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The Lifecycle of a Drug: Pharmaceutical Advertising, Patent Extension, & Me-Too Drugs ©Pharmed. Out The Lifecycle of a Drug: Pharmaceutical Advertising, Patent Extension, & Me-Too Drugs ©Pharmed. Out 2013 Georgetown University Medical Center Part of the Drug Ads Exercise Presentation Series

Disclaimer: Intellectual Property In this presentation, you will notice that we use images of Disclaimer: Intellectual Property In this presentation, you will notice that we use images of many registered trademarks, many branded drug trade names, and many copyrighted advertisements -- from many different business concerns -- including drug companies, marketing consultants and medical journals. All of the intellectual property contained therein is, and remains, the exclusive intellectual property of the respective owners. Each image is used for the purpose of educational, and critical, analysis. No endorsement of any position articulated in this presentation should be inferred from the appearance of any brand, trademark, trade name or ad copy herein. This presentation has been designed with the intent to qualify for the doctrine of "fair use" -- as to these pieces of intellectual property -- under the law of the United States.

Pharmaceutical Advertising Pharmaceutical Advertising

Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing

Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing

Pre-Launch: “Coming Soon” Pre-launch ads: • Pique interest in a new product • Introduce Pre-Launch: “Coming Soon” Pre-launch ads: • Pique interest in a new product • Introduce logos and color schemes • Introduce the brand name PRE-LAUNCH ACTIVE MARKETING

Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing

Launch: • Announcement of availability LAUNCH PRE-LAUNCH ACTIVE MARKETING Launch: • Announcement of availability LAUNCH PRE-LAUNCH ACTIVE MARKETING

Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing Marketing Timeline 1. Pre-Launch Ads and Disease/Mechanism Mongering 2. Launch 3. Active Marketing

Active Marketing Ads now include: • Brand name • Generic name • Use/indications • Active Marketing Ads now include: • Brand name • Generic name • Use/indications • Summary of side effects • Contraindications • Effectiveness ACTIVE MARKETING PRE-LAUNCH

Patent Extension Patent Extension

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Delayed-Release Preparations Controlled-release (CR) Sustained-release (SR) Extended-release (XL) Long-acting (LA) Delayed-Release Preparations Controlled-release (CR) Sustained-release (SR) Extended-release (XL) Long-acting (LA)

Ambien CR (Controlled-Release) Ambien CR (Controlled-Release)

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Patient extension may be granted for minor changes in dosing. Examples: Yasmin (ethinyl estradiol Patient extension may be granted for minor changes in dosing. Examples: Yasmin (ethinyl estradiol 30 mcg / drospirenone 3 mg) Yaz (ethinyl estradiol 20 mcg / drospirenone 3 mg) Androgel (topical testosterone 1% vs. 1. 62%)

Aricept (for Alzheimer’s Disease) To extend patent life on Aricept, the manufacturer developed a Aricept (for Alzheimer’s Disease) To extend patent life on Aricept, the manufacturer developed a 23 mg version. Aricept 23 mg failed to show a statistically significant improvement over the previously approved Aricept 10 mg formulation in both primary and secondary outcome measures. Aricept 23 mg demonstrated a higher incidence of adverse events such as nausea, vomiting, diarrhea, anorexia, and fatigue.

Aricept 23 mg: Approval Granted Aricept 23 mg was approved, despite a lack in Aricept 23 mg: Approval Granted Aricept 23 mg was approved, despite a lack in superiority over Aricept 10 mg and recommendations of non-approval by two FDA medical reviewers.

Aricept 23 mg: Approval Granted Justification of FDA approval: “The 23 mg dose is Aricept 23 mg: Approval Granted Justification of FDA approval: “The 23 mg dose is clearly superior to the 10 mg dose on the cognitive measure. In my view, this strongly argues for a conclusion that the 23 mg dose is very likely to also have an effect on overall functioning, despite this not having been demonstrated directly in this study. ” - Dr. Russell Katz, Division Director, Neurology Products

“Aricept 23 mg… did not show improvement on overall patient functioning. In the study, “Aricept 23 mg… did not show improvement on overall patient functioning. In the study, more people who took Aricept 23 mg experienced increased side effects. ”

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Fixed-Dose Combinations Fixed-dose combination: two or more drugs in one pill. Fixed-dose combinations: • Fixed-Dose Combinations Fixed-dose combination: two or more drugs in one pill. Fixed-dose combinations: • Are often more expensive than their components. • Provide less flexibility in dosing options.

Fixed-Dose Combination: Example Fosamax plus D (Vitamin D), a bisphonate, is patentprotected and costs Fixed-Dose Combination: Example Fosamax plus D (Vitamin D), a bisphonate, is patentprotected and costs six times as much as its generic, alendronate. Bisphonates must be taken with a calcium supplement. However, calcium supplements are often formulated with Vitamin D. Since a patient must still take additional calcium with Fosamax plus D, the total tablet burden remains the same. Therefore, the “plus D” component is of no use beyond marketing the product.

