Ophthalmologists concerned over increased demand for generics

Increased demand for generic drugs in the wake of the Patient Protection and Affordable Care Act of 2010 has led to intense debate among ophthalmologists, some of whom question whether patients’ best interests are being considered.

Many physicians are concerned that quality care is no longer top priority, citing what they believe to be less stringent regulatory standards for generics and marketers that are enticed by higher profits. Additionally, some criticize the U.S. Food and Drug Administration’s costly process for approving new drugs as a key motivator for generic popularity — a practice that could skew the market in favor of products that may not undergo the thorough clinical evaluation required of their branded counterparts.

While many view generics as advantageous for low-income patients, others note that the purported financial benefits of these drugs may be deceptive. Moreover, the issue of whether generics are “equivalent” to branded counterparts remains a source of contention; in particular, some question the impact of different side effect profiles on patient compliance.

However, an FDA official said that stipulations in the generic approval process distinguish ophthalmic products from other types of drugs, requiring that differences in composition between a generic ophthalmic product and its branded counterpart be coupled with evidence of safety and efficacy.

Despite a myriad of viewpoints, concerns and data, the presence of generics in U.S. health care is growing and ophthalmologists should be aware of potential effects.

“Generic drugs are clearly part of the future of medicine, but until the regulatory authorities subject them to a greater degree of scrutiny for their toxicity, physicians have to be attuned to the dangers of excipient ingredients, variability in what the patient is actually receiving and how this could affect clinical outcomes,” John A. Hovanesian, MD, FACS, OSN Cornea/External Disease Board Member, said.

Regulatory standards

The relative ease and low cost of generic approval may be “tilting” the ophthalmic drug market and de-prioritizing patient needs, some claim.

According to the FDA’s website, generics must contain the same active ingredients, but not necessarily the same inactive ones, as their branded counterparts. Additives, buffers, pH levels and the delivery system of the drug are not subjected to testing, Ehsan Sadri, MD, FACS, said, noting that such differences could pose problems for patients.

“Inactive ingredients matter in a pill but not as much as they do in an eye drop where you are putting the product directly on the target organ. In the eye, preservatives can be toxic to the ocular surface. For a glaucoma patient who takes medication day after day, year after year, the difference could be important to the patient’s well-being,” Dr. Hovanesian said.

Some argue that, without comparative evaluation, relative efficacy and safety remain undetermined.

“There is never any testing done to show that generic formulations get into the eye in a manner similar to the branded products, and there is no requirement that they be tested therapeutically against brand name products, so efficacy is not known,” Louis B. Cantor, MD, OSN Glaucoma Board Member, said. “While a majority of the time generics seem to work for most patients, there are exceptions, and those exceptions are not rare.”

Companies that manufacture generic and branded products also lack incentive to conduct trials.

“The generic companies do not do studies; they have nothing to gain. … The branded product companies have a rapidly decreasing market, so they do not want to invest either. When a generic formulation first comes out, oftentimes the conversion rate can be 60% to 80% within 6 months,” Dr. Cantor said.

Nevertheless, a few small-scale trials have shown differences between generic and brand name medications. For instance, a study published in Current Eye Research compared brand versions of latanoprost and dorzolamide-timolol with generic counterparts after 30-day exposure to temperatures of 25°C and 50°C. Outcomes suggested that high temperatures may significantly decrease the concentration of active ingredients in generic formulations, potentially affecting efficacy.

Variations in bottle design and drop volumes have also been demonstrated. In a study published in the Canadian Journal of Ophthalmology, American and Canadian versions of branded timolol maleate ophthalmic gel were shown to differ significantly from generic versions in drop volume, viscosity, surface tension and bottle tip.

“Careful consideration should be given to drop viscosity and bottle design when generic ophthalmic products are evaluated for interchangeability and market entry,” the study authors wrote.

Alterations in bottle design, which could cause difficulty with application or result in a larger dosage, may waste medication and cost patients more money in the long run, Dr. Cantor added.

“It is all a question of cost and where you can save money, and so these companies use less expensive manufacturing processes,” he said. “The only driver in the generics field is to meet the FDA standards and to do so as cheaply as possible.”

