Pharmacovigilance, traceability and building trust in biosimilar medicines

Author byline as per print journal: Professor Teun van Gelder, MD, PhD; Benedicte Lunddahl, DVM; Professor Barbara OM Claus, PharmD, PhD

Abstract:
The Medicines for Europe’s Biosimilar Medicines Group met at the 2017 European Association of Hospital Pharmacists conference in France to discuss pharmacovigilance, traceability and building trust in biosimilar medicines.

Submitted: 22 May 2017; Revised: 21 June 2017; Accepted: 21 June 2017; Published online first: 4 July 2017

Introduction

The Biosimilar Medicines Group (formerly EBG) held a satellite symposium entitled ‘Biosimilar medicines in clinical practice – important role for hospital pharmacists!’ on 22 March 2017 at the 22nd Congress of the European Association of Hospital Pharmacists (EAHP) in Cannes, France.

The Biosimilar Medicines Group represents the leading pharmaceutical companies that are developing, manufacturing and marketing generic and biosimilar medicines across Europe. It is a sector group of Medicines for Europe (previously the European Generic medicines Association).

Biosimilar medicines have been used successfully in the European Union (EU) for over 10 years and there are now 32 approved biosimilar medicine products on the market in the EU today [1]. This number has been steadily rising, with 12 products being added to the market last year [2]. Biosimilar medicines improve access to modern therapies for millions of European patients receiving both chronic and acute care. They offer more affordable treatment pathways, increase medicine accessibility and make healthcare funds available for other uses [3].

Traceability of biologicals

Dr Benedicte Lunddahl, (Head of Pharmacovigilance at the Danish Medicines Agency, Lægemiddelstyrelsen, DKMA), gave a presentation that highlighted how the agency was tackling the reporting of adverse events and traceability for both originator biological and biosimilar medicines.

In Denmark, there is a national recommendation for the use of biosimilar medicines that was initiated in 2015. This involves a nationwide tender process whereby biosimilar medicines that win the tender are those supplied to hospital pharmacies. Both treatment naïve patients, and those in established treatment regimens are treated with biosimilar medicines. Infliximab was the first biosimilar medicine to win a tender which has led to high uptake of this medicine in Denmark when compared to other EU countries. In 2016, see Figure 1, biosimilar infliximab won the tender, which has led to similar high usage of this medicine.

Figure 1

Denmark works under the legal framework set out by European pharmacovigilance legislation and EU Good Pharmacovigilance Practices (GVP) modules [4], in addition to Danish law and possible executive orders. This framework incorporates the need to trace all biological molecules, as initially outlined in EU pharmacovigilance legislation of 2010 [5]. This states that all EU Member States are required to ensure that biological medicine products can be identified and traced, and gives countries the power to impose specific obligations on healthcare professionals to ensure this. Despite this legislation being in place, Dr Lunddahl noted that there are issues associated with implementing product tracking in the hospital setting [6]. She added that similar traceability obligations can be imposed on Marketing Authorisation Holders to ensure the collection of Adverse Drug Reaction (ADR) data and any follow-up data. In the Individual Case Safety Reports of biological medicines, it is obligatory that the batch number is recorded, see Table 1.

Table 1

To address patients’ concerns and inform physicians about biosimilar medicines, the DKMA set up an Action plan on Biological Medicines, which aims to:

To improve monitoring of biological medicines in Denmark two executive orders came into effect in January 2016. These require healthcare professionals to record the brand name and batch number when prescribing a biological or biosimilar medicine. They also make it mandatory for healthcare professionals to include, where possible, the brand name and batch number when reporting suspected ADRs [7].

To facilitate the monitoring of biological medicines, the DKMA has made an electronic list of biological medicines and their alternative biosimilar medicine products. This is to be updated when new biosimilar medicines become available on the Danish market. There are also electronic reporting forms available to physicians and consumers so that ADRs can be easily recorded. The form available to physicians has popups to remind the physician to enter the brand name and batch number of the products prescribed. The patient’s form has a specific field for these details to be added.

The DKMA has concluded that their ADR data collected supports the equal safety profiles of biosimilar medicines and reference biological medicines. This data also shows no correlation between batches and reported ADRs. In addition, scientific literature, including the Norwegian NOR-SWITCH study, which is investigating the efficacy, safety and immunogenicity when switching patients from the reference biological to biosimilar infliximab, supports the similar safety profiles of reference biological and biosimilar medicines [8].

Dr Lunddahl noted that raising awareness of biosimilar medicines amongst physicians and patients is key to increasing their uptake. In Denmark, initial meetings with patient organizations were held to outline what information needed to be supplied. Targeted communication routes were then created, which included information leaflets handed out to patients by physicians designed to initiate patient–physician dialogue; a clear and straightforward Q&A on the DKMA website, and information videos available online in which patients ask questions and have these answered by regulators.

Building trust in biosimilar medicines

A presentation by Professor Teun van Gelder (internist, nephrologist and clinical pharmacologist at Erasmus MC in Rotterdam, The Netherlands), highlighted how to build trust in biosimilar medicines.

