Branded vs. Generics
Generics in Practice: Physician Perspectives
Debate continues over whether branded drugs and their generic counterparts are truly equivalent.
By Desiree Ifft, Contributing Editor
Generic medications have been part of the healthcare landscape for decades, but several proposals aimed at increasing their leverage as cost-savers placed them firmly in the spotlight during this year’s heated debate over the federal deficit. Ongoing issues, such as FDA’s implementation of the Biologics Price Competition and Innovation Act of 2009 and patent expiry for several blockbuster drugs in the next year (e.g., Lipitor and Viagra), will likely keep them center stage for the foreseeable future.
For ophthalmology in particular, two developments in the pharmaceutical industry have brought the topic of generic drugs to the forefront. First, responding to increased scrutiny of their interactions with physicians and potential promotion of off-label uses, most pharmaceutical companies have reduced or eliminated sampling, including the cataract surgery post-op kits for patients that were routinely supplied to practices free of charge. Along with items patients might need after their procedures, such as eye shields, lid scrubs and sunglasses, the kits contained one or more of the medications they would be using. “When the kits were available for patients, they might only have to purchase one of the three post-op drops we prescribed,” says Mark Packer, MD, FACS, Eugene, Ore. “Once they had to start filling all three prescriptions, cost became a concern. The end of sampling definitely increased our patients’ interest in less expensive generic alternatives.”
Also, in March of this year, as the patent on the widely prescribed prostaglandin analog Xalatan expired, many ophthalmologists wondered whether the generic alternatives—for which at least five companies had immediately secured FDA approval—would be just as effective as the brand they’d been using successfully for years. Many expected they’d have to figure that out for themselves while simultaneously dealing with intense pressure from prescription drug insurance plans and pharmacists to switch patients to generic formulations.
There have always been differing opinions among ophthalmologists when it came to the question of whether generic drugs are truly equivalent to their brand-name predecessors, or innovator drugs, but recent developments have re-energized the argument. All seem to agree that cutting healthcare costs is necessary and not all generic drugs are ineffective. However, adequately powered studies to compare the efficacy of generics with their branded counterparts have never been, and likely never will be, done. Therefore, some doctors say, they have only their experience with patients to guide their treatment decisions. In this article, several ophthalmologists explain the impact generic drugs have had in their practices and how they manage the related issues on a daily basis.
Experience Raises Questions About Equivalency
Problems with generic ophthalmics have arisen in the past. Perhaps the most serious were the corneal complications that were traced to one generic version of the nonsteroidal drug, Voltaren (diclofenac, Novartis). That generic product was removed from the market, but some doctors point to problems with other generics that are still available today. They say they’ve seen less-than-ideal IOP control in patients using a generic form of Timoptic XE (timolol, Merck), a gel-forming beta blocker. Many glaucoma specialists have reported seeing a high number of ocular allergic reactions among patients who use a generic brimonidine product, which has a 0.2% concentration rather than the 0.1% or 0.15% of the two-branded Alphagan P (Allergan) products.
Generic prednisolone acetate drops are widely prescribed. However, a number of doctors say they do their best to keep their patients from using them because unless the bottle is shaken excessively, the drops don’t dispense correctly and often clog the tip, suggesting that too much medication will be left in the bottle instead of doing its work in the eye. Some information about these experiences has been published in the literature.1,2 In one paper, based on assessment of sedimentation rate as a function of particle size, the authors concluded that the particles in the brand-name drug Pred Forte (prednisolone acetate, Allergan) were smaller and more uniform than in the compared medications, which “may result in greater homogeneity between doses and increased ocular bioavailability.” Some doctors who spoke with Ophthalmology Management acknowledged that the offending product(s) may have been discontinued, but they also say there are so many prednisolone acetate varieties that it’s difficult to keep track, let alone ensure their patients receive any specific one consistently from the pharmacy.
