Mejoras para 2021

Carried out after a medicine has been licensed, put on the market and prescribed to patients. Part of the monitoring process, these trials are designed to find out more about the long term harms and benefits of a medicine, and to discover new uses for it.

NOTE: Phase 0 is not always described in books etc it is a more recent addition. Technically phase IV trials are performed after the marketing authorisation is granted. I’m not sure the best way of dividing the marks. Assuming a mark is roughly 5% then 6 are available for this question. Maybe half a mark for each phase I – IV then a whole mark for the explanation?

Define what is meant by ‘a double blind randomised controlled trial with adequate power’, and explain the reasons for these methods? (50%)

This is the gold standard in medical research Double blind

Blinding in a trial attempts to eliminate bias. Singly blinded trials do not tell the patient which treatment they are receiving such as active or inactive drug. In some occasions this can be very difficult to achieve but investigators go to great lengths such as performing dummy procedures to maintain blinding. Blinding in the patient group is important because it helps to control the placebo effect.

In double blind trials neither the investigators nor the patients are aware of which treatment the participant is receiving. This helps to eliminate the chance of the investigators own agenda might influence the results.

Randomised

The group to which the participant is allocated to is randomly allocated. This can be achieved in a number of ways but generally patients are allocated a number which a computer program then allocates to different groups. This is an attempt to ensure that patient demographics which might influence the outcome such as age, weight, sex medical history etc are matched between each group.

Controlled

The trial is performed in two groups, the treatment and control groups. The control group might receive dummy medicines or procedures in which case it would be placebo controlled. In some trials it would be unethical to treat a patient with a placebo for example in patients with cancer. Here the control group is treated with the current standard of care and the outcome is compared with that in the group receiving the product under investigation. Controlling a trial simply allows for a comparison to be made and as long as all other variables are controlled for the effect seen can then be attributed to the product with reasonable confidence.

Adequate power

The power of a statistical test is the probability that a test will reject the null hypothesis when it is in fact false. As the power increases the chance of committing a type II error (false negative or β) decreases. Power is equal to 1 – β and is sometimes referred to as the sensitivity. By convention a power of 0.8 (β = 0.2) is an acceptable level of power. A power of 0.8 means that the study has an 80% chance of producing a p value of <0.05 when the required difference between variables is observed. A power calculation is performed to determine the minimum sample size which can be reasonably expected to demonstrate this observed difference.

Under what circumstances might an observational study be an acceptable method of investigation? (20%)

An observational study is one in which the allocation of subjects into control and treatment group is outside the influence of the researcher. Observational study is a collective term for cohort, cross sectional and case-control studies. The primary reason for using an observational study is when ethical considerations preclude allocation of asymptomatic, randomly allocated subjects to certain variables for example the link between smoking and lung cancer.

This example also demonstrates the other situation in which an observational study might be employed, specifically when it using a randomized controlled methodology would be impractical due to the long natural history of cause and effect. Studying the effects of smoking on cancer would result in a study would run for 20 or more years. In observational studies the researcher might select a group of patients with lung cancer and work backwards to identify a causative influence. The same is true when investigating conditions or effects which are rare and would therefore require a prohibitively large number of subjects in which to observe the effect. Once again patients are selected with the condition and the researcher would work retrospectively to try and determine cause and effect.

Answer Contributed by Dr. P Balaji

(a) What are the main types of studies that must be done on a drug in order to obtain marketing authorization (formerly called a product licence) from the Medicines and Healthcare products Regulatory Agency (MHRA)? (30%)

Before obtaining the marketing authorisation, the drug company has to provide more

information and paperwork to prove how the drug work, its side-effect and efficacy. MHRA is more concerned about the safety and efficacy. Any trial conducted in UK would suffice. Step wise approach would be to conduct a trial in animals followed by any evidence (trial

information) obtained elsewhere from other countries. This would be followed by Phase-2 trial (observational) in a controlled and restricted manner. Once they are satisfied, they would provide MA following which RCT could be done to know its efficacy for which every hospital has to obtain MHRA approval.

Must include: MHRA looks for safety and efficacy. Clinical trials have to be conducted in UK.

(b) Define what is meant by ‘a double blind randomised controlled trial with adequate power’, and explain the reasons for these methods? (50%)

The randomized controlled trial is one of the simplest but most powerful tools of research. In essence, the randomized controlled trial is a study in which people are allocated at random to receive one of several clinical interventions. On most occasions, the term “intervention” refers to treatment, but it should be used in a much wider sense to include any clinical manoeuvre offered to study participants that may have an effect on their health status. Such clinical manoeuvres include prevention strategies, screening programs, diagnostic tests, interventional procedures, the setting in which health care is provided, and educational models. Randomized controlled trials are used to examine the effect of interventions on particular outcomes such as death or the recurrence of disease. Some consider randomized controlled trials to be the best of all research designs, or “the most powerful tool in modern clinical research”, mainly because the act of randomizing patients to receive or not receive the intervention ensures that, on average, all other possible causes are equal between the two groups.

In addition to randomization, the investigators can incorporate other methodologic strategies like blinding to reduce the risk of ascertainment and observation biases. A single-blinded randomized controlled trial is one in which a group of individuals involved in the trial (usually patients) does not know which intervention is given to each participant. A double-blinded randomized controlled trial, on the other hand, is one in which two groups of individuals

involved in the trial (usually patients and treating physicians) do not know which intervention is given to each participant.

The most important limitations of research methods for RCT include the following:

Insufficient power.—A survey of 71 randomized controlled trials showed that most of these trials were too small (i.e., had insufficient power to detect important clinical differences) and that the authors of these trials seemed unaware of these facts. So Power is important to interpret the effectiveness of the trial. More often we talk about the power of a study to detect an effect of a specified sample size where the power is 1-beta, where beta is type-II error which is usually designed for 85-90% in order to detect a difference ( as significant) that is real (due to the drug).

Must include: definition for RCT, double blind and power

(c) Under what circumstances might an observational study be an acceptable method of investigation? (20%)

Observational studies include Cohort, cross sectional and case-control studies. Often these studies are the only practicable method of studying various problems, for example, studies of aetiology, instances where a randomised controlled trial might be unethical, or if the

condition to be studied is rare. Cohort studies are used to study incidence, causes, and prognosis. Because they measure events in chronological order, they can be used to distinguish between cause and effect. Cross sectional studies are used to determine prevalence. They are relatively quick and easy but do not permit distinction between cause and effect. Case controlled studies compare groups retrospectively. They seek to identify possible predictors of outcome and are useful for studying rare diseases or outcomes. They are often used to generate hypotheses that can then be studied via prospective cohort or other studies. On those circumstances, Observational study would be an acceptable method of investigation.

Must include that there are various studies like cohort, cross-sectional and case-control and few examples why it is acceptable and why RCT can't be done. Even a single example would be sufficient.

Reading materials: Practical statistics for medical research by Douglas Altman; very simple and easy to read.