This Powerpoint presentation will communicate the story of a drug from market approval to post-marketing compliance with emphasis on pharmacovigilance plan to monitor and minimize safety issues.

1. ArzerraTM (Ofatumumab) from Approval
to Post-marketing Compliance
By Payam Javanmardi
Academy of Applied Pharmaceutical Sciences
Canada, Toronto, December 2014
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2. 2
On Jan 30, 2009 GlaxoSmithKline (GSK) and
Genmab A/S submitted a Biologics License
Application (BLA) to the FDA for ArzerraTM
(Ofatumumab)

3. ArzerraTM (Ofatumumab) is used to treat patients whose
Chronic Lymphocytic Leukemia (CLL) is resistant to
previous therapies.
3
CLL is the most common form of adult leukemia in the
western world.
Based on 2007 worldwide estimates, leukemia accounted for
more than 330,000 new cases and more than 245,000
deaths.

4. 154 patients with limited or no response to both
fludarabine and alemtuzumab and patients who were
refractory to fludarabine and considered inappropriate
candidates for alemtuzumab
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Clinical Efficacy
The overall response rate was 58% for fludarabine
alemtuzumab refractory group (n=59) and 47% for the
fludarabine refractory group (n=79).

5. The most common AEs seen with Arzerra were related to
infusion reactions and infections (≥ 10% of patients):
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Clinical Safety
Fever, cough, diarrhea, rash, low white blood cell counts,
fatigue, pneumonia, anemia, shortness of breath, nausea
One case of Progressive Multifocal Leukoencephalopathy
One cased of Tumor Lysis Syndrome

6. There were further clinical trials being initiated at the
time of submission.
6
The companies intended to submit an application for
marketing approval in Europe shortly.
On April 3, 2009 Genmab announced that the FDA had
accepted the application (BLA) for ArzerraTM
(Ofatumumab).
In addition, the FDA had granted Ofatumumab orphan
designation for the treatment of CLL.

7. Under priority review, the FDA set the target date for a
decision from regulators at six months, rather than the
standard 10-month review.
7
On May 29, 2009 the companies announced that the
FDA Oncologic Drugs Advisory Committee (ODAC)
voted 10 to three that the Arzerra data were reasonably
likely to predict benefit for patients with refractory CLL.

8. On June 16, 2009 the FDA informed companies that
the agency had extended the action date for the
Ofatumumab BLA application by three months to
review additional chemistry and manufacturing
information submitted on 5 June.
8
On October 26, 2009, the FDA approved ArzerraTM
(Ofatumumab) for patients with CLL, whose cancer
was no longer being controlled by other forms of
chemotherapy.

9. On April 19, 2010 the European Commission granted a
conditional marketing authorization valid throughout
the European Union for Arzerra.
9
The companies committed to carry out a study
comparing treatment with Arzerra to treatment with
other medicines chosen by the doctors, in patients with
CLL whose previous treatment with fludarabine had
failed.

10. The companies also committed to develop a Risk
Management Plan (RMP) to:
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Ensure that Arzerra is used as safely as possible

Include safety information in the summary of product
characteristics and the package leaflet
Include the appropriate precautions to be followed by
healthcare professionals and patients
Provide additional information on the effectiveness
and safety of Arzerra by the companies after
marketing

11. On January 21, 2011 GSK submitted a New Drug
Submission (NDS) to seek approval for the marketing of
Arzerra.
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On March 9, 2012 Health Canada issued a Notice of
Compliance with conditions (NOC/c) to GSK.
The safety of Arzerra was evaluated in 250 patients with
relapsed or refractory CLL in two open-label, single arm
studies.

12. The assessment of the safety of Arzerra was difficult due
to the uncontrolled, unblinded design of the pivotal
study.
12
Given the single arm design, it was impossible to discern
whether causal relationships existed between AEs and
exposure to Arzerra.
Furthermore, the number of patients treated within the
pivotal study was small, making the detection of rare
events difficult.

13. Overall, 59% of patients experienced SAEs.
13
A total of 17% of patients had SAEs that were considered
to be drug-related.
The most common drug-related SAEs were neutropenia,
pneumonia, and sepsis.
Of the 223 patients enrolled in the study, 138 died as of
the safety analysis cut-off date.

14. Development of infections was a common occurrence
during treatment with Arzerra and subsequent follow-
up.
14
The most frequent type of infections reported were of
the respiratory tract, with lower respiratory tract
infections being more common than upper.
Infection was the most common reason for drug
discontinuation.

15. Infusion reactions were notably observed in both the
pivotal and supportive studies:
Anaphylactic reactions, bronchospasm, cardiac events,
chills/rigors, cough, cytokine release syndrome, diarrhea,
dyspnea, fatigue, flushing, hypertension, hypotension,
nausea, pain, pyrexia, rash, and urticaria
15
In the majority of cases, infusion reactions did not
require study withdrawal.
Furthermore, none of the infusion reactions resulted in
death.

