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Generic narrow therapeutic index drugs



European experts discussed the use of generic immunosuppressive drugs, such as tacrolimus, ciclosporin and mycophenolate mofetil and the factors influencing their uptake at a meeting sponsored by Teva Pharmaceuticals in July 2013
Hospital Pharmacy Europe hosted a European expert panel meeting in July 2013 to discuss the use of generic immunosuppressive drugs such as tacrolimus, ciclosporin and mycophenolate mofetil (MMF) in current hospital practice and to identify the factors that influence the use of these products. The panel members, from six European countries, comprised senior hospital clinicians and a pharmacist, all of whom have expertise in the handling of narrow therapeutic index drugs.
The main objectives of the meeting were to discuss the following aspects of the use of generic narrow therapeutic index drugs (NTIDs):
1. Comparison of bioequivalence of originator immunosuppressive drugs with generic versions
2. Manufacturing processes of originator and generic versions of immunosuppressive drugs
3. The clinical case for using generic immunosuppressive drugs
4. Safety issues
5. Economic considerations
    (a) Lower costs of generics versus higher monitoring costs
    (b) Theoretical costs of non-compliance
6. Prescribers’ confidence in using generic immunosuppressive drugs
7. Patient awareness and compliance with generic immunosuppressive drugs
Introduction and background
Dr Thomas Rath opened the meeting by giving a short talk on generic immunosuppressive drugs in which he presented the clinical case for using these drugs and reviewed the guidelines from professional bodies.
Generic substitution is encouraged in many countries as a means of cost containment, for example, in the US in 2003, 42% of all prescribing was for generic drugs and 20% of prescriptions for ciclosporin were generic. Generic medicines have to be manufactured to good manufacturing practice (GMP) standards and must conform to compendial and bioequivalence standards. The standard design for bioequivalence studies is a two-way, cross-over design using single oral doses of the test and reference products. The area under the plasma concentration/time curve (AUC) reflects the extent of absorption and therefore systemic exposure to the drug. The peak drug concentration (Cmax) and the time taken to reach the peak concentration (Tmax) reflect the rate of absorption (Figure 1).
In 2003 the American Society of Transplantation (AST) noted that all marketed generic formulations met the Food and Drug Administration (FDA) bioequivalence criteria. The AST stated that generic immunosuppressants provided adequate de novo immunosuppression in low-risk patients.(1) It recommended that they should be clearly labelled and distinguishable from the innovator products and that patients should be told to inform their physicians if different generic products were supplied.
More recently, the Canadian Society of Transplantation recommended that the ‘critical dose drugs’ ciclosporin, tacrolimus and sirolimus should be subject to more frequent therapeutic drug and clinical monitoring together with increased patient education.(2) The European Society for Organ Transplantation recommended that switching (to a generic product) should be initiated only by the transplant physician and patients should be followed closely.(3) In addition, repeated switching between generic products should be avoided.
The European Medicines Agency (EMA) has defined NTIDs as those in which small changes in dose can cause plasma levels to swing above or below the limits of the therapeutic range and for which over- or underdosing has serious clinical consequences. It follows that individual dose titration and plasma level monitoring are necessary. Tacrolimus and ciclosporin are all examples of NTIDs.
The EMA has recommended that the acceptance criteria for generic tacrolimus should be an AUC value for which the 90% confidence interval (CI) falls in the range 90–111% and a Cmax value (90% CI) in the range 80–125% of the reference values. The EMA also stipulated that trough levels may be used as a surrogate for AUC in clinical practice.
The innovator’s brand of ciclosporin undergoes micro-emulsification in the presence of water. When it is taken with a high-fat meal, both the AUC and Cmax are reduced. Consequently, an EMA working party recommended that generic ciclosporin should be bioequivalent in both fasting and fed states. Moreover, the 90% confidence intervals for AUC and Cmax must lie in the range 90–111% in both states.
Mycophenolate mofetil is a prodrug that undergoes rapid and extensive pre-systemic metabolism to mycophenolic acid, resulting in an AUC for the parent substance that is 10,000-fold lower than for the metabolite. The EMA states that it is acceptable for generic products to demonstrate bioequivalence for the main active metabolite without measurement of the parent compound.
Patients’ perspective
A 2011 study of 163 patients in the UK showed that 70% understood the terms ‘generic’ and ‘branded’ but 75% did not know if they were taking generic medicines and 84% felt that generic medicines were not always equivalent to branded products.
