Series 2: FDA Modernization Act of 1997 (FDAMA) — Section 112
FDA Modernization Act of 1997 (FDAMA) — Section 112
After the Orphan Drug Act passed, one reality became unavoidable:
For many rare diseases, running more than one large clinical trial was simply not possible.
Patient populations were too small.
Enrollment could be exhausted in a single study.
Repeating trials could eliminate the only chance to learn anything at all.
Congress addressed this directly in 1997 through Section 112 of the FDA Modernization Act, which states that:
In certain cases, one adequate and well-controlled clinical study may be sufficient to establish effectiveness.
This was not a shortcut.
It was a recognition of feasibility.
FDAMA §112 exists because Congress understood that for rare and serious diseases:
Replication may be impossible
Waiting for multiple trials may cause irreversible harm
Demanding “prove it twice” can mean proving nothing at all
This provision was meant to ensure that rigor adapts to reality, rather than erasing opportunity for rare patients.
Patient populations were too small.
Recruitment could be exhausted in a single study.
Repeating trials wasn’t just expensive — it was often impossible.
And so patients, advocates, and policymakers were forced to confront a question the system had avoided:
-What happens when one well-run trial is all you can ever do?
Why “Two Large Trials” Never Fit Rare Disease Reality:
The standard expectation in drug development had long been:
Prove it twice.
That logic works when:
Tens of thousands of patients exist
Trials can be repeated
Time is available
But for rare diseases:
The entire patient population may be smaller than one traditional trial
Patients age, progress, or die during studies
Enrollment can permanently drain the community
In rare disease, asking for another trial can mean asking for the impossible.
Patients Saw the Problem First
Families living with rare diseases understood something regulators and sponsors were slow to acknowledge:
“There may only be one chance to get this right.”
Patients advocated not for shortcuts, but for realism:
That a single, well-designed study could carry meaningful evidence
That repeating a trial was not always ethical or feasible
That delay itself could erase the opportunity to learn anything at all
This wasn’t theoretical.
Communities watched promising programs stall simply because there were no patients left to enroll.
Why This Question Still Matters Today
Decades later, rare patients are still asked:
“Can you replicate this?”
“Can you run another study?”
“Can you reduce uncertainty further?”
For many rare diseases, the honest answer remains:
No — not without losing the program entirely.
When feasibility is ignored, the outcome isn’t better science.
It’s no science.
Rare & Relentless Takeaway
Rare disease development doesn’t fail because patients refuse rigor.
It fails when rigor ignores reality.
When one trial may be all that exists:
Expectations must adapt
Uncertainty must be weighed
Time must be allowed to work
Otherwise, the system quietly recreates the same problem the Orphan Drug Act was meant to solve — just one step later in the process.
What Patients & Advocates Can Say Out Loud
When One Trial May Be All There Is
You don’t need to argue science.
You don’t need to cite laws.
You just need to state the reality clearly and calmly.
Here are phrases patients and advocates can use in meetings with industry or FDA.
To Establish Reality
“Because this disease is rare, we may only have one realistic opportunity to run a trial.”
To Address Replication Expectations
“I want to understand how expectations are adjusted when repeating a trial isn’t feasible for a community this small.”
To Separate Rigor From Impossibility
“We’re not asking for lower standards — we’re asking for standards that fit what’s possible here.”
When Asked for More Data
“Can you help us understand what additional data would be feasible without exhausting the patient population?”
To Address Ethical Limits
“At a certain point, asking for another study means asking patients to give something they may not be able to give again.”
If the Conversation Gets Stuck
“Can we document what’s considered sufficient in principle, given that there may not be a second chance?”
If Industry Expresses Risk Concerns
“Regulatory uncertainty is one of the biggest risks for rare disease development. That’s what we’re trying to reduce.”
One Grounding Statement (Use If Needed)
“For rare patients, ‘come back with more data’ can sometimes mean ‘come back never.’”
Patient Foundation Checklist
Industry & FDA Engagement When One Trial May Be Enough
Use this before, during, or after meetings.
1. Population Reality
☐ Is the full patient population smaller than a typical Phase 3 trial?
☐ Would one trial significantly exhaust the recruitment pool?
☐ Is disease progression rapid or irreversible?
2. Trial Repeatability
☐ Has it been acknowledged that repeating the trial may not be feasible?
☐ Has anyone stated how expectations change when replication isn’t possible?
☐ Is the burden on patients (time, risk, travel) being considered?
3. Evidence Expectations
☐ Has FDA or industry discussed what one good trial would need to show?
☐ Are meaningful clinical signals being valued, even if imperfect?
☐ Is uncertainty being discussed as expected — not disqualifying?
4. Ethical Considerations
☐ Has the ethical cost of “just one more study” been acknowledged?
☐ Has anyone considered what happens if patients decline to re-enroll?
☐ Is patient fatigue or harm part of the discussion?
5. Program Viability
☐ Has the risk of program collapse due to repeat-study demands been acknowledged?
☐ Has industry been clear about whether additional trials are financially possible?
☐ Has FDA acknowledged that ambiguity can end development?
6. Documentation
☐ Is there a written record of how feasibility affects expectations?
☐ Are assumptions about repeat trials documented — or just implied?
☐ Is there clarity on what would not be expected due to rarity?
Red Flags to Watch For
🚩 “We’ll need to see it again” — without discussing feasibility
🚩 “Can you just run another study?”
🚩 Silence when asked what happens if another trial isn’t possible
Rare & Relentless Reminder
Patients are not asking to skip steps.
They are asking not to be trapped by steps that cannot be repeated.
When one trial may be all there is:
Expectations must adapt
Uncertainty must be weighed
Time must be allowed to work
That is not leniency.
It is realism.
Official law links
Congress.gov — FDA Modernization Act of 1997 (Public Law 105-115):
https://www.congress.gov/public-law/105/115Statutory text (FDAMA §112):
https://www.govinfo.gov/content/pkg/PLAW-105publ115/pdf/PLAW-105publ115.pdf
