Series 9 Rare Laws That Already Exist (Conclusion)
If This Is My One Chance, Are You Using It Wisely?
A Rare & Relentless Conclusion
The Laws That Already Exist
(And what rare patients have learned from watching them used — or never applied)
Rare patients are not asking for new laws.
They are asking for the ones that already exist to actually work.
Here is what has already been passed — and what we’ve seen happen instead:
Orphan Drug Act (1983)
Rare diseases need different rules to survive.
Flexibility exists because patients forced it into law.FDASIA §901 (2012)
Context matters. Severity matters. Uncertainty is expected.
Yet benefit–risk still shifts unpredictably between programs.Accelerated Approval (21 CFR 314 Subpart H)
Surrogates and early signals can count when waiting causes harm.
Except when they suddenly don’t — without explanation.FDAMA §112 (1997)
One adequate study can be enough when more isn’t feasible.
But feasibility is still treated like an inconvenience, not a limit.FDA Modernization Act 2.0 (2022)
Animal testing is no longer required. Human data can count.
But real-world evidence is still dismissed when it’s inconvenient.Administrative Procedure Act (APA)
Decisions should be reasoned, consistent, and non-arbitrary.
Rare patients still see similar programs reach opposite outcomes.Patient-Focused Drug Development (PFDD)
Patient experience should inform decisions.
Too often it’s praised — then ignored.Real-World Evidence provisions (21st Century Cures / later guidance)
Learning shouldn’t stop when trials end.
But long-term data is still treated as “interesting,” not decisive.
And then there’s the one law meant to pull all of this together:
The HEART Act
Meant to operationalize flexibility.
Meant to show how it’s applied.
Meant to create consistency instead of guesswork.It has not been implemented.
So flexibility still depends on who you get, when you ask, and how much risk the system feels like tolerating that day. FDA must report every year how flexiblty has been applied yet no report has been implemented.
If You Are a Rare Patient, You Already Know This
You are not just participating in research.
You could be investing in your only chance.
There may never be:
another study
another sponsor
another window of hope
So when someone says “we’ll need more data” or “let’s wait and see,”
what you hear isn’t scientific caution.
What you hear is:
“Your chance may be gone before we decide.”
Why Rare Drug Trials Feel Different
In common diseases, trials come and go.
In rare disease, a trial is the moment that can define a lifetime of treatment options.
You don’t get to:
fail forward
enroll again
wait for the next protocol
When a rare trial ends, it often ends everything, or adds years to already progressive disorders.
So when:
endpoints don’t match reality
uncertainty is treated like failure
flexibility exists but isn’t used
It doesn’t feel neutral.
It Feels Like the Door Quietly Closing
What people don’t see — what never makes it into press releases or conference panels — is what happens after a single regulatory decision.
They don’t see the bankruptcy in small biotech, where companies live investor to investor, essentially paycheck to paycheck.
They don’t see industry slowly, quietly walking away when risk becomes unpredictable.
They don’t see researchers left without funding, unable to move forward even when the science is sound.
One wrong move at the FDA doesn’t just affect a trial. One type II error that has consequences beyond a drug.
It can end an entire field.
I am living that reality right now.
I want patients and foundations to understand this because it can and does happen — even in rare pediatric disease. Even when families did everything asked of them. Even when participation was given in good faith. Even if they advocated relentlessly for 5 years.
At this moment, I have three bottles left of my daughter’s investigational drug.
I am waiting for the phone call that decides whether it ends.
That is not drama.
That is not emotion.
Those are straight facts.
This is what the longest Complete Response Letter in rare pediatrics looks like from the inside. It’s not a headline. It’s a countdown.
And I am telling you this for one reason only:
So you don’t learn it the hard way.
This isn’t about fear.
It’s about preparation.
I’m asking you — patients, parents, foundations — to learn from me.
To understand the laws that already exist.
To ask the questions before participation is spent.
To demand clarity, feasibility, and consistency while there is still time to change course.
Not because you don’t believe in research.
But because belief without knowledge leaves you unprotected.
