Global Pharma Primer

GLOBAL PHARMA PRIMER

PHARMACEUTICAL INDUSTRY…AND HOW IT FUNCTIONS

I. HUMAN CRISIS

II. OPERATIONAL ENVIRONMENT

III. SYSTEMIC VULNERABILITIES & RISK REDUCTION MEASURES

IV. LEGAL BATTLES

V. GLOBALIZATION

The material included in these modules serves many interests by facilitating understanding of construct, dynamics, and influences affecting regulatory policies and corporate decision-making that ultimately determine access, availability, and effectiveness of pharmaceutical products. 

`In the following modules we will introduce and describe the highly specialized and often disconnected components of pharmaceutical research, drug development/manufacturing, marketing, regulatory policies and practices, and use case studies to qualify the relative effectiveness of safeguards to prevent harm.  Additionally, how have pressures to reduce health care costs or increase safety actually affected both aspects of public concern within a global context because transnational interests influence national circumstances.  

GLOBAL PHARMA PRIMER

MODULE I: HUMAN CRISIS

Acceptance of the germ theory changed the practice

of medicine toward evidence-based interventions.

Miasmic theory enjoyed support of the medical community till the 1850s.

REACTIVE APPROACH » 18-19th century: PATENT MEDICINES» 1902: BIOLOGICS CONTROL ACT

» Response to tetanus outbreak caused by contaminated serum (1901) » 1906: FOOD AND DRUGS ACT (THE WILEY ACT) – “Labeling Law”

» Response to secret ingredients and misleading labels» Sinclair’s book The Jungle (1906)

» 1914: HARRISON NARCOTICS ACT » Response to the Hague Conventions of 1912 » Opium addiction after the Civil War, more potent opioids emerged (heroin)

» 1938: THE FOOD, DRUG, AND COSMETICS ACT» Response to the Elixir Sulfanilamide disaster (1937)» Addressed compulsory toxicity testing

» 1962: KEFAUVER-HARRIS AMENDMENT» Response to the thalidomide disaster in the U.S. » Addressed compulsory proof of efficacy » Thalidomide only addressed in Germany in mid-1970’s

» 1965: DRUG ABUSE CONTROL AMENDMENTS & CONTROLLED SUBSTANCE ACT (1970)» Response to the widespread use of psychedelic drugs and opioids in the 1960’s

Life Science Doctrine

American Military Tribunal in Nuremberg American judges (top row, seated) during the Doctors Trial. Presiding Judge Walter December 9th, 1947 – August 20th, 1947

REACTIVE APPROACH » 18-19th century: PATENT MEDICINES» 1902: BIOLOGICS CONTROL ACT

» Response to tetanus outbreak caused by contaminated serum (1901) » 1906: FOOD AND DRUGS ACT (THE WILEY ACT) – “Labeling Law”

» Response to secret ingredients and misleading labels» Sinclair’s book The Jungle (1906)

» 1914: HARRISON NARCOTICS ACT » Response to the Hague Conventions of 1912 » Opium addiction after the Civil War, more potent opioids emerged (heroin)

» 1938: THE FOOD, DRUG, AND COSMETICS ACT» Response to the Elixir Sulfanilamide disaster (1937)» Addressed compulsory toxicity testing

» 1962: KEFAUVER-HARRIS AMENDMENT» Response to the thalidomide disaster in the U.S. » Addressed compulsory proof of efficacy » Thalidomide only addressed in Germany in mid-1970’s

» 1965: DRUG ABUSE CONTROL AMENDMENTS & CONTROLLED SUBSTANCE ACT (1970)» Response to the widespread use of psychedelic drugs and opioids in the 1960’s

Doctors Trial

Nuremberg 1947

Thalidomide

Target Validation

Lead Generation

Lead Optimization

Pre-clinical Development

IND

HARM TO PATIENTS AND TRIAL SUBJECTS

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

Causes of harm to patients and trial subjects

Injury and death to trial subjects

Injury and death to patients after drug approval

Safety v Security

Hazard identification in engineering vs. pharma

Pharmacovigilance system

Public health implications of unidentified/unmitigated risks

Individual assessment of risk

Plaintiffs: Subjects in a trial of a new vaccine against melanoma. They alleged that the investigators failed to provide full informed consent, committed research malpractice (non-compliance with protocol) and research fraud by deliberately misrepresenting the risks and benefits of the study.

