Public Access
the scientific process. Dr. Rice founded the
“Science in Balance” website (curt-rice.com),
which addresses OA issues.
“Publishing has two main legitimate
goals: dissemination of scientific results
to the scientific community and quality control,” Dr. Rice told ASH Clinical
News. “The latter is embodied today in the
peer-review part of the process. As you
can imagine, there are many variants on
peer review – including ‘crowd-sourcing’
review through preprints – but it cannot
be abandoned.”
Regardless of how an article reaches
the public eye, OA or preprint, “the substantial move toward digital publishing
– independent of business model – opens
the door to new approaches to quality
control,” he added.
While other scientific fields may be
optimistic about preprint, Dr. Löwenberg
questioned whether it would be as popular
in biomedicine. Blood, and most other major clinical journals, does not currently accept preprint papers, he noted, reiterating
the importance of research being validated
and reviewed prior to public release.
Notably, since preprint refers to
published material, when a traditional
journal selects to formally publish the
ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated]
Lyophilized Powder for Solution For Intravenous Injection
Brief Summary of Prescribing Information: Please see package insert for full Prescribing Information.
INDICATIONS AND USAGE
ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated,
is a human antihemophilic factor indicated in adolescent and
adult patients (12 years and older) with hemophilia A
(congenital factor VIII deficiency) for:
• On-demand treatment and control of bleeding episodes
Table 1: Adverse Reactions Reported for ADYNOVATE
MedDRA
Preferred
Term
Number of
Subjects n (%)
(N=169)
Percent per
Infusion
(N = 13579)
Diarrhea
1 (0.6%)
0.01%
Nausea
2 (1.2%)
0.01%
Nervous System Disorders
Headache
5 (3.0%)
0.06%
Vascular Disorders
Flushing
1 (0.6%)
0.01%
MedDRA
System Organ Class
Gastrointestinal Disorders
• Routine prophylaxis to reduce the frequency of bleeding episodes
ADYNOVATE is not indicated for the treatment of
von Willebrand disease.
CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior
anaphylactic reaction to ADYNOVATE, to the parent molecule
(ADVATE), mouse or hamster protein, or excipients of ADYNOVATE
(e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE.
Allergic-type hypersensitivity reactions, including anaphylaxis,
have been reported with other recombinant antihemophilic factor
VIII products, including the parent molecule, ADVATE. Early signs
of hypersensitivity reactions that can progress to anaphylaxis may
include angioedema, chest tightness, dyspnea, wheezing, urticaria,
and pruritus. Immediately discontinue administration and initiate
appropriate treatment if hypersensitivity reactions occur.
Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to factor VIII can
occur following administration of ADYNOVATE. Monitor patients
regularly for the development of factor VIII inhibitors by appropriate
clinical observations and laboratory tests. Perform an assay that
measures factor VIII inhibitor concentration if the plasma factor VIII
level fails to increase as expected, or if bleeding is not controlled
with expected dose.
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated onestage clotting assay to confirm the adequate factor VIII levels have
been achieved and maintained.
• Monitor for the development of factor VIII inhibitors. Perform the
Bethesda inhibitor assay to determine if factor VIII inhibitor is
present. If expected factor VIII activity plasma levels are not
attained, or if bleeding is not controlled with the expected dose of
ADYNOVATE, use Bethesda Units (BU) to determine inhibitor levels.
ADVERSE REACTIONS
Common adverse reactions (≥1% of subjects) reported in the
clinical studies were headache and nausea.
Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in clinical trials of
another drug and may not reflect the rates observed in practice.
The safety of ADYNOVATE was evaluated in 169 previously treated
patients (PTPs) with severe hemophilia A (factor VIII less than 1% of
normal), who received at least one dose of ADYNOVATE in 2 multi-center,
prospective, open label clinical studies and 3 ongoing clinical studies.
The median duration of participation per subject was 333 (min-max:
1-593) days and the median number of exposure days to ADYNOVATE
per subject was 96 (min-max: 1-170). Table 1 lists the adverse
reactions reported during clinical studies.
No events of hypersensitivity were reported.
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of
ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical
trials. Study subjects consisted of adult (n=143 with ≥ prior 150 EDs)
and pediatric PTPs [(< 6 years of age with ≥50 prior EDs (n= 3),
≥6 years of age with ≥150 prior EDs (n= 23)]. In 120 adult and pediatric
PTPs who were treated for at least 50 exposure days with ADYNOVATE,
the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.03) for the
risk of any factor VIII inhibitor. None of the 169 individual subjects
who received at least one infusion of ADYNOVATE developed
neutralizing antibodies to factor VIII.
article, the article essentially becomes
“reprinted.” In this case, most journals
require that copyright to the published
material be transferred from the author
to the journal. Springer Science+Business
Media, for example, specifies in its policies that authors can keep prior versions
of the accepted article on non-commercial preprint servers like arXiv.org, but
the final published version of the article
becomes the copyrighted material of
the publisher. Copyright policies differ among publishers, though, and
“many legal issues surrounding the
internet and intellectual property
are still murky and rapidly changing,” Mr. Tomaiuolo and Ms. Packer
noted.