Commenting on generic ophthalmic medications in general, Eric Donnenfeld, MD, FACS, Rockville Centre, N.Y., says “I think most ophthalmologists believe the generics aren’t as good as the original drugs. The question doctors have to ask themselves is ‘is the cost savings to the patient worth the cost of potentially reduced efficacy?’ In other words, are you feeling lucky?”
Dr. Donnenfeld described a recent case in his practice, one of many he says that illustrates why he can’t assume every generic medication is equal to the original innovator drug. A 65-year-old female with diabetes presented for a cataract evaluation. She had minimal background diabetic retinopathy, and OCT showed normal retinal thickness. She wanted to proceed with cataract surgery, so she was instructed to use steroid and nonsteroidal drops prior to and following the procedure. Brand-name drops were prescribed. The surgery itself was uneventful, and on day 1 post-op, her eye was fine. On that day, when Dr. Donnenfeld typically asks patients about their medication use, he saw that her anti-inflammatory prescriptions had been filled with generic ketorolac tromethamine and prednisolone. When the patient returned for her 2-week visit, OCT showed florid CME, and her visual acuity had dropped to 20/50. Dr. Donnenfeld rewrote the original prescriptions, and by 1 month post-op, the CME had resolved and vision had improved to 20/25. However, the patient reported problems with glare and loss of contrast.
“I believe that if the brand medications were used in the first place, the chances of this occurring would have been greatly reduced,” Dr. Donnenfeld says. “Her quality of vision may not reach its full potential because the change in retinal architecture from the CME may be irreversible. I don’t tell patients to never use a generic, but in this case, we could have done better. This is a patient who should not have been switched.”
Dr. Packer’s experience with generic medications has been mixed. “I have patients who have shifted from Xalatan to generic latanoprost products, and so far, I haven’t seen any out of control pressures; all of those patients seem to be maintained, and I haven’t heard complaints about irritation,” he says. “But I’ve seen problems in patients using generic steroids and NSAIDs.”
When an increasing number of patients began expressing concern about medication costs, Dr. Packer and his partners decided to put together two different “menus” of options for cataract surgery care. “We understand the cost issues,” he says. “Basically, with our usual instructions, we recommend a branded antibiotic, steroid and NSAID, but we also list three generic alternatives.” For high-risk and premium IOL patients, however, the doctors strongly recommend the branded drugs. Since the initiation of the “options” approach, not all post-op eyes are as quiet as he was accustomed to seeing, Dr. Packer says. “Much more frequently with the generics, I see residual inflammation, which makes a prolonged course of NSAIDs and steroids necessary.”
As Dr. Packer explained, newer ophthalmic steroids and NSAIDs have actually been tested in clinical trials in ocular surgery patients and are specifically labeled for the treatment of inflammation in those situations. Generic anti-inflammatories are based on older drugs that were never tested in those specific populations. They were used off-label peri-operatively because they were the only available options. “Furthermore,” he says, “the point of developing new drugs is to make them better. Generics may be OK for many patients, but they certainly aren’t the latest and greatest we have to offer.” Durezol (Alcon), for example, the topical steroid approved by the FDA in 2008, contains the active ingredient difluprednate, a difluorinated derivative of prednisolone that is a molecule new to ophthalmology. It is formulated in an emulsion that is designed to allow the drug to dissolve more effectively, so dosing can be more consistent. In contrast, generic prednisolone products are based on an older suspension formulation, which may make them more prone to the problems previously described.
After 5,000 Surgeries, a Changed Outlook
Like Dr. Packer, John Hovanesian, MD, FACS, Laguna Hills, Calif., was hearing from an increasing number of his patients about the cost of medications surrounding cataract surgery. About 2 years ago, thinking generic alternatives would be a fine way to address their concerns, Dr. Hovanesian switched to an all-generic regimen. He was surprised by the consequences. No increase in infections occurred, but about a year after the change, he was compelled to take a closer look at his patient data. “My patients were experiencing far more inflammatory sequelae than I’d ever seen before,” he says. “It wasn’t full-blown CME, but conditions like iritis, surface toxicity and patient complaints of discomfort surfaced. It was frequent enough that my patients and I were both frustrated. They see these scenarios as ‘something went wrong with my surgery; my neighbor had a positive experience, and I had a negative one.’ Also, while most of the inflammation was technically mild, there’s no way to be sure that it won’t have a long-term impact on the eye.”
