Blood, 1 December 2002, Vol. 100, No. 12, pp. 4242-4242
CORRESPONDENCE
To the editor:
Human recombinant factor IX: safety and efficacy studies in
hemophilia B patients previously treated with plasma-derived factor IX
concentrates
Roth et al1 recently published the results of
clinical studies to evaluate the safety and efficacy of recombinant
human factor IX (rFIX; brand name BeneFIX) in previously treated
patients (PTPs) with severe or moderate hemophilia B. These
studies were conducted in North America and Europe from February 1995 to April 1999 and are part of the 3 pivotal clinical studies on which
the marketing authorization for BeneFIX is based.
In June 2001, the Committee for Proprietary Medicinal Products
(CPMP) expressed concern, following the outcome of a Good Clinical Practice (GCP) inspection conducted on behalf of the European Agency
for the Evaluation of Medicinal Products (EMEA) about the conduct of
these studies and the reliability of their outcome.
Therefore, the author of this letter wishes to bring to the reader's
attention the following information regarding rFIX, which was
originally published by the EMEA on its website.2
At the same time, the CPMP asked the marketing authorization holder
(Genetics Institute of Europe BV) to bring the EMEA-published
information to the attention of prescribing physicians.
The outcome of the GCP inspection of the 2 published studies revealed
GCP deficiencies that cast doubts on the reliability of the clinical
data. An independent audit of the 3 pivotal clinical studies,
commissioned by Genetics Institute of Europe BV, confirmed the GCP
deficiencies but found the data to be real and representative of the
population studied.
rFIX has been commercially available in Europe since 1999 and in the
United States since 1997. Postmarketing data accumulated since then
from physicians treating hemophilia B patients support the safety and
efficacy profile of rFIX. The CPMP considers that the benefit/risk
balance of rFIX for the treatment and prophylaxis of bleeding in PTPs
with hemophilia B is positive, based on the data presently available.
However, the data are insufficient to be certain of the frequency of
some adverse drug reactions, especially those linked to inhibitor
formation and to allergic reactions. Because of these concerns, there
is a need for enhanced surveillance of new patients receiving rFIX.
This intensive postmarketing surveillance will include a registry for
all new patients treated with rFIX in Europe. Patients already treated
with rFIX may continue their therapy. However, patients who experience
suspected adverse drug reactions should be monitored carefully and the
risks/benefits of continued treatment should be evaluated.
The recommendation to check for the presence of an inhibitor when
a lack of efficacy is observed at the recommended dose was reinforced.
Additionally, a recommendation to switch patients to another factor IX
product if doses greater than 100 IU/kg have been repeatedly needed
during routine prophylaxis or treatment, even if an inhibitor is not
detected, has been implemented by the marketing authorization holder.
At the request of the CPMP, 2 new clinical trials will be conducted by
Genetics Institute of Europe BV in accordance with the Note for
Guidance on Good Clinical Practice (CPMP/ICH/135/95)3 and
the recent CPMP Note for Guidance on the Clinical Investigation of
Recombinant Factor VIII and IX products
(CPMP/BPWG/1561/99).4
Genetics Institute of Europe BV is in the process of implementing
corrective actions to address the deficiencies found in the GCP inspection.
Manfred Haase
Correspondence: Manfred Haase, Paul-Ehrlich-Institute,
Paul-Ehrlich-Strasse 51-59, D-63225 Langen, Germany; e-mail:
haama{at}pei.de
Acknowledgments
M.H. is Chairman of the CPMP Ad Hoc working group on Blood
Products (BPWG).
References
1.
Roth DA, Kessler CM, Pasi KJ, Rup B, Courter SG, Tubridy KL.
Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates.
Blood.
2001;98:3600-3606[Abstract/Free Full Text].
2. The European Agency for the Evaluation of Medicinal Products. Intensive
post-marketing surveillance for all new patients
new clinical trials.
Available at: http://www.emea.eu.int/pdfs/human/press/pus/277701en.pdf.
October 4, 2001.
3. The European Agency for the Evaluation of Medicinal Products. Note for
guidance on good clinical practice. Available at:
http://www.emea.eu.int/pdfs/human/ich/013595en.pdf. January 1997.
4. The European Agency for the Evaluation of Medicinal Products. Note for
guidance on the clinical investigation of recombinant factor VIII and
IX products. Available at:
http://www.emea.eu.int/pdfs/human/bpwg/156199en.pdf. October 19, 2000.
Response:
Human recombinant factor IX: safety and efficacy studies in
hemophilia B patients
Wyeth Pharmaceuticals is committed to providing physicians and
patients with the most comprehensive safety and efficacy information available about rFIX (commercially distributed as BeneFIX). Dr Haase's letter is a valuable reminder to the readers of
Blood of the importance of this information. The company
continues to work diligently with the Committee for Proprietary
Medicinal Products (CPMP) to provide the necessary and appropriate data
to support the safety and efficacy of rFIX. Together with the European
regulatory agency, we have sent specific information on the rFIX
clinical trial data collection process and on modifications to the rFIX Summary of Product Characteristics (SPC) to the community through letters to hemophilia physicians and through contact with hemophilia advocacy organizations.
