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(solution) Pretend you are a member of the Regulatory Affairs team at a

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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


be necessary.


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


resonance imaging


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, shorter overall survival, more rapid disease




(higher incidence of metastasis),


and resistance to chemotherapy




retrospective studies. 1.2 HerceptinO


Herceptin@ (trastuzumab)


is a recombinant








antibody that targets the extracellular dc*main of the ErbB-2/HerYneu




It was


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




that participates


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


(neu differentiation


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


activities. Constitutive


tyrosine kinase


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




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


Breast Cancer


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




52.2 H0639g


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


dimension measurable


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


Brain metastases


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@






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


6.3.1 Ohicctives


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.


Secondanr endooints


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:


Documented PD


Treatment discontinuation due to adverse event


Patient?s request to discontinue study


Patient death


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


(AC) chemotherapy


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


Double Blind


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


Target enrollment


Primary endpoint


Secondary endpoints KPS


HER2 expression


Prior anthracycline




Prior chemo for metastatic disease


Prior hormonal therapy for metastatic




Prior radiation therapy for metastatic






measurable disease


Bone metastases as sole site of disease


Brain metastases


Baseline labs and clinical studies VYHA Class Ill or IV CHF


Hcrccptin administration










extension times study H0659g to 450 Overall response


Duration of response


Survival at one year Time to progression


Overall response


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


No 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


subsequent cycles


Weeks 8,20,32,44,56,




Yes, initiated November for first cycle


chemo for


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) T


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)


76% (42)


70% (24)


74% (19)


80% (59)


75% (61)


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


and score.


HER2 score of




2+ (CR+PR)


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)




GO) (3)


14% (19)


49% (21)


27X0 (11) (87) (46) (2)




(29) (18)




(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 TH


months T


months 2+ (CR+PR)


95% Cl 7.6


5.3. 10.1 7.1 4.4 3.2


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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