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Transcript
ASBMT POSITION STATEMENT
Generic Immunosuppressants in Hematopoietic
Cell Transplantation
Corey Cutler,1,* Aaron Kesselheim,2 Steven Gabardi,3 Borje S. Andersson,4 Paul Carpenter,5
Hanna J. Khoury,6 Mark Litzow,7 Scott D. Rowley,8 Scott Lanum,5 Helen Leather,9
Ya-Chen Tina Shih,10 Robert Peter Gale,11 John R. Wingard,12
Frederick R. Appelbaum,5 Claudio Anasetti13
SCOPE OF THE ISSUE
Successful immune suppression and modulation is
a cornerstone in the hematopoietic cell transplantation
(HCT) process. Only a limited number of active
immunosuppressive compounds are commonly used
in HCT. Despite the relatively limited number of
HCTs performed in the United States each year, there
is a multimillion dollar market for pharmaceutical
immunosuppressants, given the more extensive use of
these drugs in solid organ transplantation. As such,
an active generic immunosuppressant industry has
evolved over the past few years.
Clinical studies comparing outcomes from the use
of brand-name and generic immunosuppressant drugs
From 1Hematologic Malignancies and Stem Cell Transplantation,
Dana-Farber Cancer Institute, Boston, Massachusetts; 2Pharmacoepidemiology and Pharmacoeconomics, Brigham and
Women’s Hospital, Boston, Massachusetts; 3Transplant Surgery, Renal Division and Pharmacy Services, Brigham and
Women’s Hospital, Boston, Massachusetts; 4Stem Cell Transplantation and Cellular Therapy, University of Texas M.D.
Anderson Cancer Center, Houston, Texas; 5Fred Hutchinson
Cancer Research Center, Seattle, Washington; 6Hematology
and Medical Oncology, Winship Cancer Institute of Emory
University, Atlanta, Georgia; 7Hematology, Mayo Clinic,
Rochester, Minnesota; 8Blood and Marrow Transplantation
Program, Hackensack University Medical Center, Hackensack,
New Jersey; 9NucleusX, New York, New York; 10Health Services Research, University of Texas M.D. Anderson Cancer
Center, Houston, Texas; 11Celgene Corporation, Summit,
New Jersey; 12Hematology/Oncology, University of Florida
College of Medicine, Gainesville, Florida; and 13Department
of Blood and Marrow Transplant, Moffitt Cancer Center,
Tampa, Florida.
Approved for publication by the ASBMT Executive Committee,
October 2010.
Financial disclosure: See Acknowledgments on page 289.
* Task Force Chair
Correspondence and reprint requests: Corey Cutler, MD, MPH,
FRCP(C), Dana-Farber Cancer Institute, 44 Binney Street,
Boston, MA 02115 (e-mail: [email protected]).
Received November 3, 2010; accepted November 4, 2010
Ó 2011 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2010.11.006
in HCT have not been performed, and the use of generic immunosuppressants has not been recommended or discouraged by the American Society of Blood
and Marrow Transplantation (ASBMT). In September
2009, the ASBMT’s Executive Committee convened
a Task Force to evaluate the use of generic immunosuppressants in HCT. The Task Force examined
issues of drug bioequivalence, drug safety, and pharmacoeconomics in HCT and prepared this report by
consensus. Opinions were solicited from members of
the brand-name pharmaceutical industry, the generic
pharmaceutical industry, and the insurance industry,
as well as university-based healthcare economists and
researchers.
GENERIC IMMUNOSUPPRESSANTS
Many different pharmaceutical companies produce generic immunosuppressant agents. At the time
of this writing, there are at least 8 generic versions of
mycophenolate mofetil (CellCept; Roche, San Francisco, CA) and 3 generic versions of tacrolimus (Prograf; Astellas, Deefield, IL) on the market in the
United States (Figure 1). Numerous generic versions
of cyclosporine have been marketed for years, and
the transplantation community has long used generic
versions of prednisone without issues.
