Patent Cliffs: Ocular Branded v Generic Drugs

In any language, the value of the (legal) generic drug market in Australia is big business. In 2009, the Australian generics market was estimated to be AUD$1.3 billion.¹ Generic penetration is approximately 30 per cent by volume and 14 per cent by value,¹ and growing. With a number of big name drugs having come off patent and more to follow, experts are tipping the pharmaceutical manufacturing giants will lose a further AUD$1billion in generics sales in the near future.¹

There is an automatic government imposed 16 per cent price reduction across the market (on the originator patented product and the generic product) once a generic is listed. This saves both the patients (excluding community card users) and the PBS some money, however it does not mean that the generic is always cheaper than the brand when dispensed by a pharmacist to a patient.

PBS Generics on the Rise

Australia’s Pharmaceutical Benefits Scheme (PBS) subsidises 75 per cent of prescription drug costs.² The PBS is divided into two separate formularies – single-branded patented medicines are grouped under F1 while medicines with expired patents for which generic versions can be manufactured are grouped under F2.

Eye drops shouldn’t be held to the same rules of equivalency as some other forms of medications

In recent times, there has been a marked increase in the number of generic drugs listed under the Schedule of Pharmaceutical Benefits and that trend is expected to continue for the next few years.^2-4 Patents on four key (non ophthalmic) brands recently expired making way for the arrival of generics – Lipitor (atorvastatin, Pfizer, used to treat high cholesterol), Zyprexa (olanzapine, Eli Lilly, an antipsychotic), Seroquel (quetiapine, AstraZeneca, used to treat schizophrenia or bipolar disorder) and Crestor (rosuvastatin, AstraZeneca, used to reduce high cholesterol).1 Several monoclonal antibodies are due to come off-patent in the next five years.¹

“Within the next five years, some of the biggest eye drops will be coming off patent so we’re going to find ourselves dealing more and more with generics,” says David Foresto a therapeutically endorsed Brisbane based Optometrist.

A potential implication for eye health in Australia is that Xalatan and Xalacom, two of the main products used to treat glaucoma, lose patent in July 2012. Travatan comes off patent in 2013, and Patanol in 2015.

“There are already two court cases of generic manufacturers challenging the Patanol patent expiration date so it looks like these formulas will be aggressively pursued by the generic manufacturers,” said Mr. Foresto.

Bioequvalence

Once a drug patent expires, generic brands are required to show “bioequivalence” to their branded counterparts. In Australia, the responsibility to do this (within acceptable levels identified in a particular standard) lies with the generic manufacturers and the Therapeutic Goods Administration.

Once approved as an equivalent, the Schedule of Pharmaceutical Benefits indicates which brands are bioequivalent, using either an ‘a’- or ‘b’-flag status.

Brands of any therapeutic substance marked ‘a’ can be substituted one for the other. Likewise, brands marked ‘b’ are also substitutable. However, those marked ‘a’ cannot be substituted with those marked ‘b’.⁵

While generic ophthalmic formulations may contain the same active ingredient as patented drugs, they may still differ in their inactive ingredients such as preservatives and adjusters of pH
and tonicity.

According to some experts, this poses unique challenges for ophthalmic drugs, in particular. Unlike systemic medications, ocular absorption of the active ingredient cannot be assessed as easily.⁶ Minor formulation differences can compromise the bioavailability of the drug by interfering with its solubility and ocular penetration, and affect patient comfort too.^6,7

As generic manufacturers need to demonstrate bioequivalence but not therapeutic equivalence, it has, therefore, been suggested that patients may notice differences in how their generic eye drops feel and work.^6-8

Mr. Foresto says one particular incident will stick in the minds of eye care professionals. “In 1998 a generic version of Voltaren Ophthalmic was brought to market in America but it was withdrawn around a year later due to an associated increase in corneal melts.

“The thing about this problem was that it was the first clear example of why eye drops shouldn’t be held to the same rules of equivalency as some other forms of medications. In this example the problem didn’t lie in the active ingredient – the diclofenac was fine. It was the inactive ingredients that caused all the problems.

“In a summarised way, the FDA rules at the time only dictated that the generic must have the same bioequivalence, i.e. the same amount of active ingredient must enter the bloodstream, as well as having the same route of administration as the original. The rules didn’t outline a need for the inactive ingredients to be the same. That might be fine for tablets, but a small change in osmolarity or even pH of an eye drop can have vast changes on how the eye handles the drug,” he said.

Mr. Foresto says it’s important to remember that generic eye drops have a history of excellent safety. “The generic diclofenac example is one of only a few known cases of problems,” he said.

However, Sydney ophthalmologist, Dr. Con Moshegov points out that the example of Voltaren Ophthalmic serves to illustrate the importance of monitoring new, generic preparations, once the original molecules come off patent and are copied. “But from what I can gather, our TGA is very stringent with new generic alternatives and requires trials which are as stringent as for patented drugs before approving them for us in Australia,” he said.

Confidence in Australia

The Royal Australia and New Zealand College of Ophthalmologists (RANZCO) also has faith in the function of the TGA. “The quality of generic medications is purely within the TGA’s jurisdiction. They function to protect our health and safety by regulating therapeutic goods sold in Australia, and ensure that therapeutic goods available for supply are safe and fit for their intended purpose,” said Susi Tegen, Chief Executive of RANZCO.

