Replimune and the FDA

The stages of grief are: denial, anger, bargaining, depression, and acceptance, although in no particular order. You can feel them all at once, or back and forth, all jumbled up like spaghetti. 

The first time I was laid off was in 2023. That was when I started running, exactly three years ago. That time, they said I needed to report to a meeting at 11:30 in a conference room I had never been to, with a person I had never met. I went as I was told, and in the back of my mind, I had this crazy notion that maybe I was getting a promotion. Optimism bias at work. But there was no promotion, only an HR rep with a blue folder and the details of my severance pay. The VP joined via video from his office in Switzerland. At first, they couldn't get the audio to work, and they kept repeating, “Can you hear me now?”

Six months ago, Replimune got the first CRL. The bottles of champagne were left unopened. The balloon arch had to be deflated. That first rejection letter gave me time to think. We had enough money to get us to a commercial launch. It was bad, but we didn't give up. We were going to fight. We would get support from the advocacy groups. We would meet with the FDA and bring all the doctors to support us so that the FDA could see the mistake they were making.  And so we went on, spending millions, working hard, and preparing for April 10, 2026, the date the FDA promised a final decision. 

That week was stressful. Not only did we have to be fully prepared, but we were still not 100% sure. I am an engineer, and I know that nothing is ever 100%. You can be 95% confident, maybe 99%, but never 100%. I sat outside during lunch with my boss and co-worker, and we asked ChatGPT about our chances. It said 40/60. You see, artificial intelligence is not hindered by optimism bias. It knows that about half of all biotech startups get a rejection letter on their first try. Of those, another 10% get a second rejection letter. 

On April 17, 2026, Replimune cut 60% of its staff. The HR representative sat in the conference room all day repeating the same information over and over again, every 15 minutes in groups of 10. This time, they asked us to leave our computers and badges at our desks. There were too many to collect all at once. It was like a funeral. Some people were outright crying, some just had tears in their eyes. Some were numb and walking around like zombies. 

"Were you impacted?" a co-worker asked. "Yes, I was, I mean I am," I replied. One of my friends had taken the day off, so I left him a post-it with my number in hopes that he would see it. 

 "It was a pleasure working with you. Good luck at the Boston marathon." I wrote.

I always ask myself, what would Toyota do in this situation? We know that the FDA is a Latent. To keep these types of stakeholders satisfied, Toyota uses the following tactics:

• Satisfy without overcomplicating: Fulfill all legal and regulatory requirements perfectly, without question. Provide concise, high-level summaries that respect the stakeholder’s limited bandwidth.

• Authorities are Allies: This is similar to the philosophy, “suppliers are partners.” Don’t treat them as enemies that you have to fight; instead, view them as only a regulator. Work with them, not against them. Maintain positive relationships.

• Nemawashi (Relationship Building): “Nemawashi” is a Japanese term that means digging around the roots. Quietly build a relationship, and nourish it like a bonsai tree. Toyota invests heavily in U.S. lobbying to manage issues before they become public scandals.

Biotech companies fail when they underestimate how much evidence is required to remove doubt. The same thing happened at Biogen when they received their first rejection letter. In that case, it was much harder to prove because it is not trivial to demonstrate that a patient’s mind is not deteriorating. In Replimune’s case, the evidence was clear-cut. The lesion is there, or it isn't.

In retrospect, one of the key tensions appeared to be the level of evidence required by the FDA to eliminate regulatory uncertainty. The stakeholder in this case holds all the cards. 

Let’s analyze this a little. What are some of the common reasons that a Biotech startup would receive a rejection letter?

• Misaligned expectations from earlier FDA meetings

• Filing too early (trying to “take a shot”)

• Statistical fragility (marginal p-values, subgroup dependence)

• Lack of confirmatory evidence (only one pivotal trial when two were expected)

• Missing diversity or key subpopulations

The first step of any project is to create a charter. The charter specifies key deliverables and a clear goal or objective. Not spending enough time on the charter is unwise. If the goal is unclear, the work and money spent do not matter. Ask yourself these questions: Would a conservative FDA reviewer be convinced? What would we criticize if we were the FDA? The FDA has nothing to lose if they reject an application. They have a lot to lose if they approve something that later turns out to be ineffective or worse, unsafe. They are naturally going to be conservative. What can we do to go beyond a reasonable doubt? 

Were we asking ourselves these questions? Or were we blinded by “optimism bias”? Were we interpreting silence as implicit agreement? Were we moving forward without fully closing the loop? Or were we assuming ambiguity as a risk? Did we employ internal FDA skeptics to keep the company on a sanity check? Simple, right? It doesn’t matter. At this late stage, the company is on its last breath.

I need to rest and focus on myself now. No point worrying about what could have been. I need a job, or my own money will soon run out. I started a journal, and I'm writing down all the positive things that happen in my life. It is called positive psychology. I'm not a psychologist, but it's supposed to help. I'm also running more. Running is always good as long as you don't hurt yourself. My right knee is starting to hurt a little. 

I can't sleep. I wake up at odd hours, like 3 or 4 in the morning. I dream about getting a new job and being shown around, or being in my old job and Teams not working, and I think to myself, "It doesn't matter, I'll be gone in a couple of weeks." 

I need to save money on eating out and cut down on unnecessary expenses until the unemployment checks kick in. A few companies rejected my application, but I have 22 applications pending. 

I started going to church every Sunday. Last Sunday, I started driving to my old job. I was on my way to church, but my mind was on automatic, and by the time I realized I was on the road to my old job. 

I went to the doctor because I am hearing ringing in my ears. The doctor said my brain MRI was normal. I don't have a brain tumor, thank God. 

This week, I'm cleaning and doing things around the house and the yard. I wake up early and shower because they say you have to keep a routine. Some friends invited me to the Yard House for drinks, but when I got there, I was not myself. I stayed quiet for long stretches just thinking and lamenting. It feels surreal. I sometimes feel sick to my stomach. I'm anxious and irritable a lot of the time. 

Acceptance - I don't think I'm there yet. Give me some time to forgive, to come to terms with my circumstances and the people around me, and to put it in God's hands. Something better will come. Let’s be like kids again and learn new things, and be joyful, and run, and laugh, and live. Let me be grateful for what I have. 

This experience made me realize that breakthrough ideas alone are not enough. Great organizations survive by aligning people, processes, and stakeholders before uncertainty becomes a crisis. The last time I was laid off, I started teaching and running. Both are good things that changed my life for the better. What will the future bring this time?