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IMF-097-02-0001-en	Why is an association between a target and disease not enough to validate the target?	Validation needs independent evidence that manipulating the target changes disease-relevant biology, an understood direction and timing of intervention, and human variation that predicts compatible effects.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0002-en	What are the trade-offs between phenotypic and target-based discovery?	Phenotypic screens preserve integrated biology but complicate mechanism and optimisation, whereas target-based screens are tractable but may oversimplify disease.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0003-en	Why is increasing a compound's lipophilicity a mixed benefit during optimisation?	It can improve membrane passage while increasing nonspecific binding, metabolic turnover, or tissue accumulation, showing that optimising one feature may worsen another.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0004-en	Why does lowering a biomarker not guarantee clinical benefit?	A biomarker can support mechanism without being a validated surrogate; if the marker is not causal or off-target harm offsets the gain, a better laboratory value does not guarantee better outcomes.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0005-en	Why is in-vitro activity seen only at unrealistically high concentration weak translational evidence?	Experimental concentration must be compared with achievable unbound human exposure, and activity far above that exposure says little about what will happen in people.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0006-en	Why is the no-observed-adverse-effect level not proof of safety, and what shapes the starting human dose?	It is an experimental boundary, not proof of zero risk; the starting dose integrates animal exposure, pharmacologically active dose estimates, uncertainty factors, target biology, and possible steep or delayed toxicity.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0007-en	Why is manufacturing part of pharmacology, and why do process changes need comparability evidence?	Identity, purity, stability, formulation, particle size, excipients, and release characteristics determine delivered exposure, and impurities may have distinct toxicity, so a changed process can change what patients receive.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0008-en	In first-in-human studies, why are patients sometimes chosen instead of healthy volunteers?	Healthy volunteers are used when risk is acceptable, but toxicity, an irreversible mechanism, or disease biology can make exposing healthy people inappropriate.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0009-en	Why is phase two dose selection an estimation problem rather than a search for the highest tolerated dose?	Too little exposure can discard an effective mechanism and too much can create adverse effects that obscure benefit, so several doses with exposure-response modelling beat a single arbitrary choice.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0010-en	Why does intention-to-treat analysis preserve the protection of randomisation, unlike per-protocol analysis?	It analyses participants in their assigned groups, whereas per-protocol analysis answers a different question and is vulnerable to selection after randomisation.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0011-en	How can a composite endpoint mislead?	It increases event counts, but frequent minor components can drive the result while the severe components remain unchanged.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0012-en	Why are poor adherence and crossover a particular threat in a non-inferiority trial?	They make treatments look falsely similar, while non-inferiority already depends on confidence that the active control would have worked in that trial.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0013-en	What distinguishes a legitimate adaptive design from changes made after seeing results?	Adaptive designs modify enrolment, allocation, dose, or sample size by prospectively defined rules that preserve error control; unprespecified changes after seeing results are ordinary bias.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending
IMF-097-02-0014-en	What are the value and limits of spontaneous adverse-event reports?	They are valuable signals, but they lack reliable denominators and are influenced by publicity, so a signal should be investigated proportionately rather than dismissed or assumed causal.	Integrated Medical Foundations; chapter 97, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 87e531aebe333aaa10983015e9601227c067370e2a9d7ddc966c41bcf86952d8; editorial review pending	imf lang::en chapter::097 module::097-02 review::pending