Post Marketing surveillance

Post-Marketing Surveillance (PMS):

1. Introduction

• Definition:
  Post-Marketing Surveillance (PMS) is the monitoring of safety, efficacy, and quality of medicines after they are approved and marketed.
• Need:
• Pre-marketing clinical trials (Phase I–III) are limited by:
• Small sample size
• Short duration
• Selected patient population (excludes elderly, pregnant, comorbidities, polypharmacy)
• Hence, many rare, delayed, or long-term ADRs are detected only after marketing.
• Role: Protect public health by detecting risks → modify drug use (label changes, restricted use, or withdrawal).

2. Objectives of PMS

👉 Mnemonic: DR CARE DL

1. D – Detection of new, rare, or unexpected ADRs
2. R – Risk quantification (true incidence & severity)
3. C – Comparative safety assessment between drugs
4. A – Assessment of effectiveness in real-world use
5. R – Risk factor identification (age, comorbidities, drug interactions)
6. E – Evaluation of long-term & cumulative effects
7. D – Drug utilization studies (patterns, misuse, off-label use)
8. L – Look for drug–drug or drug–disease interactions

3. Methods of PMS

3.1 Spontaneous Reporting System (SRS)

• Definition:
  Voluntary reporting of ADRs by healthcare professionals, patients, or companies.
• Examples:
• USA: FAERS (FDA Adverse Event Reporting System)
• EU: EudraVigilance
• WHO: VigiBase (UMC, Sweden)
• India: PvPI (Pharmacovigilance Programme of India, IPC Ghaziabad)
• Advantages:
• Inexpensive
• Detects rare or unexpected ADRs
• Wide geographical coverage
• Disadvantages:
• Under-reporting (only 5–10% ADRs reported)
• Reporting bias (serious ADRs more likely reported)
• Cannot calculate incidence or risk (no denominator)
• Weak causality assessment

3.2 Cohort Studies

• Definition:
  Follow groups of exposed vs. unexposed patients over time.
• Types:
• Prospective (forward-looking)
• Retrospective (using past medical records)
• Advantages:
• Can calculate incidence rates & relative risk
• Establishes temporal relationship
• Useful for multiple outcomes
• Disadvantages:
• Expensive, time-consuming
• Requires large sample size
• Inefficient for rare ADRs
• Risk of loss to follow-up, confounding

3.3 Case-Control Studies

• Definition:
  Compare patients with ADR (cases) vs. without ADR (controls), looking for prior exposure.
• Measure: Odds Ratio (OR).
• Advantages:
• Best for rare ADRs
• Relatively fast & inexpensive
• Can study multiple exposures
• Disadvantages:
• Recall bias (patients may not remember exposures)
• Selection bias in choosing controls
• Cannot measure incidence
• Temporal relationship sometimes unclear

3.4 Prescription Event Monitoring (PEM)

• Definition:
  All patients prescribed a new drug are followed up (e.g., questionnaires sent to doctors).
• Example: UK PEM system.
• Advantages:
• Provides denominator (number of patients exposed) → event rates possible
• Covers large populations systematically
• Useful for detecting common ADRs
• Disadvantages:
• Relies on physician compliance → incomplete data
• Misses ADRs if patients do not report
• Time lag before results

3.5 Record Linkage Studies

• Definition:
  Linking existing healthcare databases (EHR, hospital records, mortality, insurance claims) to study drug safety.
• Examples: CPRD (UK Clinical Practice Research Datalink), US Medicare data.
• Advantages:
• Large population coverage
• Long-term follow-up possible
• Cost-effective (uses existing data)
• Useful for rare ADRs
• Disadvantages:
• Data quality varies
• Coding errors, missing information
• Confounding by indication
• Privacy and ethical concerns

3.6 Active Surveillance Systems

• Definition:
  Proactive collection of safety data (not passive like spontaneous reporting).
• Types:
• Sentinel systems (e.g., US FDA Sentinel Initiative)
• Disease/Drug Registries (e.g., pregnancy registries, vaccine safety monitoring)
• Advantages:
• Real-time monitoring
• Stronger causality
• Detects both common & rare ADRs
• Disadvantages:
• Very costly
• Resource-intensive
• Complex infrastructure needed

