Brand Alternatives (Dr Brown-Myrie)

BRAND ALTERNATIVES

Examining Issues of Quality and Effectiveness

OBJECTIVES

At the end of the presentation, participants should be able to:1. Define terms commonly used in the understanding of brands and

generics formulations.

2. Objectively discuss the concerns that surround the issues of generic substitution or interchangeability with branded drugs.

3. Outline the reasons for the increasing use of generics

4. Discuss the role that bioequivalence plays in the guarantee of quality in generic products.

5. Explain the standards that are built into the determination of bioequivalence of pharmaceutical equivalent products

6. Explain the Regulatory Processes employed in the maintenance of quality among generics.

2CariMed CE, Sep. 9, 2012

INTRODUCTION

• When buying medicines nowadays, patients are commonly presented with a choice between two seemingly different but really similar products: branded and generic medicines.

• Since the introduction of generic drugs to the pharmaceutical market, there is often emotional debates about whether they are well-investigated and of high quality.


Introduction

• There is uncertainty about whether evidence of bioequivalence is enough to guarantee efficacy and safety of generic drugs.

• Consequently, the substitution of generic drugs for brand-name products is highly controversial and is often met with suspicion by health care providers and patients.

• The Generic Substitution Act and the Registration process used by the MOH ensures the patients have the best alternatives


Definitions

• Brand-name drug: A brand-name drug is a drug marketed under a proprietary, trademark-protected name.

• Generic drug: A generic drug is identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.

• Pharmaceutical equivalents: Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration


Definitions cont’d

• Pharmaceutical alternatives: These are drug products that contain the same active moiety but contain different chemical forms such as esters or salts of the active moiety or they may differ from the innovator’s product in the dosage form or strength.

• Reference listed drug (RLD): A reference listed drug is an approved drug product to which new generic versions are compared to show that they are bioequivalent.

• Bioavailability (BA): The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.


Definitions cont’d• Bioequivalence (BE):demonstration that both the

rate and extent of absorption of the active ingredient of the generic drug fall within established parameters when compared to that of the reference listed drug.


Bioavailability & Bioequivalence

• Bioavailability (BA) and bioequivalence (BE) studies play a major role in the drug development phase for both new drug products and their generic equivalents, and thus attract considerable attention globally.

• BE is a strategy to introduce generic equivalents of brand-name drugs (innovator drugs) to lower the cost of medication through proper assessment as directed by the international regulatory authorities.


History• The Drug Price Competition and Patent Term Restoration

Act of 1984 (Hatch-Waxman Act) gave generic drug companies greater access to the market for prescription drugs, and gave innovator companies greater patent life.

• The patent gives a company the sole right to sell the drug while the patent is in effect. When patents or other periods of exclusivity expire, manufacturers can apply to the FDA to sell generic versions.

http://www.fda.gov/cder/ogd/ 9CariMed CE, Sep. 9, 2012

History• Drug companies must submit an abbreviated new drug

application (ANDA) for approval to market a generic product.

• The ANDA process does not require the drug sponsor to

repeat costly animal and clinical research on ingredients or dosage forms already approved for safety and effectiveness. This applies to drugs first marketed after 1962. Therefore, generic medications are priced/can be priced lower than brand name medications.

http://www.fda.gov/cder/ogd/


Reasons Underlying Use of Generic Medicines

• The rising cost of medication has been contributing to the total overall cost of health care and thus receives considerable attention globally.

• A major strategy for lowering the cost of medication, and thereby reducing its contribution to total health care costs, has been the introduction of generic equivalents of brand-name drugs (innovator drugs).

AAPS J. 2009;11:664–670.



• This introduction of generic equivalents has been effective in reducing total prescription costs by 11% without sacrificing quality. Ann Intern Med. 2005;142:891–897.

• Generic drugs have captured more than 65% of the global market and account for 66% of prescriptions filled in the United States but for less than 13% of the cost. Health Aff. 2009;28:546–556.



• The increase use of generics is an economic issue • Need by payers, including government, and formularies

to reduce healthcare costs– Congressional Budget Office estimates generics save consumers

$8 to $10 billion a year at retail pharmacies (http://www.fda.gov/cder/ogd/)

• Expense of brand name drugs for patients, such as seniors on fixed income, can be substantial


Reasons Underlying Use of Generic Medicines• FDA’s commitment to generic medicines

– “FDA will continue to make the generic drug approval process more efficient with the goal of lowering national health care costs by reducing the cost of bringing safe and effective generic drugs to market.” FDA press release August 8, 2003

• Belief by payers, some physicians and some patients that brand products and generic versions are entirely equivalent and interchangeable


• Since generic drugs are so important in health care, it is imperative that the pharmaceutical quality, safety, and efficacy of generics be reliably compared with the corresponding innovator drugs (brand-name drugs).


Regulatory Process for Generics in U.S.

• A very rigorous, successful program has been established by the US Food and Drug Administration (FDA) and its European and Canadian counterparts to insure that every marketed form of the same medication has the same biological effect.

• That means that generic drugs are for all practical purposes the same as the brand name drug .



• Food and Drug Administration (FDA), the US government entity that approves pharmaceuticals for the market, has standards in place to ensure that drugs offered as generics perform as effectively as the original brand name substance.


Regulatory Process for Generics in U.S.• To gain FDA approval, a generic drug must: – contain the same active ingredients as the

innovator drug (inactive ingredients may vary)

– be identical in strength, dosage form, and route of administration

– have the same use indications



Regulatory Process for Generics in U.S.• To gain FDA approval, a generic drug must: – be bioequivalent –meet the same batch requirements for

identity, strength, purity, and quality – be manufactured under the same strict

standards of FDA's good manufacturing practice regulations required for innovator products

http://www.fda.gov/cder/ogd/ 20CariMed CE, Sep. 9, 2012


• The FDA regulates all facilities creating drugs, and no matter what type of drug a facility creates, it has to meet exactly the same rigorous guidelines.

