Department of Nephrology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Received date: October 29, 2018; Accepted date: December 23, 2018; Published date: December 31, 2018
Citation: Rottembourg J (2018) Generic Immunosuppression in Transplantation: A Controversial Analysis. J Med Toxicol Clin Forensic Med Vol.4 No.1:4 doi: 10.21767/2471-9641.100034
Generic immunosuppression; Solid organ transplantation; Ethic; Substitution
Solid organ transplantation is one of the greatest medical advances of the twentieth century for patients with end stage organ dysfunction. In heart, liver and lung disease, transplantation represents the only alternative to death; for kidney and pancreas, transplantation represents an improvement in quality, as well as in duration of life. The number of successful organ transplantation, estimated in 2015 around 120,000 per year, with an increase of about 3% [1,2] per year, worldwide, has increased in the past two to three decades due to improvement in surgical techniques and post-transplant medical care. This medical success has been possible through the continuous innovation in immunosuppressive drugs, preventing graft rejection and improving survival outcomes following transplantation. Patients are required to take these drugs for the graft life span, balancing over and under-immunosuppression: an over-immunosuppression increases the risk for some of the side effects of transplantation including infectious complications, and malignancy, whereas an under-immunosuppression increases the risk for allograft rejection [3,4].
The immunosuppressive drugs are not cheap, all over the world: the monthly cost for an immunosuppressive regimen post organ transplantation may be between 2000 and 4000 US dollars per month, depending on the medications and doses utilized . High costs may limit access to medications and influence medication adherence . The cost to develop and market a new medication is extremely high, and following approval, innovator medications only remain under patent protection under 10 to 15 years . Once the patency has expired, generic products may be approved and become available on the market.
Generic substitution has the potential for huge cost savings and is therefore an essential component to maintaining comprehensive and equitable healthcare, especially within public healthcare systems, often with limited resources. For certain classes of drugs, published studies show no difference in outcomes between the generic and innovator preparations and generic substitution is therefore not a concern . For other drugs such as iron complexes, numerous publications underline variations in the efficacy and tolerance making the substitution difficult [8-12]. The substitution of drugs with a narrow therapeutic index, such as immunosuppressive drugs, however, is more controversial. Before approval, each generic drug must show bioequivalence (the property wherein two drugs with identical active ingredients or two different dosage forms of the same drug possess similar bioavailability and produce the same effect at the site of physiological activity) to the innovator version in healthy adults, but there is no requirement to show bioequivalence or clinical efficacy in patients with transplanted organ. Over the past 15 years, different agencies have approved several generic immunosuppressants (Table 1). Given that some of the immunosuppressive drugs require therapeutic drug monitoring and display a narrow therapeutic index, many transplant practitioners have difficulty in deciding whether innovator products can be safely replaced by generics . In the transplant community this aspect led to the recommendation that patients and healthcare providers should pay careful attention to drug formulations and should monitor drug concentrations more often if a patient is switched to a generic preparation [14,15].
|Drug||Generic Availability||Dosage forms||Trade Names||Generic Formulations||Patent expiration|
|Mycophenolate Mofetil||yes||Capsule||Cell Cept®||All||Expired|
|Tablet||Myfortic®||In some countries||Apr-17|
|Target Rapamycin inhibitors|
|Sirolimus||Yes||Tablet||Rapamune®||Tablets in some countries||Nov-14|
Table 1: Available maintenance immune-suppressants in Europe.
If patients and physicians remain doubtful of the equivalence of generic immunosuppressive drugs, this will limit the cost saving potential of these drugs from under prescription and more frequent laboratory monitoring when a generic is prescribed. We investigate the clinical efficacy, safety and bioequivalence of generic immunosuppressive drugs compared with innovator drugs in solid organ transplant recipients, and the position statement of various professional societies regarding the use of generic immunosuppressive drugs.
