Switching from branded to generic inhaled medications: potential impact on asthma and COPD

Abstract

Pressure on healthcare budgets is increasing, while at the same time patent protection for many branded inhaled medications has expired, leading to the development and growing availability of generic inhaled medicines. Generic inhaled drugs are therapeutically equivalent to original branded options but may differ in their formulation and inhalation device. This new situation raises questions about the potential impact of switching from branded to generic drug/inhaler combination products in patients with asthma or COPD, with or without their consent, in countries where this is permitted. Inhalation devices, particularly dry powder inhalers, vary markedly in their design, method of operation and drug delivery to the lungs. Current guidelines stress the importance of training patients how to use their inhalers but offer little or no guidance on how this should be achieved. Non-adherence to therapy and incorrect inhaler usage are recognised as major factors in poorly or uncontrolled asthma and COPD and switching patients to a different inhaler device may exacerbate these problems, particularly in patients who disagree to switch. Where switching is permitted or mandatory, adequate patient instruction and follow-up monitoring should be provided routinely.

Keywords::

• adherence
• asthma
• compliance
• COPD
• generics
• inhalers
• switching

1. Introduction

The European Directive [1] describes a “generic” medicinal product as a drug that must contain the same active substance in the same amount as the originator or reference product and whose bioequivalence with the reference product has been demonstrated by appropriate bioavailability studies. It is the responsibility of regulatory authorities to ensure that a generic product is equivalent to the originator product in all important respects, and to assure patients and prescribers that there is no significant difference between the two products in the clinic [1]. One of the most important ways of providing this assurance is to demonstrate that the generic product is “bioequivalent” [2] to the reference product. Although bioequivalence principles have firmly been defined [2], at present there is no international consensus on many of the details regarding the requirements for the design, conduct and evaluation of bioequivalence studies. Consequently, each regulatory authority (see e.g., [3,4]) has issued its own corresponding guidelines.

The expiration of the patent protection covering the established inhaled bronchodilators, steroids and their fixed combinations has contributed to the development of several generic inhaled drugs that are therapeutically equivalent [5] to the original reference inhaled medications. Generic inhaled medications have the same chemical structure as branded medications but they are not necessarily delivered by the same devices as the original branded options, the original devices often being protected by ongoing patents. Rather, generics are delivered by relatively low-cost inhalation devices, such as pressurized metered dose inhalers (pMDIs) and dry powder inhaler devices (DPIs), that can vary markedly in design, drug delivery and method of operation from devices of the original branded drugs. Since inhaled drugs differ significantly from oral medicines as their performance is determined by the drug formulation, primary packaging, device and patient administration behavior, it is very difficult to develop generic versions that are interchangeable and substitutable with the originator products. In this connection, it should be recalled that the European Medicines Agency made it clear that “orally inhaled products are definitively not generics but hybrids” and that “simple bridging to the bioequivalence model is not sufficient” [3].

As in the management of other diseases, the cost of prescription treatments for asthma [6] and COPD [7] is an easily identified direct cost and, given current pressures on healthcare budgets, it is understandable that extending the use of generics is considered an important element in most prescribing strategies to achieve substantial savings theoretically that is not detrimental to patient care. Prescribing cost-containment measures are increasing in many countries and, as more inhalers become available, there may be pressure to switch patients to a cheaper inhaler device. Thus, switching from branded inhaled drugs to lower-cost generic inhaled drugs may represent an opportunity for reducing cost of drug treatments in asthma and COPD [8].

In this article, we review the current regulations on generic substitution of marketed branded inhaled medications in some European countries and we question if switching patients from branded to generic inhaled drugs may have potential deleterious effects on asthma control and COPD outcomes. Description of current regulatory requirements associated with the development and submission of dossiers for inhaled medications is outside the scope of this article; excellent descriptions of this aspect can be found in the literature (see e.g., [2,9,10], also for further references).

