Per-protocol analysis US Medical PG Practice Questions and MCQs
Practice US Medical PG questions for Per-protocol analysis. These multiple choice questions (MCQs) cover important concepts and help you prepare for your exams.
Per-protocol analysis US Medical PG Question 1: A research team develops a new monoclonal antibody checkpoint inhibitor for advanced melanoma that has shown promise in animal studies as well as high efficacy and low toxicity in early phase human clinical trials. The research team would now like to compare this drug to existing standard of care immunotherapy for advanced melanoma. The research team decides to conduct a non-randomized study where the novel drug will be offered to patients who are deemed to be at risk for toxicity with the current standard of care immunotherapy, while patients without such risk factors will receive the standard treatment. Which of the following best describes the level of evidence that this study can offer?
- A. Level 1
- B. Level 3 (Correct Answer)
- C. Level 5
- D. Level 4
- E. Level 2
Per-protocol analysis Explanation: ***Level 3***
- A **non-randomized controlled trial** like the one described, where patient assignment to treatment groups is based on specific characteristics (risk of toxicity), falls into Level 3 evidence.
- This level typically includes **non-randomized controlled trials** and **well-designed cohort studies** with comparison groups, which are prone to selection bias and confounding.
- The study compares two treatments but lacks randomization, making it Level 3 evidence.
*Level 1*
- Level 1 evidence is the **highest level of evidence**, derived from **systematic reviews and meta-analyses** of multiple well-designed randomized controlled trials or large, high-quality randomized controlled trials.
- The described study is explicitly stated as non-randomized, ruling out Level 1.
*Level 2*
- Level 2 evidence involves at least one **well-designed randomized controlled trial** (RCT) or **systematic reviews** of randomized trials.
- The current study is *non-randomized*, which means it cannot be classified as Level 2 evidence, as randomization is a key criterion for this level.
*Level 4*
- Level 4 evidence includes **case series**, **case-control studies**, and **poorly designed cohort or case-control studies**.
- While the study is non-randomized, it is a controlled comparative trial rather than a case series or retrospective case-control study, placing it at Level 3.
*Level 5*
- Level 5 evidence is the **lowest level of evidence**, typically consisting of **expert opinion** without explicit critical appraisal, or based on physiology, bench research, or animal studies.
- While the drug was initially tested in animal studies, the current human comparative study offers a higher level of evidence than expert opinion or preclinical data.
Per-protocol analysis US Medical PG Question 2: A group of investigators seeks to compare the non-inferiority of a new angiotensin receptor blocker, salisartan, with losartan for reduction of blood pressure. 2,000 patients newly diagnosed with hypertension are recruited for the trial; the first 1,000 recruited patients are administered losartan, and the other half are administered salisartan. Patients with a baseline systolic blood pressure less than 100 mmHg are excluded from the study. Blood pressure is measured every week for four weeks, with the primary outcome being a reduction in systolic blood pressure by salisartan within 10% of that of the control. Secondary outcomes include incidence of subjective improvement in symptoms, improvement of ejection fraction, and incidence of cough. 500 patients withdraw from the study due to symptomatic side effects. In an intention-to-treat analysis, salisartan is deemed to be non-inferior to losartan for the primary outcome but inferior for all secondary outcomes. As the investigators launch a national advertising campaign for salisartan, independent groups report that the drug is inferior for its primary outcome compared to losartan and associated with respiratory failure among patients with pulmonary hypertension. How could this study have been improved?
- A. Increased study duration
- B. Posthoc analysis of primary outcome among patients who withdrew from study
- C. Randomization (Correct Answer)
- D. Increased sample size
- E. Retrial of primary outcome for clinical effectiveness instead of non-inferiority
Per-protocol analysis Explanation: ***Randomization***
- The study allocated patients **sequentially** (first 1,000 to losartan, next 1,000 to salisartan), introducing **selection bias** as the two groups may not be comparable at baseline for unmeasured confounders.
- **Randomization** ensures that both known and unknown confounding factors are evenly distributed between treatment groups, making the groups comparable and increasing the reliability of the observed treatment effects.
- The lack of randomization explains why independent groups found **different results**—the study's internal validity was compromised by systematic differences between groups that were not due to the intervention itself.
- Sequential allocation is particularly problematic because patient characteristics may **change over time** (e.g., seasonal variations, changes in referral patterns, or evolution in diagnostic criteria).
*Increased study duration*
- While a longer study duration might reveal long-term effects or adverse events, the primary issue of **baseline incomparability** due to the lack of randomization would persist.
- Increasing duration would not address the fundamental flaw in the **patient allocation method** that led to potential bias.