In The Netherlands, generic medicines are procured via a tendering system whereby prescribed drug products have the potential to be changed every six to 12 months as they are replaced by the lowest price alternative. This means that patients may receive a different formulation time and time again. Professor van Gelder highlighted that it is likely they will be switched from the expensive originator, to a generic, and then to another cheaper generic medicine, and so on. If not managed properly by the physician and/or pharmacist, this can lead to patient confusion and ultimately also to reduced adherence or to duplicate treatment. In this scenario, physicians have lost control over the actual medication that a patient receives. It is possible for physicians to apply for a specific formulation to be dispensed, but only if they provide medical justification. This perceived lack of control over drug formulations dispensed has instigated concerns over the introduction of biosimilar medicines in The Netherlands.

When it comes to biosimilar medicines, there are three generations of therapeutic proteins, see Table 2.

Table 2

There are a number of reasons that can impede the penetration of biosimilar medicine usage in a given EU country. In some cases, physicians may lack education and understanding of the concept of biosimilarity [9] and, even when knowledgeable on biosimilar medicines, they may not trust in their safety and efficacy [10].

Professor van Gelder described a scenario in which there were side effects associated with an approved biological medicine. This example was chosen to emphasize that there can be issues related to such approved medicines when products are manufactured, stored or handled incorrectly. Here, he explained that erythropoietin (EPO) is a hormone secreted by the kidneys that increases the rate of production of red blood cells in response to falling oxygen levels in tissues. In patients suffering from anaemia due to chronic kidney disease, the decreased production of EPO with declining renal mass is considered the primary etiologic factor. Anaemia is associated with symptoms that include fatigue, weakness and dyspnea, as well as worsening quality of life and performance status. To treat this condition, the first biological recombinant human EPO produced was epoetin alfa. He explained that, when trying to attain a normal patient haemoglobin level by increasing the dose of this biological EPO, patients could develop hypertension and higher risk of cardiovascular events. There were also increased reports of epoetin-associated pure red cell aplasia [11, 12] when Eprex was the formulation treatment (this was one of a number of approved formulations available on the market at the time). After procedures were adopted to ensure appropriate storage, handling and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83% worldwide. Professor van Gelder noted that the main concern expressed in the case of biosimilar medicines is that of immunogenicity, as when compared to the original biological medicine these products undergo different manufacturing processes and processing and purification techniques and have different master cell lines, inert ingredients and packaging.

Despite the issues related to first-generation innovator, Eprex, highlighted, there are currently a number of epoetin biosimilars on the market in Europe, see Table 3. These have undergone a registration procedure that includes demonstration of safety and efficacy through clinical studies [11], see Table 4. To date, there is no evidence for an increase in pure red cell aplasia or any other adverse events associated with biosimilar epoetins. However, despite the apparent safety of these biosimilar medicines, the extent of their uptake by patients in EU countries is widely varied.

Table 3

Table 4

Professor van Gelder’s example emphasized the need for doctors and patients to be made aware that, within the life cycle of an originator biological medicine, there will be numerous changes in the manufacturing processes, including its purification, inert ingredients and packaging. These changes can also lead to the induction of an unexpected immune response, such as that which occurred after the formulation of Eprex was changed [12, 13].

Professor van Gelder noted that doctors would rather stick to what they know, especially as there is no therapeutic advantage, but only a cost benefit in using a biosimilar medicine. It will therefore take a very long time to build trust in these products. This is where regulators have an important role to play in passing on their knowledge. They need to inform doctors that, over the past 10 years, there has not been a single serious incident involving a biosimilar medicine, that the regulatory system is working as expected, and that the mistrust of biosimilar medicines is unjustified. As a result, prescribers should be convinced that biosimilar medicines offer a (financial) benefit to society without compromising the quality of treatment. Prescribers need to be well informed to increase their trust in biosimilar medicines.

Professor van Gelder concluded by noting that at the Erasmus Medical Centre in The Netherlands, pharmacists, doctors and representatives from drug producers meet and discuss the pros and cons of introducing biosimilar medicines when they become available. This improves transparency and increases trust. Overall, despite the proven safety and efficacy of biosimilar medicines, medical doctors may still feel uncertain or reluctant to use biosimilar medicines and we need to:

Pharmacists have a key position and can act as independent educators for prescribers and patients.

The role of hospital pharmacists

Professor Barbara Claus, a pharmacist from the University Hospital Ghent, Belgium, gave a presentation highlighting what needs to be considered by hospital pharmacists when biosimilar medicines enter the hospital.

Professor Claus highlighted the importance of pharmacists’ understanding and knowledge of biosimilar medicines. They should be able to answer questions from other healthcare professionals on biosimilar medicines. This means that they need to be aware of the regulatory approval process for biosimilar medicines and how this process differs from that for originator biological medicines:

Originator medicine: phase I–III trials to demonstrate a positive risk–benefit balance

Biosimilar medicine: physicochemical and functional characterization and pharmacokinetic/pharmacodynamics (PK/PD) studies to demonstrate comparability

The approval of biosimilar medicines is based on an inverse triangle, see Figure 2, with most evidence of biosimilarity being required for structural and physicochemical characterization. Biosimilar trials are then based on sensitive endpoints, e.g. in oncology ‘response rate’, rather than hard endpoints, such as ‘overall survival rate’.

