THE USE OF STAMP IN DRUG DEVELOPMENT

THE POTENTIAL OF UTILIZATION OF STAMP IN DRUG DEVELOPMENT

SYSTEMS THEORETIC ACCIDENT MODELING AND PROCESSES HAZARD IDENTIFICATION & RISK MINIMIZATION

THE USE OF STAMP IN DRUG DEVELOPMENTR&D Success Rate and CostKey steps and participantsParticipants’ objectives Causes of harm to subjects Hazards in drug development Milestone I – IND review Milestone II – NDA review System goalsDesign requirements of a safe systemWhat is STAMP The value of STAMPSTAMP in regulatory review STAMP in drug development (process) STAMP in drug development (molecular level)STAMP in Post-market drug surveillance

SUCCESS RATE & COST

Target Validation

Lead Generation

Lead Optimization

Pre-clinical Development

IND NDA/BLACLINICAL DEVELOPMENT

1 year1.5-2.5 years

1-2 years

P1 P2 P3 Submission

1-3 years

Approval

Until withdrawn

<2 years4-8 years

10,000 Compounds

screened

250 animal testing

1 approved drug

Phase I to Phase II

Phase II to Phase III

Phase III to Submission

Submission to Approval

Small molecule 63% 38% 61% 91%

Large molecule 84% 53% 74% 96%

P1 to Approval:13% for small molecules 32% for large molecules

The estimated average pre-tax industry cost per new prescription drug approval (inclusive of failures and capital costs) is: $2,558 million

Cost of developing new drug

Clinical trial success rates

DRUG DISCOVERY | PRE-CLINICAL DEVELOPMENT

KEY STEPS & PARTICIPANTS1 year

Target Identification & Validation

Lead Generation

Lead Optimization

Pre-clinical Development

Clinical Development

NDABIOTECH PHARMA

1-3 years

Approval

Launch

Acquisition of technology Acquisition of biotech company

CONTRACT RESEARCH ORGANIZATION

SPONSOR

INVESTIGATOR

RESEARCH HOSPITAL

IRB/EC

Until withdrawn4-8 years

NDA HOLDER

filed

granted

RESEARCH SUBJECT PATIENT

1.5-2.5 years

<2 years

BIOTECH

1-2 years

<2 years1 year1.5-2.5 years

1-2 years

Target Identification & Validation

Lead Generation

Lead Optimization

Pre-clinical Development

Clinical Development

NDAIND* Compartmentalized data sets/intellectual property

1-3 years 4-8 years

Approval

Thorough understanding of the disease mechanisms and the role of enzymes, receptors or proteins within the disease pathology. simple experiments carried out to confirm regulation of the target and development of assay

Identification of chemical start points for drug discovery projects. Identification of related compounds with improved potency, reduced off-target activities (undesirable activities at other biological targets), and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics.

Optimise potency against the enzyme target, cellular and toxicity assays as well as those that govern good oral absorption, slow metabolic clearance in vivo and display activity in an animal model of the disease.

Toxicology in vitro and in vivo ADME studies pharmacokinetics Pharmacodynamics Chronic toxicity, Acute toxicity, Safety pharmacology

Phase 0: Very limited human exposure to the drug, with no therapeutic or diagnostic goalsPhase 1: Healthy volunteers , emphasize safety. What the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted. Phase 2: Data on effectiveness (whether the drug works in people who have a certain disease or condition). The drug may be compared with placebo or a different drug. Safety continues to be evaluated. Phase 3: Data on safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after launch. Additional information about a drug's safety, efficacy, or optimal use.

PARTICIPANTS’ OBJECTIVES

Target Validation

Lead Generation

Lead Optimization

Pre-clinical Development

IND

CAUSES OF HARM TO PATIENTS

PRE-CLINICAL DEVELOPMENT NDA MARKETCLINICAL DEVELOPMENT

1 year1.5-2.5 years

1-2 years

Clinical Development

1-3 years

Approval

Until withdrawn

<2 years4-8 years

To regulators To physicians To patients

Information available

Existing safety hazard detected? Limiting safety hazard? Mitigated safety hazard? IND Approved?

Existing safety hazard detected? Limiting safety hazard? Mitigated safety hazard? NDA Approved? Appropriately labeled and advertised?

HAZARDS RELATING TO NATURE OF DRUGS AND INFORMATION ABOUT THE DRUGS

Injury and death to trial subjects before drug approval Injury and death to patients after approval of the drug Medication error / inappropriate medication Failure to treat conditions for which safe and effective treatments are available Failure to develop and approve safe and effective medications for major public health problems

MAIN DRIVER OF CLINICAL RESEARCH IS BUSINESS OPPORTUNITY DEFINED BY UNMET MEDICAL NEED IN SOLVENT POPULATION

LABELING does not accurately reflect safety and efficacy of approved drug• Inappropriate marketing and advertising • Published studies do not accurately reflect research findings

• Inadequate/insufficient/misleading information provided• Critical safety information withheld from