*Posthoc analysis of primary outcome among patients who withdrew from study*
- A **post-hoc analysis** of withdrawn patients would be useful for understanding reasons for withdrawal but cannot correct for the initial lack of randomization or the **attrition bias** caused by the large number of withdrawals (500/2,000 = 25%).
- This approach would also be susceptible to **selection bias** because the reasons for withdrawal might differ between the two groups.
- While **intention-to-treat analysis** was performed, the fundamental allocation bias remains.
*Increased sample size*
- A larger sample size generally increases statistical power and precision, but it does not correct for **systematic errors** introduced by a flawed study design, such as lack of randomization.
- Increasing the sample size would simply replicate the biased allocation across more participants, potentially **amplifying** the effects of selection bias rather than reducing them.
*Retrial of primary outcome for clinical effectiveness instead of non-inferiority*
- Changing the trial design from **non-inferiority** to **superiority** would alter the hypothesis being tested but would not address the underlying methodological flaws.
- The mode of patient allocation (sequential assignment) remains the critical weakness, invalidating any conclusions regarding either non-inferiority or superiority.
- The discrepancy between this study's findings and independent reports highlights that the **study design** (not the research question) was flawed.
Per-protocol analysis US Medical PG Question 3: An investigator is measuring the blood calcium level in a sample of female cross country runners and a control group of sedentary females. If she would like to compare the means of the two groups, which statistical test should she use?
- A. Chi-square test
- B. Linear regression
- C. t-test (Correct Answer)
- D. ANOVA (Analysis of Variance)
- E. F-test
Per-protocol analysis Explanation: ***t-test***
- A **t-test** is appropriate for comparing the means of two independent groups, such as the blood calcium levels between runners and sedentary females.
- It assesses whether the observed difference between the two sample means is statistically significant or occurred by chance.
*Chi-square test*
- The **chi-square test** is used to analyze categorical data to determine if there is a significant association between two variables.
- It is not suitable for comparing continuous variables like blood calcium levels.
*Linear regression*
- **Linear regression** is used to model the relationship between a dependent variable (outcome) and one or more independent variables (predictors).
- It aims to predict the value of a variable based on the value of another, rather than comparing means between groups.
*ANOVA (Analysis of Variance)*
- **ANOVA** is used to compare the means of **three or more independent groups**.
- Since there are only two groups being compared in this scenario, a t-test is more specific and appropriate.
*F-test*
- The **F-test** is primarily used to compare the variances of two populations or to assess the overall significance of a regression model.
- While it is the basis for ANOVA, it is not the direct test for comparing the means of two groups.
Per-protocol analysis US Medical PG Question 4: A 57-year-old man presents to his oncologist to discuss management of small cell lung cancer. The patient is a lifelong smoker and was diagnosed with cancer 1 week ago. The patient states that the cancer was his fault for smoking and that there is "no hope now." He seems disinterested in discussing the treatment options and making a plan for treatment and followup. The patient says "he does not want any treatment" for his condition. Which of the following is the most appropriate response from the physician?
- A. "You seem upset at the news of this diagnosis. I want you to go home and discuss this with your loved ones and come back when you feel ready to make a plan together for your care."
- B. "It must be tough having received this diagnosis; however, new cancer therapies show increased efficacy and excellent outcomes."
- C. "It must be very challenging having received this diagnosis. I want to work with you to create a plan." (Correct Answer)
- D. "We are going to need to treat your lung cancer. I am here to help you throughout the process."
- E. "I respect your decision and we will not administer any treatment. Let me know if I can help in any way."
Per-protocol analysis Explanation: ***"It must be very challenging having received this diagnosis. I want to work with you to create a plan."***
- This response **acknowledges the patient's emotional distress** and feelings of guilt and hopelessness, which is crucial for building rapport and trust.
- It also gently **re-engages the patient** by offering a collaborative approach to treatment, demonstrating the physician's commitment to supporting him through the process.
*"You seem upset at the news of this diagnosis. I want you to go home and discuss this with your loved ones and come back when you feel ready to make a plan together for your care."*
- While acknowledging distress, sending the patient home without further engagement **delays urgent care** for small cell lung cancer, which is aggressive.
- This response might be perceived as dismissive of his immediate feelings and can **exacerbate his sense of hopelessness** and isolation.
*"It must be tough having received this diagnosis; however, new cancer therapies show increased efficacy and excellent outcomes."*
- This statement moves too quickly to treatment efficacy without adequately addressing the patient's current **emotional state and fatalism**.
- While factual, it **lacks empathy** for his personal feelings of blame and hopelessness, potentially making him feel unheard.
