Please review and complete attached assignment (instructions are included). Example has also been provided.
Pretend you are a member of the Regulatory Affairs team at a leading biotechnology company.
Your company has developed Herceptin, a recombinant DNA-derived, humanized monoclonal
antibody that targets the extracellular domain of the ErbB-2/HER2/neu receptor (i.e., human
epidermal growth factor receptor 2; ?HER2?).
?Approximately 25-30% of breast cancers overexpress HER2. Abnormal expression of
HER2/neu is frequently observed in a number of primary tumors, suggesting that
overexpression may contribute to transformation and tumorigenesis. HER2 receptor
overexpression has been correlated with poor
clinical outcome in patients with breast cancers?.
The company has recently completed multinational Phase II and Phase III clinical studies of the
product?s safety and efficacy. Given the favorable results, your company is now preparing a
Biomarker Qualification Submission to be certain that the proposed biomarker will be valid for:
a) patient inclusion/exclusion criteria in subsequent trials, b) determining the indicated
population in the product labeling, and c) supporting a marketing approval decision to market
the product to specific patient population(s). The company has specifically proposed that the
product be indicated for ?the treatment of patients with metastatic breast cancer who have
tumors that overexpress HER2?.
The Director of Regulatory Affairs has asked you to develop the Context of Use section of the
Biomarker Qualification Overview (as required for Section 2 of the Biomarker Qualification
Submission) for the relevant biomarker.
Assignment: Using only the information provided within this assignment, write the Context of
Use statement for the Biomarker Qualification Submission. Use the information and examples
described in Guidance for Industry E16 Biomarkers Related to Drug or Biotechnology Product
Development: Context, Structure, and Format of Qualification Submissions as well as the
?Biomarker Qualification Context of Use? information from the FDA website (attached here as a
reference) as a guide for composing the Context for Use statement. Additional sources will not
Your Context for Use statement should correctly address the following areas:
1. Identification of the biomarker (2 points)
2. Aspect of the biomarker that is measured and the form in which it is used for biological
interpretation (2 points)
3. Species and characteristics of animal or subjects studied (1 point)
4. Purpose of use (for the biomarker) in drug development (2 points)
5. Drug development circumstances for applying the biomarker (3 points)
6. Interpretation, and decision/action based on biomarker (5 points)
The assignment should be submitted as a well-written and clear document, typed (Microsoft
Word) using 11-point Arial font, double-spaced, with one-inch margins. Total length is limited to
5 pages (not including references). BACKGROUND INFORMATION:
? List of Abbreviations (2 pages)
Background of the Product (3 pages)
Overview of Phase II Study (2 pages)
Overview of Phase III Study (3 pages)
Protein Overexpression and Clinical Benefit (4 pages) Clinical Herceptin@
BLA 98-0369 Review 12.0 APPENDIX C - ABBREVIATIONS AC anthracycline plus cyclophosphamide chemotherapy ACH Herceptin@ ADCC antibody-dependent Am2 Amendment BLA Biologics CAD coronary Chemo chemotherapy CHF congestive cm centimeter CR complete response CRF Case Report Form CT computed CXR chest X-ray Dig. digoxin DOE dyspnea on exertion DVT deep venous thrombosis Echo echocardiogram ECG or EKG electrocardiogram EGFR endothelial FISH fluorescence H Herceptin@ HER2 human epidermal growth factor receptor 2 HEM/neu human epidermal growth factor receptor 2 HR heart rate plus AC
cell-mediated cytotoxicity 2 to the protocol H0648g pivotal study
License Application artery disease or atherosclerosis heart failure tomographic scan growth factor receptor
in siru hybridization 96 regimen Clinical Herceptin@
BLA 98-0369 Review ICU intensive IHC immunohistochemistty
JVD jugular venous distension NP jugular venous pressure MoAb or MAb monoclonal MRI magnetic NYHA class New York Heart Association 0? oxygen therapy PD progressive Plt platelet count PND paroxysmal PR partial response RBC red blood cell count rhuMAb HER2 care unit antibody