If you take anything from Rare & Relentless, let it be this:
Asking questions does not jeopardize progress.
Silence does.
And if this is your one chance —
you deserve to know whether the system is using it wisely.
That is not emotion.
That is responsibility.
Rare Patients Are Afraid to Say
Most rare patients will never say this in a meeting —
but they think it every time:
“Please don’t waste my participation.”- In the last year I have asked this, pushed industry and FDA for deeper conversations.
Not on:
the wrong endpoint
an unworkable design
a trial no one could realistically win
placebo
Because participation isn’t symbolic.
It costs time.
It costs function.
It sometimes costs life.
Rare patients say yes knowing they may get no benefit at all —
only the hope that someone after them might.
That changes the math.
That changes the responsibility.
What Rare Patients Actually Know
Rare patients aren’t naïve or “uneducated”
They aren’t desperate.
They aren’t asking for miracles.
They know:
the science is hard
certainty may never come
the drug might not work
What they cannot accept is failure caused by rigidity instead of reality.
They understand something the system still avoids saying out loud:
A system that waits for perfect certainty often delivers no answer at all.
What We Should All Be Saying — Without Softening It
If bureaucracy didn’t mute the truth, this is what would be said plainly:
Stop pretending big trials are possible
“There are not enough patients to do this twice.”Give guidance before patients are spent
“Rare trials are not rehearsal runs.”Stop treating uncertainty like failure
“If certainty were possible, this wouldn’t be rare.”Admit when stability is the win
“For progressive disease, not getting worse is success.”Stop designing trials patients won’t enroll in
“A trial no one joins has already failed.”Use patient experience — don’t just compliment it
“Listening without action is choosing ignorance.”Count real-world data or admit you don’t want it
“Disease doesn’t stop when the protocol ends.”Apply flexibility the same way every time
“Flexibility that depends on who reviews you is luck, not law.”Write it down or it didn’t happen
“Undocumented promises don’t protect patients.”Admit ambiguity ends programs
“Unclear expectations eliminate options.”
The One Question That Ends Every Meeting
Every Rare & Relentless patient should leave meetings asking:
“How did rarity change the rules in this case?”
If no one can answer clearly —
flexibility didn’t happen.
What We Need Now
We do not need:
another paper
another listening session
another rebranding of flexibility
We need operationalized action.
That means:
feasibility first
clarity early
consistency always
documentation every time
Flexibility must be standard practice, not a discretionary favor.
The Rare & Relentless Truth
Rare patients aren’t asking for less rigor.
They are asking for rigor that fits reality.
And every rare patient entering a trial is quietly asking the same thing:
“If this is my one chance — are you using it wisely?”
That is the question the system still has to answer.
The Ultimate Rare Disease Drug Trial Checklist
For Patients Facing a “One-Shot” Trial
If you are a rare patient considering a drug trial, you are not just enrolling in research.
You are spending time, energy, function — and possibly your only chance.
This checklist is here to help you ask the questions before your participation is spent.
1. Reality Check: Is This Trial Built for a Rare Disease?
☐ Is the total patient population very small?
☐ Does the trial design acknowledge that this may be the only trial?
☐ Has anyone explicitly said, “There may not be another opportunity”?
🚩 Red flag: Trial is designed as if another study will always be possible.
2. Endpoint Fit: Will This Trial Recognize Real Benefit?
☐ Does the primary endpoint reflect how the disease actually progresses?
☐ Is stability considered success if the disease is progressive?
☐ Does the endpoint capture changes patients actually feel?
Ask out loud:
“If this treatment slows decline but doesn’t reverse disease, will that count?”
🚩 Red flag: “No change” automatically labeled as failure.
3. Placebo & Math: Does the Design Actually Work?
☐ Is there a placebo arm?
☐ Has anyone explained how placebo affects statistical power in a small population?
☐ Is this trial at high risk for a Type II error (false negative)?
Ask out loud:
“With this few patients, can this trial realistically show benefit?”
🚩 Red flag: Placebo required “because that’s the gold standard,” without math explained.
4. Feasibility: Will Patients Actually Enroll?
☐ Is enrollment realistic given disease severity and placebo risk?
