I’ve noticed that first-time biotech founders often don’t have a clear idea of their path through the clinic. Clinical trials remain this semi-mystical black box that eats tons of money in exchange for the hope that one’s therapy “passes” and eventually, reaches patients. I think this is partly because it can be hard to know where to start with clinical trials (they are big, they are daunting), and partly because clinical knowledge is possessed by relatively few people, most of whom rely on consulting/service revenue. So I’m writing this post in hopes of demystifying clinical trials and helping founders approach them with a clearer idea of what should happen.
The Bottom Line Upfront
Clinical trials are costly, challenging, and complex, but there are many ways to “run” them and different parts you can keep in-house versus contract out. As with many things in life, you’re trading time for money, though I think there’s a lower limit to the amount of time you save for the money you spend. Or, you can spend increasing amounts of money but there are diminishing returns on the time you save for it – the contract research organizations (CROs) you’re working with will still need some of your time to run your trial.
You’ll almost always need at least 0.4 – 1 FTEs to work with these CROs, depending on the complexity of your trial and how fast you want to move. But beyond that, there’s flexibility on whether keep work in-house (add more FTEs on your payroll) or send it out to a CRO. Your therapeutic modality, disease target, long-term strategy, and amount of capital available will usually determine what makes the most sense.
What Needs to Get Done
To give you an idea of why trials are so costly: each clinical trial is a project on the same magnitude and timeline as launching a startup (if not greater). Each will involve years of effort, multiple organizations (your startup, at least one hospital/medical institution, the FDA, and likely several contractor organizations), dozens of people, and lots of negotiation.
We’re going to assume that you’re somewhat familiar with the stages of clinical trials. If not, you can find great resources here and here. I’ve captured the steps in a rough timeline below:
To get through this timeline, you or someone else will need to complete the following:
Determine a path to market: Chances are that if you’re reading this, you think you’ll need FDA approval for your therapy and so you’ll need to figure out a clinical roadmap.
Outline your clinical roadmap: Even if your main plan is to find a pharma partner to run clinical trials, it pays to understand the possible path(s) through clinic to approval. It helps you negotiate with pharma and show investors you’re serious. And it serves as a way your company can still succeed and help patients if you don’t land that coveted pharma partnership. Some questions to consider: Should you do separate Phase 1 and Phase 2 studies, or a combined Phase 1/2? Roughly how big does each of your trials need to be in terms of patients and time they run? How will your therapy be dosed? What are your endpoints and some high-level inclusion/exclusion criteria? Much of this can be figured out with some background research and talking to physician experts (i.e., ‘KOLs’). Once determined, the clinical roadmap can give you an idea of costs (and how much you’d need to raise) to get to approval.
Design the first (usually Phase 1, or Phase 1/2) clinical trial: Knowing the overall design of your first trial also helps you at the negotiating table. The design can vary in depth, from a 2-4 page trial summary to a full-scale (often 50+ page) trial protocol (though I don’t think you need this). If it’s a Phase 1 safety trial, this design can be pretty straightforward. If it’s a Phase 1/2 trial with both safety and efficacy endpoints, this will take more work, especially in starting to think about trial investigators and trial sites. Again, you can get a lot from background research, but it’s common to hire hourly consultants to help you/provide feedback.
Find a manufacturer CRO: Manufacturing is almost always outsourced to a CRO. Setting up Good Manufacturing Practice (GMP) compliance remains too big of a hurdle for most startups, and contract manufacturers exist for almost everything: small molecules, antibodies, RNA, microbes, and cell therapies. You may not sign a contract yet, but getting some quotes and knowing your options before going for a pre-IND meeting can be very helpful. Key issues to hammer out (besides the cost for X units of your therapy and when it will be ready), are how much the contract manufacturer will help you with the IND (particularly with the chemistry, manufacturing and controls or CMC section), what kind of quality control they do, and how your therapy will be moved from the manufacturing site to trial sites.
Consider a clinical operations CRO: I say ‘consider’ here because you can engage a clinical operations CRO at a couple of different times/scopes: a ‘full service’ where they’re doing everything from helping you with the pre-IND meeting/regulatory filings through analysis of trial results; ‘running the trial’ where they handle the trial and IRB but you’re handling the pre-IND meeting and/or IND; or purely to source trial sites but you’ll be managing the trial and interacting directly with the trial sites. After you’ve outlined your path through clinic, it helps to talk to a few clinical ops CROs to get quotes on full-service versus more limited-scope engagements. You can then do your own cost-benefit analysis and decide which scope works best for you.
Complete regulatory meetings/paperwork: This is the pre-IND meeting with the FDA (highly encouraged) and filing of the IND. If a ‘full service’ package from a clinical ops CRO isn’t in the cards, it’s totally possible to do a pre-IND meeting and IND filing solo. If you’re really strapped for cash and need guidance, call in favors from friends/mentors and ask for help from clinicians on your advisory board (side note: it is an excellent idea to add a MD/PhD with clinical trial experience in your disease area to your scientific advisory board). Or, pay independent consultants to guide and review your work. The submission process can be a bit frustrating, but after addressing FDA comments/concerns with revisions you’ll receive a ‘safe to proceed’1 that means you can start your trial. Following this, the IRB also gives its approval and your trial can begin.