A generic drug product is one that is comparable to
a brand name drug product in dosage form, strength,
route of administration, quality, performance characteristics, and intended use [1]. Generic drugs contain
active ingredients that are identical to the corresponding brand-name formulations; sometimes the active
compound is even purchased from the same chemical
manufacturer. The differences between brand-name
and generic drugs lie in the excipients included in the
formulations, as well as in the physical composition
of the drug in pill, liquid, or i.v. formulations.
Generic medications are approved by the Food and
Drug Administration (FDA) through a process known
as an Abbreviated New Drug Application (ANDA).
The key to the ANDA approval process lies in
285
286
C. Cutler et al.
Biol Blood Marrow Transplant 17:285-290, 2011
Figure 1. Images of commercially available preparations of mycophenolate mofetil and tacrolimus, where available.
bioequivalence testing. Bioequivalence testing for generic drugs is governed by the Drug Price and Competition and Patent Term Restoration Act of 1984 (also
known as the Waxman-Hatch Act), an update to the
ANDA process initially promulgated in 1970 (described in §21 CFR Parts 314 and 320). Evidence of bioequivalence is often, if not exclusively, demonstrated
in normal volunteers, whereby the pharmacokinetics
(area under the curve [AUC] and peak concentration
[Cmax]/time to peak concentration [Tmax]) of single
or multiple doses of the generic compound are compared with the brand-name compound in a crossover
fashion. Generic manufacturers do not need to recapitulate any phase I-III clinical tests that have already
been performed to demonstrate the safety and efficacy
of the brand-name drug to the FDA [2].
The statistical requirements for bioequivalence,
expressed as an average AUC or Cmax ratio of the generic compound to the brand-name compound, allow
up to 20% variability between brand-name and generic
compounds. Thus, using 90% confidence intervals,
a generic product may have pharmacokinetic properties anywhere between 80% and 125% (the inverse
of 80%) of those of the parent compound to fulfill
Biol Blood Marrow Transplant 17:285-290, 2011
the requirements for bioequivalence [3]. This wide
equivalence range represents the total variability of
the test subjects and is influenced by intersubject
variability during the testing phase, as well as the
variance of the bioanalytical assays used to measure
pharmacokinetics.
The FDA recently published a retrospective analysis of the bioequivalence testing of oral agents subjected to the ANDA approval process over the last 12
years. In this analysis of 2070 bioequivalence assays,
the average differences in Cmax and AUC were
4.57% 6 3.59% and 3.17% 6 2.69%, respectively.
These variances were slightly lower when 1788
immediate-release–only formulations were examined
(4.43% 6 3.50% and 3.15% 6 2.66%, respectively).
The FDA found that 97.8% of the immediate-release
formulations had AUC differences of \10% [4].
Two recent systematic reviews and meta-analyses in
randomized controlled trials found no evidence of
a superiority of brand-name drugs over generic drugs
in terms of efficacy in treating cardiovascular disease
(including anticoagulation with warfarin) [5] or epilepsy [6].
Anecdotal evidence has emerged of patients experiencing different outcomes on switching from brandname to generic products. Reports of possible clinical
differences between brand-name and generic drugs are
of particular concern for so-called ‘‘narrow therapeutic
index’’ (NTI) drugs, in which the effective and toxic
doses are separated by only a small difference in plasma
concentration [7,8]. Some immunosuppressants also fall
within this category of NTI drugs. It is important to
note that in the United States, no special additional
testing is generally required for NTI drugs, although
additional testing is required by other regulatory
agencies worldwide, such as Health Canada and the
European Medicines Agency [9]. For immunosuppressants, however, the FDA has released guidance for the
testing of food effects on both tacrolimus and sirolimus
pharmacokinetics [10,11].
Given that the FDA approves generic drugs on the
basis of their pharmacokinetic equivalency, in some
circumstances, it may be important to demonstrate
pharmacodynamic and efficacy equivalency as well.
To date, however, neither brand-name nor generic
pharmaceutical manufacturers have engaged heavily
in these comparative trials.
