A Playbook for Human Evidence

Shortening feedback loops in drug discovery

Clinical human evidence is the beating heart of the biotech industry. It’s the ultimate proof of new modalities, platforms, and targets which can be extrapolated and give founders agency in the backdrop of this 5-year biotech funding plateau. That’s why we’ve assembled this summary of the fastest possible routes for human evidence to provide perspectives for therapeutics founders to help in the idea maze.

The current status quo is unacceptable, with 40 million people dying yearly from non-infectious diseases like cardiovascular disease, cancer, metabolic disorders, and chronic pulmonary conditions. For a subset of these patients, promising next-generation therapies exist but are out of reach. To put this in perspective ~38 people die in clinical trials due to the experimental therapies in the US per year which, extrapolated worldwide, puts non-clinical trial death at 40,000x the number of deaths in the clinic. This number clearly does not reflect a proper risk-reward when so many patient’s treatments are ineffective.

The steelman view is that pursuing these regulatory workarounds could backfire: a single severe adverse event might trigger increased scrutiny and tighten regulations for the entire field, ultimately slowing progress rather than accelerating it. While the risk of adverse events is valid and plausible, the regulatory paths proposed here either: dose sick people faster under the FDA or find avenues to take new therapeutics outside of the US under the purview of another regulatory body. Both of these mitigate the downside by cooperation with ethically validated and nationally sanctioned systems.

It’s increasingly common for larger biotech companies to conduct trials abroad, license drugs with human evidence from China, and use other methods discussed below. However, we rarely see these paths discussed by early-stage therapeutics startup founders who might benefit most from these avenues. We wrote this playbook as a call to action for breaking the cultural inertia and increasing feedback loops for therapeutic development.

(1/9) Expanded Access of therapeutics passed IND stage

Time: 30 days (non-emergency) to immediate (emergency) + dosing course of drug

Cost: Administrative + medical care (drug often covered by company)

The FDA Expanded Access Program is an exploited path by established biotech companies. The Expanded Access Program is a relatively low lift requiring:

• A single physician to oversee the case and file necessary paperwork

• A company willing to provide the medical product and either submit the expanded access IND through a letter of authorization

• An institutional review board (IRB) which reviews expanded access protocol and consent

• Authorization by the FDA

In emergency situations, doctors can obtain consent over the phone from the FDA and execute expanded access from there. Remarkably, emergency approvals can be granted via phone call with the FDA which is an unusual example of bureaucratic agility. In non-emergency cases the paperwork typically takes 30 days.

Incredibly, Expanded Access actually has a carve out for “intermediate-size patient population” which we think founders could use as a proof-of-concept. In recent years, up to 4% of regulatory documents for drug approvals included Expanded Access case studies, with 13 drugs using Expanded Access as its primary proof. A report of Expanded Access from 2018 mentioned 9,000 applications and a 99% authorization rate for their execution. 1,000 of the Expanded Access petitions were for unique commercial drug development with only 0.2% rate of clinical hold, underscoring safety of this path.

(2/9) Phase 0 - Microdosing New Therapeutics

Time: 30 days for authorization+ 4-6 months study duration

Cost: $400K-$1.2M

The salient aspect of Phase 0 studies lies in testing new therapeutics directly in humans with the target disease, rather than the traditional Phase I approach using healthy volunteers. This creates a synergistic advancement where disease understanding and therapeutic development progress simultaneously. Phase 0 enables comprehensive assessment of safety profiles, direct measurement of drug-target engagement, and real-time evaluation of mechanism of action in the actual patient population over several days (have seen reports of 7-day courses).

Cassette microdosing represents one of Phase 0's most powerful applications, allowing simultaneous testing of multiple drug candidates to streamline compound selection or assess drug-drug interaction risks that could otherwise derail an entire therapeutic modality's long-term viability. Cassette microdosing has been used to select for the best “lead” compound among a series of options based on bioavailability, total body clearance and volume of distribution. The approach offers remarkable flexibility in dosing strategies—drugs can be administered locally to achieve therapeutic concentrations in specific target tissues (like intratarget microdosing; ITM) or systemically to evaluate whole-body pharmacokinetics, depending on the disease area and therapeutic goals.

Another useful aspect Phase 0 studies is that they generate pharmacokinetic and pharmacodynamic data with significantly higher fidelity than current preclinical standards. This enables some reliable linear extrapolation of dosing within the therapeutic window, dramatically improving predictions for full-scale clinical trials. While extrapolation uncertainties remain for entirely novel modalities, this limitation can only be overcome through broader application of microdosing across new therapeutic classes, creating a virtuous cycle where each Phase 0 study builds the knowledge base for future innovations. Phase 0’s certainly aren’t all encompassing however.