Small-molecule drugs: A generic formulation is considered appropriate and qualified for approval in most countries if it demonstrates both pharmaceutical equivalence and bioequivalence when compared with the innovator product . To achieve pharmaceutical equivalence, a generic medication should contain the same amount of the active ingredient, be available in similar dosage forms, given by the same route of administration, and meet the same or similar manufacturing standards. Innovator and generic products can differ in shape, size, packaging, scoring, additives (i.e., colors, preservatives, binders) and expiry dates . Bioequivalence studies are typically performed in a small number of healthy volunteers, generally young and predominantly male. The FDA and EMA regulatory standards impose that the geometric mean with 90% for these pharmacokinetic parameters may fall between 80% and 125%. One of the most common misconceptions about generic medications is regarding the range (80%-125%) of variance in bioequivalence and this would allow the FDA and EMA to approve different medications that may vary in Cmax and/or AUC by up to 45% (the difference between 80% and 125% is a 45% difference). Some of the generic drugs approved in the United States were analyzed secondarily and they differed by only 4.35% and 3.56%, respectively between approved generic and innovator products . But none of Narrow Therapeutic Index (NTI) drugs are concerned by these controls. Despite that immunosuppressive drugs are all under NTI designation, the FDA does not require more stringent bioequivalence parameters for these types of medications. Both Canadian Ministry of Health and EMA modified their bioequivalence standards for NTI drugs and required more stringent criteria for generic approval for this drug category, where concentration for AUC needs to fall between 90 and 112% instead of 80 and 125% [18,19]. When the generic drug is formulated in a different dosage that the innovator product, it is no more in Europe a generic but an “hybrid” drug, without legal substitution.
Biosimilars: A biosimilar is simply defined as a biopharmaceutical protein designed to have active properties similar to an innovator biologic and approved through an abbreviated regulatory process . The EMA has had regulatory pathways for biosimilars since 2005 and currently there are 22 biosimilars approved by the EMA . There are currently no EMA- or FDA approved biosimilars with a transplant indication. However basiliximab lost its patent protection in most European countries in 2013 and the FDA currently lists the anti-thymocyte globulin products as eligible for bio-similarity studies.
A number of about 50 publications have reported the use of generic immunosuppressants in solid organ transplant recipients, mainly renal transplants [21,22]. Studies included 17 randomized trials, 15 non-randomized, and 18 observational studies (Table 2).
|Study (year)||Study Population||Study Protocole||Results|
|Roza et al. ||50 stable kidney transplant recipients||Pts with Neoral®||PK interchangeable|
|Then Pts switch to Gengraf®||Trough levels were similar|
|Then Pts switch back to Neoral®||No significant dose adjustment were required|
|Carnahan et al. ||41 stable kidney transplant recipients||Pts were converted from Neoral® to Gengraf® and followed up for 1 year||Trough levels comparable|
|No significant changes in serum creatinine|
|No significant dose adjustment|
|Taber et al. ||188 de novo kidney transplants recipients||100 Pts received Neoral®||Pts on Gengraf® experienced more rejection episodes and needed antibody treatment for rejection|
|88 Pts received Gengraf®|
|Follow-up : 6 months|
|Qazi et al. ||80 stable kidney transplant recipients||9 Pts remained on Neoral®||Significant changes in trough levels with Gengraf®|
|73 Pts switched to Gengraf®||Trough levels moved back toward baseline after adjustment|
|Follow-up of 4 weeks|
|Vitko et al. ||99 stable kidney transplant recipients||52 Pts remained on Neoral®||Trough levels similar|
|47 Pts received Equoral®||No significant differences in adverse events|
|Follow-up for 6 months||Both formulations well tolerated|
|McDevitt-Poter et al. ||70 stable liver or kidney transplant recipients||70 Pts were converted from Prograf® to Generic formulation||Tacrolimus C0 did not differ significantly|