3.7 Meta-Analysis & Systematic Reviews

• Definition:
  Combine results from multiple clinical trials and observational studies to strengthen evidence.
• Advantages:
• Increased statistical power
• Resolves conflicting results
• More precise risk estimates
• Disadvantages:
• Dependent on quality of included studies
• Publication bias
• Heterogeneity between studies

4. Comparison Table

Method	Cost	Speed	Rare ADRs	Incidence Rates	Causality
Spontaneous Reporting	Low	Fast	✅ Good	❌ No	❌ Weak
Cohort Study	High	Slow	❌ Poor	✅ Yes	✅ Strong
Case-Control Study	Medium	Medium	✅ Excellent	❌ No	⚠ Fair
PEM	Medium	Medium	⚠ Fair	✅ Yes	⚠ Fair
Record Linkage	Low–Med	Fast	✅ Good	✅ Yes	⚠ Fair
Active Surveillance	High	Fast	✅ Good	✅ Yes	✅ Strong

5. Challenges in PMS

1. Statistical Issues:
• Confounding
• Missing data
• Small effect size detection
2. Regulatory Issues:
• Lack of harmonization globally
• Delayed regulatory action
• Uncertainty in signals
3. Methodological Issues:
• Causality difficult to establish
• Multiple drugs, multiple comorbidities
4. Practical Issues:
• Under-reporting
• Poor data quality
• Privacy & ethical concerns
• Limited resources in LMICs

6. Future Directions

1. Big Data & AI/ML → predictive safety analytics, real-time ADR signal detection.
2. Patient-Reported Outcomes → mobile apps, social media monitoring.
3. Pharmacogenomics → genetic predisposition to ADRs.
4. International Collaboration → global databases (e.g., VigiBase).
5. Integration with EHR & IoT → automatic ADR detection from routine care data.

7. Regulatory Framework

• ICH Guidelines (E2A–E2E) → cover expedited reporting, risk management, and pharmacovigilance planning.
• Good Pharmacovigilance Practices (GVP, EU) → structured safety monitoring guidelines.
• National Programmes:
• US: FDA Sentinel, MedWatch
• EU: EMA EudraVigilance
• India: PvPI (launched 2010, coordinated by IPC Ghaziabad)

8. Conclusion

• PMS is critical for drug safety throughout its lifecycle.
• Each method has strengths & limitations.
• Combination of methods provides best surveillance.
• The future lies in AI, genomics, digital health, and global collaboration for proactive and efficient pharmacovigilance.

PMS

Definition

🔹 Monitoring safety, efficacy & quality of drugs after approval → detect rare/long-term ADRs not seen in trials.

Objectives → DR CARE DL

• D → Detect new ADRs
• R → Risk quantification
• C → Compare drug safety
• A → Assess effectiveness
• R → Risk factor identification
• E → Evaluate long-term effects
• D → Drug utilization studies
• L → Look for interactions

Methods

1️⃣ Spontaneous Reporting (SRS)

• Eg: FAERS, VigiBase, PvPI
• ✅ Rare ADRs, cheap
• ❌ Under-reporting, no incidence

2️⃣ Cohort Study

• Exposed vs. unexposed
• ✅ Incidence, temporality
• ❌ Costly, large size, poor for rare ADRs

3️⃣ Case-Control Study

• Cases (ADR) vs. Controls
• ✅ Rare ADRs, quick
• ❌ Recall bias, no incidence

4️⃣ Prescription Event Monitoring (PEM)

• All patients on new drug tracked
• ✅ Denominator → event rates
• ❌ Depends on physician compliance

5️⃣ Record Linkage

• Connect EHR, claims, mortality data
• ✅ Large, long-term, rare ADRs
• ❌ Data errors, privacy issues

