Generic Versus Brand Medication: A Call for Comparative Effectiveness Research

Criscely L. Go, MD and Michael S. Okun, MD
National Parkinson Foundation Center of Excellence
McKnight Brain Institute Department of Neurology
Movement Disorder Center, University of Florida
Gainesville, Florida, U.S.A.

Parkinson’s disease is a neurodegenerative disorder affecting dopaminergic and other neurotransmitter systems. It has been characterized in multiple studies by both motor and non-motor manifestations. The typical motor manifestations of shakiness (tremors in 80% of patients), slowness in movement (bradykinesia), stiffness (rigidity), as well as a reasonable positive response to dopamine replacement therapy help to solidify a diagnosis. Presently, there remains no cure for the disease, nor is there a drug that can halt disease progression. The oldest and most effective therapy in the armamentarium remains Carbidopa/Levodopa also known as Sinemet. However, due to its short half life (1.5 hrs), patients usually take progressively more medication doses each day, and the amount in mgs of medication administered usually increases over the disease duration.

According to a study performed by O Brien et al [1], the annual economic cost of PD in the United States has been estimated to be $10.8 billion dollars, with 58% of this amount being tied to direct medical costs. Additionally, prescription drugs account for approximately 14% to 22% of all medical costs[1] for patients in the U.S. Hence, in an effort to minimize health-related expenditures many insurance companies have turned to utilizing generic drugs, which are a fraction of the cost when compared to the “originator” or branded form of any drug. Currently, three pharmaceutical companies manufacture generic forms of Carbidopa/Levodopa or Sinemet (Actavis, Sandoz, and Teva Pharmaceuticals).

The manufacturer of a generic formulation of Sinemet must demonstrate that there is an “essential similarity” between the generic formulation, when compared to the formulation that is commercially available (the branded/ originator). This similarity must fulfill three characteristics: (1) there must be the same quantity and type of active ingredient (2), it must follow the same route of administration as the branded originator (3), and it must be the same in therapeutic effectiveness as demonstrated by what is known as a bioequivalence study. The US Food and Drug Administration must grant final approval as to whether a generic drug formulation is bioequivalent with its branded counterpart [2]. Bioequivalence is established based on blood assessments of the rate of absorption, and area under the plasma concentration – time curve (AUC) [3,4].

The development of a brand name formulation requires the demonstration of pharmacokinetics, efficacy, safety and tolerability-- first in healthy subjects, and later in the target patient population. The development of a generic equivalent requires only the demonstration of bioequivalence with brand name counterparts in normal and healthy subjects [4], but not in subjects with Parkinson’s disease.

Pahwa et al [5] studied the pharmacokinetic difference between Sinemet (brand) and Atamet (generic carbidopa / levodopa) in 1996. This comparison involved a single-dose study among 30 patients with idiopathic Parkinson’s disease (10 previously untreated patients, 10 with early disease and 10 with motor fluctuations and/or dyskinesia). This very small pilot study suggested that the generic formulation (ATAMET) of carbidopa/levodopa was bioequivalent however, in this study the authors utilized only a single dose. In the discussion of the study, the authors observed that on longer followup patients preferred the brand drug, which they believed better addressed individual motor symptoms and drug-related fluctuations.

Apart from the above mentioned study, no other large study has addressed generic (in any of the three preparations) versus branded Carbidopa/Levodopa in clinical efficacy, adverse effect profile, or in tolerability.

Following FDA approval for a generic formulation of a drug, it is assumed simple bioequivalence translates into comparable clinical efficacy and tolerability. The idea that bioequivalence alone is enough to translate into efficacy in a complex disease such as Parkinson’s disease is troublesome. It should be kept in mind that most Parkinson’s disease patients also use other dopaminergic drugs (e.g. agonists, MAO-B Inhibitors, etc.). Also, most patients are elderly and suffer from other medical co-morbidities. Hence it is not uncommon for most of the Parkinson’s disease population to utilize other drugs (e.g for cardiovascular, rheumatologic, psychiatric disorders, etc.). Issues on drug – drug interactions with the different formulations of Carbidopa/Levodopa preparations cannot be addressed by simple bioequivalence studies. Finally, we must keep in mind that bioequivalence requirements in different countries are variable [3].

Many patients report differences between generic and brand Carbipdopa/Levodopa and a larger and more careful comparative effectiveness study should be performed to determine differences. At the present time only empirical trials in the clinic can guide the decision as to the best approach for an individual patient.

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Selected References:

[1] O'Brien JA, Ward A, Michels SL, Tzivelekis S, Brandt NJ. Economic burden associated with Parkinson disease. Drug Benefit Trends. 2009;21(6):179-190.

[2] US Food and Drug Administration, Center for Drug evaluation and Research. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug products – General Consideration. www.fda.gov/cder/guidance/4964dft.pdf.

[3] Borgheini G. The Bioequivalence And Therapeutic Efficacy Of Generic Versus Brand-Name Psychoative Drugs. Clinical Therapeutics 2003: 25(6): 1578-1592

[4] Meredith P. Bioequivalence and other unresolved issues in generic drug substitution Clinical Therapeutics 2003: 25:2875-2890

[5] Pahwa R, Marjama J, McGuire D, Lyons K, Zwiebel F, Silverstein P, Ward R, Koller WC. Pharmacokinetic comparison of Sinemet and Atamet (generic carbidopa/levodopa): a single dose study. Mov Disord. 1996 Jul;11(4):427-30. 

Posted: 7/26/2010 7:25:53 AM by Leilani Pearl
Filed under: Medications


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