EXPERIENCE WITH GENERIC
IMMUNOSUPPRESSANTS IN NON-HCT
SETTINGS
Given the lack of prospective or even retrospective
analyses of outcomes related to the use of generic
drugs in HCT, the Task Force reviewed the
experience with other organ transplantation when
ASBMT Position Statement
287
formulating this position paper. Because of the long
experience with alternate preparations of cyclosporine,
that drug is not reviewed here.
Tacrolimus
The first generic tacrolimus preparation was introduced to the US market in late 2009, and as such, data
on therapeutic conversion are limited. One small report of 4 pediatric patients inadvertently switched
from brand-name to generic tacrolimus showed a significant drop in tacrolimus trough levels in one patient
and acute rejection in another patient without a meaningful change in serum levels [12]. More important is
a large multicenter study of generic tacrolimus conversion in solid organ recipients. A total of 102 conversions were reported, and 29% of the patients
required dosage titration. Approximately half of the
patients required upward dosage titrations, and the
other half required dosage reductions. Importantly,
average drug costs fell by $53-$77 per month, but
this did not account for the extra costs associated
with increased therapeutic drug monitoring [13].
One prospective trial has compared the brandname and alternative generic tacrolimus preparations
in de novo renal transplantation. This trial demonstrated a near doubling of acute rejection episodes in
the 222 patients randomized to the alternative preparation. Patients in the alternative preparation group
had lower plasma drug levels compared with those in
the brand-name group, and this was the variable
most closely associated with acute rejection [14]. The
alternative compound used in that study was not officially a generic drug as defined in the United States,
because it had not been approved by the FDA. This
and other alternative preparations of tacrolimus, all
currently unavailable in the United States, have been
shown to have different physiochemical properties
than brand-name tacrolimus [15]. Other, nonrandomized analyses of alternative tacrolimus preparations
have been published [16-18].
Mycophenolate Mofetil
Even though generic mycophenolate mofetil was
introduced to the US market several years ago, the
lack of a defined serum therapeutic range has made
comparisons between brand name and generic compound less relevant. In a small series of patients with
stable renal function after renal transplantation, 13 patients underwent pharmacokinetic studies after changing from brand-name to generic mycophenolate
mofetil. All pharmacokinetic studies except 2-hour serum mycophenolic acid concentration were very similar in the brand-name and generic drugs. In addition,
serum creatinine levels remained unchanged at 12
months after the switch [19].
288
C. Cutler et al.
GUIDELINES FROM OTHER PROFESSIONAL
SOCIETIES ON GENERIC
IMMUNOSUPPRESSANTS
Other societies and professional organizations
have issued their own recommendations regarding
the use of generic immunosuppressants in their respective fields. The American Society of Transplantation
has recommended further clinical trials of generic immunosuppressants in at-risk populations, specifically
African Americans and pediatric patients, as well as
education programs designed to encourage patients
to inform their healthcare providers of the substitution
of a generic drug for a brand-name drug [20]. Similar
recommendations have been put forth by the International Society for Heart and Lung Transplantation
[21]. The American Society of Nephrology does not
have a published position on the topic; however, the
National Kidney Foundation previously endorsed the
use of generic immunosuppressant drugs, largely on
the basis of the potential pharmacoeconomic benefits
of these agents, while similarly calling for increased
testing in transplantation subpopulations [22].
SPECIFIC ISSUES IN HCT
In HCT, nearly all patients must contend with polypharmacy, and drug–drug interactions are often variable and unpredictable. These drug interactions exist
between multiple immunosuppressants and supportive
care medications, such as antifungal agents.
In at least one series in solid organ transplantation,
differentiation between brand-name and generic cyclosporine was determined based on drug interactions
with sirolimus [23]. This is relevant for medications
such as tacrolimus, for which drug levels can be measured and dosage modifications made as long as the
treating clinician is aware that a change in one drug
is made. However, there currently is no mechanism
to make clinicians aware of a therapeutic change in
drug supply. The consequences of these dosage
changes can be severe with respect to the level of the
changed drug as well as with potential interactions
with other drugs. Because generic drugs can have up
to a 20% difference in pharmacokinetic properties
with their brand-name counterparts (although such extreme differences were not routinely observed in the
FDA study), a change from a generic drug with an anticipated pharmacokinetic absorption profile 20%
lower than the brand-name drug to a generic drug
with an anticipated pharmacokinetic profile 20%
higher than the brand-name compound can lead to
considerable differences in serum drug concentrations.
