Branded vs. Generics: You Make The Call

Sidebar 1: Abbreviated New Drug Application

Sidebar 2: State Pharmacy Laws

Dr. Starr

Dr. Favetta

Dr. Fechtner

Rising healthcare expenditures have focused attention on increasing the use of generic medications as a way to help control costs. Data on dispensed prescriptions show that in 2016, 89% of dispensed retail prescriptions were accounted for by generic medications.¹ Controversy, however, surrounds the drive to go generic.

In a recent study, investigators analyzing Medicare Part D data found that eye care providers were responsible for a higher percentage of branded medication claims than all other providers.²

As discussed by key opinion leaders in this supplement, the finding is not surprising considering the host of issues that ophthalmologists must factor into decisions when they need to make the call between generic and branded medications.

Bases for branded preferences

Clinicians dedicated to optimizing patient outcomes say that greater confidence in the efficacy, safety, and tolerability of branded medications is a key reason why they favor the branded product when there is a generic alternative. This trust in innovator formulations and uncertainty about the clinical performance of generic products originates partly from knowledge about the different pathways generic and branded ophthalmic medications follow to gain FDA approval (see sidebar: Abbreviated New Drug Application).^3–10

Impressions about the benefits of branded medications and concerns about generics are supported both by findings of published studies and clinical experience. The advantages available from using branded drugs that have no generic alternatives along with the higher-than-expected cost of some generic medications further underlie prescribing patterns favoring branded ophthalmic drugs.

John R. Favetta, MD, is in private practice in North Arlington, NJ. With an undergraduate degree in pharmacy, he has particular insight into the requirements for generic and innovator drugs.
“The FDA requirements for determining bioequivalence of generic ophthalmic medications to the reference brand are lacking in stringency,” Dr. Favetta says.

“Clinical pharmacokinetics assays are generally not done for ophthalmic medications because they are invasive, and extrapolating results from animal studies to humans can be misleading,” he explains. “Although the FDA defines generics as being comparable to branded drugs, the generics only have to be comparable in dosage form, strength, route of administration, and indications. Characteristics of generics, including pH, tonicity, buffering capacity, and viscosity, can vary and in different ways depending on when the innovator and the generic were first approved.”

Christopher E. Starr, MD, Associate Professor of Ophthalmology, and Director, Refractive Surgery, Weill Cornell Medicine, New York, NY, believes that the Abbreviated New Drug Application (ANDA) approval process creates a general risk that a generic medication will not be comparable to the reference brand. “The facts that generic medications do not have to go through the same rigorous evaluations as the branded innovator and can differ widely in their formulations create concern that patients are getting an unproven commodity,” Dr. Starr says.

“Although the investigators analyzing Medicare Part D prescription claims postulated that incentives from industry may partly underlie the finding that eye care providers prescribed the most branded medications, that presumption raises doubt. All doctors are potentially affected by industry marketing, and there is no reason to expect eye care providers are different from any other subspecialty providers. Our preferential use of branded medications is because we, unlike those in other fields, almost exclusively prescribe topical medications that are vetted and approved with lesser scrutiny,” he explains. 

Eric D. Donnenfeld, MD, Clinical Professor of Ophthalmology, New York University Langone Medical Center, New York, and Founding Partner, Ophthalmic Consultants of Long Island and Connecticut, Garden City, NY, agrees and suggests that many clinicians hold the misconception that branded and generic medications are identical.

“The only thing that is consistently identical in a generic medication and the reference brand is the active ingredient. The formulation, purity, and other features can be extremely different, and as a result, generic and branded medications can differ significantly in their effects on the eye,” says Dr. Donnenfeld. Commenting on the report that eye care providers prescribe the highest percentage of branded medications, he observes, “The stakes are very high when it comes to vision, and practitioners appreciate the safety and efficacy of branded medications.”

Robert D. Fechtner, MD, Professor and Chair of Ophthalmology, SUNY Upstate Medical University, Syracuse, NY, says, “Generic ophthalmic solutions did not have to complete human testing to be approved. Instead, they can be approved based only on a chemical analysis. Furthermore, they cannot be considered identical to the innovator product because the quantities of the ingredients in the generic can fall within an allowed range that is broader than the innovator product.”