Classification for congestive heart failure disease nocturnal recombinant dyspnea humanized RR respiratov SD stable disease SOB shortness of breath T paclitaxel TH Herceprin@ plus T VEGF vascular endothclial WBC white blood cell count XRT radiation anti-p185KRz monoclonal rate chemotherapy regimen groivth factor therapy 97 antibody = Herceptin@ Herceptin@
BLA 98-0369 Clinical Review 1 .O BACKGROUND
1.1 Introduction OF THE PRODUCT - HERCEPTIN@ Breast cancer is one of the most common malignancies
in women. It accounts for
l/3 of female cancer in the USA and therefore, remains a serious health
care problem. Approximately
of breast and ovarian cancers overexpress
HER2/neu. Abnormal expression of the HER2/neu is frequently observed in a number of
primary tumors, suggesting that overexpression
may contribute to transformation
HEIWneu overexpression has been correlated with poor clinical outcome
in patients with breast and ovarian cancers. HER21neu overexpression
appears to be
associated with shorter disease-free inten.al, shorter overall survival, more rapid disease
(higher incidence of metastasis),
and resistance to chemotherapy
retrospective studies. 1.2 HerceptinO
is a recombinant
antibody that targets the extracellular dc*main of the ErbB-2/HerYneu
engineered by grafting the complementarity
determining regions of the parental murine
antibody (4D5) into the consensus framework of a human IgGl. Herceptin@ has been produced from CHO cells maintained in cell culture systems at
Genentech for human clinical trials sir,ce 1991. The entire cell culture process from
Master Cell Bank through final production contains no serum or other animal proteins. 1.2.1 BACKGROUN?)
The HER2 Receptor
The human epidermal grov& factor receptor 2 (ErbB-21 HER2p?85) is a member of Type I
family of growth factor tyrosine kinase receptors. The family also includes the
endothelial growth factor receptor (EGFR), HER3, and HER4 receptors. These receptors
are encoded by homeotic genes and share extensive sequence homology, suggesting a
similar mechanism of activation and signaling.
These receptors function by forming
hetero- and homo-dimers with members of the family.
The c-ErbB-21 HER2p?8S proto-oncogene encodes a 185 Kd trans-membrane
in an interactive network of receptor-receptor
interactions regulate cell fate, growth and proliferation, mainly through MAP and .-Kinases. 6 Clinical _- Herceptin@
BLA 98-0369 Review Current data indicate that HER2 acts as co-receptor or a shared signaling sub-unit,
prolonging and enhancing activation of proteins involved in signal transduction pathways
Normal Expression of Her2p?B?and Its Role in Embrvooenesis:
staining showed that HER2/neu is normally widely expressed in
differentiated adult and in fetal tissues derived from the three embry?onic germ layers.
High intensity staining was reported in the gastrointestinal tract (Press M. et al. Oncogene
1990) and the proximal tubules and loop of Henle of the urinary tract (Gullick W. et al.
Int. J. Cancer, 40246-254 (1987).
Recent studies (Lee I;. et al. Nature 378:394-396, 1995) demonstrated that espression of
HERXneu is crucial for cardiac and CN> development. Mice carrying the null allele died
at El 1 due to the lack of cardiac trabeculae formation. The development of cranial neuralcrest derived sensory ganglia as vell as the motor nerves, vas also compromised.
K. et al. Nature 378:394-396 (1995).
Role of HER2?Is5 in Sirnal Transduction
The current literature supports a normal role for HERZneu as the preferred partner of all
the other fainily members (Karunagaran D. et al. Embo J:15: 253-264). Several ligands
have been characterized that bind the EGFR, HER3 and HER4. EGF and transforming
gro\-th factor-alpha (TGF-alpha) arc among the ligands for EGFR, and heregulin/NDF
factor) is the ligand for HER3 and HER4. No specific ligand for
HER2 has been found.
Ligand binding to the respecti1.e receptors induces a conformational
change of the
receptor, lvhich in turn results in a) ty.rosine autopl,.tsphorylation
and b) increased
binding affinity for the other receptors.