After approximately 5,000 surgeries involving routine cataract removals and generics, Dr. Hovanesian switched back to an all-branded regimen. “Since then, I have seen no inflammatory complications, no cases of punctate keratitis or issues with rebound iritis,” he says. “There was a very clear and distinct cutoff when I switched back to branded drugs.” Dr. Hovanesian didn’t set out to do a study, but he is analyzing his data and plans to submit his work for publication.
Lack of Confidence in the Abbreviated Approval Process
Dr. Hovanesian and other ophthalmologists attribute the problems they’ve had with generic medications to what they see as an FDA approval process that doesn’t sufficiently ensure a generic ophthalmic drug is truly the same as the innovator drug. (For more information on the FDA approval process, see “Pathway to FDA Approval” on page 19.)
In order to receive FDA approval, a generic drug, ophthalmic or otherwise, must contain the same active ingredient, be the same strength and dosage form, and have the same route of administration as the innovator drug. In addition, it must meet the FDA standard of bioequivalence, which is based on bioavailability. Bioavailability is defined as the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action. Bioequivalence is defined as the absence of a significant difference between the bioavailability of the generic drug and the innovator drug.
Ophthalmologists cite two key concerns with these standards. First, the bioavailability of systemic drugs can be readily evaluated by measuring drug levels in the blood or other bodily fluids. For the eye, there is no comparable testing that would be practical. Furthermore, for some types of generic drugs, including ophthalmics, FDA allows the inactive ingredients, such as preservatives, buffers or thickening agents to be different from those in the innovator drug.3 Testing in patients may or may not be required for approval. “This can be problematic because the eye is a unique target organ for a drug,” Dr. Hovanesian says. (For more information on generic medications and the eye, see “Eye Presents Unique Challenges for Drug Evaluation” on page 23.)
Robert Noecker, MD, MBA, Fairfield, Conn., agrees. “Ophthalmic drugs need to penetrate into the eye, and inactive ingredients can be a major determinant of whether they do what’s intended,” he says. “Some drugs are very pH-dependent. Prostaglandin analogs, for example, are relatively unstable drugs in water-based solutions. Changing the preservative in a formulation, or the amount of a preservative or viscosity agent, could impact how effectively the drug stays in solution and therefore how much is available to get into the eye. Getting all of the ingredients just right is a substantial part of developing an efficacious new drug.”
Inactive ingredients also affect the tolerability of ophthalmic medications more than they might in a pill, Dr. Noecker says, because they’re administered directly onto the eye. “Even if a drug works well, if it causes irritation and discomfort, patients are less likely to be compliant in taking it,” he says. “In glaucoma treatment especially, compliance is already an Achilles’ heel.” Dr. Hovanesian says tolerability is an even bigger concern when treatment is long-term, as it is for glaucoma patients. “Glaucoma patients use their drops for years and years. While brand drug makers have been developing less toxic inactive ingredients, particularly preservatives, most generics contain benzalkonium chloride (BAK), which can have detrimental effects on ocular health. It’s not illogical to wonder whether the ‘advanced dry eye’ seen in so many glaucoma patients is the result of cell damage from long-term exposure to harsh inactive ingredients.”