Again, for drugs such as tacrolimus, as long as there
is forewarning, close monitoring of serum levels can
be initiated. However, for mycophenolate mofetil,
for which drug level monitoring is not routinely
Biol Blood Marrow Transplant 17:285-290, 2011
performed and an optimal therapeutic window is not
known, this change can have important clinical consequences. Both changes from a brand-name to generic
formulation and from one generic formulation to another generic formulation can have these unanticipated consequences. Similar changes in therapeutic
drug levels of supportive medications used in HCT
can occur as well, and measurement of these drugs in
the blood should be performed whenever possible.
One scenario of note relevant in HCT is the potential for a drug formulation change upon hospital discharge after transplantation. Although patients are
likely to be provided a consistent formulation while
hospitalized, the first prescription in the outpatient
setting may be a different formulation. Because close
drug-level monitoring is often maintained after transplantation, this is not likely to be associated with significant periods of time at either subtherapeutic or
supratherapeutic drug levels, when measurable. In
general, drug-level monitoring should be done at least
once at approximately 1 week after a change in drug
formulation.
PHARMACOECONOMIC AND SOCIETAL
PERSPECTIVES ON THE USE OF GENERIC
DRUGS IN HCT
The Task Force considered several other positions
when generating this report. These positions are from
two distinct groups: drug manufacturers (of both
brand-name and generic drugs) and the payers, a group
comprising individual patients, insurance agencies,
and the governmental healthcare support system.
From the patients’ standpoint, interventions that
reduce out-of-pocket costs through a reduction or
abatement of copayments for prescription drugs can
promote adherence to chronic medication therapy
[24]. In general, patients’ responsibilities for paying
for prescription medications generally decrease with
a change from brand-name to generic preparations,
because a tiered formulary is common in insurance
plans with prescription drug coverage. This was demonstrated in the recent trial of a planned switch from
a brand-name to a generic drug in renal transplantation.13 Although not yet proven in HCT or organ
transplantation, it has been demonstrated in other
fields that copayments are significantly negatively
associated with prescription medication adherence
[25-27].
From the payers’ standpoint, any intervention that
reduces costs associated with healthcare delivery without a change in patient outcomes is viewed favorably. A
reduction in medication costs for the insurer (or governmental healthcare provider) could lead to greater
coverage for services previously not covered for
HCT patients as well as others in a similar situation.
However, if switching to generic immunosuppressants
ASBMT Position Statement
Biol Blood Marrow Transplant 17:285-290, 2011
would require more intensive monitoring and/or lead
to higher rates of adverse events, then these higher
downstream costs could outweigh the initial cost
savings associated with the use of generic drugs.
Pharmaceutical companies engaged in research to
develop immunosuppressants for HCT stand to lose
the most as bioequivalent generic competitors are approved and become more widely used. Manufacturers’ substantial research and development costs
for future drugs are funded by revenues from currently marketed drugs, and thus the FDA has provided patent protection time periods meant to allow
pharmaceutical companies time to recover the costs
of drug development. On the other hand, market exclusivity leading to higher prices for brand name
drugs should not be indefinite. Current legal limits
on patent length suggest that patients should be allowed to enjoy enhanced access derived from the
availability of lower-cost generic drugs after a certain
period. It is beyond the scope of this Task Force to
comment further on the issues of the duration of
patent protection and cost recovery.
289
should be monitored, preferably after several half-lives
of the drug have passed. In general, monitoring at least
1 week from the time of a formulation change should
be sufficient.