He continues, “I am not questioning the integrity of generic manufacturers. The fact, however, is that their goals are to imitate the branded product and capture a share of the market at a lower price point. They are not incentivized to manufacture the better product, just a cheaper product.”
Reviewing the 
evidence on equivalence

Using latanoprost ophthalmic solution as an example, Dr. Fechtner points out that the active ingredient represents just 0.005% of the preparation. The converse is that inactive ingredients make up 99.995% of the solution’s contents. The allowed variability in type of inactive ingredients and their concentration creates potential for physicochemical differences between generic and brand name medications that can translate into differences in efficacy and tolerability.

Findings of a study conducted by Dr. Fechtner and colleagues along with research by other investigators document differences in the physicochemical features of generic products when comparing them to the innovator medication (Xalatan, Pfizer) and to other generic versions.^11–13 Studies of latanoprost products identified differences in active ingredient concentration-some generics contained concentrations exceeding compendial limits-along with differences in specific gravity, osmolarity, pH, buffer capacity, and viscosity.^11–13 In addition, studies showed some generic latanoprost products contained more particulate matter than the brand name and were more prone to active ingredient degradation when exposed to temperature conditions that may be encountered in routine use.¹²

Drop size was also reported to be larger for generic medications compared with brand name latanoprost.^11,13 The difference may be explained by differences in physicochemical characteristics and/or bottle/bottle tip design. Commenting on their finding, Angmo et al noted that larger drop size along with higher active ingredient concentration in the generic product could lead to more systemic absorption, more local side effects, including conjunctival hyperemia, iris pigmentation, eyelash lengthening, as well as increased risk of cystoid macular edema and uveitis in patients at risk for these prostaglandin-associated complications.¹¹

Dr. Favetta says, “Manufacturers of branded pharmaceuticals invest significant resources to develop proper packaging for their products. Their aim is to optimize stability, sterility during the medication’s shelf-life, ease of use, and accurate delivery.”

Evaluating the containers of the branded latanoprost and generic products included in their study, Kolko et al reported differences in the average force needed to dispense the medication, with the branded medication requiring the least pressure. These investigators also commented about variation in bottle shape and cap color among the five generic products they analyzed.¹³

The differences in product appearance are remarkable considering that cap color and bottle shape or size are the features that patients use most to identify their medications.¹⁴ With no guarantee that patients will be dispensed a generic from the same manufacturer at each prescription refill, lack of uniformity in medication cap color can lead to confusion and problems with proper drug administration. Increased drop size or medication wastage secondary to difficulties with handling can also cause patients to run out of medication early and leave them with significant out-of-pocket cost to obtain a refill that is not covered by their insurance.

The findings of these bench studies not only suggest the potential for therapeutic differences between generic and branded products but also support the need for clinical research. Dr. Starr comments that the literature contains a relatively limited number of clinical trials comparing generic and branded ophthalmic medications. Most of the comparative trials have looked at glaucoma drugs. Overall, their results are not consistent, he notes, but physicians considering the data must keep in mind that the studies vary in quality and design.

A recent retrospective cohort study analyzed medical claims data for patients with primary open-angle glaucoma. It concluded that the generic latanoprost was no less effective and possibly more effective than branded prostaglandins for preventing the need for additional medication or surgery.¹⁵

“Outcomes research using claims data, however, is fraught with limitations,” says Dr. Fechtner. “In this instance, I have no idea whether the lower prescribing of additional medication was driven by efficacy of the generic or cost avoidance.”

Recently published prospective, comparative clinical trials reported differences between generic and branded latanoprost. Diagourtas et al conducted a randomized, parallel study comparing the efficacy and safety of two generic latanoprost solutions and the branded product in 60 patients with treatment-naïve open-angle glaucoma.¹⁶

After 16 weeks, intraocular pressure (IOP) was significantly reduced from baseline in all three groups, and there were no treatment-related differences in the percentage reduction in IOP. Safety evaluations, including analyses of changes in tear breakup time and the Ocular Surface Disease Index, however, supported better ocular surface safety in the group using branded latanoprost.