Figure 2

The pharmacist’s knowledge should also extend to the meaning of the black triangle ▼, which is used to indicate that the medicine is part of a risk management programme for biological medicines and that traceability is mandatory. The European Medicines Agency (EMA) published a new, GVP module in 2016 (EMA/168402/2014) [4].

The role of the hospital pharmacist is important for the interchangeability, pharmacovigilance and traceability of biosimilar medicines, as well as in communication during the hospital uptake process.

Pharmacists should know that interchangeability does not mean automatic substitution. At present, there is confusion over interchangeability among physicians and pharmacists. It is thought that this may be because the EU and US definitions are not the same, and across the EU interchanging with a biosimilar medicine is a Member State decision. In the US, interchangeability includes automatic substitution, which can lead to switching at the pharmacy level without prescribers’ consent. However, Professor Claus emphasized that switching should be a controlled and informed action guided by a traceable process. It should be carried out in agreement with the prescriber with the aim of achieving the same clinical goal in a patient. Professor Claus noted that switches do currently occur and this is being monitored. Switching patterns are being recorded to track any possible issues, although none appear obvious at present.

To facilitate pharmacovigilance, as stated by Dr Lunddahl, Professor Claus reinforced the fact that pharmacists should collect both brand names and batch numbers in patient records. EAHP has suggested that pharmacists track by scanning barcodes of single units. However, increasing traceability by implementing bar-code scanning is not universal at present and manual recording can be time consuming.

Communication between all stakeholders (physicians, pharmacists, pharmacy technicians and patients) and their overall education needs to be improved. Incentivization for all healthcare providers is proving beneficial and, once a decision is made to use a specific biosimilar medicine, educational material should be available to all, so that patients are informed and are encouraged to report any adverse effects. In The Netherlands, such an initiative quickly resulted in a controlled switch of over 90% of patients to a biosimilar medicine, without an increase in meaningful ADRs.

In addition, Professor Claus noted that the landscape is changing and that the 25 top pharmaceutical companies are now developing biological and biosimilar medicines.

In conclusion, she added that pharmacists, companies, hospital boards, formulary committees and physicians need to merge ideas and exchange information. The final goal is to provide consistent information to patients and to create sustainable treatment regimes now, and in the future. In the end, the continuity of product will produce better health and well-being for patients.

Discussion: audience Q&A

Following the main presentations, the three speakers answered questions from the audience and Chair, Ms Sue Naeyaert of Merck Biosimilars.

Professor van Gelder stated that formulary committees need to involve medical doctors to avoid resistance to biosimilars and comply with traceability initiatives. It is beneficial to have doctors meet with representatives from pharmaceutical companies at an early stage of negotiations. Professor Claus added that it is important to discuss tendering and for all to understand the criteria for this, so that transitions are smooth and additional discussions are not required.

Professor Claus noted that pharmaceutical companies are coming up with incentives and services, other than reducing prices, to boost sales and the uptake of biosimilar medicines. These include 24-hour access lines for patients, travel kits and services, such as drug transport to hospital and discussions with patients. Professor van Gelder said that it takes time for a medical doctor to explain the aspects of administration to patients. When drug providers offer a service to explain the aspects of the drug administration processes to patients, doctors’ time is saved and they can go on to assess and treat more patients.

Dr Lunddahl discussed the executive order enforced when infliximab entered the Danish market. This was brought about by a medical council expert group that recommended its approval. In Denmark, it is known that when a drug product is recommended, regulatory councils will not compromise safety and efficacy of treatment when approving products. This led to significant use of biosimilar medicines in Denmark, as physicians have high levels of confidence and trust in the councils. Professor Claus added that, in Belgium, uptake was low by comparison. There is now a close follow-up of the results of the tendering processes and physicians need to consider biosimilar medicines in the same way as originator products.

Conclusion

The Biosimilar Medicines Group satellite symposium, ‘Biosimilar medicines in clinical practice – important role for hospital pharmacists?’ saw Ms Sue Naeyaert, Dr Benedicte Lunddahl, Professors Teun van Gelder and Barbara Claus, discuss the traceability of biosimilar medicines, how to build trust in biosimilar medicines, and the role that hospital pharmacists can play in improving their acceptance and usage.

Dr Lunddahl’s presentation highlighted how the Danish Medicines Agency was tackling the reporting of adverse events and traceability for both originator biological and biosimilar medicines. Their action plan aimed to encourage monitoring of biological medicines at the product level to increase traceability, raise awareness of biosimilarity, promote IT solutions to ease reporting of ADRs, and focus on the surveillance of biological and biosimilar medicines. This has led to the high usage of biosimilar medicines relative to other countries across the EU.

