While generic drugs often are somewhat different from their innovator-drug counterparts, the differences aren't usually clinically significant enough to be of concern. Let's look at how the drugs differ, the issues involved in using one type or another and the do's and don'ts of switching from brand names to generics.

How do innovator and generic drugs reach the market?
Pharmaceutical companies develop new drugs under patent protection. The patent runs 17 years from its issuance date, regardless of when the FDA actually approves the drug for patient use. Manufacturers race for patents early enough that no one else copies their drug's formula (testing data may be part of the public record) - but not so early that the patent expires before the drug reaches the market, recoups its research and development costs and becomes profitable.

Before drugs hit the market, the manufacturer must file a New Drug Application (NDA), and the drug must pass rigorous FDA-mandated tests. Once approved, the innovator drug is the only one of its kind on the market. The FDA may also issue exclusivity for a particular use, new formulations or routes of administration of the drug for three or three-and-a-half years. Once the drug goes off-patent, other companies may try to develop and market generic variations; they must prove the generic is pharmaceutically and therapeutically equivalent to the innovator drug to gain FDA approval.

What is pharmaceutical equivalence?
Pharmaceutical equivalence means the generic contains the same amount of active ingredient in the same dosage form and meets the same or other applicable standards as the brand-name drug. These standards include the drug identity, strength, quality and purity. Clinicians must also be able to administer the generic in the same manner as the brand name drug.

The pharmaceutical characteristics of generic and brand-name drugs might differ in several ways, including shape, scoring configuration, release mechanisms, packaging, labeling, expiration time and excipients - which are inactive ingredients, such as coloring, flavors and preservatives that must either be on the Generally Recognized As Safe (GRAS) list or undergo studies establishing their safety.

One reason it's important to establish this safety is excipients' components may have a clinically significant effect in patients with certain allergies. For example, you may recall the controversy several years ago involving generic propofol, which centered on a bisulfate preservative in the generic (brand-name Diprivan uses EDTA preservative). While the issue potentially affected only patients with sulfite allergies - a fraction of a percent of the general patient population and 5 percent to 10 percent of chronic asthmatics - facilities using generic propofol had to adjust their pre-op screening regimens to more carefully identify potential sulfite allergy in their patients.

Excipients can also affect the stability of the preparation or the active ingredient, depending on how the patient receives the drug. For example, a generic form of cyclosporine appeared to be therapeutically equivalent to the label brand during testing, but when patients took the generic medication in combination with certain foods, the excipients reduced the bioavailibility.

What is therapeutic equivalence?
Therapeutic equivalence refers to the drug's effect on the body, including the overall effect in potency variations and the effects of the excipients. According to the FDA, a therapeutically equivalent generic drug must

• be approved as safe and effective;
• comply with current Good Manufacturing Practice regulations;
• be adequately labeled (the label must clearly identify the active ingredients and excipients in compliance with all FDA labeling regulations) and
• have no known or suspected bioequivalence problems.

Bioequivalence is the fundamental structure of the generic drug compared to the original. For example, the manufacturer of a generic orally administered drug that uses a different binder (an excipient) to make the pill must show the FDA that pill dissolves in the right amount of time. If the drug is not bioequivalent, the manufacturer must test further to resolve the problem.

Drug-formulation differences can also cause problems if the generic doesn't deliver the active ingredient effectively. All drugs have a range - the therapeutic index - in which the benefits outweigh undesirable side effects. According to FDA regulations, for a generic to fall in the therapeutic index, the drug must deliver between 80 percent and 125 percent of the active ingredient as compared with the innovator drug.

Some drugs, such as warfarin (Coumadin), thyroid medications (levothyroxine, for instance) and certain anti-convulsants, have a narrower therapeutic index because even small differences in generic and brand-name formulations can have major clinical ramifications. Clinicians typically order these drugs from the pharmacy with a "do not substitute" or "dispense as written" designation.

In most cases, however, drugs have a wide enough therapeutic index that varying drug formulations rarely affect outcomes. Clinicians usually administer the drug until reaching the desired effect or the ceiling dose is reached. Many narcotics have generic formulations, and clinicians view them as commodities (meaning suppliers are completely interchangeable, just like No. 2 pencils). Take morphine, for example. Generic formulations vary widely, but it doesn't really matter clinically if the patient gets 10mg of Brand X morphine or 12mg of Brand Y. Fentanyl (Sublimaze) is another common example. When our facility had a fentanyl shortage a few years ago, our pharmacy obtained both brand name Sublimaze and generic fentanyl from any supplier we could find carrying either. We used both without having to worry about brand name versus generic. Patient-response variations are frequently greater than generic-formulation variation.

