More threads by David Baxter PhD

David Baxter PhD

Late Founder
Controversies in Drug Substitution
by Seema Z. Kazmi, PharmD
Medscape Pharmacists. 2007

Skyrocketing healthcare costs have become a national issue, and drug expenditures account for 11% of those costs in the United States.[1] Generic drugs have been identified as a cost-effective alternative to more expensive branded medications. In fact, according to some estimates, $8.8 billion could be saved each year in the United States alone if generic medications were prescribed and used in an optimal manner.[2]

However, some physicians continue to prescribe branded medications when generics are available, believing that the branded formulations are superior. In addition, some patients are uncomfortable with the idea of taking a "substitute" for a medication that their doctor prescribed.

Recent news reports have stirred up the matter further. An independent laboratory released test findings earlier this month that raised questions about a particular generic formulation of bupropion hydrochloride extended-release tablets (Wellbutrin XL).[3] The laboratory said that Budeprion XL (made by Teva Pharmaceutical Industries) did not perform the same as Wellbutrin XL, releasing the active ingredient more quickly and thus potentially being less effective. Although the report raised concerns for some drug safety advocates, others noted that even if it was correct, it involved only a tiny segment of the generic drug market.

A separate issue is the increasing number of drug therapies that are biologic in nature, or protein-based, making them more costly to manufacture and thus even more expensive for patients. In light of growing concerns over the high price of such therapies, "biosimilars" or "follow-on biologics" are being studied as less expensive alternatives. However, questions have been raised over whether one biologic agent can be a true substitute for another. In fact, Congress is currently wrestling with that issue and may provide new guidance within the coming months.

Meanwhile, the pharmacist must discern whether any drug substitution is really appropriate for a given patient. In most states, pharmacists can dispense generic substitutes for brand-name drugs unless the prescriber specifies otherwise. Pharmacists can be a vital resource for prescribers, providing current information about the effectiveness of appropriate substitutes. Pharmacists and prescribers can work together to educate patients about the equivalence of generic medications that may cost them significantly less.

Setting the Stage for Generic Substitutions
Generic medications undergo testing and must meet specific requirements set by the US Food and Drug Administration (FDA) before they can be used as substitutes for their branded counterparts. Over the years, various laws and regulations have been developed to guide generic substitutions. The first piece of significant legislation was the Pure Food and Drug Act of 1906, which mandated that drugs be manufactured under sanitary conditions and made free of impurities; the law also outlawed misbranding.[4] However, that law did not require that drugs be tested for safety prior to distribution to the public, and in 1937, more than 100 people died after ingesting a sulfonamide elixir containing the toxic solvent diethylene glycol.

As a result, Congress passed the Food, Drug, and Cosmetic Act in 1938, mandating that a manufacturer demonstrate a drug's safety before bringing it to the marketplace.[4] Additional amendments and laws were enacted in subsequent years to expand public protections. For example, the 1962 Kefauver-Harris Amendment added a requirement that manufacturers provide data demonstrating a drug's efficacy in treating a particular indication; it also required that drugs be manufactured in accordance with Good Manufacturing Practice.[4] The Food, Drug, and Cosmetic Act and its amendments continue to regulate drug quality today.

Laws regulating generic substitution have been very stringent as well. In the 1950s, as many as 40 states had strict antisubstitution laws, prohibiting pharmacists from substituting generic equivalents for branded drugs prescribed by physicians. The pharmaceutical industry supported these laws and helped get the legislation passed.[5]

Lawmakers were convinced that these restrictive laws served the public interest by limiting the use of "inferior imitations" of higher-quality brand-name drugs. However, in the 1960s, the public's confidence in generic drugs began to grow, along with increasing reliance on pharmacists to assist in making drug selections. In the 1970s, the American Pharmacists Association (APhA, formerly the American Pharmaceutical Association) aligned with third-party payers and consumer advocacy organizations to repeal antisubstitution laws in order to give patients access to less expensive drugs.[5] The APhA also advocated for pharmacists to be allowed to use their professional judgment in helping patients with drug product selection.