The increased binding affinity results in hetero/homodimer
formation. As a result of
ligand binding, the intracellular tyrosine kinases become activated and transphosphorylate
binding partner (e.g., HEIUp?*?). These events initiate the signal transduction
pathway. The ultimate step in all Erb family members? activation is mitogenesis.
HER 2 ?*? Overexprcssion
In humans, the oncogenic transformation
of HER2/neu has invariably correlated with
protein overexpression. Due to its constituti*e kinase activity, HER2/neu overexpression
results in enhanced tyrosine phosphorylation
activity leads to increased proliferation rate, resistance to TNFa, decreased expression of
adhesion molecules (E-cadherines and integrins) and increased vascular endothelial
growth factor (VEGF) secretion.
Mechanism of action of HerccntinQB
Herceptina acts in vitro by a dual mechanisms of action:
a) Biochemical: Exerted by binding to the HER2p?8s receptor. 7 Clinical Review HerceptinQ
BLA 98-0369 of
Herceptin binding to HER2p1*5 blocks dimer formation and induces down-regulation
the receptor. Both events lead to the blockade of the signal transduction pathway.
In addition, Herceptin has the following in vitro effects:
Cytostasis: inhibition of proliferation by interference with the mitogenic
activity of the HERZneu receptor due to the induction of the CDK2 kinase
protein, p 130;
inhibitor, ~27~? and the retinoblastoma-related
Reduction of the cellular resistance to TNFa;
Restoration of the expression of adhesion molecules (E-cadherines,
integrins) involved in metastasis development and progression,
Reduction of VEGF production
Exerted by Fc binding to the FcgRIII of CD16+ cells.
In vitro studies demonstrated that HerceptinO, in the presence of PBMN, was able to
mediate ADCC (antibody-dependent
cell-mediated cytotoxicity). This effect was due to
binding of the MAb to the FcgRIII present on the surface of cytotoxic cells (NK, CDS+ T
cells, monocytes, macrophages, and activated PMN). It is postulated that in the in vivo
setting, Herceptin@ may recruit immune cells to the tumor site.
b) Clinical Review HerceptinO
BLA 98-0369 5.0 CLINICAL TRIAL H0649a - PHASE 2, SINGLE AIM STUDY
5.1 Title H0649g
A Multinational, Open-Label Study of Recombinant Humanized Anti-p1 85HEW
Monoclonal Antibody (rhuMAb HER2) in Patients with HER2/neu Overexpression Who
Have Relapsed Following One or Two Cytotoxic Chemotherapy Regimens for Metastatic
Conducted April 24, 1995 to June 4, 1997 5.2 Study design and conduct H0649g
5.2.1 Objectives H0649g
Primary endpoints of this study were the overall response rate defined as the sum
of the complete and partial responses and delineation of the safety profile of Herceptin@
as a single agent in patients with metastaric breast cancer.
Secondary endpoints were the duration of response, time to progression, time to
treatment failure, smival, and quality of life. Please refer to Appendix D for all
This is a Phase 2, open label, single arm study of HerceptinB conducted at 54
centers in the North America, Europe, and Australia/New Zealand. The target enrollment
was 200 patients.
Desizn 18 Clinical Herceptinm Review BLA 98-0369 5.2.3 Patient Selection H0649g
The selection criteria for patients was amended in May 1996. Below is a list of
the criteria from the original protocol and in its amended format.