Professor van Gelders’s presentation highlighted the key concerns that medical doctors may have when prescribing biosimilar medicines. The main issues he highlighted are that physicians have a lack of trust in safety and efficacy of biosimilar medicines and that they do not want to relinquish their control over the prescribing of biological products. He noted that prescribers’ concerns are not validated by clinical evidence and that they need to be better informed. Discussions between physicians, pharmaceutical companies and pharmacists can lead to increased transparency and higher levels of trust.

Professor Claus’s presentation highlighted considerations that should be made by hospital pharmacists when biosimilars enter the hospital. She noted the importance of pharmacists’ understanding and knowledge of biosimilar medicines. They should be able to answer questions from other healthcare professionals on biosimilar medicines and need to be aware of the regulatory process for the approval of biosimilar medicines. In addition, improvements to healthcare systems need to be made to increase traceability.

Overall, emphasis by the speakers was on the need for increased education to improve trust in biosimilar medicines, and the need for traceability of biosimilar medicines. They demonstrated this by describing the scenarios occurring in different EU countries and determining which tactics have led to increased penetration of biosimilar medicines in Member States.

Acknowledgement

The authors wish to thank Alice Rolandini Jensen, MSci, GaBI Journal Editor, in preparing this meeting report.

Disclosure of financial and competing interests: The satellite symposium was organized by the Biosimilar Medicines Group, a sector group of Medicines for Europe. Fees were paid to the organization for the conference slot, however, none of the speakers received direct payments from Medicines for Europe.

Professor Teun van Gelder has been a member of the speakers’ bureau or has participated in advisory boards for Astellas, Chiesi, Novartis, Sandoz and Teva. He has also received research funding from Chiesi, and travel support from Roche.

Professor Barbara OM Claus and Dr Benedicte Lunddahl declare that there is no conflict of interest to report.

Provenance and peer review: Not commissioned; internally peer reviewed.

Authors

Professor Teun van Gelder, MD, PhD, Internist – nephrologist/clinical pharmacologist, Departments of Internal Medicine and Clinical Pharmacology, Erasmus University Medical Center, PO Box 2040, NL-3015 CE Rotterdam, The Netherlands

Benedicte Lunddahl, DVM, Danish Medicines Agency, Division of Pharmacovigilance and Medical Devices, 1 Axel Heides Gade, DK-2300 Copenhagen S, Denmark

Professor Barbara OM Claus, PharmD, PhD, Pharmacy Department, Ghent University Hospital, 185 De Pintelaan, BE-9000 Ghent, Belgium

References
1. GaBI Online – Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 21]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
2. Ekman N, Vulto AG, Cornes P. Reducing healthcare costs and building trust in biosimilar medicines. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(2):84-8. doi:10.5639/gabij.2016.0502.020
3. GaBI Online – Generics and Biosimilars Initiative. EMA finalises pharmacovigilance guidance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 21]. Available from: www.gabionline.net/Guidelines/EMA-finalises-pharmacovigilance-guidance
4. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Product – or Population-Specific Considerations II: Biological medicinal products. EMA/168402/2014. 4 August 2016 [homepage on the Internet]. [cited 2017 Jun 21]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08/WC500211728.pdf
5. Giezen TJ, Straus SMJM. Pharmacovigilance of biosimilars: challenges and possible solutions. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):118-9. doi:10.5639/gabij.2012.0103-4.033
6. Claus BOM, Somers A, Bauters T. Generics and Biosimilars Initiative Journal (GaBI Journal). Pharmacovigilance of biosimilars and other biologicals within the hospital: current practices and future challenges. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(1):24-6. doi:10.5639/gabij.2017.0601.005
7. Lunddahl B. Pharmacovigilance on biologicals and biosimilars: a Danish perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(3):123-4. doi:10.5639/gabij.2016.0503.030
8. GaBI Online – Generics and Biosimilars Initiative. NOR-SWITCH study finds biosimilar infliximab not inferior to originator [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 21]. Available from: www.gabionline.net/Biosimilars/Research/NOR-SWITCH-study-finds-biosimilar-infliximab-not-inferior-to-originator
9. Kurki P. Biosimilars for prescribers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):33-5. doi:10.5639/gabij.2015.0401.008
10. Annese V, Avendaño-Solá C, Breedveld F, Ekman N, Giezen TJ, Gomollón F, et al. Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(2):74-83. doi:10.5639/gabij.2016.0502.019
11. European Medicines Agency. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant erythropoietins (Revision). EMEA/CHMP/BMWP/301636/2008 Corr.* 18 March 2010 [homepage on the Internet]. [cited 2017 Jun 21]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/04/WC500089474.pdf
12. Giezen TJ, Schneider CK. Safety assessment of biosimilars in Europe: a regulatory perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):180-3. doi:10.5639/gabij.2014.0304.041
13. GaBI Online – Generics and Biosimilars Initiative. Epoetin alfa and pure red cell aplasia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 21]. Available from: www.gabionline.net/Biosimilars/Research/Epoetin-alfa-and-pure-red-cell-aplasia

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2017 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: http://gabi-journal.net/pharmacovigilance-traceability-and-building-trust-in-biosimilar-medicines.html


Commentary on the recommendations of the European Society for Organ Transplantation Advisory Committee on generic substitution of immunosuppressive drugs

Abstract:
In 2010, the Council of the European Society for Organ Transplantation formed an Advisory Committee to formulate recommendations on the use of generic drugs in solid organ transplant recipients. The initiative was taken as a result of concerns regarding generic substitution of immunosuppressive drugs. The recommendations were published in Transplant International, and this paper is a short summary of its contents.