In 1976, the Federal Trade Commission (FTC) conducted a study of generic drug substitutions.[6] The FTC report concluded that forcing consumers to use branded medications resulted in higher out-of-pocket costs. It also concluded that allowing pharmacists to make drug substitutions encouraged price competition, potentially saving costs for the Medicaid and Medicare programs as well.[6-8]

At that time, however, generic medications underwent the same drug approval process as their branded counterparts, requiring clinical studies that demonstrated safety and efficacy. Consequently, only a handful of generic medications were granted FDA approval. It was not until 1984, with the passage of the Drug Price Competition and Patent Term Restoration Act (also known as the Hatch-Waxman Act), that the approval process for generic medications became abridged. Since then, generic manufacturers have been allowed to submit an Abbreviated New Drug Application, which does not require animal or clinical studies.[5,9] Bioequivalence testing is still required.[9]

The Hatch-Waxman Act also allowed manufacturers of branded drugs to seek patent extensions. Thus, it both paved the way for generic drug makers to manufacture less expensive formulations and allowed branded drug makers to obtain longer patent lives.

When Are Substitutions Appropriate?
In order to discuss the appropriateness of substituting one drug for another, it is important to understand certain key terms.[10]

Pharmaceutical equivalents are drug products containing the same active ingredient(s), same strength, dosage form, route of administration, and identical strength or concentration. They may or may not have different shapes, coloring, packaging, or inactive ingredients.

Therapeutic equivalents are products that are pharmaceutical equivalents and that produce the same clinical effect and have the same safety profile. They must be manufactured under Good Manufacturing Practice and be labeled properly.

Pharmaceutical alternatives contain the same active therapeutic ingredient, but are formulated with a different salt, ester, or complex. They may come in different dosage forms or strengths.

Bioavailability is 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.

Bioequivalent drug products are pharmaceutical equivalents or pharmaceutical alternatives that show comparable bioavailability under similar experimental conditions.

Bioequivalence Testing
Demonstrating the bioequivalence of different drugs requires proof of therapeutic equivalence, which justifies the substitution of one product for another. According to the "Approved Drug Products With Therapeutic Equivalence Evaluations," a list produced by the FDA (better known as "The Orange Book"), bioequivalence can be determined through 1 of 4 paths: pharmacokinetic studies, pharmacodynamic studies, comparative clinical trials, or in vitro studies.[10] The latter 3 types of studies are used to test drug products in which plasma levels are not affected, such as nasal sprays, aerosols, and topical medications.

In contrast, pharmacokinetic studies test bioequivalence by measuring plasma levels to determine the rate and extent of absorption. The area under the concentration-time curve (AUC) is obtained to determine the extent of absorption. In addition, peak drug concentrations (Cmax) are used to determine the rate of absorption. These studies are conducted with a 2-treatment crossover design in 24-36 volunteers, and single doses of test and standard drugs are administered.[10] Plasma samples are collected and evaluated at various time intervals. If 2 drug products containing the same active chemical entity can reach the site of absorption in similar times and be absorbed to the same extent, bioequivalence can be established. Confidence intervals of the measured pharmacokinetic parameters are expected to fall between 80% and 125%.[10]

The FDA's Orange Book provides information on equivalency evaluations of branded medications and their generic counterparts.[10] The list is updated periodically, and pharmacists can use this reference to determine whether a particular generic product is interchangeable with its branded counterpart.

State Laws Governing Generic Substitution
Since the repeal of the 1950s antisubstitution laws, many states have allowed pharmacists to substitute brand-name drugs with less expensive, therapeutically equivalent alternatives without consulting the prescriber, unless the prescription specifically prohibits such substitution.[5,8] In cases in which the prescriber writes "brand medically necessary" or "brand necessary" on the prescription, the pharmacist must dispense that branded formulation.

In most states, pharmacists must notify patients if they intend to make a generic substitution. In fact, some states have developed their own "formularies" to guide pharmacists in making drug selections, superseding the FDA's reference. Some states have what is termed a "positive formulary," which identifies generic products that can be interchanged with their branded counterparts. States with such lists include Delaware, Maryland, New Jersey, New York, Tennessee, and Utah.[8] In contrast, some states have a "negative formulary" that specifies which drugs cannot be interchanged with other drugs.[8] These states include Arkansas, Kentucky, Minnesota, and Missouri. Pharmacists should consult their respective state boards of pharmacy for specific regulations pertaining to generic substitutions. Contact information for state boards of pharmacy can be found on the Web site of the National Association of Boards of Pharmacy.

