The Pitfall of Drug Discovery: 'No Reproducibility' in Preclinical Studies? Analysis of Failure Causes and 3 Re-evaluation Strategies

In drug development, the most regrettable thing is judging 'no effect' due to inadequate study systems rather than the drug's own effect (False Negative).

Especially in complex disease areas like NASH (MASH), IPF, and renal fibrosis, lack of reproducibility and unexpected negative data occur frequently. "Results do not come out as in the paper," "No significant difference was found in another company's study." Such cases are frequently reported throughout the industry, and investigation of the essential cause of failure is required.

In many cases, re-verifying data reveals that the problem lies in the "Method" rather than the "Molecule". In this article, we explain perspectives and strategies to scientifically "re-evaluate" failed studies and rediscover the value of buried promising compounds.

1. Why Do Studies Fail? The Trap of "Model Selection Mistakes"

Many cases of "no reproducibility" have a common cause. It is the mismatch between the drug's Mechanism of Action (MoA) and the pathophysiology of the animal model.

Lack of Metabolic Background (MASH/NASH Example)

For example, are you evaluating a drug aiming for anti-inflammation/anti-fibrosis via improvement of insulin resistance using the MCD (Methionine Choline Deficient) diet model? The MCD model shows severe fibrosis in a short period but is accompanied by significant "weight loss" and "hypoglycemia." Since obesity and insulin resistance behind human NASH are lacking, metabolic drugs like GLP-1 receptor agonists and SGLT2 inhibitors often show no efficacy (false negative) in this model.

Influence of Spontaneous Healing (IPF Example)

Are you troubled by variability in the control group in the Bleomycin pulmonary fibrosis model using young mice? Young mice have high natural healing power, and fibrosis may improve even without drug administration. If this noise of "Spontaneous resolution" is large, the add-on effect (therapeutic effect) by the drug is drowned out, making it difficult to obtain statistical significance.

Comparison of Clinical Correlation

Feature	MCD Diet Model (Traditional)	STAM™ Model (High Clinical Correlation)	Re-evaluation Perspective
Metabolic Background	Weight loss, Hypoglycemia	Obesity, Diabetes, Dyslipidemia	Metabolic drugs cannot be evaluated in MCD.
Fibrosis Progression	Rapid but artificial	Steadily and Surely (8-12 weeks)	Progression process close to human is necessary.
Clinical Correlation	Low (Similar pathology only)	High (Includes metabolism/gene expression)	Switch to appropriate model if emphasizing clinical predictability.

2. Limits of "Analog Eyes": Insufficient Sensitivity of Evaluation Systems

Even if you choose an appropriate model, you cannot scoop up gold dust (efficacy) if the evaluation tool is a "colander."

Conventional semi-quantitative scoring (stage classification like 0-4) by pathologists is a gold standard, but has the following issues:

Inter-observer variability: Score changes depending on the evaluator or timing.
Low sensitivity (Discontinuity): Even if fibrosis area decreases from 15% to 10%, it is judged as the same "Stage 3" on score, risking "No change."

Missing slight but certain drug efficacy. This is very often the hidden identity of negative data.

*Concept diagram: Bar graph (Bar) images score evaluation by humans (hard to see difference). Line graph (Line) images quantitative analysis by AI (detects difference sensitively). Not actual data.

3. 3 Re-evaluation Strategies: Picking Up Signals with High-Precision Technology

To rebuild a failed program, you need to review the pathology with a higher resolution lens.

Strategy A: Switching to Clinical Correlation Model (STAM™)

If failed with metabolic drugs, re-testing in the STAM™ model is a valid option. Since it has obesity/insulin resistance as background, efficacy of metabolic improvers can be correctly evaluated. Also, compared to spontaneous onset models, individual difference in pathology progression is small, featuring high detection power.

MASH Model Selection Guide: GAN vs CDA vs STAM

Strategy B: Slide Re-evaluation by AI Pathology Analysis

If "Trend was seen but no significant difference," AI image analysis using existing slides is recommended before conducting a new animal study. By quantifying fibrosis as continuous values, it may be possible to detect minute improvements invisible to the human eye as significant differences.

AI Pathology for Objective Fibrosis Scoring

Strategy C: Utilization of High-Sensitivity Biomarkers

"Movement" of metabolism may be changing before "Appearance" of histology changes. PRO-C3 (Type III collagen formation marker) can sometimes prove that the drug suppresses the fibrosis process even in early stages where tissue score does not change.

Non-invasive Biomarkers: FibroScan & PRO-C3

4. Decision Tree for Re-evaluation

We organized what action to take according to the type of "failure" you are facing.

Conclusion: Negative Data is Not the "End"

The fact that "reproducibility was not obtained" is not a death sentence for the compound. It is often just one result that "could not be measured with that study system."

The important thing is to factorize why it failed from pathological and metabolic mechanisms, and rebuild with appropriate models and latest measurement technologies.