In a crossover, masked, 3-month study, Egan et al found no significant changes in diurnal IOP values after patients with open-angle glaucoma were switched from branded latanoprost to a generic version.¹⁷ Tolerability was also similar for the two products. Nevertheless, the branded product was associated with a significantly greater number of IOP reductions below 14 mm Hg compared with the generic, which the investigators noted may be clinically significant considering evidence that progression from moderate to advanced glaucoma can be limited by a target IOP lower than 14 mm Hg.

A section on generic IOP-lowering medications in the European Glaucoma Society’s Terminology and Guidelines for Glaucoma notes that the similarity in efficacy and tolerability of generic and branded medications is not well studied.¹⁸ Citing reports showing variable clinical results, differences in drop size, number of drops, bottle structure, and tip configuration, along with the development of corneal epithelial disorders associated with generic products, the guidelines recommend that IOP be closely monitored when switching patients from branded to generic drugs.

Dr. Fechtner comments that he believes most attentive clinicians have seen glaucoma patients who suffered loss of IOP control when they switched from a branded to a generic product. He adds, “I have also had patients report more stinging and burning using a generic version of a certain fixed-combination IOP-lowering medication, and that is important because discomfort feeds into lack of adherence.”

Impact of real-life experiences

Encounters with patients who developed serious problems using generic medications also drive clinicians’ preferences for branded products. Many practicing ophthalmologists are probably familiar with the occurrence of corneal melts among patients who were using a particular generic diclofenac ophthalmic solution.¹⁹

Dr. Starr recalls having seen several such patients during his cornea fellowship. “Those were horrific adverse events that remain clear in my mind, and they have had a lasting effect on my view of generic medications,” he explains.

Dr. Favetta states that he will never prescribe a generic medication for a patient unless insurance constraints leave him with no choice. He cites his experience with a corneal transplant patient as the foundation for his practice.

“I started the patient on branded prednisolone acetate 1% suspension (Pred Forte, Allergan),” he says. “Well into the tapering period, he suddenly developed signs of transplant rejection. I didn’t understand the abrupt change, but when I asked the patient to bring in his medication, I saw that the pharmacy had substituted generic prednisolone acetate for the branded medication. The patient improved dramatically after he restarted on the branded medication.”

Dr. Donnenfeld reports seeing multiple patients who developed corneal melting accompanied by vision loss when using a generic topical nonsteroidal anti-inflammatory drug (NSAID) that required 4 times a day dosing. Such cases draw attention to the fact that there are brand name medications without a generic alternative that offer unique clinical advantages because of their active ingredient, recommended dosing frequency, or ocular surface safety, he explains.

Providing examples, Dr. Donnenfeld refers to loteprednol etabonate 0.5% gel (Lotemax Gel, Bausch + Lomb) that is gentle to the ocular surface and a new loteprednol etabonate product containing 1% of the active ingredient in a nanosuspension that is recommended for dosing just twice a day (Inveltys, Kala Pharmaceuticals). He also mentions the NSAIDs nepafenac 0.3% suspension (Ilevro, Alcon) and bromfenac 0.07% solution (Prolensa, Bausch + Lomb) that are administered once a day.

“The decreased drop burden and unique vehicles of these brand name products are particularly important for dry eye patients and for refractive or refractive cataract surgery patients for whom I want to optimize every aspect of their care. Because reduced dosing frequency also favors better medication adherence, it is important for all patients,” he says.

Dr. Donnenfeld prefers besifloxacin ophthalmic suspension 0.5% (Besivance, Bausch + Lomb) as his antibiotic of choice in some patients. This is because of both the vehicle, which is mucoadhesive and helps to prolong drug delivery, and the active ingredient, which has the highest in vitro potency against methicillin-resistant coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus among all fluoroquinolones.⁴

The ability to control exposure to preservatives is another reason to choose a branded medication, says Dr. Fechtner. “Various studies show that 50% of patients with glaucoma have symptoms of ocular surface disease, and benzalkonium chloride (BAK) is the primary culprit in this problem,” he explains. “I can prescribe a preservative-free branded product in almost every class of glaucoma medication, but I don’t have the same option to reduce or eliminate BAK exposure with generic medications.”

For that reason, Dr. Fechtner laments the step therapy requirements of some insurance plans that mandate patients starting treatment for ocular hypertension/glaucoma use a generic medication.