Studies in renal transplant patients
Studies in patients who have undergone renal transplantation show that the generic product Equoral can be safely interchanged with the innovator product Neoral.(4)
Generic tacrolimus exhibited considerable variability in drug dissolution, solubility and uniformity in one 2008 study. However, studies published in 2012 with a new generic tacrolimus product showed that it delivered adequate AUCs and caused no clinical problems in maintenance renal transplant patients.(5)
A comparative study of generic and originator MMF in 43 stable renal transplant recipients showed that the two products were bioequivalent with respect to AUC.(6) There was greater variability in peak plasma levels but the preliminary safety analysis raised no concerns.
In summary, Dr Rath made the following points:
  • Generic immunospuppressive agents are cost-effective medicines
  • Not all generics are the same
  • Equoral, Myfenax and Tacni satisfy the bioequivalence criteria of the EMA
  • Education of patients, physicians and pharmacists is important
  • Pharmacokinetic and clinical bioequivalence in transplant patients is important
  • Long-term safety and efficacy data are required.
The key questions of interest were discussed and the following points were made:
Comparison of bioequivalence of originator immunosuppressive drugs with generic versions 
All generic immunosuppressive drugs must be comparable with the originator product and therefore there is little to be gained from comparing generics with each other. Nevertheless, switching a patient from one generic to another could present problems. Although both products should lie with their confidence levels within the allowed limits (80–125% except for NTIDs, where the limits are 90–111%), they could be at opposite ends of the range and therefore put the patient at risk of a marked change in dose.
Using only healthy volunteers for comparative studies does not represent the true picture for patients who have renal disease or who have undergone renal transplantation – there could be differences in the ways that they handle the drugs.
Comparative studies commonly involve the use of single doses and this may not fully reflect the situation in the steady state achieved with chronic dosing.
In Italy, switching between different generic products is permitted. Often this is because of cost issues.
If a single generic product is used (and there is no switching between products), then there is no need for additional monitoring to check that patients are receiving appropriate doses – this can make its use cost effective.
It is important to use a generic product that is supported by bio-equivalence data, including data in renal transplant patients.
Patients who have received renal transplants are pharmacologically complex and differ from patients who have not undergone renal transplantation.
A pharmacokinetic study with cross-over design would be needed to produce data about the effects of switching. Ideally, there would be a randomised controlled trial (RCT) of generic versus innovator, but this would be too costly in practice.
A RCT with clinical endpoints would need to have a large number of patients included and would be too expensive to be feasible. If the pharmacokinetics of a generic drug were shown to be the same in transplant patients, it should be a good enough indicator of bio-equivalence.
Manufacturing processes of originator and generic versions of immunosuppressive drugs
In Italy, physicians are not very confident about the checking of the manufacturing processes for generic drugs. They believe that the conditions are less stringent than for innovator products and so it is important to provide physicians with information about all the manufacturing processes of generic medicines.
Most physicians are ignorant about the details of manufacturing processes. Physicians are more likely to feel confident if a product is made by a reputable manufacturer.
Sometimes generic drugs are made by the same manufacturer as the originator drugs.
All manufacturers have to comply with GMP and are subject to inspections by, for example, the FDA or the EMA.
Economic considerations
The use of generic immunosuppressive agents varies widely; in some countries it is as much as 70% and in others only 10%.  This is largely dependent on how the drug is paid for.
In the UK, doctors are required to use generic immunosuppressants as the standard because they are significantly cheaper.
In Spain, there is more freedom for doctors to decide than in the UK. If there is a big difference in the prices for generic and originator products, then it is likely that the generic product will be used but, if the difference is small, then doctors are free to continue to prescribe the product in which they have confidence, that is, the originator product.
The situation in the Czech Republic is similar to that in Spain. Each hospital has a list of approved drugs that is produced by the hospital’s Drug and Therapeutics Committee (DTC) (comprising administrators, doctors and pharmacists). In the first instance, representatives of pharmaceutical companies discuss new generic (cheaper) products with hospital administrators and then the products are evaluated by the DTC.
In Italy, the use of generic drugs is required by law unless physicians can make a strong case for using the originator brand.  If the patient does not wish to receive the generic version, then he may receive the originator brand but must pay the difference in cost. The price of generic medicines in Italy is set by an agency of the Government.
In Italy, if a cheaper generic drug is introduced, then it will be used because pharmacists have to supply the cheapest product. There is a published list of approved generic drugs and prices that is publicly available. The manufacturer of the original product would have to reduce the price in order to compete. The use of generic drugs is very low in Italy compared with other countries.