HARM TO PATIENTSACCURACY OF INFORMATION IS ESSENTIAL TO INFORMED DECISION-MAKING

• Patients were subjected to unacceptable risk during treatment• Patient casualty: ADR – injury and death

Absence of independent control mechanism that would • Detect failure to disclose relevant information• Detect fraud• Assess in real time true safety and efficacy of approved drug

• PHYSICIANS• PATIENTS• REGULATORS

HAZARD

• Undetected drug-related hazard • Detected but uncorrected/not mitigated drug-related hazard• Non-compliance with post-market surveillance requirements• Incorrect approval by regulators• Fraud in clinical trials, undetected

Root cause

• Physicians cannot properly assess risk for their patients• Patients cannot properly assess risk for themselves• Regulators cannot properly monitor changes in benefit:risk profile of marketed drug

Consequence

Outcome

HAZARD | ROOT CAUSE | CONSEQUENCE | OUTCOME

MILESTONE I: IND REVIEW

CORRECT APPROVAL | CORRECT REJECTION | INCORRECT APPROVAL | INCORRECT REJECTION

Existing safety hazard detected?

Limiting safety hazard?

Mitigated safety hazard?

IND Approved?

IND REVIEW COMPANY DATA

Approved RejectedApproved Rejected Approved Rejected Approved Rejected

PUBLICATIONS

Y N

Limiting safety hazard?

Existing safety hazard detected?

Mitigated safety hazard? LABEL, WARNINGS DIRECTIONS FOR USE

NDA Approved?

NDA REVIEW COMPANY DATA

Approval RejectionApproval Rejection Approval Rejection Approval Rejection

MILESTONE II: NDA REVIEW

PUBLICATIONS

Y N

CORRECT APPROVAL | CORRECT REJECTION | INCORRECT APPROVAL | INCORRECT REJECTION

OBSERVE ORIENT DECIDE ACT

Unfolding circumstances

Outside information

Implicit guidance and control

Action (Test)Decision

(Hypothesis)

Implicit guidance and control

Cultural traditions

Genetic heritage

New information

Previous experience

Analyses & Synthesis

Emotions

Unfolding interaction with environment

• Drugs on the market are adequately safe and effective• Drugs are manufactured according to cGMP, regardless jurisdiction• The labels attached to drugs provide correct information about safety and efficacy• Marketed drugs are monitored for adverse events, side effects, and potential negative interactions, and for safety

and efficacy profile in population treated in real life conditions• Marketed drugs found to be unsafe after they were approved are removed, recalled, restricted, or appropriate

risk:benefit information is provided• Patients get and use the drugs they need for good health• Drugs are obtainable by patients• Information is available to support decision-making about risks and benefits• Patients get the best intervention possible, practical and reasonable for their health needs• Patients get drugs with the desired dosage and purity

SYSTEM GOALSPharmaceutical product are developed to enhance long-term health

• Continuous appropriate incentives exist to develop and market needed drugs• The scientific knowledge and technology needed to develop new drugs and optimize their

use is available• Pre-clinical development of drugs is performed according to GLP, regardless jurisdiction• Clinical development of drugs is performed according to GCP, regardless jurisdiction• Drugs are subjected to effective and timely safety testing• New drugs are approved by the FDA based upon and validated and reproducible decision-

making process

Leveson, 2014

• Safety, consistent with mission requirements is designed into the system in a timely, cost-effective manner

• Hazards are identified, evaluated, and eliminated, or the associated risk reduced to a level acceptable to the managing activity (MA) throughout the entire life cycle of a system

• Historical safety data, including lessons learned from other systems, are considered and used

• Minimum risk is sought in accepting and using new designs, materials, and production and test techniques

• Actions taken to eliminate hazards or reduce risk to a level acceptable to the MA are documented

• Retrofit actions are minimized• Changes in design, configuration, or mission requirements are

accomplished in a manner that maintains a risk level acceptable to the MA• Consideration is given to safety, ease of disposal and neutralization of any

hazardous materials associated with the system• Significant safety data are documented as lessons learned and are

submitted to data banks, design handbooks, guidelines, or specifications, or communicated to legislators

• Hazards identified after production are minimized consistent with program restraints

DESIGN REQUIREMENTS OF A SAFE SYSTEM

WHAT IS STAMP

The model is based on systems theory and accounts for: • Complex human decision making• Organizational and managerial aspects of systems (safety culture, management decisions)• Adaptation of systems over time (migration toward hazardous states)

SYSTEMS THEORETIC ACCIDENT MODELING AND PROCESSES

Most hazard analysis techniques focus on failure events. Principle: identifying the failure events that can lead to a hazard.

• Fault Tree Analysis (FTA) • Failure Modes and Effects Criticality Analysis (FMECA). • Clinical research and post-market drug safety: record of past incidents (ADR reporting

systems, i.e. FAERS, EudraVigilance, WHO Vigibase)

In system accidents the losses stem from dysfunctional interactions among operating components rather than failure of individual components.• In STAMP, the cause of an accident is viewed as the result of a lack of constraints imposed on

system design and operations rather than an event. • The objective is to identify the design constraints necessary to maintain safety and to ensure that

the system design and operation enforces these constraints.