(3/9) Department of Defense (DoD) - FDA Enhanced Engagement

Time: Expedited review within existing regulatory pathways (timeline varies)

Cost: Variable - depends on underlying development pathway (IND, NDA, BLA)

This pathway of new drugs for soldiers enables access of medical products for emergency uses to reduce deaths and severe injuries caused by agents of war. Since 2017 when the Enhanced Engagement (Public Law 115-92) was passed, many products have been used by soldiers months or even years before being cleared by the FDA. Some specific examples of this FDA/DoD Enhanced Engagement include: Symvess which is the first acellular tissue engineered vessels when urgent revascularization is needed; Octapharma blood powder (octaplasLG Powder) for the treatment of hemorrhage due to military combat injury; tick-borne encephalitis vaccine (TICOVAC), and more. This pathway is not parallel but expedites the development of medical products to New Drug Applications (NDA) and biologics license application (BLA). When studying these use-cases, we noticed that companies can stack fast-track review processes to not only get human evidence but translate it quickly (e.g. Symvess also had priority review status which shrunk review times from ten months to six months). Companies still have to submit an Investigational New Drug (IND) application during this process, with Department of Defense support spanning development, IND, and NDA processes.

(4/9) n-of-1 studies for rare and ultra-rare disease patients

Time: 10-12 months from design to patient treatment

Cost: Cost: $1-3M+ (varies significantly based on support and donated services)

Unlike Expanded Access, n-of-1 studies are considered clinical trials by the FDA. These studies are uniquely aligned with the future of precision healthcare with the ability to include randomization, washout and crossover periods, as well as timing-based placebo controls in trials. For patient groups, individual treatment effects (ITEs) can be combined across patients to generate broader knowledge on diseases and treatment options. Depending on the disease type there are certainly many different types of trials possible which have extensively been written about and undertaken.

Yiwei Shi, a parent of a child with a rare disease, helped drive a therapy from sequence to treatment within 12 months and $1M in the US. The hurdles for n-of-1 trials are still pretty high. As opposed to the 30 days for Expanded Access, the fastest n-of-1 trial with a new drug takes at least 12 months to get to patients. The speed and proof of n-of-1 trials is very modality specific with ASOs having more regulatory clarity.

N-of-1 studies do require more regulatory oversight, where companies must submit IND applications of FDA 1571 which are submitted under 21 CFR 312.23 as opposed to the Expanded Access 21 CFR 312.310. For patients, which path to take is a deeply personal synthesis depending on disease severity and progression. For companies, there is slightly longer time to get into patients, the fact that there’s control/placebo segments of treatments could give deeper clarity on therapeutic efficacy.

(5/9) Geographic arbitrage - Country

Time: 4-6 weeks (Australia) to 60 days (China) with lower preclinical data packages

Cost: 40% savings (Australia with rebates), significantly lower in China and deregulated zones

The biggest upshot of the reduced animal testing announcement by the FDA is that human data acquired from international trials can be used in an IND package submitted to the FDA. This seriously changes incentive structures and makes human evidence collection much more international. Blurb below from the FDA’s published roadmap.

Today, clinical trials abroad are some of the most cost and time effective ways to get to human evidence ASAP. Some examples include Australia which offers 43.5% rebates, no IND submission (only data on CMC; chemistry, manufacturing and controls), and 35 day window to start clinical trials. This leads one to ask:

As Asimov Press recently pointed out, China has also been making strides in increasing clinical trial numbers to US-levels. What they didn’t mention though is the surge of investigator initiated trials, while registered to the government, don’t have much oversight in trial design. Rapid human evidence of new therapeutics is undoubtedly part of the China licensing boom. These are the two obvious examples to look at, but geographic arbitrage certainly *should* be explored thoroughly by every patient and drug hunter to quickly access or prove treatments.

Insilico Medicine has been pioneering this approach by jumping from Australia and New Zealand for its first-in-human and Phase I to China for its Phase II to test INS018_055 for idiopathic Pulmonary Fibrosis (IPF). Though people sometimes have questions about company legitimacy, their ability to get to human evidence as quickly as possible is something all drug hunters should be exploring.

For those who never wish to be regulated by the FDA, there are deregulated zones such as Prospera and Dubai where patients can access therapies with little evidence. Famously, Brian Johnson got follistatin gene therapy in Prospera from Minicircle and Unlimited Bio are also based there.

(6/9) Geographic arbitrage - State

Time: Immediate access post-Phase I

Cost: Unknown - 2% profit sharing requirement, but no clear cost structure yet

Montana's expansion of the federal Right to Try framework represents the most dramatic regulatory innovation within the United States. The state legislation allows patients to access clinical-stage drugs that have completed Phase 1 safety studies. While initial Right to Try legislation was focused on patients with terminal illness, Montana’s expansion enables *any patient* to access treatment which is past Phase I. This is an opportunity for patients who have a disease which may not be life-threatening but interferes with their quality of life. Not only this, but companies which are past Phase I can try their drug in broader populations to have proof-of-concept data in new indications before they fund clinical trials in a new therapeutic area. The initial bill from 2023 was expanded this year to pave a path for licensure of experimental treatment centers. Something to consider is that the experimental therapies need to be manufactured in Montana.