|Pts on generics required more adjustments|
|More than 50% decrease in monthly costs with generic|
|Momper et al. ||54 stable liver and kidney transplant recipients||54 Pts were converted from Prograf® to generic tacrolimus and followed up to 3 months||Generic tacrolimus was well tolerated|
|Trough levels did not differ significantly|
|Rosenborg et al. ||63 stable kidney transplant recipients||63 Pts were converted to Generic formulation||C0 and creatinine comparable before and after the switch|
|Serum creatinine and trough levels performed three times during each period||23% decrease in drug cost per day achieved with generic formulation|
|Spense et al. ||234 stable liver, kidney or heart transplant recipients||234 Pts were converted from Prograf® to generic formulation of Tacrolimus||No significant changes in C0 and creatinine|
|More dose titration in few Pts|
|Few Pts reverted back to Prograf®|
|Decrease in drug cost with Generic formulation|
|No deaths or allograft rejection|
|Alloway et al. ||68 stable kidney transplant recipients||2 periods of 14 days were 2 groups were on cross over||No difference in Cmax C0 et AUC|
|No difference in rejection|
|Similar adverse events|
|Hauch et al. ||39 stable kidney recipients under Generic formulation were compared with 159 Pts on Prograf®||Follow-up of 1 year||Trough levels need 5.2 vs 3.9 adjustment with Generic|
|Were studied : doses adjustments, rejection, Mg and costs.||More perfusion of Mg (p<0.001)|
|More rejection crisis (23.1% vs 10.2%)|
|Global cost enhanced with Generic formulation|
|Sunder-Plassmann et al. ||43 stable kidney transplant recipients||Days 1-14 Pts received either Cell-Cept® or Myfenax®||AUC levels remained stable, Cmax slightly outside of the range|
|Days15-28 cross-over||Few adverse events|
|Days 29-112 maintained regimen|
|Rutkowski et al. ||303 stable kidney transplant regimen||First analysis Myfenac® (60Pts) vs Cell-Cept®(273Pts)||No difference in tranplant-related outcomes between Generic and Cell-Cept®|
|Second analysis de novo Myfenac® (30 Pts ) vs Cell-Cept® (30 Pts)|
|Haroldson et al. ||30 heart transplant recipients||30 pts converted from Imuran® to generic formulation azathioprine||Similar safety and effcacy results|
|Annual cost-savings reached US$318 per Pt|
Pts: Patients; PK: Pharmacokinetics
Table 2: Summary of included published studies .
Cyclosporine: The first generic approval came in 1998, and was removed two years later after demonstration that the release of the active ingredient was 20%-30% lower when the product was mixed with apple juice . In 2000 another generic version was approved: the manufacturer performed a prospective clinical trial; there were no statistically significant differences seen in pharmacokinetic parameters between originator and generic version. More importantly, the generic formulation exhibited a comparable efficacy and safety profile to the innovator drug . Different studies were performed with the same version: one concluded to a significant cost-benefit following the conversion to the generic product . Another study revealed, with the same generic, that despite similar concentration the generic product was associated with a higher rate of rejection (39 versus 25%, p=0.04) and subsequent rejection episodes (13% versus 4%, p=0.03) .
In 2006 a study underlines the importance of close monitoring following a generic conversion . In 2010 another manufacturer conducted a multi-center, randomized trial comparing the efficacy and safety of both innovator and generic version, without any difference in outcomes or tolerability . The same generic was used in heart transplant recipients without side effects and any adverse event observed after the conversion .
Tacrolimus: In August 2009 the first FDA-approved generic for tacrolimus was on the market. The first prospective observational trial concludes that converting from innovator to generic tacrolimus is safe and does carry a cost-benefit . Nevertheless, a close monitoring is crucial as many patients require more dose adjustments following conversion . It was the same in converting 103 stable renal and liver transplant recipients . One of the largest study includes 234 stable patients (after kidney, liver or heart graft) converted to generic formulation: 15% of the patients required dose adjustments, and 2.4% were converted back to the innovator product .