16. Neutropenia (hematologic AE) occurred in 17% of
patients and was considered by investigator to be related
to treatment in 13% of patients.
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Neutropenia is common in heavily treated CLL patients.
Therefore, it may be important to manage this
complication in patients that present with baseline
neutropenia and those that develop neutropenia to
prevent infections from occurring.

17. Serious and Fatal cardiovascular events were reported
following administration of Arzerra.
17
Patients with a history of cardiac disease should be
monitored closely during and after infusions and
resuscitative measures should be readily available.

18. Post-marketing commitments
Under the NOC/c Policy, GSK agreed to submit additional
documents:
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Data from currently undertaking or completed clinical
studies
Any other analyses that have been designed as post-marketing
commitments to other international authorization granting
agencies
Provide information in relation to communications and
consultations with other agencies, when applicable
Provide reports of all SAEs occurring in Canada and all
SAEs occurring outside of Canada within 15 days to
Health Canada

19. Post-marketing commitments
Submit Periodic Safety Update Reports (PSURs) for
Arzerra on a semi-annual basis until such time as
conditions associated with the market authorization are
removed.
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Implement the Risk Management Plan (RMP) in Canada
and provide any updates to the RMP when available
The sponsor should comply with the recommendations
of Marketed Health Products Directorate (MHPD) in
regards to the RMP

20. On April 17, 2014 GSK and Genmab received
FDA approval for Arzerra as first-line treatment
in combination with chlorambucil for patients
with refractory CLL.
20

21. The safety and effectiveness of Arzerra in children has not
been established and should not be used in children unless
the benefit outweighs the risks.
21
Special Populations and Recommendations
There are no data from the use of Arzerra in pregnant
women. The effect on human pregnancy is unknown.
Arzerra should not be administered to pregnant women
unless the possible benefit to the mother outweighs the
possible risk to the fetus.

22. The safe use of Arzerra in humans during lactation
(nursing women) has not been established.
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Special Populations and Recommendations
No clinically meaningful differences in the efficacy of
Arzerra plus chlorambucil were observed between older ( >
65 years of age) and younger patients.
There were also no clinically significant differences in the
common Adverse Reactions between older and younger
patients.

23. No formal studies of Arzerra in patients with renal and
hepatic impairment have been performed.
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Special Populations and Recommendations
Cytopenias, including prolonged and late-onset
neutropenia have been reported during Arzerra therapy.
Complete blood counts should be obtained prior o therapy
and at regular intervals during therapy and more
frequently in patients who develop cytopenias.
Appropriate management should be considered should
cytopenias occur.

24. FDA searched its Adverse Event Reporting System (FAERS)
database for reports submitted between the time of market
approval of Arzerra (October 2009) and August 2012 of
patients treated with Arzerra who had fatal hepatitis B-
related acute liver injury.
24
FDA post-marketing risk identification
The search identified 3 cases.

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FDA Drug Safety Communications
On September 25, 2013 the FDA through a safety
announcement (alert) has approved changes to the
prescribing information about the risk of reactivation of
hepatitis B virus (HBV) infection.
The revised label also will include additional
recommendations for screening, monitoring, and managing
patients to decrease this risk.

26. A post-marketing case of fatal infusion reaction has
occurred during administration of the first dose of Arzerra
to a 71-year old male with CLL and no known history of
cardiac disease.
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MHRA and EMA communication
On July 25, 2014 GSK in agreement with the European
Medicines Agency (EMA) and the Medicines and
Healthcare Products Regulatory Agency (MHRA) informed
healthcare professionals of risk of Serious and Fatal
infusion reaction.

27. Recommendations:
Ofatumumab should only be administered under the
supervision of a physician experienced in the use of cancer
therapy and where facilities to monitor and treat infusion
reactions are available.
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Patients should receive premedication agents 30 minutes
to 2 hours prior to each infusion of Ofatumumab,
according to the protocol in the Ofatumumab Summary of
Product characteristics (SMP).
Despite premedications, infusion reactions may still occur.
In cases of severe infusion reaction, the infusion of
Ofatumumab must be interrupted immediately and
symptomatic treatment instituted.

28. On August 6, 2014 GSK in consultation with Health
Canada, endorsed the safety issue of fatal infusion
reaction to Canadian Healthcare professionals and made
recommendations as agreed.
The product monograph is revised accordingly.
28
Health Canada communication

29. References
http://www.drugs.com/history/arzerra.html
http://www.drugs.com/history/arzerra.html
http://www.drugs.com/newdrugs/fda-approves-arzerra-
ofatumumab-chronic-lymphocytic-leukemia-1750.html
http://www.drugs.com/nda/arzerra_090130.html
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-
med/sbd_smd_2012_arzerra_128188-eng.php
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/001131/WC500093092.pdf
http://www.gsk.ca/english/docs-pdf/product-
monographs/Arzerra.pdf
http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-
sc/2014/40851a-eng.php
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM369436.pdf
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAler
tsforHumanMedicalProducts/ucm369846.htm
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