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Generic substitutions raise growing concerns among ophthalmologists
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While the generic drug market steadily grows in Europe, and generic substitution has become the rule in all countries, concern exists among ophthalmologists about tolerance and efficacy, as well as their own power to maintain proper control of a patient’s treatment.
“The problem in ophthalmology is that bioequivalence cannot be tested. Therefore, if patients ask me whether a generic I prescribe is equivalent to the brand, I cannot answer,” Jean-Philippe Nordmann, MD, said.
In addition, due to the variety of generic drugs available, patients may be given different products in different pharmacies, and the choice is in the hands of pharmacists rather than the prescriber.
“In Switzerland, as in many countries, pharmacists can exchange the branded drug with whatever generic they want. Patients have to agree and doctors should be informed, but often they are not. There are currently eight or nine different generic latanoprost in the market. Patients are frequently and arbitrarily switched from one to the other, and it is like starting with another drug every time. Caution is mandatory. It is important to know that they can vary and differ from the branded drug,” Frances Meier-Gibbons, MD, said.
Is equivalent really equivalent?
Image: Nordmann JP
In 1994, the Uruguay Round Agreements Act set the patent term of a novel drug to 20 years after the first date of filing. Once the patent has expired, generic versions of the same drug can be produced and marketed by other manufacturers. Substantially lower sale prices can be applied because the high costs of testing have already been paid by the innovators.
“Generic drug companies are not required to perform preclinical or clinical trials to establish the active ingredient’s safety and efficacy but may use the safety and efficacy data from the innovator products,” Ingrida Januleviciene, MD, said.
Generics are required by the European Medicines Agency (EMA) to contain the same active ingredient as the corresponding branded drugs. Bioequivalence should be proved by studies, but “since there is no reliable way of assessing bioequivalence for eye drops, bioequivalence studies are not performed,” Nordmann said.
Excipients are not required to be the same, although they constitute a substantial part of the drug.
“In prostaglandin, only 0.005% is active ingredient, and the rest, 99.995%, are inactive substances,” Meier-Gibbons said.
Excipients are preservatives, pH adjusters, antioxidants, thickening agents, buffers and tonicity adjusters. They may influence penetration, absorption, retention time on the eye, bioavailability, changes in viscosity, osmolarity and pH tolerability, safety and efficacy, Januleviciene said.
Pharmaceutical heterogeneity also exists because drug companies have different manufacturing processes and production steps. For example, bottle design often influences drop size.
“Researchers have found that drop size can range from about 25 µL to 70 µL. If a patient receives a different amount of drug than intended, efficacy may be affected and adverse effects may result,” Januleviciene said.
Safety, efficacy and compliance
Decreased efficacy and increased adverse events have been reported with different classes of generic ophthalmic drugs, including topical corticosteroids, NSAIDs and glaucoma medications. In 1999, generic diclofenac was found to cause corneal ulcers and was eventually withdrawn from the market. Several reports on generic topical corticosteroids found decreased concentration of the active ingredient per drop compared with the branded drug, poorer uniformity or a tendency to precipitate. In 20% of samples of antibiotic eye drops manufactured by different companies in India, a lower-than-standard drug concentration was found.
“The comparison of Bausch + Lomb generic latanoprost with Xalatan (Pfizer) in a randomized study of 266 patients showed equivalent IOP reduction. But another randomized study carried out in India found remarkable differences, with a mean IOP reduction of 9.35 mm Hg vs. 5.76 mm Hg with brand vs. generic,” Nordmann said. “In addition, stability of the generic latanoprost was found to be affected by temperature. A significant reduction in the quantity of active principle at 25°C or more was found, while Xalatan remained stable.”
Generic timolol was found to be less effective in one study, and different timolol formulations were associated with different side effects.
“Every week I have one or two patients who are unsatisfied with generics, and yet they tolerated the branded drug very well. If there is a difference, it is always to the worse. I never had a patient who did not tolerate the branded drug and tolerates the generic better. Generics have a natural tendency to be either equivalent or worse,” Nordmann said.
Although the acceptance of generics has grown, recent surveys show that about 40% of patients do not accept a systematic substitution of the branded drug with generics and 30% have doubts about the safety of these products.
“Consumer perception is influenced on one hand by the national advertising campaign in favor of generics and on the other hand by media news reporting people complaints and highlighting the potential drawbacks and inconsistencies of generics,” Nordmann said.
“We cannot force patients’ acceptance,” Januleviciene said. “Patients should be given honest information so that they can make informed decisions in conjunction with their physician.”