A prospective randomized two-period, cross over pharmacokinetic analysis has been performed more recently, proving that this generic formulation of tacrolimus is bioequivalent to brand tacrolimus in stable renal transplant recipients [34,35]. Different batches of tacrolimus were also studied in children , elderly group of patients , switch de novo  liver transplant patients, without any difference. There are recently different formulations of tacrolimus which are hybrid forms of the drugs, including slow releasing forms, without real clinical studies, but theoretically without the possibility to be substituted by the pharmacist.
Mycophenolic acid (MPA): There are two formulations of MPA: mycophenolate mofetil and enteric-coated MPA. The first generic formulation of mycophenolate mofetil received FDA approval end of 2008. In an international, multicenter randomized, open-label, study, the pharmacokinetic profile of the innovator product was compared with a generic in stable renal transplant recipients. There were some differences in the AUC, and the Cmax, but these results have been proven to have any impact on transplant outcomes . Both products were well tolerated with comparable adverse effects . Overall, it appears that generic mycophenolate mofetil has demonstrated similar efficacy and safety profiles compared with the innovator product.
The first enteric-coated MPA generic formulation was approved by the FDA in 2012. There are today no study in Europe and United States comparing generic enteric-coated MPA, to the innovator product. A Mexican study concludes that bioequivalence was not met and that the tested generic product should not be used in transplant recipients .
Azathioprine: Azathioprine is one of the oldest immunosuppressants used for allograft rejection prevention. Routine dosage is not required with azathioprine. Doses are generally based on body weight. Thus, small fluctuations in the pharmacokinetic parameters of azathioprine should not be problematic. The first generic azathioprine formulation was launched in 1996, despite this agent loses its patent protection in 1979. There is only one study in heart transplant recipients .
Sirolimus: The first generic sirolimus product was FDA-approved on September 2014, with an approval for only tablets. Studies comparing innovator sirolimus to its generic formulation have not yet been published, except in China .
In response to the concern of transplant clinicians over the use of generic immunosuppressants, many national and international societies and transplant organizations have formed and published opinion statements regarding this issue.
American Society of Transplantation: The American Society of Transplantation published in 2003 a summary of a meeting . Participants strongly supported efforts to offer less expensive medications, hoping to improve compliance. Most agreed that the prescription of generic immunosuppressive drugs de novo was safe in low-risk transplants patients. Some expressed concerns about uncontrolled substitutions, and there were a strong support for bioequivalence studies in at-risk subpopulations.
International Society for Heart and Lung Transplantation: Their committee suggests, in 2009, that in some clinical situations, generic substitution could be used, if frequent monitoring is instituted following conversion to a generic . They also suggested increased patient education regarding appearance or labeling of the generic drugs, to signify the need for closer controls if the patient receive a different brand of immunosuppressive drug. This society also stipulated that, under certain clinical conditions, transplant practitioners should use generic immunosuppressants with extreme caution .
European Society for Organ Transplantation: In 2011, this society took the position that the choice of converting between innovator and generic immuno-suppressants should be limited to specialized transplant physicians . They were satisfied with the stricter criteria used by the European Medicine Agency. They also stated that any conversion to a generic should be accompanied by strict follow-up and monitoring to asses that adequate therapeutic levels are met, and that conversion to generic products should be avoided early after transplant because of a higher risk of rejection. They urged practitioners to avoid switching among generic formulations, and if a conversion is decided the same generic should be given to the patients .
Canadian Society of Transplantation: In 2012, this society noted that there is a lack of data and literature regarding the safety and efficacy of generic immunosuppressants , and stressed that there is a need for more strict regulatory principles. They asked for bioequivalence to be demonstrated, not only in healthy adults, but also in transplant recipients and in subpopulations known to have a high variability in blood concentration. Finally they also stressed the involvement of pharmacists in providing education for patients, and to deliver to the patient always the generic drug from the same manufacturer . It was the same for the French Society of Transplantation .