6️⃣ Active Surveillance

• Registries, FDA Sentinel
• ✅ Real-time, strong causality
• ❌ Expensive, resource-heavy

7️⃣ Meta-Analysis/Systematic Review

• Pool multiple studies
• ✅ High power, resolves conflicts
• ❌ Quality dependent, bias

Comparison Table

Method	Cost	Rare ADRs	Incidence	Causality
SRS	Low	✅	❌	❌
Cohort	High	❌	✅	✅
Case-Control	Med	✅✅	❌	⚠
PEM	Med	⚠	✅	⚠
Record Link	Low	✅	✅	⚠
Active Surv.	High	✅	✅	✅

Challenges

• Statistical → confounding, bias
• Regulatory → slow, non-uniform rules
• Practical → under-reporting, privacy, cost

Future

• AI/ML → predictive safety
• Genomics → personalized ADR risk
• Apps/IoT → real-time patient reporting
• Global databases → VigiBase, Sentinel

Regulatory Bodies

• US → FDA Sentinel, MedWatch
• EU → EMA (EudraVigilance)
• India → PvPI (IPC Ghaziabad)
• ICH → E2A–E2E, global harmonization

Phases of Clinical Trials

Phases of Clinical Trials – Introduction

Clinical research is conducted in four phases (I–IV), each addressing specific questions. Data from preclinical animal studies (therapeutic effects, dose levels, toxicity) guides the design of Phase I trials.

Phase I Clinical Trials

• Purpose: Assess safety, tolerability, pharmacokinetics (ADME), pharmacologic actions, and identify a safe dosage range.
• Subjects: Usually 20–80 healthy volunteers (patients used if the drug is too toxic, e.g., anticancer drugs).
• Duration: Around 3–6 months.
• Process: Starts with small single doses under close monitoring in a controlled setting.
• Outcomes: Determines side effects, safe dose ranges, and early evidence of effectiveness.
• Regulation: Authorities (e.g., FDA) may halt a trial if safety risks or disclosure issues arise.

Phase II Clinical Trials

• Subjects: 100–300 patients with the target disease.
• Duration: ~6 months to 2 years.
• Purpose:
• Establish clinical efficacy.
• Identify effective dosage range.
• Monitor adverse reactions in patients.
• Provide detailed pharmacokinetic & pharmacologic data.
• Outcome: Defines the optimum therapeutic dose and confirms safety in the diseased population.

Phase III Clinical Trials

• Subjects: Several hundred to several thousand patients.
• Duration: ~1–5 years.
• Purpose:
• Confirm effectiveness in large groups.
• Detect adverse effects during long-term use.
• Evaluate benefit–risk profile.
• Provide basis for drug approval and labeling (package insert).
• Special groups: Often includes children, elderly, or patients with liver/kidney impairment.

1. Regulatory Oversight in Phase II & III

• Just like in Phase I, regulators (like FDA) can impose a clinical hold in Phases II and III if:
• The study is unsafe, or
• The protocol is inadequate and doesn’t meet objectives.
• These decisions are made carefully, based on scientific knowledge, agency experience, trial design, and drug class.

2. After Phase III

• Once a Phase III trial is completed successfully, the drug company can apply for marketing approval to regulatory authorities.
• This is the stage where the company seeks formal permission to sell the drug.

Trial Organization Chart

• Sponsor → The company or institution developing the drug.
• Steering Committee → Provides oversight and guidance for the trial.
• Data Monitoring Committee (DMC) → Independent group that reviews safety/efficacy data, can recommend stopping or continuing a trial.
• Contact Research Organization (CRO) → External organization hired to run/manage the trial.
• Clinical Study Site Investigators → Doctors/researchers who actually conduct the trial on patients.
• Data Management Center → Collects and manages clinical trial data (Case Report Forms – CRFs).
• All these groups communicate to ensure the trial is safe, well-monitored, and scientifically valid.