However some ophthalmic experts argue that, in the absence of published head-to-head clinical trials comparing the safety and efficacy of topical generic ophthalmic drugs to brand-name agents, it is difficult to determine if generic ocular agents are really equivalent.⁷

Substitution Rates

Generic brand substitution is increasingly being practised both in hospitals and community pharmacies locally.⁹ Chong et al recently reported generic substitution recommendation rates of >95 per cent by Australian community pharmacists.¹⁰ Interestingly, the recommendation rates in rural and urban areas were significantly higher than in remote areas. Conversely, patients’ acceptance rates of these recommendations were notably higher in remote versus rural/urban areas.¹⁰

In an Australian retrospective analysis of three major classes of PBS medicines – statins, calcium channel blockers and selective serotonin reuptake inhibitors – Ortiz et al reported that approximately 20 per cent of patients switched brands at least twice in one year, with a direct correlation between the likelihood of substitution and the number of available brands.¹¹

This study, in addition to others, has raised concerns over the added potential for consumer and practitioner confusion that could lead to medication misadventure.^11-13

The issue of non-standardised prefixes and suffixes used by generic pharmaceutical manufacturers on drug labels has also been flagged as a potential nidus for medication error.¹⁴

According to FRANZCO ophthalmologist Prof. Paul Mitchell, there is reason to be concerned. “Patients are easily confused as they do not understand the difference between ‘generic’ and ‘trade mark’ drug names.” Furthermore, he said, “occasional patients (can) end up taking the same drug twice.”

The Bigger Picture

Any medical advice should be underpinned by Australia’s Quality Use of Medicines (QUM) policy, which highlights the importance of consultation before switching medicine brands and ensuring patients are not at risk of medication misadventure.

Patients who show cognitive impairment, confusion or an inability to manage change may be at risk of medication mishap from brand switching. Patients with visual impairment who rely on a consistent shape/colour of their medicine/packaging to identify their medications could also be subject to similar risks.¹⁵ Clinicians should monitor patients closely after they switch from a brand-name drug to a generic equivalent in order to ensure the safety and efficacy of that agent.

Even when bioequivalent brands are available and the patient consents, brand switching may not be suitable if:^16,17

• The prescriber has indicated it is not permitted;

• The medicine has a narrow therapeutic index;

• The patient has an intolerance or allergy to one of the excipients;

• The patient may become confused as a result of the change.

Controlling Switching

The availability of generic medications underscores the need for effective communication among healthcare professionals to safeguard the interests of all patients. Prescribers who wish to disallow brand switching can do so by specifically ticking the ‘brand substitution not permitted’ box on the PBS prescription form or on the particular prescribing software they use. In such circumstances, switching brands must not occur unless the patient/carer or the pharmacist, on the patient’s behalf, has obtained approval from the relevant prescriber.^16,17

“By law the pharmacy needs to dispense the original if you have ticked the ‘Brand Substitution Not Permitted’ box on the prescription and specified the desired trade name on the prescription,” said Mr. Foresto. “This gives us some level of control over the dispensed product… What I would say is that it’s important to know which eye drop your patient ends up receiving so that you can best manage any problems, which might pop up.

“What I mean by that is if your patient isn’t responding to a therapy in the way in which you would have expected, then ask to see their eye drops. You need to rule out a pharmacy error, a problem with a generic, an expired eye drop, a bad batch of the original or a lack of compliance. We all know that spectacle and contact lens labs can make errors, so we need to carry that thought process over into our therapeutic practice as well.”

Misunderstandings can also have serious implications, says Mr. Foresto, citing the example of fluoromethalone alcohol (Flucon 0.1 per cent, FML 0.1 per cent) vs fluoromethalone acetate (Flarex 0.1 per cent).

“These two are not interchangeable and there have been cases of the patient being dispensed the wrong eye drop,” he said.

In the end, it is the responsibility of pharmacists who are custodians of medicines in the community, to ensure that patients make informed and safe decisions about the use of all medications, including generic drugs. However as eye care professionals you can influence your patient by explaining the reasons for the specific prescription at the time of consultation.

References

1. Datamonitor, August 2010. Australia pharmaceutical market overview.

2. Clarke P and Fitzgerald E. Med J Aust 2010; 192: 633–636.

3. Lofgren H. Aust New Zealand Health Policy 2007; 4: 11.

4. Beecroft G. Aust New Zealand Health Policy 2007; 4: 7.

5. Department of Health & Ageing. Schedule of Pharmaceutical 3. Benefits. Available from: http://www.pbs.gov.au/ (last accessed 21 Feb 2012).

6. Cantor L. Glaucoma Research Foundation. Generic medications: Are they the same?

7. Gallardo M et al. Glaucoma Today 2006; Jan/Feb: 32–35.

8. Dalton M. EyeWorld – American Society of Cataract and Refractive Surgery. March 2011.

9. Carney S et al. Med J Aust 2011; 195: 650–651.

10. Chong C et al. Health Policy 2011; 99: 139–148.

11. Ortiz M et al. Med J Aust 2010; 192: 370–373.

12. Pharmaceutical Health and Rational Use of Medicines (PHARM) Consumer Sub-Committee. Consumer perspectives on managing multiple medicines. Canberra: Department of Health and Aged Care, 2001.

13. Hassali MA et al. J Generic Med 2006; 3: 214–225.

14. Graudins L and Dooley M. Med J Aust 2010; 193(7): 427.

15. National Prescribing Service. Generic medicines training kit: Safe and appropriate use of generic medicines. Available from http://www.nps.org.au/health_professionals/activities/pharmacy_assistants_kit (last accessed 21 Feb 2012).

16. Pharmaceutical Society of Australia. Guidelines for Pharmacists on PBS Brand Substitution. Canberra: Pharmaceutical Society of Australia; 2004.

17. Pharmacy Guild of Australia. Quality Care Pharmacy Program: 2000 Brand Substitution Policy P2B. Pharmacy Guild of Australia; 2000.