Packaging Can Pose Problems Too
With ocular drugs, the medication bottle further complicates the concept of equivalency. More often than not, a generic bottle differs from the brand bottle in several respects. “A pill just has to be swallowed, but proper use of eye drops depends on a bottle,” Dr. Noecker says. “A generic bottle can be a different size or have different rigidity. Smaller bottles can be more difficult for elderly patients to handle. With more rigid bottles, patients may not squeeze hard enough to get the right amount of medication. If they overcompensate by squeezing too hard, they may waste drops. Bottle fill amounts also make a difference. Brand manufacturers typically overfill their glaucoma bottles so the medication lasts long enough, even if some drops are accidentally wasted. Generic manufacturers may not. If patients run out of drops too soon, it can be a big ordeal convincing the insurance company to allow an early refill and it may mean days without treatment. With systemic medications, 30 pills a month is 30 pills a month—it’s much simpler.”
One of Dr. Noecker’s patients, a 78-year-old woman, experienced this problem. She’d been using Xalatan for 8 years, and it was keeping her pressure at 15-18 mmHg, the target in her particular case, from the initial mid-to-low 20s. Her latest prescription did not indicate “brand necessary,” because at the time it was written, there were no generic latanoprost products. The pharmacy dispensed a generic, and after 2 weeks, she called the office to say her bottle was empty. She was having trouble squeezing it and as a result, too much was coming out. Her insurance company wouldn’t authorize an early refill, so Dr. Noecker had her return to the office 3 months before her next scheduled visit.
He saw nothing unusual during the exam except that her IOP had returned to the 20s. They discussed specifically prescribing Xalatan, but the patient said her insurance company had either stopped covering it or moved it to a more expensive formulary tier. Even though the patient was experienced at instilling drops, it was clear this particular bottle just wasn’t going to work for her. Ultimately, she was prescribed a different branded prostaglandin drop. At follow-up 3 weeks later, her IOP was back to 15 mmHg, and she said the bottle had been easy to use. “Here we had a glaucoma patient whose IOP was well-controlled for many years, and then we had the disruption of two extra office visits, a temporary period when IOP was higher than we wanted it to be, and some anxiety on both our parts.”
Noting that any drug, brand or generic, can cause problems for some patients, Dr. Donnenfeld says he’s convinced the frequency is higher with the generics. And while Dr. Hovanesian didn’t track costs to patients during his switch to and then away from generics, he says, “It would be interesting to see whether the cost of factors such as extra office visits and having to buy rescue meds on top of the generics actually outweighs anticipated cost savings with generics.”
A Different View
The cost savings generic medications provide are very appealing to patients, according to Henry Jampel, MD, MHS, a glaucoma specialist in Baltimore, Md. “When I write a prescription for a prostaglandin, I check the box for Xalatan on my preprinted list, which has been my first choice for years,” he says. “Since the generic versions came out, more often than not, patients ask if they can use a generic. I say it’s fine because despite what others say to the contrary, generic latanoprost is identical to branded Xalatan, both in the active drug and in all the inactive ingredients. The complaints other doctors may have about generic medications are anecdotes.”
Angelo Tanna, MD, Chicago, Ill., has a similar view. “If IOP changes at one visit in a patient who recently switched to a generic, we can consider that it might be the drug, but it could also be for any number of reasons, such as the patient forgetting to use the drops that day or experiencing a high degree of IOP fluctuation that is known to occur in glaucoma.”
Dr. Tanna says one of his patients who recently switched to a generic timolol/dorzolomide product had higher IOP than usual at a subsequent visit. At the next scheduled visit, however, pressure was back where it used to be. “Some natural variation in IOP is expected,” he says. “Some doctors might change the patient’s regimen immediately based on higher IOP at one visit, but I typically wait to see what happens at the next visit. On the other hand, if there’s any kind of a drug regimen change for a patient who has severe glaucoma, an extra follow-up visit may be warranted. The question then becomes does a switch to a generic constitute a change in regimen? I say, not really. Given the bioequivalence required by the FDA, generics should be quantitatively and qualitatively identical to the brand-name product. Other than problems with generic prednisolone acetate products, I haven’t observed a difference between the brand-name and generic drugs,” he says.