How should we make the switch?
Switching from brand-name to generic drugs might be a great cost-saving move, but it's important that you first discuss it with your surgeons and anesthesia personnel. If they don't accept the economic benefits of the drugs and are reluctant to switch, you risk alienating them and leaving the impression that you care more about reduced costs than safe outcomes. To avoid this, here's a five-step plan for making the switch at your facility.

• Do your homework. Find out what the generic possibilities are and the pharmaceutical and therapeutic equivalence challenges they raise, if any. Determine which drugs are high-volume and which ones cost the most. If the volume is small, the cost saving might not justify expending resources to analyze and switch medications. Sometimes there's no generic option available. For example, remifentanil (Ultiva), a drug used in many TIVA regimens, remains under patent protection until 2009.
• Crunch the numbers. If they make sense for your facility, you might be able to save money because generics are usually cheaper (the generic manufacturer probably didn't have nearly as high research and development costs), though that's not always the case. Generics put downward pricing pressure on the innovator drugs. In our area at least, facilities saw this with generic propofol and midazolam (Versed). The cost of Versed dropped to 20 percent of its price before its patent expired. It also depends on your facility's drug-supply contracts. Our facility is in a GPO volume-pricing consortium. Despite the Versed price slashes, we paid half for generic midazolam what we paid for Versed. Conversely, while many facilities quickly realized significant cost savings switching from Diprivan to generic propofol, it didn't make sense for us. In fact, when we first investigated the costs, we found that we'd have to pay 35 percent more for a 20mL vial of generic propofol than we were paying for Diprivan under our GPO contract.
• Take the case to the medical staff. Whether you have a Pharmacy and Therapeutics (P&T) committee that reviews the formulary and has a process for making changes, I strongly recommend involving all medical staff who prescribe the drug(s) you'd like to replace before you announce a change. Before you approach them, ask colleagues at other facilities if they've switched and how the process went.

Once you raise the issue with physicians, you'll often find that there's little or no resistance to switching over to many generic drugs. Many common OR drugs such as atropine, epinephrine and neostigmine are commodity medications. They're either AA rated or old enough to pre-date the FDA ratings. It's unlikely anyone will complain if you obtain these from your best-price source.

However, since there has to be a facility mechanism for obtaining non-formulary medications - including generics ' if your doctors don't agree to the change, you may find they'll continue to specify brand names in a dispense-as-written manner.

• Understand concerns. If you do encounter physician resistance, this works well with most. Perhaps physicians are not concerned about the formulation, but like the familiarity of the branded product. For example, some drugs such as succinylcholine have brand-name followings, but they're actually brand-name generics (Anectine, Quelicin) for which there are also no-name generics available. Often, if a physician tells you there's a difference in effect, it's merely a matter of observer bias (he can, after all, read the label). Likewise, physicians can be misinformed on generics or biased toward products peddled by friendly sales reps. Alone, these are not legitimate reasons to veto switching to a lower-cost generic.
• Don't dismiss worries. Your physicians might have legitimate concerns about the true therapeutic equivalence of the generic. Managers and administrators may not have the expertise to individually evaluate these issues, but once you understand the problem, you can investigate.

In a previous practice, for example, we encountered a problem with a specific generic local anesthetic we used for spinal anesthesia - but only had the problem during the autumn. We never solved the mystery for certain, but we speculated that the problem stemmed from the drugs' sitting on a loading dock in the sweltering summer sun. Given the turnover time, the overheated summer supplies finally wound up in the OR a few months later. This wasn't a problem with the formulation but with the handling of the product.

Know when to say when
If you want to make the transition as smooth as possible, identify an opinion leader in your physicians' specialties who supports the change. Having a peer support the change is very powerful. If you still encounter resistance, you could also involve a mediator, perhaps a surgeon or anesthesiologist not involved with your facility who would be perceived as a neutral party. Ultimately, if you can't develop a consensus for switching - if many physicians have strong feelings about keeping a certain brand name - it may make more sense not to switch. After all, keeping your physicians happy is sometimes a cost-saver in its own right.