• There’s certainly not a reason to think that a generic pharmaceutical originates from a manufacturing facility with lesser standards for quality.


Regulatory Process for Generics in U.S.• Bioequivalence is a key requirement• Bioavailability and Bioequivalence

Requirements of FDA are codified under Title 21, Chapter 21, Subchapter D, Part 320 (http://www. accessdata.fda.gov/ scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320)


Regulatory Process for Generics in U.S.• Part 320, Subpart B – Procedures for Determining the

Bioavailability or Bioequivalence of Drug Products– The in vivo bioavailability of a drug product is . . .

[accepted] if the product's rate and extent of absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, urinary excretion rates, or pharmacological effects, do not indicate a significant difference from the reference material's rate and extent of absorption.



CariMed CE, Sep. 9, 2012 25

Regulatory Process for Generics in U.S.• Two formulations of the same drug or two drug products

are claimed bioequivalent if the ratio of means of the primary PK responses such as AUC and Cmax between the two formulations of the same drug or the two drug products is within (80%, 125%) with 90% assurance.

• A generic drug product can substitute for the brand name drug product if it has been shown to be bioequivalent to the brand name drug.

Chow et al. Drug Information Journal Apr-Jun 1999



• To establish BE, the calculated 90% confidence interval should fall within a BE limit of 80% to 125% using logarithm transformed data (adopted since the concentration parameters Cmax and AUC may or may not be normally distributed).

• Currently, the BE limits of 80% to 125% have been applied to almost all drug products by regulatory authorities



• The FDA, however, does not indicate that a generic drug can be substituted by another generic drug for a brand name drug product even though both of the generic drugs have been shown to be bioequivalent to the same brand name drug.

Chow et al. Drug Information Journal Apr-Jun 199928CariMed CE, Sep. 9, 2012


• FDA grades generic drugs for bioequivalence with either an A or B.

• B grades are given generic drugs that were approved before FDA started requiring that bioequivalence be established by actual human, in vivo testing

• The complete list of A and B-rated generic drugs can be accessed at http://www.fda.gov/cder/orange/default.htm



• The US Food and Drug Administration (FDA) publishes a list of drug products and equivalents, Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the “Orange Book”.

• The FDA’s designation of “therapeutic equivalence” indicates that the generic formulation is (among other things) bioequivalent to the innovator formulation and signifies the FDA’s expectation that the formulations are likely “to have equivalent clinical effect and no difference in their potential for adverse effects”.


Regulatory authorities of various countries

• US: US Food and Drug Administration (FDA)• Europe: European Medicines Agency (EMEA)• UK: United Kingdom Medicines and Health care

products Regulatory Agency (MHRA)• Canada: Health Canada• S. Africa: Medicines Control Council (MCC)• Australia: Therapeutic Goods Administration (TGA)• Korea: Korea Food and Drug Administration (K-FDA)• Mexico: Ministry of Health


The Case for the use of GenericsResearch shows that generics work just as well as brand name

drugs.

• A study evaluated the results of 38 published clinical trials that compared cardiovascular generic drugs to their brand name counterparts. There was no evidence that brand name heart drugs worked any better than generic heart drugs.

JAMA. 2008;300(21)2514-2526


The Case for the use of Generics• FDA recently evaluated 2,070 human studies conducted

between 1996 and 2007. These studies compared the absorption of brand name and generic drugs into a person’s body. These studies were submitted to FDA to support approval of generics. The average difference in absorption into the body between the generic and the brand name was 3.5 percent.

Ann Pharmacother. 2009;43(10):1583-97.


Potential Disadvantages of Generic Medicines• Rate and extent of absorption (bioavailability) differs

between different generic versions of branded products• Generic products usually differ in appearance from the

brand and from other generic versions of the same product, leading to patient confusion and anxiety

• Excipients and colorants used in generic products may differ from the brand, potentially causing problems

Crawford et al. Seizure 2006;15:168-176


Interesting Facts about Brands & Generics

• Generic prescription drugs are frequently manufactured by companies also producing brand-name drugs.

• The Food and drug administration reports that approximately fifty percent of generic pharmaceutical manufacturing is done in facilities also creating brand name drugs.


Take Home Message

• Generic drugs are bioequivalent and clinically equivalent to the brand name version.

• Generic versions of medications whose patents have expired can be prescribed without sacrificing clinical effectiveness.

• It is recommended that before making generic substitutions, the bioequivalence of the generic version of a drug be validated.

• Regulatory databases should be consulted to verify bioequivalence status of all generic forms of drugs.


Recommendations

• Physicians and pharmacists should become familiar with specific laws and/or regulations governing generic drug substitution in settings where they practice.

• Once medication for chronic diseases has been prescribed and begun, no substitution of either generic or brand-name drug products should be made without consultation with the attending physician.


Recommendations

• Serious adverse drug reactions or therapeutic failures that may be related to drug substitution should be documented and reported to appropriate drug regulatory authorities.

• Health Care Professional associations, in collaboration with the appropriate drug regulatory bodies, should evaluate and ensure the bioequivalence and the chemical and therapeutic equivalence of all similar drug products, whether generic or brand-name manufactured, in order to ensure safe and effective treatment.


Conclusion

• Generic and branded drugs undergo a rigorous process of formulation and quality assurance to guarantee bioequivalence and clinical effectiveness.

• Generic substitution is an advisable practice to reduce health care costs but careful monitoring should be conducted to ensure efficacy and safety.


Thank You


Brand Alternatives (Dr Brown-Myrie)

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