Dr. Jampel says that calls for clinical trials to compare brand and generic drugs “frankly make me angry. First of all, you would be comparing two identical things, which doesn’t make sense. I see the talk about doing clinical trials as an unwarranted, inflammatory discussion. I doubt trials would matter anyway, because no one is going to pay for a brand drug when the generic costs less.” Dr. Jampel says another reason trials wouldn’t make sense is because the drug concentration of both brand and generic medications differs from lot to lot, within FDA limits. “So, in your first study, the brand may be running a certain percentage less than its label, and the generic may be running a certain percentage more than its label. The generic might even be closer. But in your next study, it all might flip-flop. It would be a waste of time and resources. The bottom line is that the government and major manufacturers aren’t going to pay for these studies, and the generics are capturing the market anyway, so there will be no studies.”
The money saved in the healthcare system by using generic drugs is important, Dr. Tanna says. “Remember, in our system, innovators are entitled to patent protection for a limited time, after which we allow competition from generics. This should result in lower prices.”
Talking With Patients About Their Options
Regardless of how doctors feel about the value of generic medications, they find themselves talking about them to patients with increasing frequency. As far back as 2006, 53% of doctors surveyed by The Kaiser Family Foundation said they frequently talk with patients about the out-of-pocket costs for medicines they prescribe.4 The same survey found that to help patients lower their out-of-pocket costs, 62% of doctors frequently switch patients to a less expensive prescription drug.
As Dr. Packer previously described, each of his cataract surgery patients receives two menus of peri-operative medications to choose from, one branded and one generic. “For price-sensitive patients who want to use the generics, we explain that we see that option as a trade-off,” he says. “Yes, they will pay less, and the generic probably will be adequate, but in our experience, the brands are more effective. The generics aren’t going to cause permanent damage to their eyes, but they may have a longer recovery period.”
Dr. Donnenfeld has taken the same approach in his practice with cataract and LASIK patients. “I list my brand recommendations for patients, but also the generics they can substitute if cost is a consideration for them,” he says. “I explain that the brands are the optimal therapy, which I think they should have. Patients probably think generics are the same as the brands, so I feel I should guide them toward doing what I think is the right thing for their eyes.”
Dr. Jampel shares his advice on generics when patients ask about them. “My main answer is simple: To the best of my knowledge, generic medications are identical to the brands,” he says. “If a patient wants to pay for a branded medication, I am happy to include “dispense as written” on the prescription. I also tell them, however, I don’t know what might happen after that. Their prescription insurance plan could require a higher copay for the brand. I don’t like it any better than anyone else when third parties are calling the shots in the doctor-patient relationship, but I also don’t have any reason to believe generic drugs are inferior.” ■
More Guests at the “Third Party?” |
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Generic medications have saved the U.S. healthcare system billions of dollars, but other dynamics surrounding their substitution for brand-name drugs have been denounced as negatives. For example, some doctors say they would like to know more about the contracts between pharmacies and insurance plans and pharmacy benefit management companies (PBMs) and if pharmacists somehow benefit from encouraging doctors and patients to use generic medications. (For more information on the economics of generic medications, see “Generics Make Their Mark in Healthcare System” on page 25.) Dr. Donnenfeld wonders whether financial motives are behind what he has found to be aggressive switching from brands to generics at the pharmacy counter. “Sometimes they’re switching to different classes of drugs entirely, especially when they don’t have a generic of the brand I prescribed,” he says. Dr. Hovanesian has had similar experiences, with switches from Bromday (Ista) to a generic ketorolac product, for example. “They are different compounds entirely,” he says. “I suppose some of these instances could be honest mistakes, but it’s illegal, and as doctors, we should point them out to the pharmacy every time. Nonphysicians do not bear the risk of the outcomes in these situations; we do. If we allow it to happen, shame on us.” Doctors say, too, that insurance plans moving drugs from