Prep and manage the trial: You’ve got a ‘safe-to-proceed’ from the FDA and an approval from the IRB; now it’s time to run your trial. This is a combination of activities that ensure your trial runs smoothly, from designing case report forms to capture trial data, to setting up IRB check-ins (to make sure patients are safe and your trial is running as planned), to agreeing on clinic processes (and trying to harmonize them across trial sites), to recruiting patients. Dosing your first patient is a great milestone to celebrate. From there you’ll continue the trial until you’ve hit a limit on patients needed, timeline, or funding.
Determine the results: It’s time to take a deep breath and learn your asset’s fate. How you will analyze your data was already outlined in the statistical analysis plan (SAP) section of your IND. You’ll unblind and analyze the data accordingly, and find out if you reached your primary and secondary endpoints with statistical significance. If you did, hooray! You’ve won the chance to do this process again for the next phase of clinical trials — and increased the potential value of your asset by 2- to 5-fold! If not, it’s time to figure out what else you can learn from the trial data and, if your company has the funding, what to do differently with your next asset.
I’ve compiled a list of resources below that I found helpful in getting started with clinical trials. If you have additional ones, drop them in the comments below or ping me and I’ll add them.
- Clinicaltrials.gov – the list of all interventional clinical trials (meaning testing a therapy or device) taking place in the U.S. Any entity running a Phase 2 or Phase 3 interventional trial is legally required to post their study information here (including trial duration, patient sample sizes, endpoints, and inclusion/exclusion). You’ll often also find non-U.S. interventional trials (legally required if going for FDA approval) and many Phase 1 interventional and non-interventional studies posted here as well.
- EU Clinical Trials Register – an EU equivalent of ClinicalTrials.gov. I haven’t used it much and have heard it’s less complete – EU has been slower in making public registration of clinical trials legally required. But that should be changing soon.
- FDA Guidance for Industry – the FDA publishes a wide array of “Guidance for Industry” documents. Many of these remain in ‘draft’ versions for regulatory reasons we won’t get into here, but they give you insight into what the FDA is thinking or worrying about when it comes to your disease area or therapeutic modality. If you struggle with the search function in their website, try Googling “[your topic] FDA guidance for industry”. Side note: like reading peer-reviewed academic papers, there’s a learning curve to reading the FDA guidance docs. But it also pays dividends when you can reference and adopt their language in your own IND/regulatory writing.
- ExpertScape – useful to find a clinician for your scientific advisory board or find investigators for your trial. Find an expert in nearly any disease using its search and filter functions, with a ranking based on peer-review publications.
- Contract Pharma – an industry news source that also maintains an extensive directory of contract services, including manufacturing, clinical operations, and a whole host of other services needed for preclinical and clinical work. It is an excellent starting point to identify contract manufacturers and clinical operations companies and get multiple quotes/price points.
Background: where I’m coming from
My experience with clinical trials is almost entirely from the perspective of startups, where funds were scarce. As a Blavatnik Fellow at Yale, I wrote the IND package for a Phase 1/2 investigator-initiated clinical trial for phage therapy against chronic respiratory infections in cystic fibrosis, CYPHY. I had great guidance from Jon Koff, Ben Chan, Paul Turner, and Yale’s Center for Clinical Investigation (particularly Amy Hummel and Sam Henager). But the experience also involved a good amount of DIY learning, head-to-wall trial-and-error, and negotiating for the time and resources needed to get a ‘safe-to-proceed’ from the FDA and a green light from the IRB. After that, I was helping with trial operations and designing case report forms until Yale hired an amazing research coordinator (hi Claire!). CYPHY ultimately became the launchpoint for Felix Biotechnology.
When I completed the fellowship and became a co-founder at Felix, I took on our clinical work because there was no one else to do it. I led our pre-IND meeting with the FDA (getting us critical feedback for investment), handled manufacturing plans, and also plotted our in vivo preclinical path. We worked and waited for the readout from CYPHY. I eventually left Felix to work on a new startup, and CYPHY recently failed to meet its efficacy endpoint. So you can take everything in this post with a grain of salt.
I’m thinking of writing a few more posts on aspects of clinical trials, such as filing the IND and who key players are in clinical development. If you’re interested in any of those topics, drop me a line or leave a comment below.
1. Companies and individuals sometimes incorrectly refer to a safe-to-proceed from the FDA as an ‘approval’ to start a trial. Please do not do this – ‘approval’ has a very specific meaning. At best, this mistake will cause you some embarrassment as an investor or pharma eventually corrects you. At worst, you’ll accidentally mislead them into thinking you’re further along than you are and dramatically disappoint them.
2 thoughts on “Clinical trials: getting started as a startup”
Great article Natalie! Would be great to hear your insights on how to navigate the CMC aspects. CMC is a critical component especially in microbial therapeutics, and I see most startups doing this in house. So, any best practices for CMC would be greatly appreciated.
I’ll give it a shot but CMC is a pretty tough one! Often a good contract manufacturer will help you with it through references to their ‘master file’, which is a file they’ve sent to the FDA that generally covers how they manufacture, purify, and test for quality for individual therapeutic candidates.
Beyond that, the FDA will expect an overview of your therapeutic candidate, its history, chemical structure/composition (if a small molecule, that gets a bit more complicated for biologics), visual description, as well as information around its safety (hazards, toxicity, etc) and handling.