THE VALUE OF STAMP

SYSTEMS THEORETIC ACCIDENT MODELING AND PROCESSES

Imposing CONSTRAINTS on a system whilst ensuring ENFORCEABILITY of these constraints by DESIGN and OPERATIONS

Increased control and improved coordination of controls over the process as whole Reduced uncertainty of outcomes Risk minimization rather than its externalization Reduced risk resulting from uncertainty

Human supervisor(Controller)

Model of process

Model of automation

Automated Controller

Model of process

Model of interfaces

Controlled process

Sensor

Displays

Controls

Process inputs

Disturbances

Process outputsActuatorsControlled variables

Measurable variables

STAMP IN REGULATORY REVIEW

Human supervisor(Controller)

Model of process

Model of automation

Automated Controller

Model of process

Model of interfaces

Controlled process

Sensor

Displays

Controls

Process inputs

Disturbances

Process outputsActuatorsControlled variables

Measurable variables

Consistency and quality of the review process within an organization Increased confidence in own assessments (Avandia) Clear division of responsibilities between sponsor, IRB/EC, and regulators Definition of constraints and clarity on safe and hazardous states, and inclusion of methods of risk

identification and risk control on the label rather than warnings with probabilistic expression of individual risk derived from population studies

Consistent and comparable review process across jurisdictions Ability to make an informed decision on recognition of approvals of other agencies, depending on

quality of their review process Clarity of expectations on the quality of provided evidence of safety and efficacy for the industry Defined safety constraints and their enforceability by design and operations Transparency of the review outcomes is already guaranteed (PharmaPendium)

STAMP IN DRUG DEVELOPMENT I

Human supervisor(Controller)

Model of process

Model of automation

Automated Controller

Model of process

Model of interfaces

Controlled process

Sensor

Displays

Controls

Process inputs

Disturbances

Process outputsActuatorsControlled variables

Measurable variables

DRUG DEVELOPMENT PROCESS Coordination of controls among multiple participants in the whole process of drug development Definition of safety constraints, controls, and their enforcement by design and operations across all

participating stakeholders, ensuring full and coordinated control over the whole process Clear division of responsibilities between sponsor, investigator, IRB/EC, and regulator Constraints enforced by design of clinical trials as well as their operation and oversight to account for

all identified potentially hazardous states Clarity on hazardous states before incidents (SAE, SUSARs) occur Reduced uncertainty and increased confidence for investors Optimization of research planning to prioritize research into potentially limiting hazards Ability to identify critical safety and efficacy issues before they become self-evident, and address the

situation accordingly

STAMP IN DRUG DEVELOMENT II

Human supervisor(Controller)

Model of process

Model of automation

Automated Controller

Model of process

Model of interfaces

Controlled process

Sensor

Displays

Controls

Process inputs

Disturbances

Process outputsActuatorsControlled variables

Measurable variables

MOLECULAR LEVEL OF HAZARD IDENTIFICATION AND CONTROL IN DRUGS UNDER DEVELOPMENT Identification of potential hazardous states within ADMET, accounting for all known mechanisms of toxicity,

including off-target binding and genetic polymorphism affecting PK/PD Definition of safety constraints for these hazards De novo design of system of controls imposed on these safety constraints (i.e. enzymes and internal

regulation, genetic polymorphism, inter-species differences, off-target binding etc.)

Reorienting drug safety from providing warnings toward risk minimization Makes products intrinsically safer, thus limits uncertainty during drug development for investors This approach shortens significantly O-O-D-A loop, and makes timely decisions possible Definition of means of control of specific hazards for an individual patient instead of providing warnings

(probabilistic expression of risk), and inclusion of methods of risk control on the label Coordination of controls among multiple participants in the whole process of drug development Clinical trials designed to account for all identified potentially hazardous states Reduced uncertainty and increased confidence for investors

STAMP IN PMS DRUG SAFETY

Human supervisor(Controller)

Model of process

Model of automation

Automated Controller

Model of process

Model of interfaces

Controlled process

Sensor

Displays

Controls

Process inputs

Disturbances

Process outputsActuatorsControlled variables

Measurable variables

MOLECULAR LEVEL OF HAZARD IDENTIFICATION AND CONTROL IN HIGH RISK MARKETED DRUGS Identification of potential hazardous states within ADMET, accounting for all known mechanisms of toxicity,

including off-target binding and genetic polymorphism affecting PK/PD Definition of safety constraints for these hazards De novo design of system of controls imposed on these safety constraints (i.e. enzymes and internal

regulation, genetic polymorphism, inter-species differences, off-target binding etc.)

Reorienting drug safety from providing warnings toward risk minimization Makes products intrinsically safer, thus helps prevent avoidable injury (e.g. Warfarin dose-adjustment) This approach reduces significantly risk to patient by providing means of risk minimization for an individual

patient instead of a set of probabilistic warnings Reduction of individual risk for patients decreases overall burden on the healthcare system Reduced risk for patients overlaps with reduced financial risk for payers

SUMMARY