2. Generics in Europe

In Europe, regulations on generic substitution of marketed drugs vary from country to country (Table 1). Where it is allowed, a pharmacist may dispense one brand of a drug, even though the prescription is for another, provided the drugs are deemed interchangeable. This condition is usually satisfied if the manufacturer can demonstrate bioequivalence with the innovator's brand by conducting studies showing that their efficacy and safety profiles are essentially the same, at the same dose [3,5]. For inhaled products, however, conventional bioequivalence studies may be inappropriate and therapeutic equivalence must be demonstrated instead [3,5]. In Europe, two inhaled drugs are considered therapeutically equivalent if they are pharmaceutically equivalent, with the same active ingredient(s), dosage form, route of administration and strength [3]. However, one of the key inclusion criteria for such therapeutic equivalence studies is the ability of the patient to correctly use the two devices being compared and this may not be the case in real life. The regulatory authorities do not formulate criteria regarding correct use of generic inhalers.

Table 1. Prescribing requirements for generic substitution of drug/inhaler combinations in some European countries.

Country	Mandatory substitution	Substitution when generic name used on prescription	Pharmacist substitution permitted	Patient pays difference if they do not accept generic substitute	Other rules
Finland	X
France					Substitution not permitted for inhaled medicines/devices
Germany	X
Italy				X	Prescriber can prevent substitution if prescription form specifies this
The Netherlands		X			Prescriber can prevent substitution by stating ‘medical necessity' on prescription
Sweden			X		Pharmacist substitution only for oral medications, not for inhaler devices
United Kingdom		X	X		Prescriber can restrict substitution by pharmacist by careful wording of prescription

3. Generics and the FDA

In the USA, the FDA's Center for Drug Evaluation and Research requires generic manufacturers to demonstrate equivalent delivery to the lungs, equivalent systemic exposure with the generic product and comparability of the pMDI or DPI they propose to use to that of the branded product [4]. However, there is no consensus on the protocols for the necessary studies [11]. In addition, the excipients in the generic product must be qualitatively and quantitatively the same as those in the reference product. Due to the difficulties in demonstrating bioequivalence between generic and reference inhaled drugs, FDA receives few applications for generics, even though many of the older pMDI products are on the market without patent or exclusivity protection. The FDA recognises the challenges that these requirements present and is currently working with manufacturers, regulatory bodies and academia to find solutions to them [9,11]. However, the lack of clear advice leaves applicants with uncertainty; therefore, it is unlikely that new generic inhaled products will enter the market [12].

4. Switching and substitution regulations

Extending the use of generic inhaled medications in asthma may be one way to achieve substantial cost savings without it being detrimental to patient care. In Germany and Finland, such a substitution is mandated by current regulations, while in the UK, substitution is permitted at the discretion of the dispensing pharmacist, although many clinicians disapprove of this. UK prescriptions have to be specific to prevent switching, but are often still written generically. In France, there are no generics for inhaled products that can be substituted for branded products, although some pMDIs could be considered interchangeable. Interchangeability is not considered an option for DPIs or between DPIs and pMDIs. In Belgium, devices are not often switched because most prescriptions specify brand names. Despite increasing pressure for more generic medications to be prescribed, the Belgian Federal Agency for medicines and health products recommends no switching for inhaled medicines because there may be significant differences in the dose of drug and particle size delivered by different products and because of concerns about the interchangeability and handling of different devices [13]. In the Netherlands, switching devices is permitted if generic names are used on the prescription. To ensure continuity of use with a particular device, the phrase ‘Medical necessity' must be used on the prescription. The Lung Alliance Netherlands (LAN) has been working with healthcare insurers to develop guidelines that specifically address the conditions under which switching to the insurer's preferred (lower cost) inhaler device might be acceptable and which of the more than 80 inhalers currently available in the Netherlands can be considered interchangeable (Text box 1, supplementary materials) [14]. The LAN notes that Swedish and Spanish authorities have previously rejected implementation of a switching policy because the investments required to provide adequate support to patients in the correct use of inhalers to avoid any risk of harm would outweigh any potential cost savings [14]. In Italy, pharmacists may switch respiratory patients from one combination of drug and inhaler device to a generic unless the prescription specifies that the patient must not be switched. Patients who do not accept the substitution of a branded product with a generic have to pay the difference in cost. However, savings in acquisition cost with generics could be offset by costs related to deterioration in asthma or COPD control if the patient is unable or unwilling to use the generic inhaler properly.