When comparative studies are performed, it is important to incorporate pharmacoeconomic evaluations, as the use of the cheaper drug could be associated with higher monitoring costs and/or poor compliance.
Patients who start treatment with a generic immunosuppressive agent would not require additional monitoring (because the patient is stabilised on the generic product) – it is only those who are switched to a different product who require more monitoring to ensure that there is not a big change in dosage.
In Spain, hospitals (and hospital consortia) try to obtain the cheapest drugs but price is not the only consideration – it is also important for the drug to be packed in unit doses. Other factors that are considered include the quality of service offered by the company, and whether or not it produces other generic medicines. The computerised prescribing systems identify the most economical options. If a different product is required, then the clinician must justify it. The market penetration of immunosuppressive NTIDs in Spain is less than 40%, mainly because, when a generic is launched, the originator reduces the price of the branded product. Furthermore, a hospital may use, for example, generic MMF, but when the patient leaves hospital the family doctor can prescribe the originator product (because the price is similar to that of the generic).
Patient awareness and compliance with generic immunosuppressive drugs
Patients often believe that generics are less effective but in the US patients are managed more effectively on generics because they are more affordable for the patient and consequently compliance is better.
In the Czech Republic, patients are motivated to take generic immunosuppressive agents because they are cheaper.
In Italy, a survey of 1000 patients showed they are still very reluctant to use generic drugs because of the belief that generic drugs contain lower doses than innovator products; physicians need to explain the true position to patients.
The prescribing physician has a major responsibility to convey the message that the generic drug is safe and effective. If clinicians indicate that they do not believe the drug is as effective as the originator product, this will strongly influence the patient’s view.
There can be a problem if patients receive two different versions of a generic drug; it is possible that they may take both or neither – there is much scope for confusion.
Education of patients about the immunosuppressive treatment is the role of the transplant physician and all health care professionals. Repeated switching between products at the pharmacy can make the situation very difficult.
In the Czech Republic, patients on immunosuppressive treatment or chemotherapy usually understand what they are taking but it is important to ensure that they also understand all their other treatment, for example, statins, anti-inflammatory drugs.
In one London hospital, the pharmacist is a member of the transplant team.  When the patient leaves hospital, the pharmacist educates the patients about treatment.
Pharmacists are also involved in screening of drug treatment (to check that the drug regimen is safe and appropriate for the patient). When generic immunosuppressive agents were introduced, one London hospital took prescribing of immunosuppressants back into the hospital to ensure that uncontrolled switching did not occur in the community. Now the pharmacist screens the patients’ drug regimens and the immunosuppressive medicines are dispensed by a homecare company. This decision was led by physicians.
In one hospital in Germany, there is no pharmacist on the transplant team. The pharmacy department decides, in cooperation with physicians, which medicines are listed in the hospital and usually asks physicians for their recommendations. Only originator products are used in this hospital. In the outpatient department, the situation is different – if the doctor prescribes the substance, then the pharmacist can choose what is dispensed; if a specific brand is required, the prescription must be marked to show this.
In one hospital in Italy, there is no pharmacist on the transplant team – it is not a key role for a pharmacist.  There is a need for more data to convince clinicians of the effectiveness of generic immunosuppressive agents.
Safety issues
Most patients, especially renal transplant patients, have experience of taking generic drugs and most have had an ‘adventure’ or adverse experience; this colours their views and drives their reluctance to accept generic immunosuppressive agents.
None of the panel members described instances of patient harm due to the use of generic NTIDs.
Prescribers’ confidence in using generic immunosuppressive drugs
There is still a need for further studies of generic immunosuppressive drugs, especially studies in patients rather than healthy volunteers.  If satisfactory bio-equivalence patient data were available for generic products, then prescribers in Norway, Italy and Germany would switch to the generic products.
If patients start immunosuppressive treatment with one generic product and a cheaper version is subsequently introduced and patients are switched, then some care is needed. In one London centre, this has been managed by switching product two weeks before a clinic visit so that there is the opportunity to check progress at the clinic visit.
It is important to have some control over the supply chain so that patients are not randomly switched between generic versions of immunosuppressive agents in the community. One London hospital does this by arranging for immunosuppressants to be supplied by a homecare company. This avoids the possibility of a patient receiving different generic versions of a drug from different community pharmacies.