“Official sources, pharmacists and some of the press encourage patients to go for generics by saying that they are exactly the same as branded drugs. But this is misinformation, and we need to redress the balance of pros and cons,” Meier-Gibbons said.
Nordmann expressed concern about the negative impact that inconsistent results and contradictory information may have on patient compliance.
“Compliance with glaucoma medications is already low, about 50%. If on top of this patients have doubts on what they are taking, and we cannot honestly reassure them, we can only expect compliance to get worse,” he said
Do generics save money?
The 2012 Report of the Executive Agency for Health and Consumers (EAHC) – European Commission showed wide variability among countries concerning the penetration rate of generics, from 25% in Greece and Portugal to 100% in Hungary. Meier-Gibbons said that in Switzerland only one-third of drug sales are on a generic basis, while in the Netherlands, U.K. and Germany, they are up to two-thirds.
Nordmann said that the market for glaucoma generics had a rapid increase in 2012 in France, totaling 65% to 70% of glaucoma medication sales by the end of the year, but since then, sales have stagnated.
National budget savings due to the use of generics are expected to increase, with the highest impact in the United Kingdom, followed by France, Germany and Greece, according to the EAHC report.
“There has been a strong economic push by governments for generic drugs, given the financial relief provided by these compared to branded drugs,” Januleviciene said.
However, there are doubts among specialists on the long-term economic advantage of widespread generic drug use in glaucoma patients.
“Several studies involving patients switching from branded to generic drugs have shown decreased clinical efficacy and increased adverse effects, increase in mean daily dose, a higher number of dispensations for other medication, a rise in medical visits and increased hospitalization time. Cost savings may be negligible, as patient visits may increase due to poor tolerability or efficacy of generic drugs,” Januleviciene said.
“We have to do more frequent monitoring and even change the management of the patient. Eventually generics end up costing us more than we believed they do, and more than branded,” Meier-Gibbons said.
Pharmacoeconomic studies by brand pharmaceutical companies are proving that using their more expensive drugs does not cost more than using less expensive but less efficacious generic substitutes, Nordmann said.
“Decreased compliance also accounts for increased costs, as it is not less expensive if patients get worse. A well-controlled pressure means less monitoring, less surgeries, larger reduction of costs. But agencies only look at the price of the drug and not at the long-term consequences,” he said.
“The risk is that we might go backwards,” Meier-Gibbons said. “We have had so far fully tested medications with very clear-cut safety and efficacy profiles, and we are now regressing to preparations where ingredients are not fully declared. We are losing control on what we are giving to our patients.”
EGS warnings
The October 2013 “Tip of the Month” published on the European Glaucoma Society (EGS) website recommended monitoring patients more closely after switching to generics.
Gordana Sunaric Mégevand, MD, the author of the tip, wrote that “unlike the situation with systemic drugs, the concept of bioequivalence is difficult to prove with ophthalmological drops” and that “although the active principle is similar in generics and brands ... the adjuvants can vary considerably.”
She also warned about safety issues and concluded that “when switching patients from brand drugs to generic drugs the follow-up should be sooner than usual, particularly in respect to endpoints like IOP and visual field.”
New EGS guidelines for glaucoma will be released by the end of the year, and the issue of generics will be covered, providing appropriate warning, Nordmann said.
Januleviciene said that the strategy of encouraging generic drug production is important at a global level to reduce health care costs and enhance drug availability to patients. As patents for branded drugs progressively expire, generics are ineluctably going to increase their presence on the market and in clinical practice.
“Since they are here to stay, however, more stringent regulations and criteria regarding phase 4 studies should be enforced by the FDA and EMA, so that generic drugs are proven to be really equivalent to their parent drugs in clinical trials,” Januleviciene said. – by Michela Cimberle
- References:
- Allaire C, et al. Eur J Ophthalmol. 2012;doi:10.5301/ejo.5000041.
- Executive Agency for Health and Consumers-EAHC-European Commission. EU pharmaceutical expenditure forecast. ec.europa.eu/health/healthcare/docs/creativ_ceutical_eu_pharmaceutical_expenditure_forecast.pdf. Published Nov. 26, 2013. Accessed Nov. 19, 2013.
- Mégevand GS. Generic drops can differ from brand drops and it may be necessary to monitor patients more closely after switching. European Glaucoma Society website. www.eugs.org/pdf/tip_of_the_month/000065.pdf. Published October 2013. Accessed Nov. 19, 2013.
- Narayanaswamy A, et al. Indian J Ophthalmol. 2007;55(2):127-131.
