Generics from the Ground Up

US Pharm. 2008;33(6)(Generic Drug Review suppl):10-17.

Pharmaceuticals are a large part of health care expenditures in the United States. According to the Generic Pharmaceutical Association, 286.5 billion dollars were spent on medications in the U.S. in 2007.¹ Prescription medications dispensed in community pharmacies comprised 10.1% of health care expenditures. This is an increase of 6% from 1995.² Interestingly, the growth in drug expenditures has plateaued over the past few years. Prescription drugs accounted for 9.9% of national health expenditures in 2002, increasing by only 0.2% in 2005.² One of the reasons for this slowdown is the use of generic drugs.³

About 65% of all prescriptions are filled with generic drugs, yet they generics account for only 20% of total prescription costs.¹ The FDA calculated some eye-opening figures using data from the 2004 IMS Health's National Prescription Audit Plus. If patients have their prescriptions filled generically, drug costs can fall by 14% to 16% per day, depending on the condition being treated. Those patients fortunate enough to be able to fill all of their prescriptions generically could expect a 52% decrease in the daily costs of their medications.⁴ On average, generic medications cost from 30% to 80% less than the brand drug. ¹ Generic manufacturers do not have to carry the expense of research and development or the marketing of their products compared to brand manufacturers. This enables the generic manufacturers to sell the same drug at a fraction of the cost. This cost differential is a large part of the ever-increasing presence of generics in the pharmacy industry. With the filling of generic prescriptions on the rise, it is important that pharmacists know the approval process that the FDA requires to bring a generic equivalent to the market.

Drug Approval Process
The drug approval process is vastly different between the innovator product and the generic equivalent. The brand manufacturers must go through a tedious and time-consuming process in order to get their drug approved. There are several phases involved in the approval of innovator drugs, starting with the preclinical phase.

Preclinical Phase: In the preclinical phase, all testing is performed on laboratory animals. The sponsor of the drug entity determines the toxic and pharmacologic effects using in vitro and in vivo testing. Absorption, metabolism, and the rate of excretion of the parent drug and the metabolites are investigated during the preclinical phase. The sponsor also looks for the toxicity of the metabolites. After the successful completion of the preclinical phase, an Investigational New Drug (IND) Application is filed with the FDA.

Phase I: During phase I, the IND is typically tested on healthy humans. Patients may be included in phase I trials, but that is not the norm. Phase I trials consist of approximately 20 to 80 subjects and are used to determine the metabolic and pharmacologic actions of the drug in humans. The investigators assess the safety and incidence of adverse effects as well as the drug metabolism, structureñactivity relationships, and mechanism of action.

Phase II: Phase II trials are conducted on several hundred patients and are designed to gather preliminary data on the effectiveness of the drug. During phase II, common side effects and risks in patients are determined.

Phase III: Phase III trials are much larger and consist of several hundred to several thousand subjects. Phase III studies consist of both controlled and uncontrolled trials that investigate additional safety and efficacy information. The information gathered in phase III trials is used to create the package insert.

After the sponsor successfully completes all three phases of human trials, they submit a New Drug Application (NDA) with the FDA.⁵

Abbreviated New Drug Applications
The approval process for generic substitutes is far simpler, but it has not always been that way. In 1970 the FDA introduced the Abbreviated New Drug Application (ANDA). At that time, the ANDA could only be used to approve the generic versions of drugs that had been approved between 1938 and 1962.⁶ The generic manufacturers seeking approval for a generic equivalent of a brand name drug approved after 1962 had to conduct their own studies establishing safety and efficacy.⁶ These requirements served as a barrier for the development of cheaper generic versions of innovator drugs. The FDA's stringent approval process remained in effect until 1978, after which manufacturers only had to cite published reports of trials that documented the safety and efficacy of the drug entity in order to obtain approval. This became problematic, however, because many of the trials required to satisfy FDA requirements were not published.⁶

The Drug Price Competition and Patent Term Restoration Act
In 1984, the Drug Price Competition and Patent Term Restoration Act, also called the Hatch-Waxman Act, was passed. This important legislation affected the generic industry profoundly. This amendment to the Federal Food, Drug, and Cosmetic Act allowed for the use of an ANDA for approval of a "new drug." The ANDA had to include "1) information to show that the conditions of use prescribed in the labeling proposed for a new drug have been previously approved for a drug that appears on a list prepared by the Secretary of Health and Human Services (listed drug); and 2) a certification relating to such patents covering such listed drug."⁷ In other words,† no preclinical or clinical studies need to be done to demonstrate safety and efficacy.⁶ The Hatch-Waxman Act allows brand manufacturers a five-year patent extension in order to recoup their time lost in the approval process. This is allowed if the patent has not yet expired when the application for extension is submitted and the patent has never been extended before. This extension request must be submitted by "the owner of record of the patent or its agent."⁷ The act promoted research and development of new drug entities and encouraged generic manufacturers to produce equivalents by simplifying the approval process. They only had to prove bioequivalence to the innovator drug.