Submitted: 27 March 2013; Revised: 5 May 2013; Accepted: 13 May 2013; Published online first: 20 May 2013

Introduction

Solid organ transplant recipients are treated with immunosuppressive drugs in order to prevent rejection of their grafts. The most frequently used maintenance immunosuppressive drugs in Europe are the calcineurin inhibitors (tacrolimus and ciclosporin), and mycophenolic acid (mycophenolate mofetil). For all three drugs patents have expired and generic formulations have been registered. In 2010, the Council of the European Society for Organ Transplantation (ESOT) formed an Advisory Committee to formulate recommendations on the use of generic drugs in solid organ transplant recipients [1]. The initiative was taken as a result of concerns regarding generic substitution of immunosuppressive drugs. Health insurance companies encourage the prescription of generic drugs, as they have substantially lower prices compared to the original brand-name product. In some countries this led to substitutions by pharmacists, even in patients who had a prescription for a brand name drug. Prescribers felt that they were no longer in control of what drug their patients were taking. Uncontrolled substitutions by pharmacists have been linked to graft dysfunction, and the transplant community approached ESOT, and national transplant societies, which mobilized working groups and advisory committees to formulate guidelines on how to deal with generics substitution [2]. In this paper, the contents of the ESOT guidelines are summarized, as well as some recent developments in this field. For the full text the reader is referred to the original publication [1].

Bioequivalence and generic drugs

Registration of generic drugs largely depends on the demonstration of bioequivalence. The readers of GaBI Journal are very familiar with the design and interpretation of bioequivalence studies, and this will not be further discussed. There are subtle differences in regulatory requirements for bioequivalence between the American (FDA – Food and Drug Administration) and European (EMA – European Medicines Agency) agencies, but by and large the procedures are similar. An important difference however is that in 2010, for narrow therapeutic index drugs, EMA narrowed the 90% confidence interval of the ratio between the average rate and extent of bioavailability of the test formulation and the reference formulation from an interval of 80–125% to an interval of 90–111%, while FDA is still applying the wider interval. For the calcineurin inhibitors the stricter criteria are being applied by EMA, but for mycophenolate mofetil the wider range is still being used, as this drug is not considered to be a narrow therapeutic index drug.

Patients or healthy volunteers

Bioequivalence studies are generally performed in healthy human volunteers with normal renal, hepatic and cardiac function. The results of these studies are extrapolated to transplant populations. Although the smaller between-patient variability in healthy volunteers is an advantage in the detection of small differences in drug bioavailability between different formulations, many transplant physicians would favour bioequivalence studies in the respective patient populations. Some pharmaceutical companies have indeed performed such studies in transplanted patients, not as a regulatory requirement, but to convince prescribers that the generic drug is also bioequivalent to the reference product in their patients. It would offer such companies a marketing advantage, and prescribers would feel more comfortable in prescribing these formulations.

AUC and Cmax

The maximum observed drug concentration (Cmax) and the area under the curve (AUC) are the two parameters used to decide on bioequivalence. In daily practice, however, the immunosuppressive drugs are monitored by measurement of the pre-dose concentration (C0), although some argue that drug concentration measurements at other time points would be more appropriate [3]. Whether or not the correlation between the pre-dose concentration and AUC is the same for generic and reference drug product is not tested. Nevertheless, the same target concentrations for both products are strived for, although prescribers perceive this situation as a lack of evidence. In the ESOT guidelines there is a plea to investigate the relationship between the measured surrogate pharmacokinetic parameter, e.g. C0, or C2, and exposure (expressed as AUC) for the respective formulations. When such data are available, regular drug monitoring can be performed under valid assumptions.

Generic to generic substitution

Regulators claim that based on the demonstration of bioequivalence, the reference drug product and the generic formulation are fully interchangeable [4]. However, following a first substitution from the reference drug product to a generic formulation, subsequent substitutions from one generic drug to another often follow. It is important to realize that generic formulations are not necessarily bioequivalent amongst themselves. Although all generic formulations have been tested against the reference drug product, there is no requirement that generic formulations show bioequivalence with generic formulations that have been registered already. Knowing that the acceptance criteria allow for a difference between reference drug product and generic of 20%, it is theoretically possible that substitution from one generic drug to another leads to a substantial deviation in drug exposure. In the ESOT guidelines this omission in the registration process of generic formulations is highlighted.

Uncontrolled substitutions

When the prescriber has specified a particular brand-name drug and the dispensing pharmacist intends to give the patient something else, both prescriber and patient should be informed and both prescriber and patient should agree. Only then can the prescriber ask the patient to return to the clinic at a shorter time interval, to check drug concentrations and to ensure that the patient is taking the right drug in the right dose. Unfortunately, the prescriber is not always informed, and a reliable system to systematically notify the prescriber of a change in the dispensed formulation is not available. The ESOT guidelines warn of uncontrolled substitutions and recommend that pharmacists contact prescribers before dispensing alternative formulations.