ROBERTSON vs. McGEE, 2002

Defendants: Investigators, study sponsor, individual members of the Institutional Review Board and the institutional bioethicist.

Several of the defendants have settled out of court. The plaintiffs have failed to establish subject matter jurisdiction in federal court and the case was dismissed.

• The lawsuit claims the defendants' actions violated human-rights provisions of two international treaties, the Nuremberg Code and the Declaration of Helsinki. The complaint also alleges federal civil rights violations and violations of federal regulations governing clinical trials.

Case: Robertson v McGee

• In addition to these federal claims, the complaint alleges state causes of action for negligence, intentional and negligent infliction of emotional distress, fraud and misrepresentation, assault and battery, lack of informed consent, and strict products liability.

THE CASE INTRODUCED INTRIGUING QUESTION OF IRB LIABILITYUniversity of Pittsburgh Law Review: Suitability of IRB liability

In 2012, after fifty years of silence, thalidomide manufacturer Grünenthal finally apologized for birth defects caused by its drug Convergan which was prescribed to pregnant mothers for morning sickness. Survivors say it’s not enough (Smithsonian, 2012).

INJURY & DEATH TO PATIENTS

Photograph of Terry Wiles (right) who was born with phocomelia due to thalidomide (Wikimedia Commons)

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

IP protected data produced by industry in pre-clinical testing Data shared with the regulator(s) to

support IND application Published studies

Data shared with the regulator(s) to support NDA

Published studies

To regulators To physicians To patients

IP protected data produced by industry in clinical studies

Information available

VOLUNTARY DISCLOSURE | SELECTIVITY | OMMISSION | COMMISSION

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

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

CAUSES OF HARM TO PATIENTS

PUBLICATIONS

Y N

CORRECT APPROVAL | CORRECT REJECTION | INCORRECT APPROVAL | INCORRECT REJECTION

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

CAUSES OF HARM TO PATIENTS

MEDICATION ERRORS• Drug prescribed according to inaccurate instruction• Drug off-label, benefit:risk profile for a specific target group unknown • Drug benefit:risk profile for a specific group unfavorable, not communicated to physicians• Drug prescribed in unsafe combinations (correct labeling/unknown/labeled but ignored)• Drug prescribed to patients who should not take it (labeled warnings) • Physicians prescribe drug to wrong patient (wrong diagnosis, wrong patient)• Prescription choice based on economic advantage for physician

DISPENSING ERRORS, ADMINISTRATION ERRORS, ACCESS RESTRICTIONSPATIENT BEHAVIOR• Patients demand approved drug where not indicated/not appropriate• Public overreacts and stops taking useful approved drug• Unsafe combinations prescribed to patients who did not disclose their co-medications• Patients do not have access to drug which would benefit them (prohibitively expensive) • Patient’s non-adherence to treatment

Target Validation

Lead Generation

Lead Optimization

Pre-clinical Development

INDPRE-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

HAZARDS RELATING TO THE USE OF THE DRUG BY PHYSICIANS AND PATIENTS

GLOBAL PHARMA PRIMER

• Introduction• Causes of harm to patients and trial subjects• Injury and death to trial subjects • Injury and death to patients after approval • Safety v Security • Hazard identification in engineering and computer science• Hazard identification in pharmaceutical industry • Pharmacovigilance system • Public health implications of unidentified/unmitigated risks• Individual assessment of risk

SAFETY SECURITY

SAFETY vs. SECURITY ACCIDENT INTENTION

WILLFUL BLINDNESS

The condition of being free from

harm or risk

The quality or state of being free from

danger

Manufacturing accidentsSupply chain disruptionsDistribution chain disruptionMedication errorsDispensing errorsMiscommunication Unidentified and improperly mitigated hazards Design flawsRare eventsUnavoidable events

Tampering during manufacturing Supply chain disruptionsDistribution chain disruptionPiracyCounterfeitingDiversion AbuseConcealed hazards Fraud Hacking systems

GLOBAL PHARMA PRIMER• Introduction• Causes of harm to patients and trial subjects• Injury and death to trial subjects • Injury and death to patients after approval • Safety v Security • Hazard identification in engineering and computer science• Hazard identification in pharmaceutical industry • Pharmacovigilance system • Public health implications of unidentified/unmitigated risks• Individual assessment of risk