Table 1. Selection criteria H0649g
Selection Original criteria protocol - April 1995 Age 18 or older Diagnosis Metastatic Prior chemotherapy
cancer for breast Final protocol - May 1996
18 or older Breast Cancer I 1 Progression g one regimen Breast Cancer 1 Progression following
for metastatic disease regimens Metastatic / regimens following
one or t~?o
for metastatic disease. if relapsed with metastases less than a year
following adjuvant therapy g if received high dose consolidation regimen adjuvant in the setting and one prior , rerimen for metastatic disease
1 Acceptable only if both primary
c Bilateral breast cancer HER2 positivity
Lift of tumor expectancy Measurable disease tumors are 2+ or 3+ or all metastatic metastatic sites are 3+ or 3+ for status sites are 2+ or 3+ for HER2 by IHC HER2 by IHC 2+ or 3+ by
immunohistochemistry 2+ or 3+ by > 3 months eliminated immunohistochemistry Mass at lcast I cm in greatest Mass at least I cm in greatest
by physical, in 2
CT, or photos. . dimensions measurable
by physical, MRI, ultrasound, 600 b or bcner 60% or bener Creatinine Cl.7 eliminated Bilirubm 0,s eliminated White blood cell count > 3000 eliminated ?Intelet count -Iemoglobm > 80.000 eliminated > 8.5 eliminated < I I.0 Calcium or FISH dimension MRI, ultrasound,
performance only if both primary tumors are 2+ or 3+ or all dimensions
Kamofsky I 1 Acceptnblc in 2
CT, or photos. eliminated Radiation therapy Completed greater than 2 weeks Hormonal therapy Stopped more than 2 weeks prior eliminated prior lo entry
eliminated 10 entry
Investigational agents Not allowed Allowed if stable after radiation
treatment Stopped therapy more than 30 Stopped therapy more than 30
days prior to entry days prior to entry 19 Clinical Herceptin@
BLA 984369 Review 6.0 CLINICAL TRIAL H0648g - PHASE 3, TWO ARM STUDY AND
THE COMPANION EXTENSION STUDY H0659g
6.1 Title H0648g
Chemotherapy and Antibody Response Evaluation (CARE): A Phase III, Multinational,
Randomized Study of Recombinant Humanized Anti-p1 85HEWMonoclonal Antibody
(rhuMAb HER2) Combined with Chemotherapy in Patients with HER2 Overexpression
who have not Received Cytotoxic Chemotherapy for Metastatic Breast Cancer.
ongoing. conducted from June 12, 1995 to March 7, 1997; patient follow up is still 6.2 Title H0659g
An additional study sen?es as and extension trial to HO648 and it is H0659g: An Open
Label Extension Study with Recombinant Humanized Anti-p] 85mK Monoclonal
Antibody (rhuMAb HER2) For Patients Whose Metastatic Breast Cancer Progressed
During Treatment on Study H0648g.
Enrollment conducted from December 1995 and is still ongoing. 6.3 Study design and conduct of H0648g
Primarv en ,7inl
Time to disease progression was defined as the time from randomization until
documented disease progression or death. For patients who discontinued the study prior
to PD and had no assessment performed after baseline, time to progression was censored
at the time of last treatment date or date of study termination. All other patients were
censored at the time of last assessment.
Overall response rate was defined as CR + PR sustained for 4 weeks.
Duration of major response was defined as time from initial CR or PR until PD or
death, whichever occurred first.
Time to treatment failure was defined as the time from randomization to whichever
of the following occurred first:
Treatment discontinuation due to adverse event
Patient?s request to discontinue study
Commencement of concurrent immunotherapy, chemotherapy, or
hormonal therapy not specified in the protocol.
Survival was defined at the time from randomization to death.
Quality of Life as determined by a questionnaire which included the following: 31 Herceptin@
BLA 98-0369 Clinical Review EORTC
Several QLQ-C30 Core Questionnaire, version 1
breast cancer module BR-23
items from the Breast Cancer Questionnaire BCQ
items from the National Health Institute Survey
original items 6.3.2 DesiPn H0648g
This was a Phase 3, open label, randomized study comparing therapy with HerceptinO
plus chemotherapy with chemotherapy alone and employing two different chemotherapy
regimens ?epending on the patient history of anthracycline use. The study was conducted
at 150 sites in North America, Europe, and Australia/New Zealand. The target
enrollment was 450 patients.
