From Phase 3 to Pharmacovigilance: Understanding the Continuum of Drug Development Beyond Approval

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1. Introduction

Most public discussions around drug development end at Phase 3 clinical trials—the so-called “pivotal studies” that determine whether a medicine receives regulatory approval. Yet, in reality, the journey does not end there. Once Phase 3 concludes, a drug enters a complex transitional space involving regulatory review, strategic bridging studies, and ultimately the system of post-marketing surveillance (PMS) and pharmacovigilance.

Understanding this continuum is crucial: Phase 3 provides controlled efficacy data, but Phase 4 and pharmacovigilance determine whether a medicine can truly survive in the real world, where patient diversity, long-term safety, and societal trust come into play.

2. Phase 3 Characteristics – The Controlled Gatekeeper

• Design: Large, randomized, controlled trials, often multinational.

• Focus: Efficacy under optimal conditions and confirmation of safety.

• Patient selection: Strict inclusion/exclusion criteria, reducing variability.

• Sample size: Thousands of patients—large for clinical trials, but small compared to real-world populations.

• Outcome: The results, consolidated in a Clinical Study Report (CSR), form the basis of the regulatory submission for approval.

Phase 3 is the gatekeeper: it is necessary for approval but insufficient for understanding how a drug will behave once used by millions.

3. From CSR to Submission – The Regulatory Dossier

The CSR marks the formal closure of pivotal Phase 3. It becomes the backbone of the NDA/BLA (United States), MAA (European Union), or equivalent dossiers in Asia and other jurisdictions. These applications include:

• Clinical efficacy and safety data

• Preclinical toxicology

• Chemistry, Manufacturing, and Controls (CMC)

• Proposed labeling and risk management strategies

Regulatory review typically consumes 12–18 months:

• FDA: 10 months (standard) or 6 months (priority review)

• EMA: 12–15 months (standard), 150 days (accelerated)

• PMDA (Japan) / MFDS (Korea): 12–18 months

• Global average: at least one year, even with expedited pathways

This waiting period is not idle—it is a strategic interregnum.

4. Phase 3b – The Strategic Bridge

Definition: Phase 3b trials occur after pivotal Phase 3 trials are completed and submitted, but before regulatory approval is granted.

Objectives:

• Extend long-term safety data via open-label extensions (OLEs)

• Study special populations excluded from pivotal trials (pediatrics, elderly, comorbidities)

• Explore label expansion opportunities (secondary indications, new dosing regimens)

• Generate comparative or outcomes data useful for health technology assessment (HTA) and payers

Strategic role: Phase 3b mitigates the gap created by regulatory timelines and strengthens both market positioning and payer negotiations before launch.

5. Regulatory Approval and the Transition to Phase 4

Once approval is granted, a product formally enters the post-marketing stage. Key shifts occur:

• From efficacy → to effectiveness

• From selected patients → to all patients (with comorbidities and polypharmacy)

• From short-term controlled safety → to long-term real-world safety

• From clinical trial endpoints → to real-world outcomes, including quality of life and rare adverse events

This is the domain of Phase 4 studies and the broader system of pharmacovigilance.

6. Phase 4 Studies – Purpose and Scope

Phase 4 studies are designed to generate evidence once a drug is already marketed:

• Long-term safety: Detection of rare, delayed, or cumulative adverse events

• Effectiveness in heterogeneous populations: Validating performance outside controlled trial environments

• Drug–drug and drug–disease interactions: Especially relevant in polypharmacy and chronic conditions

• Regulatory obligations: Post-approval commitments mandated by FDA, EMA, MFDS, or PMDA

• Market access: Evidence requested by insurers and HTA agencies for reimbursement

Common Phase 4 designs include:

• Large pragmatic randomized trials

• Registry-based observational studies

• Comparative effectiveness studies

• Pharmacoeconomic and outcomes research

7. Pharmacovigilance Systems – Global Framework

Beyond formal trials, pharmacovigilance ensures continuous monitoring:

• Spontaneous adverse event reporting: FDA’s FAERS, EMA’s EudraVigilance, WHO’s VigiBase

• Risk management systems: REMS (U.S.), RMP (EU), local equivalents in Asia

• Periodic safety reports: PSUR/PBRER submitted at defined intervals

• Registries and real-world data mining: Oncology, cardiovascular, rheumatology, and beyond

• AI and big data analytics: Emerging tools for signal detection in electronic health records and social media

8. The Reality vs. the Ideal

In theory: Phase 4 implies structured post-marketing randomized trials.
In practice:

• Pharmaceutical companies rarely conduct true Phase 4 RCTs unless regulators mandate them.