Determining Bioequivalence
Generic drugs, called pharmaceutical equivalents, must have the same active ingredient in the same strength as the brand drug, must be in the same dosage form and be administered in the same way as the innovator drug, and must be have labeling essentially the same as that of the brand name drug. The FDA also requires the generic drug's chemistry, manufacturing steps, and quality control measures to be fully documented by the generic manufacturer. The FDA must be assured that the raw materials and finished product meet U.S. Pharmacopoeia specifications and that the potency of the equivalent will remain unchanged until the expiration date on the label. Generic manufacturers need to comply with the federal regulations of good manufacturing practices and include a full description of the facilities used to manufacture, process, test, package, and label their products.

Generic pharmaceutical manufacturers must also prove bioequivalence. Bioequivalence means "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalentsÖ.becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."^8,9 Two drug products are deemed to be bioequivalent if it can be demonstrated that they have an equivalent rate and extent of absorption. Based on these premises, it can be inferred that if two drugs products contain chemically identical drug substances and are delivered to the site of action at the same rate and extent of each other, they are equivalent. They may then be substituted for each other.¹⁰

Using a two-treatment crossover design with 24 to 36 healthy adults in the fasting state, the typical pharmacokinetic bioavailability or bioequivalence study is conducted. ¹¹ A single dose of one of the drugs being compared is administered and the blood or plasma concentrations are measured over time. The parameters used to determine the rate and extension of absorption are the area under the plasma concentrationñtime curve (AUC, determines extent of absorption) and the maximum or peak drug concentrations (Cmax, determines rate of absorption). ¹⁰ After an elimination period of the drug, at least three times the half-life of the active drug and/or its active metabolites measured in the blood, the other drug substance is administered.¹¹

Other study designs may be appropriate when blood-plasma concentrations are not useful to determine the delivery of the drug to the site of action. This would apply to inhalers, nasal sprays, or dermatological topical formulations. In these cases, an in vitro study or an equivalence study might be used to determine clinical or pharmacodynamic endpoints.¹⁰

The data resulting from these studies is statistically evaluated using the two one-sided tests procedure. ¹⁰ This is a test designed to determine equivalence with the assumption is that there may be some inequivalence.¹² The first of the two one-sided tests determines if a generic product, when substituted with a brand name product, exhibits significantly less bioavailability. The second of the two one-sided tests determines whether a brand drug, when substituted by a generic, exhibits significantly less bioavailabilty.¹⁰ A difference of greater than 20% for each of the statistical tests is considered significant and results in failure of bioequivalence between the two drugs. This translates to an 80% difference in the bioavailability of the products. All of the data is expressed as a ratio of average values of the AUC and Cmax. Therefore, the limits of acceptable bioavailability for a pharmaceutical equivalent are 80% and 125% (reciprocal of 80%) of the innovator product. ¹⁰ Even though the FDA contends that this process of approval is adequate, there are others who do not agree.

Weaknesses in the FDA Approval Process
There is some question as to whether a bioequivalent generic drug will be clinically comparable to the reference drug.⁹ Will the generic demonstrate the same efficacy and tolerability as the original brand name drug?

The use of healthy volunteers to determine bioequivalence is another suspect practice. The extrapolation of bioequivalence demonstrated in normal healthy subjects to bioequivalence in a patient population has been criticized.⁹ In order to ensure a homogeneous subject population, many variables need to be controlled. The study subjects are healthy males aged 18 to 55. They do not take any concurrent medications, do not smoke, and are of normal body height and weight. In addition, all subjects receive a controlled diet.⁹ This is an excellent study design used to ensure that any bioinequivalence is due to the formulation of the test drug and not because of any other differences between subjects. However, there are differences in pharmacokinetic properties of a drug if these variables are not so closely controlled. Concurrent diseases, concurrent medications, diet, differences in first-pass metabolism, and the presence of food in the stomach can all affect the way a drug is absorbed, metabolized, and excreted. Some gastrointestinal factors that may alter the pharmacokinetic parameters include gastric pH, blood flow, and bacterial flora.⁹ Some researchers believe these variables should be taken into consideration. There are some problems with the use of patients in bioequivalence studies.