*"We are going to need to treat your lung cancer. I am here to help you throughout the process."*
- This response is **too directive and authoritarian**, which can alienate a patient who is already feeling guilty and resistant to treatment.
- It fails to acknowledge his stated feelings of "no hope now" or his disinterest in treatment, which are critical to address before discussing the necessity of treatment.
*"I respect your decision and we will not administer any treatment. Let me know if I can help in any way."*
- While respecting patient autonomy is vital, immediately accepting a patient's decision to refuse treatment without exploring the underlying reasons (e.g., guilt, hopelessness, lack of information) is **premature and potentially harmful**.
- The physician has a responsibility to ensure the patient is making an informed decision, especially for a rapidly progressing condition like small cell lung cancer.
Per-protocol analysis US Medical PG Question 5: You submit a paper to a prestigious journal about the effects of coffee consumption on mesothelioma risk. The first reviewer lauds your clinical and scientific acumen, but expresses concern that your study does not have adequate statistical power. Statistical power refers to which of the following?
- A. The probability of detecting an association when no association exists.
- B. The probability of not detecting an association when an association does exist.
- C. The probability of detecting an association when an association does exist. (Correct Answer)
- D. The first derivative of work.
- E. The square root of the variance.
Per-protocol analysis Explanation: ***The probability of detecting an association when an association does exist.***
- **Statistical power** is defined as the probability that a study will correctly reject a false null hypothesis, meaning it will detect a true effect or association if one exists.
- A study with **adequate statistical power** is less likely to miss a real effect.
*The probability of detecting an association when no association exists.*
- This describes a **Type I error** or **false positive**, often represented by **alpha (α)**.
- It is the probability of incorrectly concluding an effect or association exists when, in reality, there is none.
*The probability of not detecting an association when an association does exist.*
- This refers to a **Type II error** or **false negative**, represented by **beta (β)**.
- **Statistical power** is calculated as **1 - β**, so this option describes the complement of power.
*The first derivative of work.*
- The first derivative of work with respect to time represents **power** in physics, which is the rate at which work is done.
- This option is a **distractor** from physics and is unrelated to statistical power in research.
*The square root of the variance.*
- The **square root of the variance** is the **standard deviation**, a measure of the dispersion or spread of data.
- This is a statistical concept but is not the definition of statistical power.
Per-protocol analysis US Medical PG Question 6: You are currently employed as a clinical researcher working on clinical trials of a new drug to be used for the treatment of Parkinson's disease. Currently, you have already determined the safe clinical dose of the drug in a healthy patient. You are in the phase of drug development where the drug is studied in patients with the target disease to determine its efficacy. Which of the following phases is this new drug currently in?
- A. Phase 4
- B. Phase 1
- C. Phase 2 (Correct Answer)
- D. Phase 0
- E. Phase 3
Per-protocol analysis Explanation: ***Phase 2***
- **Phase 2 trials** involve studying the drug in patients with the target disease to assess its **efficacy** and further evaluate safety, typically involving a few hundred patients.
- The question describes a stage after safe dosing in healthy patients (Phase 1) and before large-scale efficacy confirmation (Phase 3), focusing on efficacy in the target population.
*Phase 4*
- **Phase 4 trials** occur **after a drug has been approved** and marketed, monitoring long-term effects, optimal use, and rare side effects in a diverse patient population.
- This phase is conducted post-market approval, whereas the question describes a drug still in development prior to approval.
*Phase 1*
- **Phase 1 trials** primarily focus on determining the **safety and dosage** of a new drug in a **small group of healthy volunteers** (or sometimes patients with advanced disease if the drug is highly toxic).
- The question states that the safe clinical dose in a healthy patient has already been determined, indicating that Phase 1 has been completed.
*Phase 0*
- **Phase 0 trials** are exploratory, very early-stage studies designed to confirm that the drug reaches the target and acts as intended, typically involving a very small number of doses and participants.
- These trials are conducted much earlier in the development process, preceding the determination of safe clinical doses and large-scale efficacy studies.
*Phase 3*
- **Phase 3 trials** are large-scale studies involving hundreds to thousands of patients to confirm **efficacy**, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug to be used safely.
- While Phase 3 does assess efficacy, it follows Phase 2 and is typically conducted on a much larger scale before submitting for regulatory approval.
Per-protocol analysis US Medical PG Question 7: In a randomized controlled trial studying a new treatment, the primary endpoint (mortality) occurred in 14.4% of the treatment group and 16.7% of the control group. Which of the following represents the number of patients needed to treat to save one life, based on the primary endpoint?