To address the concerns of the CPMP, the company has implemented 2 initiatives. The first is the establishment of a prospective registry
of all new hemophilia B patients in the European Union beginning
treatment with rFIX to gather additional safety information on rFIX in
the usual practice setting. The second is the initiation of new
clinical trials to obtain more data on the safety and efficacy of rFIX.
One clinical trial will study rFIX in children younger than 6 years of
age with severe hemophilia B, including both previously treated
patients and previously untreated patients. The other trial will study
rFIX in previously treated patients with severe or moderately severe
hemophilia B who are 12 years and older. Both trials were designed
taking into consideration the CPMP Guidelines for the Investigation of
Recombinant Factor VIII and Factor IX (CPMP/BPWG/1561/99 [October
2000]).
Wyeth Pharmaceuticals and Baxter Healthcarethe exclusive distributor
of BeneFIX in the European Unionencourage physicians to support
efforts to collect additional safety and efficacy information.
Harold Marder and Bruce M. Ewenstein
Correspondence: Harold Marder, Wyeth Pharmaceuticals,
240 N Radnor-Chester Rd, St Davids, PA 19087; e-mail:
marderh{at}wyeth.com
Acknowledgments
H.M. is Senior Vice President of Global Medical Affairs at Wyeth
Pharmaceuticals; B.M.E. is Global Medical Director of
Hemophilia Therapies at Baxter Bioscience (Glendale, CA).
REFERENCES
Response:
The recombinant factor IX clinical investigator group's
response to Dr Haase
As academic hematologists and clinical investigators, we depend
on the integrity and validity of clinical research data to guide our
decisions and are committed to generating reliable data of the highest
quality. Furthermore, we are committed to publishing the outcomes of
our research, especially when they significantly contribute to
advancing our clinical knowledge and improving the quality of health
care and medical practice. Regulatory agencies, such as the European
Agency for the Evaluation of Medicinal Products (EMEA), are also
dependent on the results of well-conducted studies to make their
decisions. We thank this agency for scrutinizing data to ensure that
its objectives can be achieved.
We congratulate Wyeth Pharmaceuticals for its courage to
sponsor expensive clinical research in rare diseases, especially in
hemophilia. These investigations have required a multinational effort
and have included intricate and complex clinical protocols in both the
inpatient and outpatient settings. The investigators who participated
in these trials believe that the administrative oversights uncovered by
the EMEA-commissioned Good Clinical Practice (GCP)
inspection do not compromise the scientific integrity or robustness of the data that were generated by these studies.
We are reassured by independent audits of the data, as cited in Dr
Haase's letter, because these audits confirm that the published data
are real and representative of the population studied. Dr Haase's
letter also indicates that the postmarketing data continue to support
our published conclusions regarding the safety and efficacy profile of
human recombinant factor IX (rFIX).
Lastly, we are reassured by the fact that in light of the findings of
the GCP inspection, the Committee for Proprietary Medicinal Products (CPMP) still considers that the benefit/risk
balance of rFIX for the treatment and prophylaxis of bleeding in
previously treated patients (PTPs) with hemophilia B is positive. We
directly acknowledged in our publications that additional
studies are required to define the true risk of immune responses to
rFIX, including the development of inhibitors and allergic reactions,
and we support the need for enhanced surveillance of new patients
receiving rFIX. We must emphasize to the readership of Blood
that the publications generated by these clinical
trials1,2 were based on valid data generated and
interpreted in an objective manner. These reports accurately reflect
the investigators' favorable clinical experiences with the study
patient populations as described.
David A. Roth, Craig M. Kessler, K. John Pasi, Margaret
V. Ragni, Gilbert C. White, II, Paul L. Giangrande, Victor S. Blanchette, Hans-Hermann Brackmann, Margaret A. Heisel, W. Keith Hoots, Christine Lee, Christopher A. Ludlam, Jeanne M. Lusher, Claude Negrier, Claire Philipp, Man-Chiu Poon, Georges
E. Rivard, Cathy G. Rosenfield, Amy Shapiro, Angela Thomas, Arthur R. Thompson, and Jozef Vermylen
Correspondence: David A. Roth, Beth Israel Deaconess Medical
Center, 41 Ave Louis Pasteur, RE-302, Boston, MA 02115
References
1.
Roth DA, Kessler CM, Pasi KJ, Rup B, Courter SG, Tubridy KL.
Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates.
Blood.
2001;98:3600-3606[Abstract/Free Full Text].
2.
Ragni MV, Pasi KJ, White GC, Giangrande PL, Courter SG, Tubridy KL.
Use of recombinant factor IX in subjects with haemophilia B undergoing surgery.
Haemophilia.
2002;8:91-97[Medline]
[Order article via Infotrieve].
