Nareg M. Varjabedian, Regulatory Affairs Team Lead at ClinChoice, shared a post on LinkedIn:
“Regulatory Blind Spots: Why Some Cancer Risks Are Discovered Too Late
Cancer risk is rarely discovered in Phase III trials.
And that’s not a failure of science – it’s a limitation of how regulation works.
Most pre-approval clinical trials are:
- Short in duration
- Limited in sample size
- Excluding high-risk populations
- Designed to detect efficacy, not decades-long carcinogenic signals
Cancer is often a late signal. Regulation is often early.
Where the Blind Spots Appear
1. Time Horizon Mismatch
Many drug-related cancers require years of exposure and latency.
Regulatory approval usually relies on months, not decades.
Example:
Immunosuppressants (e.g., azathioprine, cyclosporine)
- Increased risk of lymphoma and skin cancers became evident years after widespread use, mainly through registries and real-world data.
2. Mechanistic Uncertainty at Approval
A drug may be non-carcinogenic in animals, yet still promote cancer indirectly in humans.
Example:
Hormonal therapies (estrogens, androgens)
- Act as tumor promoters, not initiators
- Risk is recognized only after long-term epidemiological follow-up.
3. Underpowered Detection of Rare Events
Rare cancers ≠ rare impact.
A 1 in 10,000 risk won’t appear in a 3,000-patient trial.
Example:
Certain diabetes or cardiovascular drugs
- Early signals emerged only through post-marketing surveillance (PV databases, registries, signal detection algorithms).
4. Labeling ≠ Awareness
Even when regulators update labels, the risk often remains: • Buried in fine print
- Not translated into clinical decision-making
- Poorly communicated to patients
Regulatory approval does not equal full risk discovery.
The Human Side of Regulation
Behind every ‘late signal’ is:
- A patient who trusted long-term therapy
- A clinician who followed guidelines
- A regulator balancing benefit vs unknown future harm
No one failed – the system simply matured too late.
The Way Forward
- Stronger post-marketing surveillance
- Real-world evidence integration
- Long-term cancer registries
- Regulatory humility: approval is not the end of evaluation
Question for the community:
Should long-term cancer risk weigh more heavily in benefit–risk decisions – even when evidence is incomplete?
Because sometimes, the most serious adverse effect isn’t immediate – it’s delayed.”
More posts featuring Nareg M. Varjabedian.