Monetary incentives

Underlying the notion of a higher profit margin for generics is their less costly approval process, which involves submission of an abbreviated new drug application (ANDA). According to the FDA’s website, this standard was established by the Hatch-Waxman Act.

“Generic drug applications are termed ‘abbreviated’ because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. … This [Hatch-Waxman] Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions … without conducting costly and duplicative clinical trials,” the website said.

Drs. Cantor, Hovanesian and Sadri all agreed that the lower cost of approval offers potential for higher revenue, which may in turn affect ophthalmic drug trends.

“The challenge that arises is that generics are a lot cheaper; a pharmaceutical company can invest a lot less money into getting these medications onto the market,” Dr. Sadri said, claiming that pharmacists are frequently encouraged to promote their usage.

“There is a huge incentive for generics, because they are more profitable to the suppliers, and the profit margin for pharmacies is greater as well, because they pay more for branded products. … The system is tilted and incentivized toward generics,” Dr. Cantor said.

Francis W. Price Jr., MD, OSN Cornea/External Disease Board Member, called the FDA’s approval process for new drugs “complex and convoluted,” noting that the expenses and complications deter companies from investing in new products.

“It is almost impossible to get a new drug approved in this country. If we had more rationality with our drug approval process, maybe our brand name products would be cheaper,” he said, noting that this might encourage a more balanced competition between generics and branded drugs.

Re-evaluating the cost issue

Financial benefits are often cited as the rationale for generic usage; without this option, some say a significant portion of patients would not be able to afford treatment.

“In today’s economic climate, patients are asking for reasonably priced drugs and demanding us to prescribe within their financial means and within their insurance plan’s formulary,” Robert S. Gold, MD, OSN Pediatrics/Strabismus Section Editor, said. “The bottom line, for me, is that generics are saving patients money.”

However, others say that the overall cost of care may not be cheaper.

“You would obviously never use a generic if there was not some sort of cost benefit to it. … [However,] there are other things in the pharmacoeconomic cost analysis than just the price of the medication, and we often lose sight of that. We think that cost is merely what you pay for a bottle,” Dr. Cantor said.

For example, if generic side effects negatively affect compliance, resulting in worsening disease and added treatment, expenses accumulate, he explained. Dr. Cantor also believes that patients on these medications should be monitored more closely, requiring extra office visits. This translates to additional legwork for the physician and further financial strain on patients and the health care system.

“Because clinical testing is not required, you cannot assume that the medication is going to work the same as the branded product, so we typically have patients come back in a month. … Even if the patient is doing fine, he or she may return to the pharmacy for a refill and be given a different generic. Then you have to start all over,” Dr. Cantor said.

Opinions vary regarding the Medicare Part D prescription plan “donut hole,” or coverage gap, and its relationship to generics. Upon surpassing the plan’s initial coverage limit, beneficiaries must pay the full cost of drugs until reaching the next financial threshold.

“The donut hole has probably been the best thing that has happened in terms of reshaping the delivery of medical care, because it has shown us that, once you have a free market, the cost of drugs can plummet,” Dr. Price said. “As soon as the donut hole opened up, that is when Walmart and Costco and other companies started offering generics for $4 because the consumer was now fully responsible for the payment without some price regulation or first dollar payment by the government or other third party.”

When viewed from a different angle, however, Dr. Hovanesian said the coverage gap actually supports use of branded medication.

“The Medicare donut hole is not what everybody thinks it is. … In 2012, there is a 50% discount on branded drugs and a 14% discount on generics. Let’s say that a branded product costs $200 and a generic costs $100; that means the patient will pay $100 for the brand drug and $86 for the generic. However, there is a catch,” Dr. Hovanesian said, noting that patients must reach a total out-of-pocket cost of $2,930 to receive coverage again.

“The full Medicare price of branded drugs, in this case the $200, counts toward the deductible, while only $86 counts for the generic. Basically, if a patient pays for the branded medication, he or she is out of the donut hole that much faster,” he said.

Side effect profiles, concerns

While most consider generics to be relatively safe, concerns are mounting over the impact of side effect profiles, particularly how they may influence compliance and thus long-term efficacy.