There is also an ethical issue to be considered if patients are used as test subjects. If the generic drug proves to be substandard, it may result in toxicity or worsening of the disease state in the patient. Another reason to avoid using patients as study subjects is the inherent variability in a heterogeneous sample. This would require larger patient populations, which may result in longer study times at a greater expense. Finally, there may be differences in the drug response and/or pharmacokinetic parameters, which are simply the result of a progressing disease process and not a problem in the formulation.⁶

The use of single-dose studies is another area of concern. The FDA states that the use of single-dose studies is generally more sensitive in assessing the release of an active metabolite from the parent drug into the systemic circulation. The problems with single-dose studies include the fact that most drugs are not given as a single dose and must be maintained at a steady state in order to obtain the therapeutic effect. Often the drug concentration at steady state is higher than that after a single dose. It is also thought that some of the inert ingredients in the generic formulation may affect the pharmacokinetics at steady state, which may not be noticed after a single dose.⁹

The use of the same regulatory limit (80% to 125%) for all medications, including narrow therapeutic index (NTI) drugs, has been under scrutiny. Some believe the bioequivalence requirements should be more stringent when evaluating NTIs.⁹

There has been concern about drug imports. Baxter's heparin recall brings this issue to the forefront again. ¹³ On December 11, 2007, an agreement was reached between the U.S. Department of Health and Human Services and the State Food and Drug Administration (SFDA) of the People's Republic of China. In general, this agreement serves to establish a consensus with regard to the exportation of drugs, excipients, and medical devices from China into the U.S. and engage in information sharing in order to better understand each party's regulation process. This will result in improvement of the authenticity, quality, safety, and efficacy of drugs, excipients, and medical devices imported from China. ¹⁴ Any firms that import drugs to the U.S. will need to be registered by the SFDA. These firms will need to be certified by the SFDA that they meet FDA requirements for drug importation into the U.S

The Orange Book
The Orange Book is a publication listing approved prescription drug products with therapeutic equivalence evaluations.¹⁰ It is published electronically (as well as in print) and can be found at www.fda.gov/cder/ob/. The Orange Book is an excellent reference tool for pharmacists practicing drug product selection. It lists evaluation codes identifying which products have been tested and deemed to be bioequivalent to the innovator product. The electronic version has a query field that may be searched by active ingredient, proprietary name, applicant holder, application number, and patent.¹⁰ This enables quick and easy retrieval of generic equivalents for a brand name drug.

The equivalence codes assigned to the generic products begin with either an A or a B. Those products designated A products have documented or potential problems resolved with in vivo or in vitro testing as appropriate. B products are those that have not had any actual or potential bioequivalence problems resolved. There are three main policies into which a B product may fall: 1) the drug products have either active ingredients or are manufactured in dosage forms that have had documented actual or potential bioequivalence problems and for which there has not been adequate evidence submitted to the FDA resolving such issues; 2) the quality standards are inadequate or there is not enough sufficient evidence for which to determine bioequivalence; and 3) the drugs are under regulatory review.¹⁰ Please refer to TABLE 1 for the equivalence codes listed in the Orange Book.

There are some special situations that require more explanation. In the case of amino acid and protein hydrolysate injections, equivalency falls in a gray area. There are different types and amounts of amino acids in each; therefore, they are not equivalent. It needs to be pointed out, though, that when nitrogen balance is the only therapeutic objective and different amino acid content is not important, products can be considered equivalent if they have the same total amount of nitrogen.¹⁰ Another special situation exists with Follitropin formulations. Based on data derived from physiochemical tests and bioassay, Follitropin Alfa and Follitropin Beta are not distinguishable from each other.¹⁰

There are multiple reference-listed drugs (those reference drugs generic products are tested against) for levothyroxine sodium. Some of these reference-listed drugs were approved by demonstrating bioequivalence to other reference listed drugs. This has resulted in the FDA not granting a blanket equivalence rating for all of the formulations. They have created a chart showing which brand drugs are equivalent to each other. For instance, the Mylan brand of levothyroxine sodium is equivalent to the corresponding strengths of Unithroid.¹⁰