Confused patients

Although brand-name drugs and generic drugs may be interchangeable with respect to their drug exposure and their clinical effects, they can differ substantially in their appearance. Consumers of generic drugs must be prepared to receive pills of a different size, colour, and shape, depending on which manufacturer is supplying their pharmacies. With numerous generic to generic substitutions over a period of time, patients may get confused and make mistakes. Such mistakes may have serious consequences [5]. The ESOT guidelines ask for a system of more uniform drug appearance in order to reduce medical error and promote patient adherence to treatment regimens that involve generic drugs [6].

Conclusion

Immunosuppressive drugs are expensive and life-long immunosuppressive therapy of transplant patients is associated with high financial costs. ESOT is not opposed to the use of generic drugs. ESOT Advisory Committee stressed that savings in the cost of immunosuppressive drugs will benefit health care and society, as long as the overall cost is not increased due to additional patient care and drug monitoring. Uncontrolled substitutions and repetitive substitutions from one generic drug to another should be avoided. The guidelines attempt to regulate the process of generic substitution of immunosuppressive drugs in transplant recipients. This is a vulnerable patient population. The demonstration of bioequivalence is not sufficient to conclude there is unconditional interchangeability [7].

Competing interests: Professor Teun van Gelder has received honoraria, research grants or lecture fees from Astellas, Pfizer, Roche, Sandoz and Wyeth; and is a member of the Dutch Novartis Transplant Advisory Board.

Provenance and peer review: Commissioned; externally peer reviewed.

References
1. van Gelder T; ESOT Advisory Committee on Generic Substitution. European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 2011 Dec;24(12):1135-41.
2. Harrison JJ, Schiff JR, Coursol CJ, Daley CJ, Dipchand AI, Heywood NM, et al. Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation. 2012 Apr 15;93(7):657-65.
3. Knight SR, Morris PJ. The clinical benefits of cyclosporine C2-level monitoring: a systematic review. Transplantation. 2007 Jun 27;83(12):1525-35.
4. Maliepaard M, et al. Equivalence of generic medicines in general and immunosuppressants in particular – a regulatory opinion on switching of cyclosporin, tacrolimus and mycophenolate mofetil. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):86-90. doi:10.5639/gabij.2013.0202.019
5. Greene JA. The substance of the brand. Lancet. 2011 Jul 9;378(9786):120-1.
6. Greene JA, Kesselheim AS. Why do the same drugs look different? Pills, trade dress, and public health. N Engl J Med. 2011 Jul 7;365(1):83-9.
7. Van Gelder, T. Why bioequivalence and unconditional interchangeability of generic drugs are not the same. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):83-5. doi:10.5639/gabij.2013.0202.020

Author: Professor Teun van Gelder, MD, PhD, Internist – nephrologist/clinical pharmacologist, Departments of Internal Medicine and Clinical Pharmacology, Erasmus University Medical Center, PO Box 2040, NL-3015 CE Rotterdam, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: http://gabi-journal.net/commentary-on-the-recommendations-of-the-european-society-for-organ-transplantation-advisory-committee-on-generic-substitution-of-immunosuppressive-drugs.html


Why bioequivalence and unconditional interchangeability of generic drugs are not the same

Abstract:
The patents for a number of cornerstone immunosuppressive drugs used in the field of solid organ transplantation have expired. Generic formulations are now available and several professional societies and individual physicians have given their opinions on the issue of generics substitution. In this issue of GaBI Journal, several hot topics related to implementation of generic immunosuppressive drugs in clinical practice were discussed in different perspectives.

Submitted: 27 September 2012; Revised: 26 March 2013; Accepted: 4 April 2013; Published online first: 9 April 2013

Introduction

This paper focuses on the immunosuppressive drugs used in the field of solid organ transplantation. Within the treatment of organ transplant recipients, roughly three eras can be distinguished. Before 1980, treatment consisted of high dose corticosteroids and azathioprine, often combined with anti-thymocyte globulin induction therapy. With this treatment the majority of renal transplant patients developed one or more acute rejection episodes, and the one-year graft survival was close to 50%. In the early 80s, ciclosporin was introduced, and this revolutionized pharmacotherapy. The incidence of acute rejection not only decreased, rejections were also less severe, and graft survival at one year increased to 80%. For non-renal organs the impact was even more dramatic. Results of liver, lung and heart transplantation were very poor prior to the introduction of ciclosporin. In the years after 1982 many centres were able to successfully start liver, heart or lung transplant programmes. The third era started in 1995, when tacrolimus was introduced as an alternative for ciclosporin. Both drugs are calcineurin inhibitors, but their side effect profiles differ and with tacrolimus lower incidences of acute rejection were achieved (although one-year graft survival was similar). Mycophenolate mofetil also became available in the mid 1990s, and was shown to reduce the incidence of acute rejection by 50%, compared to azathioprine-based immunosuppressive therapy [1].

