From Preclinical Data to Early Clinical Trials: Structure, Ethics, and Integrity
Click here to hear in youtube: https://youtu.be/HgIRZyvqEhc
1. Preclinical Foundations
Every clinical trial begins long before the first human volunteer receives a dose. In the preclinical phase, scientists work in laboratories and with animal models to understand how a drug behaves and whether it can be considered safe enough for people. This stage is not about proving that the drug cures disease, but about answering two urgent questions:
Does the drug have a plausible biological effect?
Can it be given without immediate, obvious harm?
The work is meticulous. Researchers measure how the drug binds to its target (pharmacodynamics), how it moves through the body (pharmacokinetics, ADME), and whether it causes toxic effects in organs. They also perform safety pharmacology tests to check for effects on the heart, lungs, and brain — systems where sudden failure could be catastrophic. Alongside this, manufacturing teams confirm that the drug can be produced consistently and will remain stable during storage.
When this body of evidence is assembled, it forms the Investigator’s Brochure (IB), a kind of dossier that explains to regulators and researchers what is known so far. This document is the backbone of the next step: asking permission to move into humans.
2. Ethics and Regulation
No matter how promising the science, human studies cannot begin without an ethical and regulatory framework. The gold standards are set by ICH-GCP (Good Clinical Practice) and the Declaration of Helsinki. Together, they state that the safety and dignity of participants must always come before scientific ambition or commercial interest.
Before a single patient can be enrolled, the sponsor submits all preclinical data and the proposed trial protocol to a regulatory agency — for example, the FDA in the United States or the EMA in Europe. At the same time, an independent ethics committee (IRB/IEC) reviews the protocol to make sure informed consent is clear, the risks are justified, and the rights of participants are fully protected.
In this system, science and ethics are inseparable. A trial that is scientifically unsound is also unethical, because it exposes people to risk without a chance of generating reliable knowledge.
3. Phase 1 – First-in-Human Trials
If the regulators and ethics committees give the green light, the drug can enter Phase 1, the very first time it is tested in humans. Traditionally, this stage enrolls 20–100 healthy volunteers who receive carefully measured doses. In some cases, such as cancer drugs or gene therapies, only patients are included, because exposing healthy people would be unjustifiable.
The goals are narrow but essential: determine whether the drug is safe, tolerable, and traceable in the body. Researchers look at pharmacokinetics (how fast the drug is absorbed, how long it stays in circulation, how it is eliminated) and pharmacodynamics (early signals of how the drug affects the body).
The dose is not chosen arbitrarily. Scientists take the NOAEL (No Observed Adverse Effect Level) from animal studies, convert it into a Human Equivalent Dose (HED) using body surface area formulas, and then apply a safety factor (often 10-fold) to set the Maximum Recommended Starting Dose (MRSD). For biologics or highly potent molecules, an even more conservative method is used: the MABEL (Minimum Anticipated Biological Effect Level), which considers receptor binding and in vitro potency.
Every dose is escalated cautiously, often in small cohorts of three patients at a time, with strict rules for stopping if side effects appear.
4. Phase 2 – Proof of Concept
If a drug passes Phase 1, the next question is: does it actually work in patients with the disease? This is the mission of Phase 2. Here, between 100 and 300 patients are enrolled, and the trial design becomes more complex — often randomized, sometimes blinded, and usually with several dosing arms.
Phase 2 is divided into two flavors:
Phase 2a (exploratory): Looks for an early signal of efficacy, often using biomarkers or surrogate endpoints.
Phase 2b (confirmatory): Compares different doses, refining which one should move into large-scale Phase 3 testing.
The stakes are higher. Many drugs that seem safe in healthy volunteers reveal their weaknesses here, either by failing to produce a meaningful effect or by showing toxicities that only emerge with longer exposure.
5. Combined Phase 1/2 Trials
Sometimes, speed and ethics converge to produce a combined Phase 1/2 design. This is common in oncology, rare diseases, or with therapies that are too risky for healthy volunteers.
In such trials, the same protocol begins with dose escalation (Phase 1 logic) in patients, then transitions seamlessly into efficacy expansion cohorts (Phase 2 logic) once a tolerable dose is identified. This fusion saves time and avoids unnecessary risk to healthy people, but it requires even stricter oversight, since the boundary between “finding a safe dose” and “testing efficacy” is crossed in real time.
6. The Human Network of Clinical Research
A clinical trial is not just a document; it is an ecosystem of roles and responsibilities:
Participants are at the center, offering their trust and bodies to science.
The Sponsor (a company or institution) finances and oversees the trial.
A CRO (Contract Research Organization) may be hired to manage daily operations.
An IRB/IEC ensures ethics are respected.
