problems with levothyroxine medications is that, as FDA notes, "the active ingredient degrades quickly with exposure to light, moisture, oxygen, and carbohydrate excipients."¹⁹ As a result, many products are manufactured using an overage, which results in inconsistent tablet-to-tablet equivalence.

Dr Dong's 1990 study of 4 levothyroxine products found that, "The major problems reported with generic products have resulted from subpotent levothyroxine tablet content rather than from actual poor bioavailability." As previously noted, the occurrence of batch-to-batch discrepancies was a primary determinant in FDA's decision to declare levothyroxine a "new drug."

Overage or "spiking" refers to the manipulation of active ingredient proportions during the manufacturing process of a drug. Because levothyroxine is susceptible to various forms of degradation and because tablets may contain as little as 25 mcg of active ingredient, manufacturers have had difficulty maintaining the correct amount of active ingredient in tablets from production through the time that the patient takes the medication. Simply stated, by the time the patient takes the drug, it is possible that it no longer contains as much active ingredient as its package claims. To bridge this gap, some manufacturers have resorted to "spiking" their batches. It has been reported, for example, that Synthroid has been at times produced with 106% to 109% more active ingredient in order to maintain 100% status at the time of administration.¹⁵

Clearly, this process is dangerous in that it is based on estimates, both of what percent of the active ingredient will degrade and of the time between the drug's production and final distribution to the patient. The use of the overage technique has led researchers and medical investigators to be more worried about differences between batches than between manufacturers.

INFLUENCING THE MARKET

Current FDA regulation reports the bioequivalence of several sources of levothyroxine. This reality raises a fundamental question: If there are several approved safe, effective, and bioequivalent levothyroxine products that can be purchased at reduced prices compared with the industry leader, how has Synthroid maintained an 82% market share?³

Within the first 6 months of patent expiration, most branded drugs lose a significant portion of their market share to competition from generic brands. Synthroid appears to be unique in its retention of market share. One possible explanation may be the extensive marketing campaign undertaken by the various manufacturers of Synthroid over the last 2 decades. Synthroid's manufacturers have used the narrow therapeutic index argument to convince physicians and patients that switching levothyroxine medications would result in serious medical consequences. Over the years, Synthroid's manufacturers have (directly or indirectly) enlisted the support of various thyroid associations to support the cause of retaining Synthroid's substantial market share.^20–25

On October 1, 2003, the presidents of the American Thyroid Association (ATA), The Endocrine Society (TES), and the American Association of Clinical Endocrinologists (AACE), the leading professional thyroid associations, sent a letter to FDA regarding levothyroxine. The letter cites various issues concerning the approval of new levothyroxine medications, including "bioequivalence testing baseline correction, optimal test subjects, and acceptable confidence limits; and TSH as a pharmacodynamic measure."²⁶ The letter called on FDA to "suspend approval of new formulations until these matters are resolved."

In a subsequent letter, dated June 24, 2004, and posted on the ATA website, the ATA, TES, and AACE reacted to the FDA decision to approve substitutes for levothyroxine stating that they were "deeply disappointed that the FDA has moved to approve generic levothyroxine preparations as equivalent to branded preparations."²⁴ In the same letter, the associations called on physicians to "encourage your patients to ask to remain on their current levothyroxine preparation."

The question of a potential conflict of interest or appearance of conflict of interest does arise as related to these associations, which represent more than 4,600 clinical endocrinologists nationwide. Abbott is an active sponsor of the aforementioned endocrinology associations and is mentioned as a sponsor on each of the thyroid associations' websites. Previously, according to Washington Monthly, "the Boots Company, which manufactures a thyroid product [Synthroid], has at various times provided 60% of the funding for the American Thyroid Association."²⁵

CURRENT CHOICES

While the difference may only be a dollar or 2 for 1 month of treatment, with the number of people currently prescribed levothyroxine, the stakes are high. As was recently stated in a public meeting before FDA, "The potential savings to taxpayers, out-of-pocket payors, and insurers from reversing this unjustified domination of the levothyroxine market by Synthroid is thus $214 million per year."³

CONCLUSION

The history of levothyroxine sodium is one of great complexity and importance. While concerns remain regarding the subpotency of some brands of levothyroxine, consumers can be assured that the approved preparations are bioequivalent and interchangeable. Today, with FDA's ratings known, formulary decision-makers have the ability to make evidence-based, price-conscious decisions.

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