Combined treatment with tacrolimus and mycophenolate mofetil has become the most frequently used regimen to prevent acute rejection after renal transplantation. For both drugs the patent has expired, both in the US and in most European countries. Generic formulations have reached the market, but there is debate regarding the pros and cons of generics substitution.

In this paper I will not discuss pharmaceutical quality. As a medical doctor I assume that drugs that have received marketing authorization meet the rigorous quality standards for product identity, strength, and purity. National and international regulators check whether or not drug products are manufactured under the strict standards required for good manufacturing practices.

Evidence that generics substitution is either safe or risky is lacking. The studies that have attempted to relate substitution to clinical outcome are underpowered. While there are case histories published concerning this, the evidential value of these cases is small at best. As a result there are many expert opinions on this subject. I have personally contributed to the ongoing debate, with my personal opinions, as both the secretary of the Dutch Society for Transplantation and as the Chair of an advisory committee of the European Society for Organ Transplantation [2]. For the record, this editorial reflects my personal opinion and the contents cannot be linked to either of the two societies.

The patient

There are many stakeholders involved in this issue, and as always, money plays an important role. One viewpoint that is often forgotten is the opinion of the patient. For patients, the function of their transplanted organ is of utmost importance. For liver, heart and lung transplants these grafts are life saving. For renal transplant patients the grafts offer much better quality of life compared to dialysis. Many patients were on waiting lists for substantial periods of time prior to transplantation, and they are very much aware of their poor prospects in case of graft loss. Patients who have been treated with the originator drug for a considerable length of time, with good experience, feel uncertain about any proposed switch to another formulation, even with their doctor’s consent. Surveys show that a large percentage of renal transplant patients believe that generics are not equivalent and many patients are uncertain whether generics have the same quality as do innovator medicines [3]. When generics substitution is intentionally or unintentionally forced upon such patients this may adversely affect adherence to medication, potentially influencing clinical outcome. There definitely should be more information for patients on this topic, in language that they can understand.

The confusion that patients experience due to substitution from one formulation to the other [4] is also important. In many countries purchasing policies of either the pharmacist or the health insurance company will lead to dispensing of numerous generic formulations from various sources over time. Not all of my patients will be able to figure out that boxes that look so different and are labelled with different names in fact contain the same drug [5]. The resulting confusion can and will certainly lead to mistakes. In view of the narrow therapeutic index of transplant medications such mistakes may have serious consequences. Following the first substitution from an innovator drug to a generic formulation there should be no subsequent generic–generic substitutions. Prescription of a so-called branded generic drug may help to avoid such subsequent substitutions. Dispensing of immunosuppressive drugs only through one or more designated pharmacies may provide a way to achieve better control over what product is handed to the patient. And it would certainly help if registration authorities would demand that the shape and colour of the tablets and capsules of generic formulations are the same or at least similar to the innovator medicines they can replace. This would help patients to correctly identify their medication, and could reduce confusion and mistakes.

Registration

Immunosuppressive drugs are considered narrow therapeutic index drugs. For such drugs relatively small changes in exposure may lead to differences in clinical outcome. For many years it was felt that the limits for the 90% confidence intervals (90% CI) of the Cmax and AUC ratios, between the two preparations should be stricter than the range of 0.80–1.25.

The European Medicines Agency currently recommends that the acceptance interval be tightened for products for which there is a risk of clinically relevant differences in efficacy or safety between two products even when the conventional criteria for assuming bioequivalence are met. For such products the acceptance interval for concluding bioequivalence should be narrowed to 0.9–1.11%. The US Food and Drug Administration has not changed its policy, and in the US the wider range (80–125%) is still applied even for narrow therapeutic index drugs [6].

What is not required for registration is the need to demonstrate bioequivalence with other generic formulations of the same drug. This is surprising, since the acceptance criteria for generic formulations have been chosen to minimize the risks associated with substitution of one formulation with another. Substitutions of one generic formulation with another generic formulation are likely to happen when pharmacists may assume that the prescriber has agreed to use any generic formulation once a first substitution has taken place. The dispensing pharmacist may therefore not inform the prescriber of any such subsequent changes in what the patient actually takes. I understand that for most drugs the generic formulations have ratios for Cmax and AUC that are close to the middle of the range of 0.8–1.25. For such drugs the changes in exposure following substitution are assumed to be small, but this is not necessarily true for all drugs. I would expect that registration authorities would build in safeguards to prevent this from happening, even if this would occur in less than 5% of all drugs [6]. In my view the requirement to not only demonstrate bioequivalence with the innovator drug but also with other generic formulations would increase the safety of generics substitution. If such testing were required a company that wanted to register a new generic formulation of a drug for which there were already five other formulations on the market, the registration hurdle would become higher. But do we really need a sixth generic version? In this issue Dr Marc Maliepaard, working for the Dutch Medicines Evaluation Board, discusses an alternative view of the potential changes in exposure following substitution from one generic drug to another.