The Principal Investigator (PI) leads the trial at a site, with support from sub-investigators and a Study Coordinator who manages logistics and patient contact.
Monitors (CRAs) visit sites to verify compliance and data accuracy.
Behind the scenes, Data Managers clean the databases, Statisticians design and interpret analyses, Medical Writers prepare reports, and Regulatory Affairs specialists keep communication with agencies transparent.
Finally, the regulatory authorities themselves have the ultimate power: they can halt, approve, or demand changes to protect the public.
This multi-layered network exists to ensure that no single failure — whether ethical, clinical, or scientific — can put participants or data at undue risk.
7. Safety Reporting – AE, SAE, and SUSAR
Safety is tracked through a highly structured system. Every Adverse Event (AE) — from a mild headache to a lab abnormality — must be recorded. If the event is serious (SAE) — leading to death, hospitalization, or disability — it must be reported to the sponsor within 24 hours.
The sponsor evaluates whether the event is related to the drug and whether it was expected. If it is serious, unexpected, and suspected to be drug-related, it becomes a SUSAR. Such cases must be reported to regulators within 7 days (fatal/life-threatening) or 15 days (others). Ethics committees are also informed, ensuring independent oversight.
Periodic safety updates, like the DSUR (Development Safety Update Report), give regulators a cumulative view of the risk profile.
8. Protocol Deviations and Violations
No trial ever runs perfectly. Sometimes a patient misses a visit, or a lab test is delayed. These are protocol deviations. When a deviation has the potential to affect patient safety, data integrity, or ethics, it is called a violation.
Investigators must document these cases, explain why they occurred, and report them to the sponsor and ethics committee. Regulators may audit the records. A single deviation can be harmless, but repeated or serious violations can lead to the rejection of data or even the suspension of the study.
9. The Investigator’s Authority
The Principal Investigator is more than an administrator; they are a physician with the duty to act in the best interest of their patients. Even if the protocol does not demand it, an investigator can interrupt or stop treatment if clinical judgment suggests risk — for example, if early lab results hint at a dangerous trend.
Such actions must be documented as deviations, but they are ethically justified. This independent authority is what protects participants from becoming mere “subjects” of a rigid plan.
10. When Deviations Accumulate
While one or two deviations may be explainable, patterns of deviation signal structural weakness. If many patients are dosed incorrectly, if inclusion criteria are repeatedly ignored, or if procedures are skipped, the entire trial may lose credibility.
Consequences can include:
Loss of data validity (regulators may reject entire centers or trials).
Increased risk for patients.
Audits, sanctions, or site closures.
Reputational damage for investigators and sponsors.
In essence, deviations are like cracks in a building. One crack can be monitored. Many cracks, or a deep fracture, can bring the whole structure down.
11. Historical Case Example — Troglitazone (Rezulin)
Troglitazone was the first drug of the thiazolidinedione (TZD) class, developed to treat Type 2 diabetes. It was approved in the United States in 1997 and marketed under the brand name Rezulin. At the time, it was celebrated as a breakthrough therapy, because it improved insulin sensitivity in patients who were resistant to other treatments. Doctors and patients saw it as a much-needed innovation in diabetes care.
During preclinical studies, no major red flags suggested catastrophic liver toxicity. Some signals of mild enzyme changes appeared during the clinical trial program, but these were not considered severe enough to stop development. Regulators accepted the risk, reasoning that diabetes was a serious condition and that regular liver function monitoring could manage any problems.
Once the drug reached the market, however, the real picture emerged. Patients who had never shown warning signs during monitoring developed sudden and irreversible liver failure. By 2000, regulators had collected nearly 100 reports of acute liver failure, many resulting in death or the need for urgent liver transplants. What was most alarming was that the toxicity often appeared without prior elevation of liver enzymes, meaning the monitoring strategy failed to protect patients.
The FDA eventually withdrew Troglitazone in March 2000, just three years after approval. Other TZDs (pioglitazone, rosiglitazone) remained on the market, but only after much stricter evaluation of their safety profiles.
Structural Lessons
Preclinical and clinical trials cannot always predict rare but severe toxicities. Troglitazone looked safe enough in early studies, yet post-marketing revealed a fatal flaw.
Post-approval pharmacovigilance is as critical as pre-approval testing. No matter how strong the early data, regulators and sponsors must act quickly when real-world signals emerge.
Regulatory risk tolerance can shift overnight. What seemed acceptable at approval became unacceptable once deaths accumulated.
Integrity of monitoring systems matters. A protocol requiring liver tests gave the illusion of safety, but the biology of Troglitazone made sudden failure impossible to predict.
Troglitazone remains a landmark cautionary tale: a drug hailed as a therapeutic advance that, within a few years, became an example of why structural vigilance across all trial phases and post-marketing surveillance is essential.