- A. 1/(0.144 - 0.167)
- B. 1/(0.167 - 0.144) (Correct Answer)
- C. 1/(0.300 - 0.267)
- D. 1/(0.267 - 0.300)
- E. 1/(0.136 - 0.118)
Per-protocol analysis Explanation: ***1/(0.167 - 0.144)***
- The **Number Needed to Treat (NNT)** is calculated as **1 / Absolute Risk Reduction (ARR)**.
- The **Absolute Risk Reduction (ARR)** is the difference between the event rate in the control group (16.7%) and the event rate in the treatment group (14.4%), which is **0.167 - 0.144**.
*1/(0.144 - 0.167)*
- This calculation represents 1 divided by the **Absolute Risk Increase**, which would be relevant if the treatment increased mortality.
- The **NNT should always be a positive value**, indicating the number of patients to treat to prevent one adverse event.
*1/(0.300 - 0.267)*
- This option uses arbitrary numbers (0.300 and 0.267) that do not correspond to the given **mortality rates** in the problem.
- It does not reflect the correct calculation for **absolute risk reduction** based on the provided data.
*1/(0.267 - 0.300)*
- This option also uses arbitrary numbers not derived from the problem's data, and it would result in a **negative value** for the denominator.
- The difference between event rates of 0.267 and 0.300 is not present in the given information for this study.
*1/(0.136 - 0.118)*
- This calculation uses arbitrary numbers (0.136 and 0.118) that are not consistent with the reported **mortality rates** of 14.4% and 16.7%.
- These values do not represent the **Absolute Risk Reduction** required for calculating NNT in this specific scenario.
Per-protocol analysis US Medical PG Question 8: A pharmaceutical company conducts a randomized clinical trial in an attempt to show that their new anticoagulant drug prevents more thrombotic events following total knee arthroplasty than the current standard of care. However, a significant number of patients are lost to follow-up or fail to complete treatment according to the study arm to which they were assigned. Several patients in the novel drug arm are also switched at a later time to a novel anticoagulant or warfarin per their primary care physician. All patients enrolled in the study are subsequently analyzed based on the initial group they were assigned to and there is a significant improvement in outcome of the new drug. What analysis most appropriately describes this trial?
- A. Per protocol
- B. As treated
- C. Non-inferiority
- D. Intention to treat (Correct Answer)
- E. Modified intention to treat
Per-protocol analysis Explanation: ***Intention to treat***
- **Intention-to-treat (ITT)** analysis includes all participants randomized to a treatment arm, regardless of whether they completed the intervention or switched treatments, reflecting a real-world scenario and preserving randomization benefits.
- This approach minimizes bias from **loss to follow-up** or **treatment crossovers** and provides a more conservative estimate of treatment effect.
*Per protocol*
- **Per-protocol analysis** only includes participants who completed the study exactly as planned without any deviations.
- This method is susceptible to **selection bias** because it excludes patients who may have experienced adverse events or treatment failures, potentially overestimating treatment efficacy.
*As treated*
- **As-treated analysis** analyzes patients based on the actual treatment received, rather than the treatment to which they were randomized.
- This approach can introduce **confounding** and selection bias, as patients who switch treatments may do so for reasons related to their prognosis or treatment response.
*Non-inferiority*
- A **non-inferiority trial** design aims to show that a new treatment is not appreciably worse than an active control, rather than proving superiority.
- This describes a **type of study design** or hypothesis, not an analysis method for handling patient data after randomization with non-adherence.
*Modified intention to treat*
- A **modified intention-to-treat (mITT)** analysis typically excludes a small, predefined group of patients from the ITT population, such as those who never received any study drug or were found to be ineligible after randomization.
- While similar to ITT, it involves specific exclusions that are not described in this scenario, where all randomized patients were analyzed **based on initial assignment**.
Per-protocol analysis US Medical PG Question 9: A study seeks to investigate the therapeutic efficacy of treating asymptomatic subclinical hypothyroidism in preventing symptoms of hypothyroidism. The investigators found 300 asymptomatic patients with subclinical hypothyroidism, defined as serum thyroid-stimulating hormone (TSH) of 5 to 10 μU/mL with normal serum thyroxine (T4) levels. The patients were randomized to either thyroxine 75 μg daily or placebo. Both investigators and study subjects were blinded. Baseline patient characteristics were distributed similarly in the treatment and control group (p > 0.05). Participants' serum T4 and TSH levels and subjective quality of life were evaluated at a 3-week follow-up. No difference was found between the treatment and placebo groups. Which of the following is the most likely explanation for the results of this study?