4. Clinical trials. Clinical trials for equivalence,
focusing on graft-versus-host disease and related outcomes, should be encouraged. Well-controlled observational trials also may provide insight into the
question of the clinical equivalence of brand name
and generic immunosuppressants. Individual drug
levels, although relevant, are less important than
trends and associations with poorer control of the adverse immunologic consequences of HCT.
5. Analysis of true cost. Although generic drugs
may have lower retail costs and lower insurance copayments compared with brand-name drugs, studies of
the true cost of these substitutions, including the costs
associated with increased drug monitoring and the potential costs of adverse events associated with altered
drug levels, should be performed to determine the
financial implications of the use of generic immunosuppressants in HCT.
RECOMMENDATIONS OF THE TASK FORCE
1. Patient education. Patients should be educated
on the possibility that their immunosuppressant medications could be altered in shape, size, or color. They
should be educated that the FDA approves generic
drugs as being bioequivalent to brand name products,
and that there is no evidence suggesting that brand
name drugs are superior. However, patients also
should be encouraged to inform their healthcare providers of any change in their immunosuppressant
drugs. Figure 1 should be provided to patients, made
available on the ASBMT Web site for providers, and
periodically updated when new drug formulations are
approved for use.
2. Consistent use of one drug formulation. Providers should attempt to use only one formulation of
an immunosuppressant drug, either consistently prescribing a brand name or a generic formulation, to reduce the possibility of changes in drug levels.
Specifying which generic formulation in a prescription
might not be feasible, however, given that a pharmacy
is likely to only carry one generic formulation at a time.
HCT physicians also should be encouraged to engage
patients in conversations about their drug costs and the
financial burden of these costs. If such a discussion
suggests a concern for reduced adherence due to
continued prescription of a more costly brand name
formulation, then a monitored switch to a generic
version should be encouraged.
3. Enhanced monitoring after formulation
changes. Whenever patients change drug formulations, either between brand name and generic formulations or between two generic formulations, drug levels
ACKNOWLEDGMENTS
The Task Force appreciates the input of Agnes
Costello, PharmD, (Genzyme Corporation) and
Marc Goshko (TEVA Pharmaceuticals), as well the
administrative leadership of Thomas Joseph, MPS
CAE.
Financial disclosures: Corey Cutler has received research support from Otsuka, Astellas, and Pfizer and
serves on the Advisory Board or as a consultant to
Otsuka, Astellas, Celgene, and Spectrum. Aaron
Kesselheim serves as a consultant to the Alosa Foundation/Independent Drug Information Service. Scott D.
Rowley serves on the Eusa speaker’s bureau and has
equity in Pfizer and Johnson & Johnson. John R.
Wingard has received honoraria from Pfizer, Astellas,
Vical, and Merck. None of the other authors has any
conflicts of interest to disclose.
REFERENCES
1. Food and Drug Administration. Abbreviated New Drug Application (ANDA): generics. Available at: http://www.fda.gov/
drugs/developmentapprovalprocess/howdrugsaredevelopedand
approved/approvalapplications/abbreviatednewdrugapplication
andagenerics/default.htm. Accessed September 15, 2010.
2. Tichy E, Alloway RR. Generic immunosuppressants. Available
at: http://www.a-s-t.org/rss/all.xml. Accessed January 12, 2010.
3. Food and Drug Administration. Orange Book preface. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
ucm079068.htm. Accessed September 15, 2010.
4. Davit BM, Nwakama PE, Buehler GJ, et al. Comparing generic
and innovator drugs: a review of 12 years of bioequivalence data
from the United States Food and Drug Administration. Ann
Pharmacother. 2009;43:1583-1597.
290
C. Cutler et al.
5. Kesselheim AS, Misono AS, Lee JL, et al. Clinical equivalence of
generic and brand name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300:2514-2526.
6. Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand name antiepileptic drugs: a systematic review and meta-analysis. Drugs.
2010;70:605-621.
7. Makus KG, McCormick J. Identification of adverse reactions
that can occur on substitution of generic for branded lamotrigine
in patients with epilepsy. Clin Ther. 2007;29:334-341.