“Generic timolol and generic latanoprost are the lowest cost options for IOP lowering, and they are both preserved with BAK,” he notes. “This is a potential penalty that is paid when our patients are pushed into lower-cost generic medications.”

Cost considerations

Dr. Fechtner says that even though he strongly prefers branded medications for the reasons he discussed, he can appreciate how economics can drive the decision to use a generic alternative. Nevertheless, he observes that choosing a generic medication does not always translate into substantial cost savings.

Rising costs of some generic ophthalmic medications is one factor that is leveling the cost difference. A study by Dr. Fechtner and colleagues analyzing data from five national pharmacy chains found that from 2014 to 2015, costs for generic latanoprost, timolol, dorzolamide, timolol/dorzolamide, brimonidine 0.15%, and brimonidine 0.2% increased significantly more than the national inflation rate, changing by as much as 45%.²¹ Significant increases in the cost of generic phenylephrine and prednisolone acetate have also been reported.^2,22

“I have had patients tell me they paid more than $100 for generic atropine,” Dr. Fechtner says.

“In theory, our electronic health record can give me insight on preferred medications and cost, but that requires that the correct pharmacy benefit carrier is entered into the system and the data are up to date. The reality is that when I am prescribing for a patient, I am still completely in the dark about what the out-of-pocket cost will be for the medication I want them to use.”

Dr. Donnenfeld also notes that he has been very surprised by the cost of some generic medications. “Patients have to be aware that presumed cost savings of generic medications may be an illusion,” he comments.

Furthermore, there are opportunities for cost savings with branded medications available through manufacturers’ rebates, coupons, discount cards, and patient assistance programs. Samples may also be available that can give patients access to the branded product when short-term treatment is needed.

“It is important for physicians to be aware that there are services that can help with prior authorization and for lowering the cost of medications. Clinicians should have their staff research these programs and find ways that we can help our patients stay on the brand,” Dr. Fechtner says.

Dr. Donnenfeld says his office staff is knowledgeable about cost-saving opportunities available from manufacturers of branded products and passes the information along to patients. He also takes advantage of samples and informs patients about manufacturer assistance programs that can allow patients in need to overcome economic barriers. “I think not all clinicians are aware of these programs that are a real service to the patients we care for,” he remarks.

Dr. Favetta agrees that the offers available from companies marketing the branded medications are very helpful and a unique benefit of brand name medications. “Industry is very, very generous with rebates and coupons that can lower the cost of many branded products to make them affordable,” he says.

Dr. Starr notes that skyrocketing costs have also stopped some patients from acquiring the generic medication. He adds, “Coupons and other manufacturer incentives can lessen the cost difference between branded and generic products. When you add in the advantages of using the branded medications, I think that paying a little more for a product that has proven to be safe and efficacious is worth every penny,” he says.

Looking at the potential for cost savings with generic medications from a broader perspective, Dr. Starr points out that the issue is not as black and white as some simple analyses suggest. Although there may be immediate direct cost savings associated with purchasing generic medications rather than branded products, a complete economic analysis would incorporate the indirect costs associated with differences in efficacy and safety that can occur using a generic.

“It needs to be considered that when using a generic medication, a certain percentage of patients can have a worse outcome via reduced efficacy or increased side effects leading to additional visits, increased chair time, and more interventions, both surgical and medical,” he comments. When you add in the indirect costs of those consequences, for some patients, it becomes more expensive to use a generic medication.”

Practical decisions

Concerns about generic medications are more relevant under some circumstances than others. Dr. Starr says he finds it acceptable to prescribe a generic antibiotic for a patient with a mild conjunctival or corneal infection that is not vision threatening. If he sees a patient on referral who is successfully using a generic product for a nonserious condition, such as seasonal allergic conjunctivitis, he won’t insist that the patient switch. He will, however, offer to prescribe a branded medication that has an advantage of less-frequent dosing.

On the other hand, Dr. Starr says he has a clear and strong preference for using a branded product when treating patients with a serious condition such as uveitis, corneal ulcer, or massive corneal inflammation. “When using a topical corticosteroid to treat these patients, I am concerned about consistency of the dose delivered with every drop. I feel more confident using a branded product that has a nonsettling formulation, like loteprednol etabonate 0.5% gel (Lotemax Gel, Bausch + Lomb) or difluprednate ophthalmic emulsion 0.05% (Durezol, Alcon), rather than a generic suspension because the suspension needs to be shaken vigorously prior to instillation,” he explains.