“Surgeons are put in an awkward position of bearing responsibility for the outcome without having control, in some cases, over what medications are used,” Dr. Hovanesian said, referring to the ability of pharmacies to switch from branded to generic medications.

In the case of a chronic disease such as glaucoma, in which compliance is already an issue, many are worried that minor differences in tolerability could affect treatment.

“Even under the best circumstances, our patients do not use their medications properly a high portion of the time. … The main thing we are concerned about then is tolerability. Any small difference in how a glaucoma drop feels can affect long-term compliance,” Dr. Hovanesian said.

Dr. Sadri said safety risks for cataract patients are more acute, given that the postoperative eye is weakened and inflamed, but his concerns still center on tolerability.

“Everyone talks about corneal melts as being the catastrophic complication of generics, but those are rare. In all my years of practice, I have seen two cases. … Side effects are what is intolerable, and these include blurry vision, corneal epithelial changes, pain and therefore discontinued or poor adherence,” he said.

The two cases of corneal melt observed by Dr. Sadri were in patients treated with the generic NSAID diclofenac from Falcon. According to Dr. Price, corneal melts are highly uncommon with other non-steroidals; however, he is still hesitant to use these medications as generics, because a minor change in their chemical makeup could considerably alter effects, as it did with generic diclofenac.

“One of the issues with nonsteroidals is that they inhibit prostaglandins. Prostaglandins are like a knob you turn to determine how loud you want the volume for pain, itching, inflammation, etc. … But there are other prostaglandins that regulate healing and mucus production that you may not want to inhibit, so non-steroidals are tricky and need to be evaluated individually,” Dr. Price said.

According to an editorial Dr. Price wrote in the Journal of Cataract and Refractive Surgery, researchers have shown high doses of NSAIDs to cause apoptosis in various tissue-cultured cells. This apoptosis is associated with upregulation of a COX-2-type enzyme, the inflammatory enzyme traditionally blocked by NSAIDs, he said.

“The dose of NSAIDs necessary to produce widespread apoptosis and increased COX-2 enzyme may be in the range of what is normally nonphysiological systemically but within the range possible with high-dose ocular use,” Dr. Price wrote.

‘Good’ and ‘bad’ substitutions

Dr. Sadri is hesitant to use generic nonsteroidals and mentioned generic ketorolac as being particularly painful. Regarding corticosteroids, he frequently substitutes generic prednisolone acetate ophthalmic suspension 1% for Pred Forte (Allergan) in his cataract practice, except in the case of formulations that may clump.

“These are suspensions that you have to shake, and a lot of my patients are older, sick or just plain forgetful, and the clumping prevents the same amount of active molecules from being delivered evenly on the tissue,” Dr. Sadri said.

Dr. Price, on the other hand, is uneasy about substituting generic prednisolone acetate, because the drug is applied for its high potency in his cornea practice. He mentioned an analysis published in the Journal of Ocular Pharmacology and Therapeutics that demonstrated that particles in Pred Forte may be smaller and more uniform, allowing them to remain in suspension longer and potentially increase homogeneity between doses and increase ocular bioavailability.

“We want to know exactly how much we are getting and do not want variability. The generics for prednisolone acetate have been around a long time, so I do not think they are regulated as heavily as some of the newer ones,” he said, adding that generic formulations of the weaker corticosteroid fluorometholone are not problematic, because potency is less critical in cases involving their use.

Disparities may also be associated with drug delivery. For instance, in glaucoma management, Dr. Cantor has witnessed increased comfort in patients using the beta-blocker Timoptic-XE (Aton) vs. generic timolol, potentially due to the branded version’s xanthan and gellan gum.

He has also observed less variability among generic formulations of timolol, as well as generic miotic agents, compared with generic prostaglandins such as dorzolamide.

FDA distinctions for ophthalmics

According to Wiley A. Chambers, MD, deputy director of the Division of Transplant and Ophthalmology Products in the Center for Drug Evaluation and Research at the FDA, physicians should be aware that just because an ophthalmic product has the same active ingredient, it does not mean that it is a generic copy.