Narrow Therapeutic Index Drugs
Drugs that are classified as having a narrow therapeutic index (NTI) generate the greatest controversy in regard to generic substitution. According to FDA regulations, drugs are defined as having a NTI if:

  • They have less than a 2-fold difference in median lethal dose and median effective dose values;
  • They have less than a 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood; or
  • Safe and effective use of the drug products requires careful titration and patient monitoring.[11]
Examples of such medications include carbamazepine, digoxin, levothyroxine sodium tablets, phenytoin, theophylline, and warfarin.

The FDA has stated that NTI drugs do not need special guidelines to determine bioequivalence for their generic counterparts.[11] However, some healthcare professionals disagree, arguing that generic substitutions could be too toxic or not effective enough.

Drug Classes That Invite Special Consideration
Beyond these general guidelines, there are certain classes of drugs that have specific characteristics that should be taken into account when considering a substitution.

Antihypertensive Agents
A large number of patients take medications for high blood pressure, and generic formulations of these classes of drugs have made treatment more affordable for many people. Classes of medications commonly substituted with generic therapeutic equivalents include beta-blockers, thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers.

However, there continue to be disparities in access to generic medications. A recent study of Medicare beneficiaries found that patients who were treated by a primary care physician were more likely to be prescribed generic medications than those who were under a cardiologist's care.[12]

Among the 5 classes of medications, only in the cases of beta-blockers and thiazide diuretics were there no apparent prescribing differences. This may be due to the fact that generic medications for these drug classes have been in the marketplace for over 20 years.[12] In contrast, generic formulations of calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers appeared much later.

The study noted that half of the patients using these latter 3 classes of drugs were not receiving generic formulations.[12] This implies that a significant number of elderly patients could reduce their out-of-pocket costs by switching to a generic medication.

Antiepileptic Medications
The American Academy of Neurology (AAN) has taken a firm position on the issue of generic substitution: "The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician's approval.[13]"

Neurologists argue that subtle differences between branded medications and their generic equivalents can result in toxic or subtherapeutic levels. In the case of a patient with epilepsy, subtherapeutic levels can manifest themselves in seizures, which are precisely what the medications are supposed to prevent.

Antiepileptic agents are considered to have an NTI. According to a recent study, antiepileptic drugs (AEDs) have had a higher "switchback rate" from generics to branded medications than is seen with other classes of medications.[14] This may indicate that patients were not satisfied with generic AEDs. The same study also noted that some patients had to increase their dosage while taking the generic AED, which could be due to bioavailability issues (needing more drug to maintain the same effect) or due to progression of the disease.

In general, neurologists tend to oppose the switching of branded drugs with generics unless it is medically indicated.[13] However, it should be noted that compliance with prescribed therapies is especially important for patients taking AEDs for seizure control. If cost is a critical issue for a patient, generic AEDs provide an effective alternative. Neurologists, pharmacists, and patients need to communicate when such issues arise, so that appropriate changes can be made to ensure compliance with therapy.

Thyroid Medications
Patients with thyroid disorders will need to take medications to treat their condition throughout their lives. Therefore, maintenance with appropriate medication is paramount.

According to a joint statement by the American Association of Clinical Endocrinologists, The Endocrine Society, and the American Thyroid Association, patients should continue taking the same formulation of levothyroxine throughout therapy.[15] Any changes to generic equivalents or between brands should be monitored closely by a physician, and should be followed up after 6 weeks with laboratory work.[15]

Patients should be made aware of the type of levothyroxine tablets that they are taking. In cases in which the patient would like to switch to a generic formulation in order to save money, the pharmacist should communicate with the prescriber first, to ensure appropriate follow-up care.