Dr. Starr also relies on branded products for medications that need to be used long term, such as treatments for glaucoma, dry eye, or preventing infection in a patient with a keratoprosthesis.

“We know that compliance and adherence is affected by tolerability and dosing frequency, and with the use of certain branded medications that have no generic version, I have the opportunity to optimize those issues,” he says.

Dr. Fechtner admits that he often starts treatment for lowering IOP using a generic prostaglandin. He adds that he is troubled doing so, however, knowing that it contains BAK and that most patients eventually need more than one glaucoma medication. “I know that very likely, the next drop I will be able to prescribe also contains BAK, and when a patient is on two medications with BAK, the incidence of ocular surface disease increases dramatically,” says Dr. Fechtner.

Similarly, in the interest of minimizing medication-related ocular surface toxicity, Dr. Donnenfeld and Dr. Favetta underscore the importance of using branded medications in patients with dry eye. Looking ahead to the future release of a generic cyclosporine 0.05% emulsion, they both questioned whether a generic will have the same efficacy and safety as the innovator (Restasis, Allergan).

“Cyclosporine is a very difficult medication to formulate because of its poor aqueous solubility, and ophthalmic emulsions are complex systems that are difficult to engineer,” Dr. Favetta notes.

He and Dr. Donnenfeld observed that Allergan spent a lot of time and invested significant resources developing its cyclosporine emulsion. “Considering the challenges to replicating the innovator formulation, I have significant concerns about whether a generic cyclosporine product will achieve the desired therapeutic goals and if it may cause more toxicity. Time will tell,” Dr. Donnenfeld comments.

Because of concerns about the clinical performance of generic cyclosporine, Dr. Favetta says that when a topical immunomodulatory agent is indicated for dry eye treatment, he will prescribe only the innovator brand of cyclosporine or lifitegrast 5% (Xiidra, Shire). “There is no generic alternative that can be substituted for lifitegrast, and lifitegrast has both a unique mechanism of action and indication because it is approved for the treatment of the symptoms of dry eye disease in addition to the signs,” he explains.

Counseling conversations

Research shows that patients may not be forthcoming with their physician if they have concerns about the cost of their medication.²³ Therefore, it is important that clinicians ask questions to identify if cost presents an issue. Because many patients assume that the only difference between a branded and generic medication is cost, additional counseling may be needed.

Dr. Starr notes that in his practice setting, which is at an academic institution located in an affluent neighborhood in Manhattan, he encounters minimal pushback from patients about the cost of branded medications. Yet, he recognizes that it can be a common occurrence for other practitioners. “It may be hard to make an argument that will convince a patient to use a branded drug if there is a significant cost difference compared with the generic,” Dr. Starr says.

He adds: “Depending on the indication for use and the patient’s circumstances, however, I think you can make a compelling case for using the branded medication by explaining its potential advantages for better efficacy and safety. It is important that patients know the possible repercussions of using the generic.”

Dr. Donnenfeld says that if there is a significant cost saving that is important for the patient, he is willing to prescribe a generic as long as he is fairly confident that the medication will not compromise the ocular surface or the patient’s outcome in any other way. In situations in which he has concerns about the generic, patients who are refusing the brand name are told they will need to be followed more closely or Dr. Donnenfeld will refuse to prescribe anything other than the brand name.

As he further explains, “I will not allow a patient who already has superficial punctate keratitis from dry eye to use a generic NSAID. In this situation, I make it very clear that I would rather the patient not use an NSAID than use one that may cause worsening because of its potential toxicity.”

Dr. Favetta says that when he is confronted by patients requesting generic medications, he tells them that the branded medication is what he would choose for himself. “I also say that I want them to use the best product available,” he states. “And, in my opinion, that is the branded medication.”

If a patient still objects, he looks to see if he can provide a sample of the branded product. As well, a patient who is using a generic is monitored more closely.

