According to ICH guidelines, when should the investigator ensure that a subject's primary physician is informed?

The correct answer highlights the principle of respecting a subject's autonomy and preferences in the context of clinical research. Under ICH guidelines, specifically focusing on ethical considerations in research involving human subjects, the investigator must prioritize the subject's rights and wishes regarding their medical information. If a subject expresses the desire for their primary physician to be informed about their participation in a study, then the investigator must ensure that this request is honored.

This approach aligns with the ethical obligation of the investigator to maintain transparency and communication regarding the subject’s medical care, which supports the patient's right to involve their primary physician in decisions about their health.

Other options lack this emphasis on the subject's agency. Informing the primary physician at the beginning of the study or when the consent form is signed may not consider the subject's wishes. Additionally, contacting the physician only if the subject is being treated outside the trial fails to uphold the same standard of communication for all participants. Thus, the importance of the subject’s request is foundational in maintaining ethical standards in clinical trials.