Follow-on Biologics Introduce New Wrinkle
Perhaps the most pressing question in drug substitution is the role to be played by "biosimilar" drugs that are the next generation of new biologic therapies, such as human insulin, growth hormones, and immunologic agents. A biologic product is defined by the Public Health Service Act as "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product...applicable to the prevention, treatment or cure of a disease or condition of human beings.[16]" Because biologic therapies are so expensive, there is hope that "follow-on" biologics will provide a less costly alternative.

"The need is high," says Duane M. Kirking, PharmD, PhD, Director of the Center for Medication Use, Policy and Economics at the University of Michigan College of Pharmacy in Ann Arbor, Michigan. "There is pressure to come up with the products, [but it is] harder to show that they are equivalent." In addition, he said, the price differential may not be as great as that seen with the generics of nonbiologic medications.

The complex nature of biologic therapies creates particular challenges in manufacturing and regulating follow-on biologics, which may be similar but not exact duplicates of the original protein products. Janet Woodcock, MD, Deputy Commissioner and Chief Medical Officer of the FDA, described the issues recently in a statement before Congress:

"There is general recognition that the idea of sameness, as the term is used in the generic drug approval process...will not usually be appropriate for more structurally complex molecules of the type generally licensed as biological products....Additionally, as a related matter, there are clearly scientific challenges involved in determining that a molecule that is not the same as an approved or licensed version is nevertheless similar enough that the Agency's conclusions about the safety and effectiveness of the approved or licensed version could be relied on to support approval of the follow-on product.[16]"​
She went on to say that it would be difficult to demonstrate that a follow-on product was truly interchangeable with the original biologic therapy:

"A finding by the Agency that a follow-on protein product may be approved as safe and effective is distinct from a determination that the follow-on protein product would be substitutable for the referenced protein product....Therefore, the ability to make determinations of substitutability for follow-on protein products may be limited.[16]"​
For example, the follow-on biologic somatropin (Omnitrope) is a human growth hormone product that is less costly than Genotropin, but it is not rated by the FDA as therapeutically equivalent and thus is not substitutable at the pharmacy level. Other follow-on biologics that have been approved by the FDA include glucagon recombinant for injection (GlucaGen), hyaluronidase recombinant human (Hylenex), hyaluronidase (Hydase and Amphadase), and calcitonin salmon recombinant (Fortical) nasal spray.

A critical issue arises when a patient wants to switch to a less expensive follow-on biologic. Communication between the patient, pharmacist, and prescriber will be essential to properly manage any changes. State pharmacy boards may need to provide more detailed guidance for how pharmacists should handle such situations.

Meanwhile, the FDA and Congress are looking for ways to establish new approval and regulatory processes for follow-on biologics in order to expand access to these less expensive therapies. Sen. Orrin Hatch (R, Utah), a co-author of the Hatch-Waxman Act, is also a sponsor of the Biologics Price Competition and Innovation Act of 2007, which is expected to become law by early 2008. Sen. Hatch explained the importance of these efforts in a recent public statement:

"It's crucial that Congress get this right because biologics are the future of medicine. It's taken a lot of effort, but we've achieved a good balance in this bill. Just as we did with Hatch-Waxman in 1984, we're giving incentives for both pioneer and generic drug firms. We're ensuring that we continue to get the latest medical breakthroughs while creating a clear pathway to get less expensive biologics on the market quickly.[17]"​
The bill offers manufacturers of an original biotech drug 12 years of market exclusivity, but lobbyists for the biotech industry are pushing for even longer patent lives and would like to prohibit pharmacists from substituting a biosimilar drug for a brand-name biologic without explicit approval from the patient's physician.[18,19]

The high costs of branded medications can be overwhelming for patients, and generics may offer a more economic alternative. Prescribers need to be informed about generic equivalents, and they should be aware that cost can play a role in patient compliance.

At the point of dispensing, pharmacists must assess whether generic substitution is appropriate on the basis of the medication prescribed and the state's pharmacy practice laws. Pharmacists can be a valuable resource for prescribers, providing current information on available generics that is supported by scientific research.

Pharmacists and prescribers can work together to educate patients about generic equivalents. A number of drug classes, and especially new follow-on biologic drugs, require special considerations. Pharmacists must stay apprised of the latest developments in drug substitution guidelines and laws.