Preventing substitution

To assure that patients get the intended medication when they go to the pharmacy, prescribers need to be aware of their state’s pharmacy laws pertaining to generic and therapeutic substitution that vary widely from state to state [see sidebar: State Pharmacy Laws].²⁴

Despite having made the necessary notation on the prescription order to prohibit generic or therapeutic substitution, both Dr. Fechtner and Dr. Starr note they have been surprised at times to see the medication a patient received.

“Physicians have the knowledge to make the best choices and recommendations for our patients and are devoted to providing the best care. It is disturbing that our expertise and interest in the patient’s well-being can be undermined by pharmacy laws that allow someone who does not have our training or judgment to second guess our decision and dispense another medication,” Dr. Fechtner says. “To help ensure that patients get the right medication at the pharmacy, physicians should take the time to explain their beliefs about the benefits of using the branded medication,” he adds.

Maintaining vigilance

Recognizing the potential for substitution at the pharmacy, Dr. Starr instructs surgical patients to bring their medications to their follow-up visit so that he can check what they are using. “The worst-case scenario for me,” he explains, “is if a patient was dispensed a generic NSAID. I prescribe a once-daily branded NSAID for my postoperative regimen. When a patient gets a generic NSAID instead, I am concerned about its efficacy and its potential to cause side effects and/or interfere with wound healing.”

Although he will not insist the patient discard the purchased medication and obtain the recommended branded version, Dr. Starr explains that he counsels patients about the potential for differences in efficacy and safety and the expected postoperative course. Then, he emphasizes that they should contact the office if they are failing to improve or experiencing side effects.

When treating patients with comorbid glaucoma, Dr. Starr checks to see what medications they are using for IOP lowering. When appropriate, he consults with the glaucoma specialist about alternatives for decreasing preservative exposure. 

“With branded medications for IOP control, there are options that are preservative-free, formulated with a BAK alternative, or administered less frequently,” he says. Similarly, Dr. Starr carefully reviews medications being used by patients with dry eye to make sure they are using products that will not worsen their condition.

Subsequent to his experience with the corneal transplant patient who switched from the branded prednisolone acetate to a generic, Dr. Favetta has his office staff call surgical patients to check that they have filled their prescriptions and verify they received what he intended. He notes that “In the interest of avoiding problems that can occur with generic products, I think we have an obligation to make certain our patients are using the right medication.”

Concluding comments

Reiterating his preference for exclusively using branded medications, Dr. Favetta says that he has confidence that a branded product will deliver the active ingredient and be safe and efficacious. “I know I can rely on a branded product because of its quality and consistency,” he comments.

Dr. Donnenfeld says that the Latin phrase “Caveat emptor” (meaning “Let the buyer beware”) applies very well to the controversy surrounding generic and branded medications. “In certain circumstances, patients may be putting themselves at considerable risk for the trade-off of a small cost saving,” he explains.

While acknowledging there can be a role for generics, optimizing care is his main concern. “I am conscious about the cost a patient is paying out of pocket for medication, and so I balance the economics of generics with the quality of the medication. But my number one consideration is the health and integrity of the eye,” Dr. Donnenfeld says. He adds that “It is important clinicians understand the cost of generic medications and the efficacy of branded medications and use this knowledge to make an informed and intelligent choice, which for many patients is a branded medication.”

Dr. Starr says he prefers branded medications for a number of reasons but also accepts there is a place for generics depending on the medication, the indication, and the patient. “Each prescriber needs to make individualized decisions taking these variables into account to decide what is best for the patient,” he says. Further, he observes, “It is important that ophthalmologists be knowledgeable about the FDA approval process for generic medications, the potential for generic and therapeutic substitution at the pharmacy, and the evidence about differences between generic and branded medications so they will make good informed decisions that will help their patients.”

Dr. Fechtner notes that educating patients about potential differences between branded and generic medications, becoming informed about their out-of-pocket costs, and following up to make sure that patients are using the intended medication is time consuming but important. He explains, “I am spending a significant amount of time talking to patients about generic and branded medications and in ongoing battles with insurance companies to get patients access to branded medications when needed.”

“Meanwhile,” Dr. Fechtner adds, “physician reimbursement continues to spiral downward, and my time is the only thing I can leverage to compensate for the decline. But our patients deserve what is best. Physicians are their last remaining advocate, and so it is important that we take the time to make sure they get the medications that will optimize their care.”

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