(7/9) Human Challenge Trials (HCTs)

Time: 8-24 months

Cost: ~$6-17M

Human Challenge Trials (HCTs) represent one of the most controlled and deliberate approaches to generating human evidence by intentionally exposing healthy volunteers to a pathogen under medical supervision. While ethically sensitive, this method enables early insights into efficacy, mechanism of action, and immune response with significantly reduced cost. Put another way, drug or vaccine efficacy can be tested for 1-2 orders of magnitude less than in historical Phase III studies, again short-circuiting the drug development path. Admittedly, HCTs are only relevant for infectious diseases without mild side effects and where pathogens can be controlled in some capacity.

In pandemic situations, regulation can be shifted from a 24 month process to 8 months as it was with COVID-19 challenge trials. Normally there are much fewer participants and faster timelines than traditional Phase 3 trials (100’s vs. 10,000+). Volunteers are carefully selected (typically young and healthy), and studies are conducted in high-containment facilities with rigorous oversight. Though rare and logistically complex, this approach has gained traction in areas like influenza, malaria, and COVID-19, and continues to be explored for diseases where treatments exist to mitigate risk. HVivo ($HVO) is a public company which conducts human challenge trials.

(8/9) Braindead cadavers

Time: Context-specific

Cost: Context-specific

Certainly the most unconventional (and most ethically ambiguous) approach we've encountered involves first-in-human testing using brain-dead organ donors before organ harvesting. Although standards are ambiguous around this type of testing, for organ transplants there have been protocols established to determine brain death and irreversibility of state. This approach, pioneered by academic researchers, allows for assessment of initial biodistribution, pharmacokinetics, and early safety signals without risk to living patients. The legal framework exists because organ donors remain on life support with functioning metabolism until organ procurement. We’ve only seen two companies proposing this type of human evidence and expect it to remain small though potentially expeditious.

(9/9) Off-label use of already approved drugs

Time: Prescription filling

Cost: NA

Off-label is probably the fastest, albeit the least innovative way, for patients to get new therapeutic options. Since FDA clinical testing has been carried out for all drugs on the market, physicians can prescribe approved drugs for unapproved uses when they believe it's in the patient's best interest. While doctors front the liability if things go wrong, the risk/reward can be very much in the patient's favor and requires only the time to write a prescription (after normal avenues have been explored). In fact, some companies have found repurposed supplements can help support patients. Some companies/projects working here include: CUREID and CuresWithinReach.

A new “Golden Age” of drug discovery

High regulation and cost of clinical trials didn’t evolve in a vacuum. Severe fetal defects caused by thalidomide in the 1960’s elicited large changes in how the FDA regulates drugs. Before thalidomide, the standard of the Food and Drug Administration (FDA) through the 1938 Federal Food, Drug, and Cosmetic Act was to allow any drug to come to market if the FDA hadn’t acted in 60 days of application. After thalidomide though, the Kefauver-Harris Amendments rightfully increased necessary safety and efficacy studies before being marketed to the general public. While safety and efficacy are absolutely critical, we have over-corrected to the point that new innovations can take 6+ years to get to the clinic and 10+ years, if not longer, to get to patients at large. The current state of clinical trials is dire with the execution of all three clinical trial phases totalling from 8-10 figures, only giving companies 1-2 shots on goal for clinical evidence, if they get that far, limiting innovation, new ideas, and new cures.

In the first Golden Age (1940’s-1970’s), there was rapid human testing of new drugs and in a few decades we discovered Cortisone (rheumatoid arthritis treatment), Streptomycin (first antibiotic effective against tuberculosis), Enovid (first oral contraceptive), Chlopromazine (first chemical treatment of schizophrenia) and many more. In this Golden Age, we worked exclusively with small molecules and had a limited understanding of biology.

Today, we have an impressive range of modalities at our disposal: biologics, mRNA vaccines, gene editing, engineered cell therapies, protein degraders, antibody-drug conjugates. New, efficacious tools coupled with our deeper understanding of disease mechanisms position the field to dramatically increase the number of therapeutics commercialized and patients treated. We see a future where the status quo of 50 new drugs per year could increase to 100 and eventually many more approvals per year, all enabled by faster feedback loops in people.

If you’re thinking about building to shorten feedback loops for human evidence or are using some of these methods, we’d love to speak with you. Please reach out to shelby@compound.vc.

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Thanks to Michael Dempsey for the comments on Trevor Klee for pointing me towards the DoD path.