New Drug Application (NDA)

• After completing Phases I–III, the company compiles all clinical and preclinical data and submits it as a New Drug Application (NDA) to the FDA.
• Contents of NDA: Safety, efficacy, pharmacology, toxicology, manufacturing details, labeling info, etc.
• Size: Typically 100,000+ pages.
• FDA Review Timeline:
• Legally, FDA has 6 months to review an NDA.
• In practice, it often takes longer. Example: In 1992, the average review time for new molecular entities was 29.9 months.

✅ In short:

• Phases II & III are still under regulatory monitoring (can be stopped for safety issues).
• After Phase III success, the company applies for marketing approval via an NDA.
• NDA is a huge scientific dossier reviewed by FDA before the drug can reach the market.

Phase IV Clinical Trials (Post-Marketing Surveillance)

• Conducted after the drug is approved and marketed.
• Purpose:
• Detect rare or long-term adverse effects that may not appear in earlier trials (because those involve fewer patients and shorter durations).
• Monitor real-world effectiveness in diverse patient populations.
• Example: Thalidomide tragedy (1960s) – severe birth defects were only discovered after widespread use, leading to stricter regulations.
• Outcome: Drugs may be restricted or withdrawn from the market if serious risks are found.

Abbreviated New Drug Application (ANDA)

• Filed to market generic drugs (low-cost alternatives to branded drugs).
• Called "abbreviated" because:
• No new preclinical or clinical trials are required.
• Instead, the company must show bioequivalence (generic drug has the same active ingredient, strength, dosage form, route of administration, and works in the same way as the original brand drug).
• Review Focus:
• Bioequivalence studies
• Chemistry & microbiology data
• Manufacturing plant inspection
• Drug labeling

Essential Clinical Trial Documents

These are mandatory documents to ensure scientific validity, safety, and regulatory compliance in clinical research.

1. Protocol – The official trial plan (objectives, design, methods, statistics).
2. Informed Consent Document (ICD) – Ensures participants voluntarily agree after being fully informed.
3. Investigator’s Brochure (IB) – Summary of preclinical & clinical data for investigators.
4. Case Report Form (CRF) – Standardized form to record trial data for each participant.
5. Source Data/Document (SD) – Original records (lab reports, hospital charts, ECGs, etc.).
6. Regulatory Approval – Authorization from drug regulatory bodies to conduct the trial.
7. Ethics Committee Approval (ERB/IRB/IEC/EC) – Protects rights, safety, and well-being of participants.
8. Advertisement – Materials used to recruit participants (must be approved).
9. Financial Agreement – Contract about trial funding and payments.
10. Insurance Statement – Proof of insurance coverage for participants against trial-related harm.
11. Curriculum Vitae (CV) – Investigator’s qualifications.
12. Laboratory Reference Range – Normal lab value ranges for interpreting trial results.
13. Monitoring Report – Reports from monitors who oversee trial conduct.
14. Investigational Product Accountability Log – Tracks drug supply, storage, dispensing, and return.
15. Certificate(s) of Analysis (COA) – Confirms drug quality and purity.
16. SAE Report Form – Used to report Serious Adverse Events quickly to regulators and sponsors.
17. Correspondence – Communication between sponsor, investigator, regulators, etc.
18. Queries – Questions raised during data review and their resolutions.
19. Clinical Study Report (CSR) – Final detailed report of the trial, submitted to regulatory authorities.

✅ In summary:

• Phase IV checks long-term safety after marketing.
• ANDA allows generics to be marketed without full clinical trials, focusing on bioequivalence.
• Essential documents ensure trials are ethical, valid, and regulatory-compliant.

condensed table for quick exam revision:

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·        Clinical Trials & Regulatory Applications – Summary Table