- A. Observer effect
- B. Berkson bias
- C. Latency period (Correct Answer)
- D. Confounding bias
- E. Lead-time bias
Per-protocol analysis Explanation: ***Latency period***
- A **latency period** refers to the time between exposure to a cause (e.g., treatment) and the manifestation of its effects (e.g., symptom improvement). The study's **3-week follow-up is too short** to observe the therapeutic benefits of thyroxine in subclinical hypothyroidism.
- Levothyroxine (T4) has a **half-life of approximately 7 days**, and it typically takes **6-8 weeks or longer** for steady-state levels to be achieved and for clinical symptoms to improve. The slow onset of action for thyroid hormone replacement and the gradual nature of symptom resolution mean a longer observation period (typically 3-6 months) is needed to assess efficacy in hypothyroidism.
- The null results likely reflect insufficient follow-up time rather than lack of treatment effect.
*Observer effect*
- The **observer effect**, or Hawthorne effect, occurs when subjects change their behavior because they know they are being observed. This study used **double-blinding** (both investigators and subjects), which effectively minimizes the observer effect.
- The primary issue here is the lack of observed therapeutic effect due to timing, not a change in behavior due to observation.
*Berkson bias*
- **Berkson bias** is a form of selection bias that arises in case-control studies conducted in hospitals, where the probability of being admitted to the hospital can be affected by both exposure and disease.
- This study is a **randomized controlled trial**, not a case-control study, and the selection of participants does not illustrate this specific bias.
*Confounding bias*
- **Confounding bias** occurs when an extraneous variable is associated with both the exposure and the outcome, distorting the observed relationship. The study states that **baseline patient characteristics were similarly distributed (p > 0.05)**, indicating successful randomization and minimization of confounding.
- While confounding is a common concern in observational studies, the RCT design and reported baseline similarities make it unlikely to be the primary explanation for the null results compared to an insufficient follow-up period.
*Lead-time bias*
- **Lead-time bias** is a form of detection bias where early detection of a disease through screening appears to prolong survival, even if the treatment does not change the course of the disease.
- This study is evaluating the **efficacy of treatment** in asymptomatic individuals with subclinical hypothyroidism, not the effect of screening on survival, making lead-time bias irrelevant to these results.
Per-protocol analysis US Medical PG Question 10: In the study, all participants who were enrolled and randomly assigned to treatment with pulmharkimab were analyzed in the pulmharkimab group regardless of medication nonadherence or refusal of allocated treatment. A medical student reading the abstract is confused about why some participants assigned to pulmharkimab who did not adhere to the regimen were still analyzed as part of the pulmharkimab group. Which of the following best reflects the purpose of such an analysis strategy?
- A. To minimize type 2 errors
- B. To assess treatment efficacy more accurately
- C. To reduce selection bias (Correct Answer)
- D. To increase internal validity of study
- E. To increase sample size
Per-protocol analysis Explanation: ***To reduce selection bias***
- Analyzing participants in their originally assigned groups, regardless of adherence, is known as **intention-to-treat (ITT) analysis**.
- This method helps **preserve randomization** and minimizes **selection bias** that could arise if participants who did not adhere to treatment were excluded or re-assigned.
- **This is the most direct and specific purpose** of ITT analysis - preventing systematic differences between groups caused by post-randomization exclusions.
*To minimize type 2 errors*
- While ITT analysis affects statistical power, its primary purpose is not specifically to minimize **type 2 errors** (false negatives).
- ITT analysis may sometimes *increase* the likelihood of a type 2 error by diluting the treatment effect due to non-adherence.
*To assess treatment efficacy more accurately*
- ITT analysis assesses the **effectiveness** of *assigning* a treatment in a real-world setting, rather than the pure biological **efficacy** of the treatment itself.
- Efficacy is better assessed by a **per-protocol analysis**, which only includes compliant participants.
- ITT provides a more **conservative** and **pragmatic** estimate of treatment effect.
*To increase internal validity of study*
- While ITT analysis does contribute to **internal validity** by maintaining randomization, this is a **broader, secondary benefit** rather than the primary purpose.
- Internal validity encompasses many aspects of study design; ITT specifically addresses **post-randomization bias prevention**.
- The more precise answer is that ITT reduces **selection bias**, which is one specific threat to internal validity.
- Many other design features also contribute to internal validity (blinding, standardized protocols, etc.), making this option less specific.
*To increase sample size*
- ITT analysis includes all randomized participants, so it maintains the initial **sample size** that was randomized.
- However, the primary purpose is to preserve the integrity of randomization and prevent bias, not simply to increase the number of participants in the final analysis.
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