6.3.3 Maior amendments made to the studs H0638~ and selection criteria
H0648g began as a randomized double blind study with clearly outlined entry criteria; the
two arms of the trial were anthracyclinekyclophosphamide
combined with herceptin and AC with placebo. However, multiple major changes in the
protocol were enacted during the conduct of the study, the majority of which were added
after 97 patients had enrolled. In its final form it was an open label study with relatively
broad entry criteria employing two different chemotherapy regimens. While there were
still two arms to the study (in terrns of randomization), there were 4 clinically distinct
subgroups: AC + Herceptin@, AC alone, paclitaxel (T) + Herceptin@, and paclitaxel (T)
alone. In addition, study H0659g was initiated in order to enable all patients from
H0648g meeting eligibility criteria for H0659g to receive Herceptin@. Below is a table
comparing the original and final study designs for H0648g: 32 Clinical Review Table 7. Herceptin@
BLA 98-0369 Comparison of original
.protocol and final protocol H0648r. Parameter H0648g original study
Initiated May 1995 H0648g final study
May 1996 Randomized
Blinding Herceptin vs placebo
Yes Herceptin vs control
Open label with blinded REC
Time to progression AC or T if prior anthracycline
at least 6 with no limit Placebo
Number of cycles of chemo
Secondary endpoints KPS
Prior chemo for metastatic disease
Prior hormonal therapy for metastatic
Prior radiation therapy for metastatic
Bone metastases as sole site of disease
Baseline labs and clinical studies VYHA Class Ill or IV CHF
extension times study H0659g to 450 Overall response
Duration of response
Survival at one year Time to progression
Duration of response
Survival at one year 60 or better
2+ or 3+; Ab 4D5
> 2 weeks prior 60 or better
2+ or 3+, Ab 4D5 or CBI 1
No limit > 2 weeks prior NT limit Yes
Yes, lytic lesions only No
Creatmine < 1.7
Bilirubin < 2.0
Protime < 14
W?BC > 3500
Platelets > 100,000
Hgb > IO
Calcium > II.0
FEV, > 60% of predicted
Cardiac EF > 45%
Herceptin given one day prior
to chemo for all cycles Yes if treated and stable
?Suitable candidates for receiving
concomitant cytotoxic chemotherapy
as evidenced by screening lab
assessments of hematologic, renal,
hepatic, and metabolic functions.? Weeks 8, 17,26,36,52,
every 12 weeks
No then No limit
Herceptin give day prior
then at the same time as
Yes, initiated November for first cycle
then every I2
1995 According to the sponsor, enrollment on the trial was very slow and they had deterrnined
that the reasons related to investigator and patient concerns. The sponsor decided that the
above outlined amendments were necessary in order to improve the rate of enrollment.
However, this resulted in a study which was difficult to analyze for a variety of reasons.
Below are listings of the reasons proposed by the sponsor for making the extensive
modifications of the ongoing clinical trial and problems which this created for the
analysis of the study. 33 Clinical Review Herceptin@
BLA 98-0369 7.0 Relationship
and Clinical Benefit
T.evel of HER2/peu protein Level of HERZ/neu Protein Overexpression overexpression As discussed earlier in the document, the tumor samples of patients with metastatic
cancer were tested for the presence of HER2/neu protein over-expression by
(IHC). Two different antibodies w?ere employed. breast 4D5 antibody - binds to the extracellular domain of
HERYneu and is the parent antibody of Herceptin CB 11 antibody - binds to the intracellular domain of HERYneu Parenthetically, the PMA for the test kit, HercepTest. with the proposed indication for the
selection of patients appropriate for treatment with Herceptina was simultaneously under
review by, the FDA. The test kit used a polyclonal antibody Lvhich binds to the
intracellular domain. For all the abo
e assays, tumor samples were scored as 0, l+, 2+ or
3+. Only patients with scores of 2+ or 3+ were enrolled into studies HOG49g (Phase 2)
and H064Q (Phase 3).
We examined the data (FD.4 data sets) for differences in the efficacy endpoints (time to
progression and response rate) between patients who were 2+ 1s. 3+ overexpressers of
the HER2ineu protein by IHC testing. There was one patient scored as l+ by the protein
assay and 2-e by FISH who vas entered on study as an exemption; she did not have a
tumor response and progressed by week 8. For purposes ofthe analysis she is included as
a 2+ overespresser.