Sometimes, an equivalence code contains a number at the end (AB1, AB2Ö). This is done when there are two or more reference-listed drugs with the same active ingredient in the same strength but which are not bioequivalent. For instance, Procardia XL and Adalat CC are listed under the active ingredient nifedipine, yet they are not bioequivalent to each other. Therefore, generic products that are equivalent to Adalat CC are given an AB1 rating and those equivalent to Procardia XL are given an AB2 rating.¹⁰ It is important to remember that most states have a formulary dictating which products may be substituted

Narrow Therapeutic Index Drugs

Narrow Therapeutic Index Drugs (NTIs) are defined as having less than a two-fold difference between the minimum toxic concentrations and the minimum effective concentrations in the blood.¹² Some examples of NTIs are digoxin, lithium, phenytoin, theophylline, and warfarin. These products do not have any specialized conditions required by the FDA. Despite this and other misgivings with the ANDA approval process, generic medications are generally accepted by physicians and patients. There are some variables, though, that influence a patient's acceptance of a generic substitution.

The Pharmacist's Role

The concern about generic substitution among many patients stems from lack of information. They wonder if generics are as strong as the brand. They worry that generics may cause more adverse effects. Some have had a negative experience with a generic drug.

The pharmacist is perfectly poised to educate patients on the use of generic drugs. When a patient drops off a prescription, the pharmacist can take that opportunity to clear up any confusion with regard to the use of generic products. Generic drugs are a cost-containing alternative to higher priced brand name drugs. Informed consumers are better equipped to make decisions regarding their prescriptions.

References

1. Generic Pharmacy Association Statistics. www.gphaonline.org/Content/NavigationMenu/
AboutGenerics/Statistics/. Accessed April 4, 2008.

2. National Health Expenditures, average percent change, and percent distribution, by type of expenditure: United States, selected years 1960-2005. Health, United States. 379. www.cdc.gov/nchs/data/hus/hus07.pdf#summary. Accessed April 5, 2008.

3. Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures--2007. Am J Health Syst Pharm . 2007;64:298-314.

4. Savings from generic drugs purchased at retail pharmacies. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. May 3, 2004. www.fda.gov/cder/consumerinfo/savingsfromgenericdrugs.htm. AccessedApril 19, 2008.

5. The new drug development process: steps from test tube to New Drug Application review. Center for Drug and Evaluation and Research, U.S. Food and Drug Administration. www.fda.gov/cder/handbook/develop.htm. Accessed April 18, 2008.

6. Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic approval process. J Am Pharm Assoc. 2001;41:856-867.

7. A bill to amend the patent laws of the United States. Public Law 98-417 (summary). Thomas, Law Library of Congress. http://thomas.loc.gov/cgi-bin/bdquery/z?d098:SN01538:@@@D&summ2=m&|TOM:/bss/d098query.html|. Accessed April 15, 2008.

8. Code of Federal Regulation-21 CFR 320.

9. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003;23:2875-2890.

10. Approved Drug Products with Therapeutic Equivalence Evaluations. Rockville, MD: Center for Drug Evaluation and Research, U.S. Food and Drug Administration; 2008. www.fda.gov/cder/ob/. Accessed March 31, 2008.

11. Code of Federal Regulation-21 CFR 320.26.

12. Lung KR, Gorko MA, Llewelyn J, Wiggins N. Statistical method for the determination of equivalence in automated test procedures. J Auto Methods Manag Chem. 2003;25:123-127.

13. Statement of Janet Woodcock, MD, Director, Center for Drug Evaluation and Research, before the subcommittee on Oversight and Investigations Committee on Energy and Commerce. http://google2.fda.gov/search?q=cache:vwaQUqwXxWgJ:www.fda.gov/ola/2008/heparin042908.html+GMP+drugs+china&access=p&output=
xml_no_dtd&ie=UTF8&lr=&client=FDA&proxystylesheet=FDA&oe=ISO-8859 1. AccessedMay 9, 2008.

14. Agreement between the Department of Health and Human Services of the United States

of America and the State Food and Drug Administration of the People's Republic of

China on the Safety of Drugs and Medical Devices. www.fda.gov/oia/agreements/
China_Drugsdevices.htm. Accessed May 9, 2008.

15. Ganther JM, Kreling DH. Consumer perceptions of risk and required cost savings for generic prescription drugs. J Am Pharm Assoc. 2000;40:378-383.

16. IMS Web site. www.imshealth.com/ims/porta/pages/homeFlash/us/0,2764,6599,00.html. Accessed May 9, 2008.