In theory, the transition from branded to generic drugs should have no deleterious effects on patient care; the products should be equally effective. However, there is considerable potential for patient harm from confusion, anxiety and mishandling of a different inhaler device and some patients are uncomfortable with accepting a substitute for a medication that their doctor has prescribed.

5. Pharmaceutical considerations

Recent reports from different therapeutic areas illustrate the uncertainties regarding generics. For example, a generic formulation of slow-release bupropion used for smoking cessation was found to release the active ingredient more quickly than the branded formulation, thereby potentially being less effective [15]. As another example, the American Academy of Neurology has declared that generic substitution of anticonvulsant drugs for the treatment of epilepsy is not recommended without the attending physician's approval [16]. Similarly, the American Association of Clinical Endocrinologists states that for patients with thyroid disorders, any changes to generic equivalents or between brands of levothyroxine should be monitored closely by physicians and be followed up after six weeks with laboratory evaluation [17].

6. Confidence and compliance

Additional concerns may arise when considering medications delivered topically to the lungs, as pMDIs, DPIs and nebulisers have different flow-dependent pulmonary deposition patterns that could account for differences in therapeutic effect, independent of pharmacokinetics. DPIs, in particular, can vary markedly in design and method of operation [18] and this could lead to different handling errors in a real-life context [19]. When long-term users of branded inhaled drugs are dispensed generics delivered by a different inhaler, they are likely to be unfamiliar with the new device and could become aware of a change in taste/sensation [20]. This may reduce their confidence in the efficacy of the generic drug, increasing the risk of poor compliance and possibly loss of asthma control [20]. There was an example of this in 2005, when New Zealand's medication funding authority removed the subsidy on the branded salbutamol pMDI (Ventolin®), intending to gradually replace it with the cheaper generic, the Salamol® pMDI [21].

7. Real-world experience

Bioequivalence between Ventolin and Salamol pMDIs has been demonstrated in patients with asthma [22]. However, its introduction in New Zealand led to anecdotal reports [23] of decreased therapeutic effect, inhaler blockage and unpleasant taste. A study by Reti [24] investigated asthma stability in patients who switched from Ventolin to Salamol inhalers and found that half of those patients converted to the Salamol pMDI withdrew prematurely due to ineffectiveness and that, in those who continued to use Salamol, nearly all had worse asthma stability. In contrast, Chang et al. [25] found no difference in the efficacy of Salamol and Ventolin pMDIs in relieving bronchoconstriction. Differences in the patient population, study design and methodology used may account for the conflicting results. However, Chang et al. [25] administered both salbutamol formulations using pMDIs in conjunction with spacers, thus affecting drug deposition, and consequently, the effectiveness of both preparations. An earlier study showed that failure to shake the canister before each inhalation halved the systemic availability of budesonide from a pMDI compared with that from the pMDI used with a spacer [26], confirming that suboptimal usage can have a profound effect on drug delivery from a pMDI and that use of a spacer can mitigate this variability [26].