HAZARD IDENTIFICATION: ENGINEERING• Includes both safety and security component• Numerous structured hazard identification and risk assessment tools• Applied in medical devices but not pharmaceuticals

Examples of HAZARD IDENTIFICATION Techniques in engineering • Hazard and Operability Study• Equipment failure case definition• Checklists• What-If Techniques• Brainstorming• Task Analysis• Failure Modes Effects Analysis (FMEA)• Failure Modes Effects and Criticality Analysis (FMECA)• Fault Tree and Event Tree Analysis• Systems-Theoretic Accident Model and processing (STAMP )• Historical records of incidents

HAZARD IDENTIFICATION technique in

pharmaceutical industry

How severely it could hurt someone How ill could it make someone

Very likely Could happen anytime

Likely Could happen sometime

Unlikely Could happen but very rarely

Very unlikely Could happen but probably never will

Kill or cause permanent disability or ill health

1 1 2 3

Long term illness or serious injury

1 2 3 4

Medical attention and several days off work

2 3 4 5

First aid needed 3 4 5 6

RISK COMMUNICATION & LIABILITY

LIABILITY Design defects Manufacturing defects

Failure to warn (marketing)

Products

Original drugs

Generics

GLOBAL PHARMA PRIMERIntroductionCauses of harm to patients and trial subjectsInjury and death to trial subjects Injury and death to patients after approval Safety v Security Hazard identification in engineering and computer scienceHazard identification in pharmaceutical industry Pharmacovigilance system Public health implications of unidentified/unmitigated risksIndividual assessment of risk

HAZARD IDENTIFICATION: PHARMA

Diethylstilbestrol was marketed as a prevention of miscarriage; it was marketed under more than 260 trade names by about 100 companies. Daughters of women who had been treated by this medication were at higher risk of developing certain types of cancer.

RISK COMMUNICATION: PHARMA

1 Patient Information Leaflet 2 Summary of Product Characteristics

3 Physician Prescribing Information 4 Patient Product Information

EUROPE USA

Practical exercise: Answer the questions below utilizing the four documents above: - Which of these documents is intended for a U.S. based physician? - Which of these documents is intended for a U.K. based patient? - Where a U.S. patient can find labels for FDA approved drugs? - What are the odds of developing rhabdomyolysis when taking this drug? - How many patients were treated by this drug in placebo-controlled clinical trials?- The most commonly reported adverse drug reaction was nasopharingitis. Does it

mean that the drug can cause nasopharyngitis? - What is placebo-controlled trial? - Do women have to stop taking this drug if they plan to become pregnant?

GLOBAL PHARMA PRIMER• Introduction• Causes of harm to patients and trial subjects• Injury and death to trial subjects • Injury and death to patients after approval • Safety v Security • Hazard identification in different industries • Hazard identification in pharmaceutical industry • Pharmacovigilance system • Public health implications of unidentified/unmitigated risks• Individual assessment of risk

PHARMACOVIGILANCE SYSTEM

EudraVigilance database of EU reports of ADRs

FAERS database of U.S. reports of ADRs

National databases of ADRs

VIGIBASEWHO database

Healthcare professional, pharmacists

Patients and consumers

Drug license holder

Medical journals

PHARMACOVIGILANCE SYSTEM IS BASED ON ACTIVE REPORTING OF SUSPECTED ADRs IN NATIONAL DATABASES AND DETECTION OF SAFETY SIGNALS WITHIN THESE DATABASES.

Outputs: Label updates and warningsRegulatory reportsDear doctor lettersPublic announcements

Access by general public:Relatively limited FOIA requestsRegulatory updates

Direct reporting to regulators depending on jurisdiction

PHARMACOVIGILANCE SYSTEMThis figure illustrates the number of reports received (solid bars) and entered (checkered bars) into FAERS by type of report since the year 2004 through 2013.

Source: FDA

PHARMACOVIGILANCE SYSTEMThis figure illustrates the patient outcome(s) for reports in FAERS since the year 2004 until the end of 2013. Serious outcomes include death, hospitalization, life-threatening, disability, congenital anomaly and/or other serious outcome.

