In case there’s any chance that Dr. Van Zwet’s article might mention “responders,” I thought it could be useful to highlight the type of evidence that’s needed to actually label a patient a “responder.”
If we call someone a “responder,” we are implying that their therapy has “caused” them to experience a certain effect of interest. In other words, this label requires demonstration of a causal effect of therapy at the level of an individual patient. The purpose of this post is to show that the type of evidence needed to call a patient a “responder” will depend on 1) the UNtreated natural history/trajectory of the disease in question; and 2) the expected impact of the therapy being tested.
The solid lines in the five clinical scenarios below show typical UNtreated disease trajectories for various diseases. We’ll imagine what might happen if we were to apply a therapy with intrinsic efficacy/biological activity. The arrow shows the time at which the therapy is applied. The highlighted dotted line after each arrow shows the potential effect of the therapy (with regard to sign/symptom severity/disease activity). The solid line extending past the arrow shows the patient’s expected trajectory if the therapy hadn’t been applied. Examples of conditions that conform to each trajectory are provided, with therapeutic options noted in brackets.
Scenario 1:
“Waxing and waning” disease course- e.g., asthma (inhalers), chronic pain (analgesics), depression (antidepressants), mild to moderate autoimmune disease (e.g., IBD, RA)
Requirement for demonstrating causality at the level of an individual patient: EITHER RCT with multiple crossover periods OR N-of-1 trial is needed. Observing a single period of therapy exposure is INSUFFICIENT to infer therapeutic efficacy for the particular patient in question.
Rationale; With a waxing/waning natural history, the causal effect of the intervention, in a specific patient, can only be disentangled from spontaneous improvement/natural fluctuation by observing REPLICATIONS of the effect via therapy dechallenge then rechallenge. Dechallenge/rechallenge helps to isolate the causal effect of the intervention from other (often unknown) factors that can lead to natural fluctuation in disease course.
Scenario 2:
Temporary “slowing” of disease progression, underlying disease is relentlessly progressive- e.g., Alzheimer’s disease (cholinesterase inhibitors)/other neurodegenerative diseases
Requirement for demonstrating causality at the level of an individual patient: Very challenging
Rationale: Therapy doesn’t generally cause net improvement in patient’s clinical state, but rather might temporarily slow the rate of deterioration for some subset of patients. Identifying “responders” hinges on valid and highly granular mapping of disease trajectory before and during treatment but is confounded by heterogeneous rates of disease progression/undulating deterioration. Scores on cognitive/functional tests for some diseases can vary from day to day or hour to hour for unclear reasons.
Scenario 3:
Rapid improvement in signs/symptoms very soon after therapy is started, for a disease that has been highly symptomatic for a prolonged period of time- e.g., steroid-dependent autoimmune diseases (asthma/RA/IBD/psoriasis) (biologics)
Requirement for demonstrating causality at the level of an individual patient: Causal effect of therapy is easy to identify clinically for individual patients- crossover/N-of-1 design not necessarily needed
Rationale: Abrupt improvement in the signs/symptoms of a disease that has been highly symptomatic for many years provides clinically compelling evidence that the therapy has caused the patient’s improvement. Therapies that cause such rapid/dramatic improvement are ones that tend to be highly efficacious.
Scenario 4:
Reduction in disease burden (e.g., tumour burden) soon after start of therapy, for a disease that is known, otherwise, to be relentlessly progressive- e.g., a tumour “melting away” on imaging after starting a new cancer therapy.
Requirement for demonstrating causality at the level of an individual patient: Causal effect of therapy might be easy to identify clinically for individual patients (“objective response”), provided techniques for measuring disease burden serially are granular/reliable.
Rationale: Tumour burden is NOT expected to improve “spontaneously.” Therefore, reduction in tumour burden in a patient after application of a therapy indicates that the effect was caused by the therapy.
Scenario 5:
Rapid resolution of signs/symptoms soon after the start of a therapy for an acute, highly symptomatic medical condition- such therapies are considered “curative.” e.g., epinephrine for anaphylaxis, primary PCI for STEMI, naloxone for opioid overdose.
Requirement for demonstrating causality at the level of an individual patient: Causal effect of therapy is easy to identify clinically for individual patients.
Rationale: UNtreated clinical course for many acute conditions is often stereotypical/well-known. Clinically rapid reversal of such conditions is not expected to occur spontaneously. Therefore, abrupt reversal after applying the therapy provides clinically compelling evidence that the therapy caused the reversal/cure.