Phase / Application	Subjects	Duration	Purpose / Key Features
Phase I (First-in-human)	20–80 healthy volunteers (patients if drug is too toxic, e.g., anticancer drugs)	3–6 months	- Assess safety & tolerability - Study PK/PD (ADME) - Find safe dose range
Phase II (Proof of concept)	100–300 patients with target disease	6 months – 2 years	- Test clinical efficacy - Define optimal dose - Monitor adverse effects in patients
Phase III (Confirmatory)	Several hundred – several thousand patients	1–5 years	- Confirm effectiveness & long-term safety - Evaluate benefit–risk ratio - Basis for regulatory approval - Includes special subgroups (children, elderly, renal/hepatic impaired)
Phase IV (Post-marketing)	General population (after approval)	Ongoing	- Detect rare/long-term adverse effects - Monitor real-world effectiveness - May lead to drug withdrawal
NDA (New Drug Application)	–	FDA review: ~6 months (avg longer)	- Submitted after Phases I–III - Contains all safety, efficacy, manufacturing, labeling data - ~100,000+ pages
ANDA (Abbreviated New Drug Application)	–	FDA review	- For generic drugs - No new animal/human data - Must show bioequivalence to innovator drug

Introduction to Clinical Trials

Definition:
Clinical trials are systematic studies of new drugs in humans to assess their safety, efficacy, pharmacokinetics, pharmacodynamics, and adverse effects.

Participation

• Participants may gain early access to new treatments and contribute to medical research.
• Inclusion/Exclusion Criteria decide eligibility based on factors like age, gender, disease stage, medical history, and prior treatments.
• These criteria ensure reliable results and participant safety, not personal rejection.
• Trials may involve patients with specific illnesses or healthy volunteers.

Process

• Varies by type of trial.
• Conducted by a team of doctors, nurses, social workers, and other healthcare professionals.

Clinical Trials – Summary Notes

Process

• Health of participants is checked before the trial.
• Participants receive instructions, are closely monitored during the trial, and followed up after completion.
• Success depends on adherence to protocol and regular contact with the research team.

Informed Consent

• Ongoing process of providing trial information before and during participation.
• Doctors/nurses explain study details; translation provided if needed.
• Consent form covers purpose, duration, procedures, and contacts.
• Not a contract – participants may withdraw anytime.

Benefits

• Active role in personal health care.
• Early access to new treatments.
• Expert medical care during trial.
• Contribute to advancement of medical research.

Safety

• Governed by medical ethics and legal codes.
• Federally regulated with safeguards for participant protection.

Clinical Trials – Key Points

Protocol & Reporting

• Trials follow a strict study plan (protocol).
• Results shared in journals, meetings, and with agencies; participant identities remain confidential.

Information for Subjects

Before joining, participants should ask about:

• Purpose, eligibility, prior testing of treatment.
• Tests/procedures involved.
• Risks, benefits vs. current treatment.
• Impact on daily life, duration, need for hospitalization.
• Costs and who pays.
• Who will manage care.

Ideas for Clinical Trials

• Origin: Researchers → lab studies → animal studies → human trials.
• Goal: Evaluate safety, risks, and effectiveness of new treatments.

Do you want me to merge all your sections (Intro, Process, Consent, Benefits, Safety, Protocol, etc.) into one complete concise “exam notes” document?

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Types & Phases of Clinical Trials

Types of Clinical Trials

1. Treatment Trials – Test new drugs, combinations, surgeries, or radiation.
2. Prevention Trials – Find ways to prevent diseases or recurrence (drugs, vaccines, lifestyle).
3. Diagnostic Trials – Develop better diagnostic tests/procedures.
4. Screening Trials – Improve detection of diseases/conditions.
5. Quality of Life (Supportive Care) Trials – Enhance comfort and well-being of chronic illness patients.

Phases of Clinical Trials

• Phase I (20–80 people): Safety, dosage, side effects.
• Phase II (100–300 people): Effectiveness + safety.
• Phase III (1000–3000 people): Confirm effectiveness, compare with standard treatment, monitor adverse effects.
• Phase IV (Post-marketing): Long-term risks, benefits, and optimal use.

Expanded Access Protocol (Treatment IND)

• Allows patients (not eligible for trials) with life-threatening diseases to access investigational drugs.
• Provides treatment + additional safety data.
• Allowed only if ongoing/completed controlled trials show potential benefit without unreasonable risk.