Single Patient Use of Investigational Anticancer Agents: An Industry Perspective Gerard T. Kennealey, MD Vice President, Clinical Research, Oncology AstraZeneca Pharmaceuticals December 14, 2000

Rising Public Expectations Make Earlier Access Necessary Patients are better informed than ever before: Worldwide web Worldwide web Patient advocacy groups Patient advocacy groups Media coverage (health and medicine, including cancer, is the single most covered issue in the general media.) Media coverage (health and medicine, including cancer, is the single most covered issue in the general media.)

Single Patient INDs Provide Needed Access to Promising Experimental Anticancer Compounds: Usually initiated near NDA submission Usually initiated near NDA submission Extremely low prevalence diseases where there may no other therapeutic option Extremely low prevalence diseases where there may no other therapeutic option Unresponsive tumors Unresponsive tumors Responsive tumors that have exhausted all standard therapies Responsive tumors that have exhausted all standard therapies

Initiating the Single Patient IND Substantial activity Substantial activity Safety data sufficient for filing Safety data sufficient for filing Standard therapy exhausted Standard therapy exhausted Positive risk benefit ratio Positive risk benefit ratio Single patient INDs are a useful tool in meeting patients’ needs:

Additional Treatment Approaches Are Needed Patients with more common tumors are exhausting currently available approved and experimental treatment options Patients with more common tumors are exhausting currently available approved and experimental treatment options The sheer number of patients who meet this description requires a more efficient means of meeting their legitimate medical needs The sheer number of patients who meet this description requires a more efficient means of meeting their legitimate medical needs

AstraZeneca Experience ZD1839 (Iressa™) EGFR tyrosine kinase inhibitor EGFR tyrosine kinase inhibitor Orally bioavailable, once daily dosing Orally bioavailable, once daily dosing Phase I clinical trials begun May 1998 Phase I clinical trials begun May 1998 AACR presentations May 2000, including plenary session showed activity AACR presentations May 2000, including plenary session showed activity AACR and institutional media focus AACR and institutional media focus

The drug unexpectedly shrank tumors and prolonged survival in a first stage study, where efficacy is rarely shown. Targeted therapies offer best hope for beating cancer

Initial Plan: Initiate Phase III Trials Since AACR, AstraZeneca’s information center and various patient and professional groups have received more than 7500 inquires about the compound Since AACR, AstraZeneca’s information center and various patient and professional groups have received more than 7500 inquires about the compound Calls from elected representatives, celebrities, and other high profile individuals expecting “instant access” were received every week Calls from elected representatives, celebrities, and other high profile individuals expecting “instant access” were received every week

Expanded Access Program (EAP) Previous Precedents Treatment IND, parallel track, and compassionate use programs for HIV/AIDS drugs, e.g., ddI Treatment IND, parallel track, and compassionate use programs for HIV/AIDS drugs, e.g., ddI The first such Expanded Access Programs in oncology, including Herceptin and STI 571 The first such Expanded Access Programs in oncology, including Herceptin and STI 571

Principles: Iressa Expanded Access Program (EAP) Driven by clinical data in ~300 patients (NSCLC) Driven by clinical data in ~300 patients (NSCLC) Patient safety is primary concern Patient safety is primary concern Equal access throughout the world Equal access throughout the world No special cases – backing of senior management No special cases – backing of senior management Drug supply a potential issue Drug supply a potential issue No interference with registration program No interference with registration program

Registration Is The Best Route To Expanded Access Patients Patients Physicians Physicians FDA FDA Pharmaceutical company Pharmaceutical company

The Iressa (EAP): Initial Steps Create dedicated EAP Team Create dedicated EAP Team Involve FDA Oncologic Drugs Division and Cancer Liaison Office Involve FDA Oncologic Drugs Division and Cancer Liaison Office Inform and collaborate with patient advocacy groups eg. ALCASE Inform and collaborate with patient advocacy groups eg. ALCASE Identify experienced CRO Identify experienced CRO Collaborate with National Organization for Rare Disorders (NORD) Collaborate with National Organization for Rare Disorders (NORD)

Iressa EAP Protocol Restricted to patients with NSCLC Restricted to patients with NSCLC Disease that failed to respond to or relapsed on standard therapy Disease that failed to respond to or relapsed on standard therapy No concomitant therapy for tumor No concomitant therapy for tumor Not a candidate for registration trials Not a candidate for registration trials Adequate general health Adequate general health Informed written consent Informed written consent

EAP Challenges Create effective communication pathways Create effective communication pathways Create one informed consent document acceptable to all Create one informed consent document acceptable to all Determine what data must be collected, recognizing that safety data allows for only minimal safety signals EACH IS A BARRIER TO CORPORATE PARTICIPATION Determine what data must be collected, recognizing that safety data allows for only minimal safety signals EACH IS A BARRIER TO CORPORATE PARTICIPATION

EAP Concerns Potential for impact on registration trials Potential for impact on registration trials Potential impact on submission Potential impact on submission Adequacy of drug supply in view of rapidly expanding clinical trial programs Adequacy of drug supply in view of rapidly expanding clinical trial programs Demand created by the media Demand created by the media Insuring equity Insuring equity Other tumor types Other tumor types

EAP Opportunities Focus corporate talent, energy, and resources on a promising compound beyond registration trials Focus corporate talent, energy, and resources on a promising compound beyond registration trials Develop productive ties with partner groups, e.g., FDA, patient and professionals Develop productive ties with partner groups, e.g., FDA, patient and professionals Potential for additional safety data at time of approval and launch Potential for additional safety data at time of approval and launch Reinforce commitment to timely, well controlled clinical trials Reinforce commitment to timely, well controlled clinical trials

Implications for the Future Cancer drug development now operates in the public eye Cancer drug development now operates in the public eye An Expanded Access Protocol should be considered to meet patient needs, particularly those with advanced disease An Expanded Access Protocol should be considered to meet patient needs, particularly those with advanced disease Successful programs require commitment from all parties involved Successful programs require commitment from all parties involved

FDA Guidance Needed To ensure appropriate understanding, FDA may wish to offer guidance on these unresolved issues: The role of these data in NDA filings The role of these data in NDA filings Potential opportunity for early registration Potential opportunity for early registration

Thank You 150+ patients enrolled in this program 150+ patients enrolled in this program AstraZeneca EAP Team AstraZeneca EAP Team National Organization for Rare Disorders National Organization for Rare Disorders Patient Advocacy Groups Patient Advocacy Groups Patty Delaney & the Cancer Liaison Office Patty Delaney & the Cancer Liaison Office Oncologic Drugs Division Oncologic Drugs Division Mark Krueger & Associates, Inc Mark Krueger & Associates, Inc