8. Reiffel JA, Kowey PR. Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias.
Am J Cardiol. 2000;85:1151-1153.
9. Christians U, Klawitter J, Clavijo CF. Bioequivalence testing of
immunosuppressants: concepts and misconceptions. Kidney Int.
2010;115(Suppl):S1-S7.
10. Food and Drug Administration. Draft guidance on sirolimus. Available at: www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM089640.pdf. Accessed
November 4, 2010.
11. Food and Drug Administration. Guidance on tacrolimus. Available at: www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/UCM181006.pdf. Accessed.
12. Abdulnour HA, Araya CE, Dharnidharka VR. Comparison of
generic tacrolimus and Prograf drug levels in a pediatric kidney
transplant program. Pediatr Transplant. 2010;14(8):1007-1011.
13. McDevitt-Potter L, Sadaka B, Tichy E, et al. Experience with
generic tacrolimus conversion. Submitted 2010.
14. Corzo H, et al. A post-hoc analysis of the safety and efficacy of
tacrolimus (Prograf) versus a generic formulation of tacrolimus
(Tenacrine) as primary immunosuppressive therapy in LRD
and CAD adults and pediatric renal transplant recipients. Presented at the 22nd International Congress of the Transplantation Society, 2008. August 10-14, 2008, Sydney, Australia.
15. Petan JA, Undre N, First MR, et al. Physiochemical properties
of generic formulations of tacrolimus in Mexico. Transplant
Proc. 2008;40:1439-1442.
16. Crespo M, Mir M, Marin M, et al. De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to
get therapeutic levels. Transplant Proc. 2009;41:2115-2117.
Biol Blood Marrow Transplant 17:285-290, 2011
17. Guleria S, Kamboj M, Chatterjee A, et al. Generic tacrolimus
(Pan Graf) in renal transplantation: an experience of 155 recipients in India. Transplant Proc. 2008;40:2237-2239.
18. Kim SJ, Huh KH, Han DJ, et al. A 6-month, multicenter, singlearm pilot study to evaluate the efficacy and safety of generic
tacrolimus (TacroBell) after primary renal transplantation.
Transplant Proc. 2009;41:1671-1674.
19. Videla C, Godoy C. Converting to a generic formulation of mycophenolate mofetil in stable kidney transplant recipients: 1 year
of drug surveillance and outcome. Transplant Proc. 2007;39:
602-605.
20. Alloway RR, Isaacs R, Lake K, et al. Report of the American
Society of Transplantation conference on immunosuppressive
drugs and the use of generic immunosuppressants. Am J Transplant. 2003;3:1211-1215.
21. Uber PA, Ross HJ, Zuckermann AO, et al. Generic drug immunosuppression in thoracic transplantation: an ISHLT educational advisory. J Heart Lung Transplant. 2009;28:655-660.
22. Sabatini S, Ferguson RM, Helderman JH, et al. Drug substitution in transplantation: a National Kidney Foundation white
paper. Am J Kidney Dis. 1999;33:389-397.
23. Kovarik JM, Noe A, Wang Y, et al. Differentiation of innovator
versus generic cyclosporine via a drug interaction on sirolimus.
Eur J Clin Pharmacol. 2006;62:361-366.
24. Shrank WH, Hoang T, Ettner SL, et al. The implications of
choice: prescribing generic or preferred pharmaceuticals
improves medication adherence for chronic conditions. Arch
Intern Med. 2006;166:332-337.
25. Kane SV, Accortt NA, Magowan S, et al. Predictors of persistence with 5-aminosalicylic acid therapy for ulcerative colitis.
Aliment Pharmacol Ther. 2009;29:855-862.
26. Shah NR, Hirsch AG, Zacker C, et al. Predictors of first-fill
adherence for patients with hypertension. Am J Hypertens.
2009;22:392-396.
27. Shah NR, Hirsch AG, Zacker C, et al. Factors associated with
first-fill adherence rates for diabetic medications: a cohort study.
J Gen Intern Med. 2009;24:233-237.
Ó 2011 American Society for Blood and Marrow
Transplantation