Another issue in the registration process which is often debated is whether healthy volunteers are the appropriate study population. Some argue that for immunosuppressive drugs bioequivalence studies should be done in transplanted patients. I personally do not believe that patients are the preferred population. The higher degree of intra-subject variability in patients would complicate the demonstration of bioequivalence. Studies in patients would have to include substantially more subjects to bring the 90% confidence intervals for the ratios within the bioequivalence limits. In some cases, to fulfill the perceived need for bioequivalence studies in actual patient populations, generics manufacturers have sponsored studies in transplanted patients [7] even when such studies were not required by the registration authorities. The main goal of such studies was to convince transplant physicians that the generic product was also bioequivalent with the innovator drug in the target patient groups.

It has been pointed out that although the innovator and generic formulation contain the same amount of the active substance, differences in excipients may alter the disposition of co-administered drugs. An example of this phenomenon is the study by Kovarik et al. [8], where sirolimus pharmacokinetics were different in the presence of generic versus innovator ciclosporin.

Therapeutic equivalence

Therapeutic equivalence is assumed on the basis of demonstrated comparative bioavailability (‘bioequivalence’). There is no regulatory requirement to perform clinical trials comparing clinical outcomes in patients treated with the innovator versus the generic formulation. I believe that it is unlikely that a difference in drug exposure of less than 10% will result in a difference in clinical outcome, and I would not personally be interested in participating in a trial to test this hypothesis. More importantly, if such a non-inferiority trial would be done it would not reflect daily practice. In the trial setting, patients would all be supplied with a single study drug, either innovator or generic, for the duration of the study. Throughout the study patients in both arms of the study would remain on the same formulation. In daily practice, however, subsequent and often uncontrolled substitutions from one generic formulation to another take place. As already mentioned above, these substitutions may result in deviations from the therapeutic target concentrations or compliance, and more importantly will lead to confusion and mistakes that could affect outcomes. Head-to-head comparisons between an innovator drug and a specific generic formulation do not reflect clinical practice, and cannot provide evidence for the safety of repeated generics substitution [6].

Implementation

In The Netherlands, generics substitution is the standard of practice for drugs such as proton pump inhibitors, anti-hypertensive drugs and for statins. Increasing numbers of physicians use an electronic prescription system, within which the default is the generic drug name. In my practice transplanted patients are still treated with innovator immunosuppressive drugs. On my prescriptions for immunosuppressive drugs I add the trade [brand] name, and the words ‘medical necessity’. This tells the pharmacist that I do not want a generic substitution. My main motivation is the fear for subsequent repetitive substitutions. As described above such subsequent substitutions are likely to happen without my knowledge. As a result, I would not be alerted to check drug exposure, and even if I do check drug concentrations I cannot check whether or not the patient is taking the drugs correctly. And again, patients may make mistakes. If there would be a guarantee that following a first substitution from innovator immunosuppressive drug to a specific generic drug under controlled conditions that there would be no further substitutions, this would certainly change my position on the use of generic anti-rejection drugs.

Conclusion

This issue of GaBI Journal offers you different perspectives on the generic substitution of immunosuppressive drugs. Regulators, insurers, pharmacists, physicians and patients are all stakeholders in this controversial area. Hopefully, you will find useful new perspectives and opinions in this issue. However, do not expect to find much evidence that substitution is always safe.

Competing interests: Professor Teun van Gelder has received honoraria, research grants or lecture fees from Astellas, Pfizer, Roche, Sandoz and Wyeth; and is a member of the Dutch Novartis Transplant Advisory Board.

Provenance and peer review: Commissioned; externally peer reviewed.

References
1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004 Dec 23;351(26):2715-29.
2. van Gelder T. European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 2011 Dec;24(12):1135-41.
3. Al Ameri MN, Whittaker C, Tucker A, Yaqoob M, Johnston A. A survey to determine the views of renal transplant patients on generic substitution in the UK. Transpl Int. 2011 Aug;24(8):770-9.
4. Greene JA. The substance of the brand. Lancet. 2011 Jul 9;378(9786):120-1.
5. Greene JA, Kesselheim AS. Why do the same drugs look different? Pills, trade dress, and public health. N Engl J Med. 2011 Jul 7;365(1):83-9.
6. van Gelder T, Gabardi S. Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs. Transpl Int. 2013 Feb 27. doi:10.1111/tri.12074.
7. Alloway RR, Sadaka B, Trofe-Clark J, Wiland A, Bloom RD. A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients. Am J Transplant. 2012 Oct;12(10):2825-31.
8. Kovarik JM, Noe A, Wang Y, Mueller I, DeNucci G, Schmouder RL. Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus. Eur J Clin Pharmacol. 2006 May;62(5):361-6.

Author: Professor Teun van Gelder, MD, PhD, Internist – nephrologist/clinical pharmacologist, Departments of Internal Medicine and Clinical Pharmacology, Erasmus University Medical Center, PO Box 2040, NL-3015 CE Rotterdam, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

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Related article
Equivalence of generic medicines in general and immunosuppressants in particular – a regulatory opinion on switching of ciclosporin, tacrolimus and mycophenolate mofetil

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