The distribution of patients who were 2+ or 3+ lvas comparable between the two study
arms of H0648g. The data appear below in Table 29. Table 29. Percent of patients testing 2+ or 3+ by IHC in study H0648g and H0649g.
N = 143
% (n) AC
N = 138
% (n) I-H
N = 92
N = 96
% (n) H+Chcmo
N = 235
% (n) Chemo
N = 234
% (n) H (6495)
N = 713
___ 2+ 24% 3 0% 26% 30% 25% 26% 22% 3+ (35)
74% (108) (96) (68) (77) (176) (173) (50)
(172) Sccire - The data for the overall response rate
score (2+ vs. 3+) appear in Table 30.
achieved a significantly higher tumor
AC or paclitaxel compared with those O/b(n) (responses sustained for at least 4 weeks) by IHC
The patients with tumors which scored as 3+
response rate when treated with Herceptin@ plus
treated with AC or paclitaxel alone: 53% vs 36% 73 Herceptin@
BLA 98-0369 Clinical Review for ACH 3+ vs AC 3+, respectively and 44% vs 14% for TH 3+ vs T 3+, respectively. The benefit for the patients who were 3+, again, was greater for those in the paclitaxel
subgroup. Patients with tumors which scored as 2+ treated with the same regimens
showed no difference in response rate between those treated with Herceptin plus
chemotherapy and those treated with chemotherapy alone: 40% vs 43% for ACH 2+ vs
AC 2+, respectively and 2 1% vs 16% for TH 2+ vs T 2+, respectively. Table 30. Response rate by IHC score for HER2/neu protein expression H0649g. The denominator
HER2 score of
3+ (CR+PR) H0648g and
value (n) appears in Table 29 for each corresponding subgroup ACH AC TH T % (N) % (N) % (N) % (N) % (N) % (N) % (N) 40%
(57) 43% 2I% 16% 32 % 34 % J% .(5)
27X0 (11) (87) (46) (2)
(35) H+Chemo Chemo H We also examined the time to progression for 2+ vs 3+ patients and found that there v~as
no difference in time to progression for patients with 2+ tumors ( p > 0. IO), but there was
a significant increase in time to progression for those with 3+ tumors (p < 0.001).
Statistical testing for an interaction (i.e. testing of the difference between the differc-ces
of the cumes) vvas significant with a p 1,alue < 0.05. The curves for time to progression
appear in Figures 11 and 12 and the median time to progression v*alues are in Table 3 1.
Table 31. Median time to progression
HER2 score ACH of 2+ 1?s 3+ patients enrolled on HO648 months AC
months 2+ (CR+PR)
95% Cl 7.6
5.3. 10.1 7.1
2.0, 5.6 3+ (CR+PR)
9s!! Cl 7.3
7.1. 9.8 4.9
4.5. 6.9 7.1
6.7. 12.0 2.2
I .s, 4.3 by IHC These studies (H0649g and H0648g) were not designed to test whether or not there was a
relationship between the impact of Herceptina on time to pr -gression, response rate, or
survival and the extent of HER2 overexpression (2+ vs. 3+); therefore, this analysis is
exploratory in nature. There were far fewer patients with tumors that scored 2+ and this
affects the power of such an analysis. Nonetheless, the observed difference in clinical
outcome and the interaction of the level of overexpression were significant. 74 Clinical HerceptinQ, Review BLA Time to Progression , b - 5 Her 2+ Patients I I I I 10 15 20 25 I Time to Progression
Figure 11. Time to progression Herccptin plus chemotherapy (Months) for patients whose tumors were scored as 2+ for protein vs chemotherapy alone. 75 98-0369 Study H0638g . overexpression. Clinical Herceptin@J Review BLA Time to Progression 0 5 Her 3+ Patients I 1 10 15 J Time to Progression
tlerceptin 1 20 vs chcmolhcrap). alone....
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