In the case of many older products, such as the ophthalmic corticosteroids, multiple different companies developed their own versions of the same corticosteroid. They were not abbreviated applications, according to Dr. Chambers, and these companies conducted their own clinical trials to demonstrate that their product was safe and effective. They made no attempt to make the product identical to another product, and it should not be surprising that they are not the same, he said.

However, recent ophthalmic generic products are distinguished from oral generic products in the regulations. An ophthalmic generic application can be refused to be accepted based solely on attempts to change inactive ingredients, but these regulations did not take effect until 1992 and do not apply to products first approved before 1992, according to Dr. Chambers.

The portions of Title 21 of the Code of Federal Regulations that apply to generic drug products were finalized in 1992 and say: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for ophthalmic or otic use unsafe and will refuse to approve the abbreviated new drug application unless it contains the same inactive ingredients, other than preservatives, buffers, substances to adjust tonicity, or thickening agents, in the same concentration as the listed drug, and if it differs … the application contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product.”

In other words, any differences in the inactive ingredients are required to demonstrate that the difference does not affect the safety or efficacy of the drug.

“In order to change any ingredient, a company would have to demonstrate that the difference did not affect safety or efficacy, and a clinical bioequivalence trial would have to be conducted,” Dr. Chambers said.

The consequence is that for newer ophthalmic generic products, the active and inactive ingredients are rarely changed.

Suggestions going forward

While the debate regarding generic equivalency will continue, ophthalmologists are advocating for stronger awareness of these drugs and determining ways to adjust to their increased presence.

“What is happening is patients get to a pharmacy, and the medication we prescribe is not the medication they are given … and we have to be aware of this,” Dr. Gold said.

Dr. Hovanesian said he asks certain patients to specify that they want branded products and to return to his office for guidance if their out-of-pocket costs exceed $200. Moreover, he collaborates with local pharmacies to try to ensure fair pricing.

“What we want to do is to be in control of the situation if the pharmacist is going to try to switch the patient to generic medication. … We offer to print a pharmacy’s name on the prescription pad after verifying that they will provide reasonable pricing to our patients, which might include offering medications for both eyes for a single co-pay,” Dr. Hovanesian said.

He recommended ReportGenerics.com as a place where physicians can submit information on complications that will ultimately be delivered to the FDA by William B. Trattler, MD, and colleagues.

“To be fair, the majority of patients who go on generics do fine, but we cannot assume so,” Dr. Cantor said.

Dr. Sadri encouraged U.S. practitioners to not undervalue the approval process for branded drugs, as it is envied by many of his international colleagues and promotes patient education.

“Patients are going to decide what they are going to decide; our job is to advocate best practice. … I am not saying that every patient in my clinic is on branded medication, but at least they all know where I stand and why I stand there,” he said. “I think they need that guidance.” – by Michelle Pagnani

References:

Abbreviated new drug application (ANDA): generics. U.S. Food and Drug Administration website. http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/default.htm. Updated Jan. 3, 2012. Accessed March 28, 2012.

CFR code of federal regulations title 21. U.S. Food and Drug Administration website. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.127. Updated April 1, 2011. Accessed March 30, 2012.

Facts about generic drugs. U.S. Food and Drug Administration website. http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandinggenericdrugs/ucm167991.htm. Updated April 2, 2012. Accessed March 28, 2012.

Kahook MY, Fechtner RD, Katz LJ, Noecker RJ, Ammar DA. A comparison of active ingredients and preservatives between brand name and generic topical glaucoma medications using liquid chromatography-tandem mass spectrometry. Curr Eye Res. 2012;37(2):101-108.

Mammo ZN, Flanagan JG, James DF, Trope GE. Generic versus brand-name North American topical glaucoma drops. Can J Ophthalmol. 2012;47(1):55-61.

Price FW. New pieces for the puzzle: nonsteroidal anti-inflammatory drugs and corneal ulcers. J Cataract Refract Surg. 2000;26(9):1263-1265.

Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther. 2007;23(2):182-187.

For more information:

Louis B. Cantor, MD, can be reached at the Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, 1160 W. Michigan St., Indianapolis, IN 46202-5175; 317-278-2651; fax: 317-278-1007; email: lcantor@iupui.edu.