☐ Could the design discourage the sickest patients from joining?
☐ Has dropout risk been discussed honestly?
Ask out loud:
“What happens if families decline to enroll because of this design?”
🚩 Red flag: Enrollment struggles blamed on “patient reluctance,” not design.
5. Timing: Is the Trial Long Enough — or Too Short?
☐ Is the trial long enough to detect meaningful change?
☐ Does the disease progress slowly or unevenly?
☐ Is benefit expected after the trial ends?
Ask out loud:
“If benefit appears later, how will that be captured?”
🚩 Red flag: Short trial for a long, progressive disease.
6. Flexibility: What Happens If the Data Is Mixed?
☐ Has the sponsor discussed alternative interpretations if the endpoint is missed?
☐ Are secondary or supportive endpoints meaningful?
☐ Will real-world data be used after the trial?
Ask out loud:
“If the endpoint doesn’t move but patients improve, what happens?”
🚩 Red flag: “The endpoint decides everything.”
7. Real-World Data: Does Learning Stop When the Trial Ends?
☐ Will patient outcomes be followed after the trial?
☐ Is there a registry or natural history study connected?
☐ Will patient experience inform next steps?
Ask out loud:
“How does learning continue after this study?”
🚩 Red flag: No plan beyond the protocol window.
8. Consistency: Are Expectations Clear and Stable?
☐ Have trial expectations been clearly explained before enrollment?
☐ Could requirements change late in development?
☐ Are decisions documented?
Ask out loud:
“How can we rely on these expectations not changing later?”
🚩 Red flag: “We’ll see how the data looks” without clear standards.
9. Risk vs. Opportunity: Is This Worth Your Cost?
☐ What do you personally risk by participating?
☐ What function, time, or health could be lost?
☐ What happens if the trial fails — to you and the community?
Ask yourself:
“Would I still say yes if I never benefit personally?”
(This is not selfish. It’s honest.)
10. The One Question That Matters Most
Before enrolling, you should be able to ask — and get a real answer to — this:
“If this is my one chance, how is this trial designed to use it wisely?”
If no one can answer clearly, that is your answer.
Rare & Relentless Reminder
You are not “too emotional” for asking these questions.
You are being responsible with something irreplaceable.
A trial that cannot recognize benefit, cannot enroll patients, or cannot survive uncertainty
is not rigorous — it’s risky.
Your participation matters.
Make sure the trial is worthy of it. Your time, your physical and emotional strength to join a trial is worth these questions.
Rare & Relentless Disclaimer
Asking these questions is not a rejection of research.
It is not being “difficult.”
It is not a lack of gratitude.
Consent to treatment means knowing enough to make a real decision — to weigh benefit against risk with eyes open. For ultra-rare disease, one of those risks is the reality that there may be no clear pathway, no backup plan, and no second chance.
I would participate in a rare disease trial again.
I believe in research.
I believe in progress.
I believe in saying yes.
But not at the cost of patients.
It is unfair to ask patients to compromise everything just to participate — especially when there is no alternative. When there is only one option, there is no real leverage. Families learn to stay quiet, to be grateful for the opportunity, to walk the line — even when they have serious questions.
That is the dilemma of rare disease:
What do you do when there are no treatment options?
For me, the answer starts with asking better questions.
With saying clearly: I want this done differently.
With asking for flexibility, clarity, and realism — even while knowing how narrow the line can be.
Experience teaches what brochures cannot.
Rare disease teaches what theory cannot.
Standard consent forms do not answer the hardest questions — the ones about uncertainty, feasibility, and what happens when things don’t go as planned. Education and questions are not signs of a difficult patient. They are the marks of an informed, empowered patient who is worthy of more.
These questions are not meant to discourage participation.
They are meant to ensure that participation is used wisely, transparently, and responsibly — especially when patients may only get one chance.
In rare disease, asking better questions does not weaken science.
It strengthens consent.
I would participate in a rare disease trial again — but I would do so with more questions answered. These questions are not about rejecting research. They are about protecting patients when participation may be their only chance.