When a company tests a new generic medication, it is only required to be tested against the innovator product. None of the regulatory agencies require one generic medication to demonstrate bioequivalence with any other approved generic formulation . In such cases all generic formulations are deemed interchangeable. This is certainly a potential shortcoming of the current generic approval process. Unfortunately for clinicians, without generic-to-generic bioequivalence data, and the great probability that generic-to-generic conversions will take place at the pharmacy level, at each monthly prescription, with sometimes the combination of different generics in the same delivery, it is difficult to determine when to institute more aggressive monitoring in maintenance transplant recipients.
Given that generic-to-generic conversion is likely what happens in real-life scenarios, and the current literature only has studies where one generic formulation is compared with the innovator product, a six-way cross-over study was recently designed, whereby patients are converted not only between innovator and generic tacrolimus, but also between five different generic tacrolimus formulations . This study will represent the type of real world situation where patients can be dispensed different generic tacrolimus formulation depending what is in stock at their pharmacy at the time their prescription is filled. The recruitment was stopped in March 2016. Results were coming soon.
The role of the immunosuppressive agents in the improvements in transplant outcomes over the past three decade is undeniable (Table 3). The registration of generic immunosuppressive drugs is not going to change in the next ten years, although the transplant community has request to do so . Bioequivalence studies, performed in healthy volunteers and not in transplant patients, will remain the backbone of the registration process. There is a decided drug acquisition cost-benefit when using generic immune-suppressants which may improve medication access and adherence. The majority of the data with generic immune-suppressants demonstrate their efficacy and safety both when used de novo and for conversion in transplanted patients [52,53], with a cost benefit effect. The first substitution should made on the initiative of the prescriber with consent of the patient. Therapeutic activity should be controlled carefully thereafter. After the first switch from innovator to generic under the conditions mentioned above, no further substitution from one generic to another should be performed. Therefore for the first substitution it is better to prescribe a branded generic specifying which formulation should be dispensed to the patient; the successive one should be the same one. Health insurance agencies, and other payers should not force pharmacists to deliver any generic formulation to patients, but always the same one. Bioequivalence should not be interpreted as drugs being identical, and it is not true that patients can unconditionally switched from one generic formulation to another [54,55].
|• Generic immunosuppressants have been available in the global market place for more than 20 years.
• Generics are only required to prove pharmaceutical equivalence and bioequivalence approval by regulatory authorities.
• Pharmaceutical equivalence means having the same amount of the active ingredient and in similar dosages, being given by the same route of administration, and meet the same or similar manufacturing standards.
• Bioequivalence depicts the rate and extend to which the active ingredient reaches the systemic circulation by measuring area under the curve (AUC) and Cmax of both the generic and the innovator products in healthy volunteers.
• Bioequivalence standards according to the US FDA require that the geometric mean with 90% CI for the AUC and Cmax fall between 80 and 125% for all medicines.
• Both the EMA and the Canada recognize that narrow therapeutic index drugs should have stricter bioequivalence ranges and require generic narrow therapeutic index products, with Cmax between 90 and 112% of the innovator product.
• Biosimilars are not yet available for any biopharmaceutical with a transplant indication.
• Very few well-designed clinical or pharmacokinetic studies are available regarding the use of a generic immunosuppressant in a solid organ transplant population.
• The data that are available point the fact that generic immunosuppressants appear to be equally safe and effective compared with innovator product, but require close monitoring when converting a patient from a brand product to a generic.
• Several transplant organizations have create consensus statements regarding immunosuppressants and generally support their use under controlled conditions where therapeutic drug monitoring is utilized to monitor patients’ response to a generic.
• One concern that remains in the transplant community is the potential for generic-to-generic conversions at the pharmacy level that might necessitate intensified monitoring or be done without notification to the patient or prescriber.
Table 3: Key points in the use of generic immunosuppressive drugs in solid organ transplantation.
High quality data showing bioequivalence and clinical efficacy of generic immune-suppressants in solid organ transplants are lacking. Well designed, randomized controlled trial comparing clinical end-points are unlikely to be performed because of the large sample sizes that would be needed and the additional costs. What may be more easily obtained is that switching from one generic formulation to another should be prohibited. Only the, generic substitution will be safe.
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