Mostly, the sources who spoke
with ASH Clinical News advised authors to keep an open mind: OA is a
rapidly evolving, thriving community
with both good and bad aspects. If an
OA journal looks too good to be true,
then it probably is.
OA is certainly not a panacea;
along with the promise, there are
problems. The sustainability of the
OA business model, and whether it
can afford to support a strict peer
review process, is still undetermined.
The OA movement represents a
cultural shift in scientific publishing.
Without practices in place to ensure
that that knowledge is as accurate
and correct as possible, having people
buy into that new model will be an
uphill battle. —By Shalmali Pal ●
REFERENCES
Immunogenicity also was evaluated by measuring the development
of binding IgG and IgM antibodies against factor VIII, PEGylated
(PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein
using validated ELISA assays. None of the 169 treated subjects with
at least one infusion of ADYNOVATE developed a persistent binding
antibody response to any of these antigens. Thirteen subjects in total
showed pre-existing antibodies to factor VIII (n=1), PEG-factor VIII
(n=12) and/or PEG (n=3) prior to the first exposure to ADYNOVATE.
Eight subjects who tested negative at screening developed
transient IgG antibodies against factor VIII (n=5), or PEG-FVIII (n=3)
at one or two consecutive study visits. Binding antibodies that were
detected prior to exposure to ADYNOVATE or that transiently
developed during the study could not be correlated to an impaired
treatment efficacy, altered PK parameters or adverse reactions.
No subject had pre-existing or treatment-emergent antibodies to
CHO protein.
1. Cold Spring Harbor Laboratory Library. Guide to Open Access:
History of the OA movement. Accessed August 4, 2016 from
http://cshl.libguides.com/c.php?g=474046&p=3243855.
The detection of antibodies that are reactive to factor VIII is
highly dependent on many factors, including: the sensitivity
and specificity of the assay, sample handling, timing of sample
collection, concomitant medications and underlying disease.
For these reasons, comparison of the incidence of antibodies to
ADYNOVATE with the incidence of antibodies to other products
may be misleading.
7. B lood. Public Access. Accessed September 25, 2016 from
http://www.bloodjournal.org/page/public-access.
BAXALTA, ADVATE, ADYNOVATE, and BAXJECT are trademarks
or registered trademarks of Baxalta Incorporated, a wholly
owned, indirect subsidiary of Shire plc. SHIRE and the Shire
Logo are trademarks or registered trademarks of Shire
Pharmaceutical Holdings Ireland Limited or its affiliates.
Patented: see www.shire.com/productpatents/.
2. B udapest Open Access Initiative. About. Accessed July 22,
2016 from http://www.budapestopenaccessinitiative.org/
read.
3. Washington DC Principles for Free Access to Science.
Statement. Accessed September 25, 2016 from http://www.
dcprinciples.org/statement.pdf.
4. Shattil, S. Open access, yes! Open excess, no! Blood. 2004;
103:3257; doi:10.1182. Accessed September 25, 2016 from
http://www.bloodjournal.org/content/103/9/3257.
5. PLOS. Who We Are. Accessed September 4, 2016 from
https://www.plos.org/who-we-are.
6. BioMed Central. BioMed Central journals see growth
in impact. Accessed July 22, 2016 from https://www.
biomedcentral.com/about/press-centre/business-pressreleases/03-07-2015.
8. N ational Institutes of Health. Frequently Asked Questions
about the NIH Public Access Policy. Accessed September 26,
2016 from http://publicaccess.nih.gov/faq.htm.
9. ASAPBio. bioRxiv: A Progress Report. Accessed September
25, 2016 from http://asapbio.org/biorxiv.
10.Bohannan J. Study of massive preprint archive hints at
the geography of plagiarism, December 11, 2014. Accessed
September 25, 2016 from http://www.sciencemag.org/
news/2014/12/study-massive-preprint-archive-hintsgeography-plagiarism.
11. Tomaiuolo NG, Packer JG. Preprint Servers: Pushing the Envelope of Electronic Scholarly Publishing. Accessed September
24, 2016 from http://www.infotoday.com/searcher/oct00/
tomaiuolo&packer.htm.
Shire
Westlake Village, CA 91362 USA
U.S. License No. 2020
Issued 11/2015
15E001-ADY-US
USBS/MG159/16-0070
October 2016