Companion Diagnostics
Continued from page 39
changes throughout the genome – that
are not considered “driver gene” mutations, they continued. “They are simply
passenger changes that confer no selective
growth advantage.”
While normal cells also undergo
genetic alterations as they divide and are
programmed to enter cell death in response,
they explained, cancer cells have evolved to
tolerate genome complexity by acquiring
mutations. “Thus, genomic complexity is,
in part, the result of cancer, rather than the
cause,” Dr. Vogelstein and colleagues added.
Given this genomic complexity, how can
clinicians who treat patients with hematologic malignancies interpret genetic data in a
reliable, meaningful way for their patients?
“That’s a tough question,” Geoffrey
Ginsburg, MD, PhD, professor of medicine at Duke Center for Applied Genomics and Precision Medicine at Duke
University in Durham, North Carolina,
admitted. “In general, we are still learning
how to interpret genetic information from
AFSTYLA®, Antihemophilic Factor (Recombinant), Single Chain
For Intravenous Injection, Powder and Solvent for Injection
Initial U.S. App roval: 2016
----------------------------DOSAGE FORMS AND STRENGTHS-----------------------------AFSTYLA is available as a white or slightly yellow lyophilized powder supplied in single-use
vials containing nominally 250, 500, 1000, 2000, or 3000 International Units (IU).
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AFSTYLA
safely and effectively. See full prescribing information for AFSTYLA.
--------------------------------------CONTRAINDICATIONS------------------------------------Do not use in patients who have had life-threatening hypersensitivity reactions, including
anaphylaxis to AFSTYLA or its excipients, or hamster proteins.
------------------------------------INDICATIONS AND USAGE---------------------------------AFSTYLA®, Antihemophilic Factor (Recombinant), Single Chain, is a recombinant,
antihemophilic factor indicated in adults and children with hemophilia A (congenital Factor
VIII deficiency) for:
• On-demand treatment and control of bleeding episodes,
• Routine prophylaxis to reduce the frequency of bleeding episodes,
• Perioperative management of bleeding.
--------------------------------WARNINGS AND PRECAUTIONS------------------------------• Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms
occur, immediately discontinue AFSTYLA and administer appropriate treatment. (5.1)
• Development of Factor VIII neutralizing antibodies (inhibitors) can occur. If expected
plasma Factor VIII activity levels are not attained, or if bleeding is not controlled
with an appropriate dose, perform an assay that measures Factor VIII inhibitor
concentration.
• If the one-stage clotting assay is used, multiply the result by a conversion factor of 2
to determine the patient’s Factor VIII activity level.
Limitation of Use
AFSTYLA is not indicated for the treatment of von Willebrand disease.
--------------------------------DOSAGE AND ADMINISTRATION-----------------------------For intravenous use after reconstitution only.
• Each vial of AFSTYLA is labeled with the amount of recombinant Factor VIII in
international units (IU or unit). One unit per kilogram body weight will raise the
Factor VIII level by 2 IU/dL.
• Plasma Factor VIII levels can be monitored using either a chromogenic assay or a
one-stage clotting assay – routinely used in US clinical laboratories. If the onestage clotting assay is used, multiply the result by a conversion factor of
2 to determine the patient’s Factor VIII activity level.
----------------------------------------ADVERSE REACTIONS----------------------------------The most common adverse reactions reported in clinical trials (>0.5% of
subjects) were dizziness and hypersensitivity.
To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring
Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
-------------------------------USE IN SPECIFIC POPULATIONS-------------------------------• Pediatric: Clearance (based on per kg body weight) is higher in pediatric patients 0 to
<12 years of age. Higher and/or more frequent dosing may be needed.
Calculating Required Dose:
Dose (IU) = Body Weight (kg) x Desired Factor VIII Rise (IU/dL or %
of normal) x 0.5 (IU/kg per IU/dL)
Routine Prophylaxis:
• Adults and adolescents (≥12 years): The recommended starting regimen is 20 to
50 IU per kg of AFSTYLA administered 2 to 3 times weekly.
• Children (<12 years): The recommended starting regimen is 30 to 50 IU per kg of
AFSTYLA administered 2 to 3 times weekly. More frequent or higher doses may be
required in children <12 years of age to account for the higher clearance in this age
group.
• The regimen may be adjusted based on patient response.
Perioperative Management:
• Ensure the appropriate Factor VIII activity level is achieved and maintained.
Based on May 2016 version
genome sequencing. Much of what we
derive from this information and how we
use it depends on the reference databases
that we use for germline sequencing.”
“When it comes to sequencing in
hematologic malignancies, most clinicians
are going to get back a report from the lab
suggesting that certain variants may be
underlying the etiology of the tumor. In
many cases, it could be several variants,” he
added. “So, if there are three or four potential drivers of a tumor, each with a different
targeted therapy, which one should be
selected as a target? And which one is
more likely to be the underlying cause of a
patient’s tumor? That is a really tough area.”
Duke, for instance, is one of many institutions that has set up multidisciplinary
tumor boards specifically to discuss
these complex cases and make treatment
recommendations for these patients. “I’d
recommend that hematologists/oncologists partner with tertiary cancer centers,
and bring their cases into the mix,” Dr.
Ginsburg said. “It would be an opportunity to learn more about interpreting these
genetic abnormalities.”
Large-scale, global efforts are underway to develop interpretive algorithms
for genetic data, he noted. For instance,
the Genomics England program combines genomic sequencing and medical
records data to sequence 100,000 genomes
from 70,000 participants. This and other
projects hopefully will help clinicians
answer those tough treatment questions,
Dr. Ginsburg added. “Eventually, we can
begin to designate genomic data in clear
categories, such as ‘definitely pathologic’
or ‘uncertain significance,’” he said.
Having these algorithms would also help
in communicating complex genetic data and
the significance of these data to patients, Dr.
Zehnder added. “There is clearly a need for
more health-care professionals, like genetic
counselors, with the skills to explain this
challenging genetic information to patients
in a clear way,” he said. “Physicians who
have been in practice for a long time may
not necessarily have those skills.”
The FDA and the Future
Companion diagnostics are federally
regulated under the same rules as any
other diagnostic device, but they are approved together wit h a targeted therapy.
The FDA’s Center for Drug Evaluation
and Research or the Center for Biologic
Evaluation and Research approves the
therapeutic product, while the Center for
Devices and Radiological Health okays
the companion diagnostic.1
“We need to understand the analytic
and clinical performance characteristics
of the test,” Drs. Becker and Mansfield
wrote, explaining the review and approval
process of these products. “We evaluate
the measurement quality of the testing
system, the actual clinical information
that the diagnostic can produce, and the
correspondence of that measurement with
August 2016