8. Switching without consultation

Current asthma [6] and COPD [7] guidelines emphasise the importance of training patients how to use their inhalers correctly, but provide very little guidance on how this should be achieved. It is not clear how inhaler technique training would be provided when a patient is switched from a branded drug to a generic alternative. Patients receiving an unfamiliar device without a consultation may be unable or unwilling to use the alternative inhaler, thereby reducing adherence to therapy [20]. Thomas et al. [27] retrospectively evaluated the impact on asthma control of steroid inhaler switching without an accompanying visit or consultation in the UK. Of note, over half of device switches were from DPIs to pMDIs [27]. Compared with matched controls, patients whose steroid inhaler was switched were significantly more likely to experience unsuccessful asthma treatment [27].

Worsening asthma control after steroid inhaler switching without consultation could occur because of inadequate dosing secondary to poor inhalation technique, or because of reduced patient adherence to therapy. Correct inhalation technique is necessary for attaining the full benefit of inhaled medications [18] but inhalers are often used incorrectly unless patients receive adequate instruction [19,28]. Patient education and involvement in treatment decisions can improve adherence to therapy [29] but adherence is likely to decline in patients who have treatment switched without consultation [30,31]. Non-compliance rates already range from 16 to 50% among patients with asthma and COPD, and this contributes to the morbidity, mortality and associated costs of these conditions [6,7]. Increasing the risk of poor adherence by switching inhalers without consultation is likely to add to these problems. Both healthcare professionals [30,32] and patients [31] are generally negative toward switching of DPIs without adequate consultation.

9. Conclusions

Looking forward, as more generic inhaled drugs delivered by cheap inhaler devices become available, caution should be exercised before switching to these alternatives. This is particularly true for DPIs, which differ widely in the way they operate, their appearance and delivery characteristics [18]. Indeed, patient preference for different DPIs varies [18], indicating that they are not all the same from the patient's perspective, although patient preference for a device does not ensure either improved compliance or adherence. Thus, inhaler devices should be prescribed with no switching of device without the involvement of both physician and patient. Should substitution of a generic for a branded inhaler be permitted, safeguards are required to ensure that patients receive adequate training and are willing to use the new device. Monitoring is also required to ensure that disease control is not compromised. The responsibility for such training and monitoring needs to be clarified because physicians may not be aware that a prescribed device has been replaced with a generic drug at the pharmacy. Perhaps pharmacists should be required to demonstrate their ability and availability to instruct patients correctly before they are permitted to dispense alternative devices.

When evaluating the potential cost benefits of switching inhalers, all relevant costs should be considered, including those arising from additional consultations, the time required for training and the management of any subsequent acute events [6,7]. These costs, plus the likelihood of repeat consultations and prescriptions among patients switched to cheaper, less familiar devices, may outweigh any cost benefits obtained from switching.

Acknowledgements

The authors thank D Candlish and M Weitz of in Science Communications, for medical writing assistance funded by AstraZeneca.

Declaration of interest

Federico Lavorini has received reimbursements for attending meetings, fees for speaking from Meda Pharma, Teva, Mundipharma, Chiesi, Menarini Industrie Farmaceutiche, and AstraZeneca. Vincent Ninane has received reimbursements for attending symposia, fees for speaking or fees from consulting from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Roche, Lilly and Olympus. John Haughney has received reimbursements for attending symposia, fees for speaking, organising educational events, funds for research or fees for consulting from Almirall, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, Novartis, Nycomed, and Teva. Leif Bjermer has during the last three years received honoraria for attending advisory boards or giving lectures for the following companies: Almirall, AstraZeneca, Airsonette, Andre Pharma-Chiesi, Boehringer, GlaxoSmithkline, Meda, Merck, Mundipharma, Nigaard Pharma, Novartis, Pfizer, Takeda/Nycomed, and Teva. Mathieu Molimard is a consultant to or has participated in advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithkline, Novartis, Pfizer, and Stallergen. Richard Dehuijzen has received reimbursements for attending symposia, fees for speaking, organising educational events, funds for research or fees for consulting from AstraZeneca, Boehringer-Ingelheim, Chiesi, Merck Sharp & Dohme, Mundipharma, Novartis, Takeda, and Teva.