• Instead, most rely on Post-Marketing Surveillance (PMS) and pharmacovigilance reporting systems.

• Public health agencies and academic consortia often lead genuine Phase 4 studies (e.g., vaccines, antibiotics, high-risk therapies).

• Cost, commercial risk, and regulatory flexibility explain why companies prioritize PMS and label-expansion studies over large Phase 4 RCTs.

Important note: In some jurisdictions (e.g., Korea, Japan), PMS is officially categorized as Phase 4, blurring the distinction between formal post-approval trials and surveillance activities.

9. Conclusion

The transition from Phase 3 to Phase 4 is not a simple continuation—it is a paradigm shift from controlled experimental conditions to open societal oversight. While Phase 3 secures regulatory entry, Phase 4 and pharmacovigilance determine survival, sustainability, and trust.

In reality, most companies rely on PMS and pharmacovigilance rather than true Phase 4 RCTs, leaving public institutions to fill the gap. This tension between regulatory theory and industrial practice highlights why post-approval evidence is as much about governance and societal trust as it is about science.

Annex 1 – The Success Story of Dupilumab (Dupixent)

When Dupilumab was first developed, it was only meant to help patients with severe eczema who had no other good options. In 2017, the FDA approved it after strong Phase 3 results showed that it could control symptoms safely and effectively.

But the story didn’t end there. Instead of stopping at eczema, researchers continued to test Dupilumab in new studies after approval—what we might call Phase 3b/4 work. They tried it in asthma, in patients with nasal polyps that block breathing, in eosinophilic esophagitis, and even in very itchy skin disorders like prurigo nodularis.

These additional studies, combined with real-world patient registries, showed that Dupilumab remained effective and safe over the long term. The result? A drug that started as a treatment for one skin disease became a multi-indication blockbuster, generating over $10 billion a year and improving lives in many different conditions.

Takeaway: Careful post-approval research can turn a single-use medicine into a powerful therapeutic platform.

Annex 2 – The Collapse of Vioxx (Rofecoxib)

Vioxx was launched in 1999 as a new kind of painkiller. Unlike older anti-inflammatory drugs, it promised pain relief without the stomach problems that often came with long-term use. Phase 3 trials looked good, regulators approved it, and millions of prescriptions were written.

But soon after, troubling signs began to appear. Patients using Vioxx started showing higher rates of heart attacks and strokes. These rare but serious problems had not been seen clearly in Phase 3, but as millions began taking the drug, the pattern became undeniable.

By 2004, the evidence was overwhelming. Merck voluntarily pulled Vioxx from the market, and later faced billions of dollars in lawsuits. What had started as a blockbuster drug became one of the biggest pharmaceutical scandals in modern history.

Takeaway: Passing Phase 3 does not guarantee safety. Post-marketing vigilance is essential, because rare risks only show up when a drug is used by millions.

Annex 3 – Thalidomide: From Tragedy to Redemption

Thalidomide’s story is perhaps the most dramatic in pharmaceutical history. In the late 1950s, it was sold as a sedative and a treatment for morning sickness in pregnancy. At the time, drug testing standards were much weaker, and no robust Phase 3 data existed.

Soon after, a wave of tragedy struck. Thousands of babies were born with severe birth defects caused by thalidomide’s effect on fetal development. The drug was banned worldwide, and it became a symbol of pharmaceutical failure.

Decades later, however, researchers returned to study thalidomide carefully, this time with strict modern standards. They discovered it had powerful effects in treating multiple myeloma, a type of blood cancer. Under extremely strict safety programs (to ensure it would never again be used in pregnancy), thalidomide was approved by the FDA in 2006 as part of cancer therapy.

What was once a symbol of disaster became, under the right controls, a valuable medicine for very sick patients.

Takeaway: With rigorous investigation and strong safety systems, even a drug once considered untouchable can be given a second life.

BBIU Perspective

These three stories show the different faces of what happens after Phase 3:

• Dupilumab: how smart post-approval research can expand a drug’s impact.

• Vioxx: how hidden risks can destroy a drug once it reaches the market.

• Thalidomide: how tragedy can be transformed into redemption through strict pharmacovigilance and re-investigation.

Together, they illustrate why the journey does not end with approval—it is only the beginning of the real test.