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Enantiomers: Definition Many drugs are a racemic mixture, containing equal parts of the left-handed Enantiomers: Definition Many drugs are a racemic mixture, containing equal parts of the left-handed and right-handed enantiomer. Receptors may only accept one enantiomer. Effectively one-half of the drug molecules in a racemic drug are active and the other half are inactive. Left-handed enantiomers of drugs use the prefix “es” or “levo” Right-handed enantiomers of drugs use the prefix “ar” or “dextro”

Enantiomers: Definition 1. It has become common practice to introduce a drug as a Enantiomers: Definition 1. It has become common practice to introduce a drug as a racemic mixture. 2. Then, when the patent is close to expiring, the company releases the active enantiomer as a “new, improved” product. Ask yourself: Why is the racemic mixture marketed first when it was technically possible to market the active enantiomer initially?

Omeprazole (Patient Care, 2000) Esomeprazole (JAMA, 2005) Omeprazole (Patient Care, 2000) Esomeprazole (JAMA, 2005)

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

Metabolites, Prodrugs, and Analogs Although there are exceptions, many metabolites, analogs, and prodrugs have Metabolites, Prodrugs, and Analogs Although there are exceptions, many metabolites, analogs, and prodrugs have no advantages over the originator drug. Example: Desloratidine (Clarinex) is the main metabolite of loratidine (Claritin). There is no evidence that desloratidine is superior

Vyvanse (for ADHD) Vyvanse (lisdexamfetamine) is dextroamphetamine linked to a lysine molecule, allowing for Vyvanse (for ADHD) Vyvanse (lisdexamfetamine) is dextroamphetamine linked to a lysine molecule, allowing for it to be cleaved to its components upon ingestion. While this allows for peak doses to be reached earlier, there is no advantage to this and could theoretically increase rates of adverse effects.

Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, Strategies for Patent Extension Delayed-release preparations Minor changes in dosing Fixed-dose combinations Enantiomers Metabolites, prodrugs, analogs Renaming

The Rename Game A new indication can extend the patent life of a drug. The Rename Game A new indication can extend the patent life of a drug. Some drugs are renamed upon approval for a new indication, allowing for patent extension. Bupropion = = Sildenafil

The Rename Game: Example = Example: • Fluoxetine is the generic version of both The Rename Game: Example = Example: • Fluoxetine is the generic version of both Prozac and Sarafem. • After Prozac lost patent exclusivity, Sarafem provided new life to the patent. • Fluoxetine could only be substituted for Prozac, NOT Sarafem, because the indications for which the drugs were approved were different. • Now that Sarafem has lost patent exclusivity, both drugs are available as generics.

Me-Too Drugs Me-Too Drugs

Me-Too vs. First-In-Class Drugs First-in-class drugs are novel drugs. Me-too drugs are similar, related Me-Too vs. First-In-Class Drugs First-in-class drugs are novel drugs. Me-too drugs are similar, related drugs to first-in-class drugs. Marketing may exaggerate the benefits of a me-too drug versus the original first-in-class drug.

Me-Too Drugs A me-too drug could be better than a first-in-class drug, or it Me-Too Drugs A me-too drug could be better than a first-in-class drug, or it could be worse. Example: Simvastatin, a me-too drug, is a more effective statin than lovastatin, a first-in-class drug. Graphic reprinted by permission from Pill Advised. On the other hand, Baycol (cerivastatin) was withdrawn from the market due to a disproportionate number of cases of rhabdomyolysis.

NEJM, January 1999 “Rare cases of rhabdomyolysis have been reported with cerivastatin” NEJM, January NEJM, January 1999 “Rare cases of rhabdomyolysis have been reported with cerivastatin” NEJM, January 2001 “Cases of rhabdomyolysis have been reported with cerivastatin”

Baycol was withdrawn from the market in August 2001 due to excess cases of Baycol was withdrawn from the market in August 2001 due to excess cases of rhabdomyolysis.

Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of action Fewer unwanted effects Improved receptor selectivity • Conversely, first-in-class drugs may market their longer history and larger body of research

Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of action Fewer unwanted effects Improved receptor selectivity

Increased Potency or Longer Duration of Effect May add no clinical benefit May increase Increased Potency or Longer Duration of Effect May add no clinical benefit May increase the risk of adverse events May increase flexibility in dosing options

Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of action Fewer unwanted effects Improved receptor selectivity

Faster Onset of Action In chronically used drugs, such as statins, faster onset of Faster Onset of Action In chronically used drugs, such as statins, faster onset of action would only affect the first dose.

Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of action Fewer unwanted effects Improved receptor selectivity

Fewer Unwanted Effects Unwanted effects take time to be discovered and reported. Pre-market studies Fewer Unwanted Effects Unwanted effects take time to be discovered and reported. Pre-market studies cannot pick up longterm adverse effects, drug interactions, or effects that occur only in elders, diabetics, or other subpopulations. Claims of increased safety for new drugs are not trustable without long-term data.

Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of Me-Too Drugs: Marketing Messages Increased potency or longer duration of effect Faster onset of action Fewer unwanted effects Improved receptor selectivity

Decreased Risk for Drug Interactions Molecular stories, such as improved receptor selectivity, may not Decreased Risk for Drug Interactions Molecular stories, such as improved receptor selectivity, may not necessarily have a clinical benefit.

To properly assess a me-too drug, adequate controlled studies with patient-oriented endpoints in relevant To properly assess a me-too drug, adequate controlled studies with patient-oriented endpoints in relevant populations are required. Ask yourself: Does treatment with the metoo drug result in the patient living longer or better?

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