Source: FDA

GLOBAL PHARMA PRIMER• Introduction• Causes of harm to patients and trial subjects• Injury and death to trial subjects • Injury and death to patients after approval • Safety v Security • Hazard identification in different industries • Hazard identification in pharmaceutical industry • Pharmacovigilance system • Public health implications of unidentified/non-mitigated risks• Individual assessment of risk

PUBLIC HEALTH IMPLICATIONS

Discovered in the 1930s, Sulfanilamides were the first anti-bacterial drugs; this was a game-changer in the treatment of infected wounds and had huge impact on survival of battlefield casualties in WWII.

PUBLIC HEALTH IMPLICATIONSAn adverse drug event (ADE) is defined as harm experienced by a patient as a result of exposure to a medication.

• ADEs are the cause of nearly 700,000 emergency department visits • ADEs account for 100,000 hospitalizations each year• ADEs affect nearly 5% of hospitalized patients (most common type of inpatient errors)• Ambulatory patients may experience ADEs at even higher rates• Medication error: clinician prescribes a medication and the patient receives it in error• Preventable adverse drug events: result from medication error and cause harm• Ameliorable ADE: harm to patient not preventable but could have been mitigated• Adverse drug reactions (side effects): non-preventable ADEs• Expected ADRs are mentioned on product label, unexpected ADRs are unforeseen

U.S. clinicians have access to more than 10,000 prescription medications

30% of U.S. adults take 5 or more medications

Source: AHRQ

PUBLIC HEALTH IMPLICATIONS

• Estimated excess hospital costs $5.6 million (1993 USD)• ADEs contribute an additional $3.5 billion (2006 USD) to U.S. healthcare costs • Highest risk: older adults, Medicare beneficiaries • 75% ADEs are attributable to the most common medications

ADEs impose a large financial burden on health care expenditures

ED visits and hospital admissions resulting from ADEs contribute to overburdened MedicareSource: National Action Plan fro ADE Prevention

Source: International prevalence of adverse drug events in hospitals: an analysis of routine data from England, Germany, and the USA, 2014.

PUBLIC HEALTH IMPLICATIONS

Source: National Action Plan fro ADE Prevention

Strengths and limitations of federal systems that conduct ADE surveillance

GLOBAL PHARMA PRIMER• Introduction• Causes of harm to patients and trial subjects• Injury and death to trial subjects • Injury and death to patients after approval • Safety v Security • Hazard identification in different industries • Hazard identification in pharmaceutical industry • Pharmacovigilance system • Public health implications of unidentified/unmitigated risks• Individual assessment of risk

INDIVIDUAL RISK ASSESSMENT

INDIVIDUAL RISK ASSESSMENT

Source: International prevalence of adverse drug events in hospitals: an analysis of routine data from England, Germany, and the USA, 2014

DRUG v HUMAN INTERACTIONS: Absorption into the body e.g. from the gut Distribution to their site of action in the bodyTarget interaction binding to cellular receptors or ion channelsMetabolic processingExcretion from the body

Genetic differences account for anywhere between 20 and 95% of variations in drug response between individuals. PHG

• Approach of regulators is inherently reactive. Major legislation changes were triggered by disasters.

• Change of life science doctrine from miasmic theory toward germ theory and evidence-based medicine was a major contributing factor in development from patent medicines to current regulated environment.

• Principles introduced during The Doctors Trial in front of American Military Tribunal after WW2 are the cornerstone of principles in medical experimentation.

• Harm to trial subjects and patients can occur in all stages of drug development and marketing. The nature of harm involves characteristics of the drug, information provided with it, and its use.

• Regulatory response to provided information significantly affects the outcome. Correct approval (safe and effective medicine becoming available); correct rejection (prevents unsafe drug from entering the market); incorrect approval (available unsafe/ineffective drug); and incorrect rejection (useful drug not available).

• Worst pharmaceuticals disasters on record – thalidomide and diethylstilbestrol - did not result in just compensation for the victims.

• Hazard identification techniques in pharma are largely based on historical record of incidents (patient casualties).

• Unidentified and non-mitigated hazards have significant impact on public health and inflict substantial costs on healthcare systems.

• Individual genetic differences account for anywhere between 20 and 95% of variations in drug response between individuals. Harm caused by individual differences is predictable and preventable only if the mechanism of action is well understood and if there is a way how to identify patients at risk.

SUMMARY