Wiley A. Chambers, MD, can be reached at the FDA, Building 22, Room 6336, New Hampshire Ave., Silver Spring, MD 20903; 301-796-0690; email: wiley.chambers@fda.hhs.gov.

Robert S. Gold, MD, can be reached at 790 Concourse Parkway South, Suite 200, Maitland, FL 32751; 407-767-6411; fax: 407-767-8160; email: rsgeye@gmail.com.

John A. Hovanesian, MD, FACS, can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Suite 300, Laguna Hills, CA 92653; 949-951-2020; fax: 949-380-7856; email: drhovanesian@harvardeye.com.

Francis W. Price Jr., MD, can be reached at Price Vision Group, 9002 N. Meridian St., Suite 100, Indianapolis, IN 46260; 317-844-5530; fax: 317-844-5590; email: fprice@pricevisiongroup.net.

Ehsan Sadri, MD, FACS, can be reached at Atlantis Eyecare, 26730 Towne Centre Drive #240, Foothill Ranch, CA 92610; 949-916-6428; email: e_sadri@yahoo.com.

Disclosures: Dr. Cantor is a consultant, researcher and speaker for Allergan. He also receives research support from Alcon. Drs. Chambers and Price have no relevant financial disclosures. Dr. Gold is on the speakers bureaus for Bausch + Lomb and Alcon. Dr. Hovanesian is a consultant for Fera, Ista and Bausch + Lomb. Dr. Sadri is a consultant for Ista.

Do you advocate the use of generic ophthalmic medications?

Slight formulation differences can influence absorption, toxicity

 

William B. Trattler

Generic ophthalmic drugs clearly play a role in the care of patients, and in general, they appear to be well-tolerated and efficacious. However, the challenge with these medications is that they may not undergo any human safety and/or efficacy testing prior to being released. Each generic just needs to have the same general formulation as its brand name “equivalent.”

Unfortunately, when it comes to topical medications, formulation differences can have a substantial impact on absorption as well as toxicity. More than a decade ago, a generic version of topical diclofenac was released, and a series of corneal melts ensued, which eventually led to the voluntary removal of this medication from the market by its manufacturer. More recently, we have seen complications with generic ketorolac and generic bromfenac, including corneal melts following routine cataract surgery.

To help track these types of adverse events, we have set up a website where physicians can briefly report any toxicity issues seen with ocular generic medications. The website is www.reportgenerics.com.

William B. Trattler, MD, is an OSN Healio.com/Ophthalmology Board Member. Disclosure: Dr. Trattler is a consultant for and receives research support from AMO, Allergan, Bausch + Lomb and Ista.

Physicians should play within rules of the game to help patients

 

Anthony P. Johnson

As a pediatric ophthalmologist, although I have altered my prescribing pattern for the same reason that other physicians have altered their patterns regarding increased emphasis on use of generics, I have not actually seen that it has affected the outcomes of the patients that I care for nearly as much as I would have expected. I have lost a lot of sleep over this, but I have realized that whether I agree with the regulations or not, and whether I agree with the PhRMA guidelines or not (which I have read), we all have that same environment that we have to live in and we can either fight it or live with it.

For me, even though there will be an occasional vision-threatening problem that I feel compelled to recommend the brand name product for, as a pediatric ophthalmologist I do not run into that very often and have acquiesced to using generic medication. Broad-spectrum antibiotics, for instance, some of the old reliable ones — gentamicin and tobramycin type products — are generic, and I have found that they work pretty well for the purposes that I use them for.

The other thing is that I know it is unbelievably expensive to get a product from the beginning of a phase 1 clinical trial all the way to market, so I can understand why the excellent pharmaceuticals that are out there tend to cost a lot. But now we are seeing it go full circle. Some of the preparations that have been around for 25-plus years and have in the recent past only cost a couple of dollars, especially when bought for our surgery center, are now costing 10 times that much, and they are generics.

We can whine and complain and say it is not as profitable, but if we are really doing what we have taken an oath to do, which is to help people, then we have to be creative and still play within the rules of the game to serve people.

Anthony P. Johnson, MD, is an OSN Pediatrics/Strabismus Board Member. Disclosure: Dr. Johnson has no relevant financial disclosures.