- For more information:
- Ingrida Januleviciene, MD, is president of the Lithuanian Glaucoma Society and head of the Outpatient Department at the Eye Clinic of Kaunas Medical Academy Hospital. She can be reached at the Eye Clinic of Kaunas Medical Academy Hospital, Lithuanian University of Health Sciences, Eiveniu str 2 Kaunas 50009, Lithuania; +370-37-326760; email: ingrida.januleviciene@kaunoklinikos.lt.
- Frances Meier-Gibbons, MD, is a private ophthalmologist and co-founder of the Swiss Glaucoma Group. She can be reached at Tiefenaustrasse 2, 8640 Rapperswil/SG, Switzerland; +41-55-220-65-22; email: frances.meier@bluewin.ch.
- Jean-Philippe Nordmann, MD, is head of Ophthalmology at the Hôpital des Quinze-Vingts, Paris. He can be reached at the Hôpital des Quinze-Vingts, 28, rue de Charenton, 75012 Paris, France; +33-1-40-02-12-00; email: jpnordmann@quinze-vingts.fr.
Disclosures: Januleviciene is a lecturer for Alcon, Allergan, MSD, Santen and Pfizer. Meier-Gibbons is a consultant for Alcon, Allergan and MSD and a lecturer for Santen and Théa. Nordmann is a consultant for Allergan, Alcon, Théa and MSD.
Has your government introduced demand-side policies directing physicians to prescribe generic medications?
Italy: Mandatory prescriptions and differences in co-payment
The Italian government has introduced generic entry regulations that are strongly coercive for physicians. Prescription by international nonproprietary name is mandatory whenever generics are available, and pharmacists are under strict obligation to dispense the generic product. Only when the branded drug has been used previously for a chronic disease, the physician is allowed to maintain it and is required to clearly indicate on the prescription that no substitution can be made. On first-time prescriptions, the choice for branded drugs needs a synthetic explanation of the reasons for this choice. Also under National Health Service prescription, the fixed amount the patient is asked to pay for branded drugs is on average double when a generic is available. Should patients want to buy a branded drug when this has not been specifically prescribed, they have to pay the difference.
This policy has affected not only our freedom of choice, but also our ability to be in control of the therapy. There are several generics for the same active ingredient, and we neither know which one of them is given by the pharmacist, nor if it will remain the same the following time. Efficacy and tolerability may vary considerably between generics, and unless we continuously monitor patients, we do not know if effective IOP control is maintained. Patients are also affected. Should problems with decreased efficacy or side effects arise, we cannot give them the answers they need and, due to the waiting lists in NHS, it may take weeks or even months before we properly address the problem and readjust the therapy. In the meantime compliance might drop. In a disease such as glaucoma, in which the damage is often asymptomatic for a long time, we know how important it is to maintain IOP under constant control, to avoid fluctuations, to take medications regularly. By rocking the boat, we could lead many well-controlled glaucoma situations to progress to the stage of visual field loss.
Costantino Bianchi, MD, is the President of the Ophthalmology Section – European Union of Medical Specialists. Disclosure: Bianchi has no relevant financial disclosures.
Austria: Policy maintains freedom of choice
Generic drug policy has kept a fairly good balance in Austria among competitors on the market and has granted physicians with sufficient freedom of choice on what they want to prescribe. First of all, the generics entries affect the price of the whole class by regulatory rules. The first generic has to be 48% cheaper than the original branded drug, and then the original company has three months to reduce the price of its product by 30%. When a second and third generic come in, their price is scaled down by a further 15% and 10%, respectively. With three generics on the market, the original medication is mandatorily sold at the same price. In addition, whether a patient is prescribed branded drugs or generics, prescription charges do not change. There is a fixed amount of 5.30 to pay per medication, and differences in price only become apparent when a drug is cheaper than prescription charges.
Pharmacists are not allowed to change what we write on the prescription. They cannot change Xalatan for generic latanoprost unless we write “aut idem” on the prescription. If we write “aut simile,” they can give the patient another prostaglandin. But we usually do not do this; we just prescribe the drug we think is best for the patient.
If patients are doing well with the branded drug, I prefer to maintain it. There is no point in changing a winning horse. I might propose generics to new patients in some cases, but I have to explain clearly to them that there is no trial to ensure that they are equally effective and well tolerated. Most glaucoma patients are elderly and can get very confused if they are switched to generics. They see a new name, a different bottle of a different color, and because there are at least 10 generics of latanoprost on the market, more changes may occur over time. This might have a negative influence on compliance, and then the very small financial benefit of switching to generics ends up being negatively compensated by loss of efficacy.
Anton Hommer, MD, is a member of the Department of Ophthalmology, Hera Hospital, Vienna, Austria. Disclosure: Hommer is a consultant for Santen, Allergan and Bausch + Lomb.