one tier of their formularies to another, which they say happens more than ever, are based more on profit margin for the plan than medical considerations. A recent assessment by The Kaiser Family Foundation found that to be the case.1 Its report called attention to the complexity of the pharmaceutical supply chain, which it stated can “result in substantial variations in what different purchasers pay for the same drugs. As we have shown, the price of prescription drugs paid by the consumer is determined by a constellation of negotiated contracts between manufacturers, PBMs, wholesale distributors, pharmacies, and plan sponsors. The price charged by each entity in the chain is largely driven by the ability of contracting entities to sell specific volumes of certain drugs or achieve a certain share of a specified market. It is also affected by the value each entity brings to the subsequent actors in the supply chain.” PBMs in particular have been singled out as manipulating the system, resulting in more rather than less money being spent on pharmaceuticals. PBMs are companies hired by health plans and other large buyers of health care to administer the pharmacy benefits portion of their insurance plans. They often have input into plan formularies. David Balto, a lawyer who has practiced antitrust law in the Department of Justice, the Federal Trade Commission and private practice, has frequently testified before Congress about PBMs,2 saying in 2010: “Although PBMs offer a great deal of promise in terms of the potential to control pharmaceutical costs, there is a pattern of conflicts of interest, self-dealing, and anticompetitive conduct, all of which ultimately means that consumers pay far more for drugs than necessary.” “They try to maximize the profit margin on every bottle,” says Dr. Jampel. “It’s getting very complicated. It’s supposed to be complicated. A confused doctor and patient are more easily taken advantage of.” REFERENCES1. The Kaiser Family Foundation. Follow the pill: understanding the U.S. commercial pharmaceutical supply chain. Available at: www.kff.org/rxdrugs/upload/Follow-The-Pill-Understanding-the-U-S-Commercial-Pharmaceutical-Supply-Chain-Report.pdf; accessed August 8, 2011. |
A History of “Bioequivalence” |
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In a recently published paper,1 co-authors Daniel Carpenter, PhD, and Dominique Tobbell, PhD, chronicle how the concept of bioequivalence came to be the standard on which the U.S. Food and Drug Administration bases its approval of generic medications. A brief excerpt: “ ‘Bioequivalence’ gives legitimacy and reality to generic drugs. It implies that one pharmaceutical commodity can substitute for another in most (if not all) critical therapeutic respects, and by so doing bioequivalence establishes a framework for market transactions based upon price. It is a joint regulatory and scientific creation, not purely a technical construct, and not purely a legal concept. Bioequivalence developed at the interstices of state, commerce, professional and academic medicine, professional and academic pharmacy, administrative law, and even the politics of federalism. Its development was political in ways that have escaped appreciation by both contemporaries and historians.” Dr. Carpenter is the Allie S. Freed Professor of Government and Director of the Center for American Political Studies at Harvard University. One of his main research interests is how regulations and laws create a basis for new markets. He told Ophthalmology Management that the idea to explore the history of bioequivalence was suggested to him by J. Richard Crout, who was Director of FDA’s Bureau of Drugs from 1973-1982. “We thought what was missing from the ongoing debate over substitution of generics, what constitutes a generic drug, etc., was an account of where this all came from,” Dr. Carpenter says. “As we say in the paper, the nation and world are confronting issues of the comparative effectiveness of drugs, and the narrative of the concept of bioequivalence can provide guidance for the collective dialogue.” Reference1. Carpenter D, Tobbell DA. Bioequivalence: the regulatory career of a pharmaceutical concept. Bull Hist Med 2011;85(1):93-131. |
References
1. Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther 2007;23(2):182-187.
2. Fiscella RG, Jensen M, Van Dyck G. Generic prednisolone suspension substitution. Arch Ophthalmol 1998;116(5):703.
3. Code of Federal Regulations Title 21; CFR314.94, content and format of an abbreviated application. Available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm; last accessed August 8, 2011.
4. The Henry J. Kaiser Family Foundation. Prescription Drugs: Advertising, Out-of-Pocket Costs, and Patient Safety from the Perspective of Doctors and Pharmacists. National Survey of Physicians, 2006. Available at: www.kff.org/kaiserpolls/upload/7583.pdf; last accessed Aug. 8, 2011.