In Italy, physicians often believe that generic medicines are less effective and that patients could be harmed. There is a considerable need for education here – large savings could be made by using generic versions of many non-NTIDs.
Additional points 
In addition to the items on the main discussion agenda, panel members felt that the following points should also be made:
If a company has good bio-equivalence data in patients, then the only factor that will determine use is price.
It is important to build up trust amongst prescribers, who tend to rely on branded products. The first step is data, especially pharmacokinetic and clinical data. Pharmaceutical companies can also educate physicians and provide them with materials to educate patients.
Publications in peer-reviewed journals, preferably those with high impact factors, are better than in-house data.
Bio-equivalence studies in public hospitals would be useful – sometimes physicians feel that they have to confirm the data with their own independent studies. They also need to show that a drug formulation is good in long-term, real-world situation.
In Italy, there is one example of a pharmacokinetic study being funded by a patient group. In general, it is not realistic to expect patient organisations to fund independent studies – this would not be feasible in the UK, Spain or the Czech Republic.
It is important that a pharmaceutical manufacturer can provide a reliable ongoing supply of a drug so that switching back after a change has been made can be avoided. There have been many examples of drug shortages (in Norway) recently and this is a serious concern.
Better internal biomarkers are needed, for example, to see what is happening inside lymphocytes during immunosuppressive treatment.
Conclusions and recommendations
  • There is pressure to use generic immunosuppressive drugs throughout Europe because they can be significantly cheaper than the originator products. However, some physicians feel there is still a need for additional data to demonstrate the safety, effectiveness and interchangeability of generic immunosuppressive agents.
  • While it is accepted that generic immunosuppressive products are bio-equivalent to the originator products, there is concern about switching patients from one generic product to another because the drug content of two generic products could be at the opposite ends of the acceptable ranges (defined by the FDA and EMA) and therefore patients could be at risk of under- or overdosing when the switch is made.
  • Ideally, patients should be monitored when a switch is made. If switches are made randomly or in an uncontrolled way, this is not possible and the quality of treatment could be compromised.
  • Ideally, studies of immunosuppressive drugs for use in renal transplant patients should include patients who have undergone renal transplantation. Such patients exhibit more complex responses than healthy volunteers and better represent the situation in which the drugs will be used.
  • When comparative studies are performed, it would be useful to incorporate pharmacoeconomic evaluations, as the use of the cheaper drug could be associated with higher monitoring costs and/or poor compliance.
  • One survey of patients (in Italy) showed they were reluctant to use generic drugs because they believed that generic drugs contained lower doses than innovator products.
  • Education of patients about the immunosuppressive treatment is the role of the transplant physician and all other health care professionals.
  • The prescribing physician has a major responsibility to convey the message that the generic drug is safe and effective. If clinicians indicate that they do not believe the generic drug is as effective as the originator product, this will strongly influence the patient’s view.
  • Pharmaceutical companies should educate physicians about the safety and effectiveness of generic immunosuppressive medicines and provide them with materials to pass on to patients.
  • Ideally, comparative studies should be published in peer-reviewed journals with high impact factors as these have greater credibility.
  • It is important that a pharmaceutical manufacturer can provide a reliable supply of a drug so that switching back after a change has been made can be avoided. There have been many recent examples of drug shortages and this is a serious concern.
Roundtable participants
Dr Anders Asberg
Department of Hospital Pharmacy
University of Oslo, Norway
Dr Iain MacPhee
Reader in Renal Medicine at St George’s University of London, UK
Dr Thomas Rath
Department of Nephrology and Transplantation Medicine
Kaiserslautern, Germany
Czech Republic
Dr Irena Netikova
Hospital Clinical Pharmacist
Teaching Hospital Na Bulovce
Prague, Czech Republic
Dr Daniel Cattaneo
Clinical Pharmacologist
Luigi Sacco University Hospital
Milan, Italy
Dr Daniel Seron
University Hospital Vall d’Hebron
Barcelona, Spain
Mr Laurence Goldberg
Independent Pharmaceutical
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  2. Knoll G et al. Am J Kidney Dis 2010;56(2):219–46.
  3. Van Gelder T. Transplant Intl 2011;24: 1135–41.
  4. Vitko S, Ferkl M. Kidney Intl 2010;77:12–16.
  5. Alloway RR et al. Am J Transplant 2012;12:2825–31.
  6. Sunder-Plassmann G et al. Transplant Intl 2012;25:680–6.

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