  1. Smith C, Cowan C, Heffler S, et al. National health spending in 2004: recent slowdown led by prescription drug spending. Health Aff. 2006;25:186-196.
  2. Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Potential savings from substituting generic drugs for brand-name drugs: medical expenditure panel survey. 1997-2000. Ann Intern Med. 2005;142:891-897. Abstract
  3. Stenson J. Report questions generic antidepressant. MSNBC. October 12, 2007. Available at: Report Questions Generic Antidepressant - More From News Story - WTVJ | Miami Accessed October 22, 2007.
  4. Abood RR, Brushwood DB. Pharmacy Practice and the Law. 3rd ed. Sudbury, Mass: Jones and Bartlett Publishers; 2004.
  5. Facchinetti NJ, Dickson WM. Access to generic drugs in the 1950s: the politics of a social problem. Am J Public Health. 1982;72:468-475. Abstract
  6. Drug Product Selection. Washington, DC: Bureau of Consumer Protection, Federal Trade Commission; January 1979. Staff Report.
  7. Parker RE, Martinez DR, Covington TR. Drug product selection-part I: history and legal overview. Am Pharm. 1991;NS31:72-79. Abstract
  8. Christensen TP, Kirking DM, Ascione FJ, Welage LS, Gaither CA. Drug product selection: legal issues. J Am Pharm Assoc. 2001;41:868-874.
  9. Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic drug approval process. J Am Pharm Assoc. 2001;41:856-867.
  10. US Food and Drug Administration (FDA) Electronic Orange Book. Approved Drug Products With Therapeutic Equivalence Evaluations. 27th ed. Washington, DC: US Department of Health & Human Services; 2007. Available at: Electronic Orange Book Home Page Accessed November 2, 2007.
  11. US Food and Drug Administration. Therapeutic equivalence of generic drugs response to National Association of Boards of Pharmacy. April 16, 1997. Available at: Accessed November 2, 2007.
  12. Federman AD, Halm EA, Siu AL. Use of generic cardiovascular medications by elderly Medicare beneficiaries receiving generalist or cardiologist care. Med Care. 2007;45:109-115. Abstract
  13. Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW. Position Statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007;68:1249-1250. Abstract
  14. Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007;48:464-469. Abstract
  15. AACE, TES, and ATA. Joint position statement on the use and interchangeability of thyroxine products. December 8, 2004. Available at: AACE, TES, and ATA Accessed November 2, 2007.
  16. Woodcock J. Assessing the impact of a safe and equitable biosimilar policy in the United States. May 2, 2007. Available at: Statement by Janet Woodcock, M.D., Deputy Commissioner, Chief Medical Officer, on Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States?, May 2, 2007 Accessed September 27, 2007.
  17. Senators Announce FDA Biologics Agreement. June 22, 2007. Available at: US Senator Orrin Hatch Accessed September 27, 2007.
  18. Simons J. Why the biotech party is winding down. Fortune Magazine. September 5, 2007. Available at: Biotech firms will soon lose patent protection - Sep. 5, 2007 Accessed September 28, 2007.
  19. US biosimilars law: opposing interests hinder progress. PharmLive. September 27, 2007. Available at: Accessed September 28, 2007.


The article is interesting and provides a comprehensive overview of generic medications.

I would submit for consideration that the article is written from the perspective of a pharmacist whose interests and orientation is different from a prescribing physician.

The information is accurate, but in my view, and from a patient's perspective, the person with whom to discuss the benefits and possible pitfalls of using a generic substitute should be the prescribing doctor.

Retail pharmacists may be in a position of conflicting interest to objectively counsel the patient on whether or not the generic would provide equivalent effectiveness and bioequivilance.

A patient who chooses to use generic substitutes, should be prepared for potential differences in the way the medication might work or make you feel. There may not be any differences, but one should be aware of that possibility.

These differences should be taken seriously and be reported and discussed with the prescribing physician, to ensure the desired therapeutic effect is being achieved.

If the desired effect is achieved and any adverse effects are tolerated, then the substitution is a success.

Do you have good or bad experiences with generic medications to report?
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