Randomised control trials: what makes them the medical research gold standard? Plus how do drugs get from discovery to approval?

[AussieNeil]

Here are a couple of articles by biostatistics academics explaining in easily readable articles -

(1) Why the randomised control trial is the best way to compare a new treatment to the standard treatment.

(2) The four phases of drug development and how clinical trials are performed to assess new drugs

When a new treatment becomes available for a particular health condition, such as a new medication to treat a disease, it’s tested to see whether it’s effective for its intended purpose. It’s also tested for potential side effects. This is done through a series of human trials, known as clinical trials.

Every day hundreds of people are invited to participate in clinical trials to test new treatments. Clinical trials are conducted across four phases, from early studies to test the treatment’s safety in a small group of people (phase one), to much larger studies testing whether the treatment works in patients (phases three and four). People are invited to participate in all of these phases.

theconversation.com/randomi...

Not every drug designed by pharmaceutical companies makes it to the market; very few do. Only 9.6% of new drugs in development in the years 2006-2015 successfully made it to the market to be used by patients. That’s because there’s quite a process a drug needs to go through to make sure it’s not only effective for what it’s designed for, but that it’s not harmful.

After animal trials, that provide essential information on the effects of the drug on vital organs and how toxic the drug is at different doses, the drug progresses to testing in humans. This is done through a number of clinical trials conducted over four phases.

theconversation.com/explain...

Note the strong representation of biostatisticians and data management academics in the authorship of these articles - you need the power of statistics to make accurate assessments of how drugs perform on those enrolled in clinical trials.

Added 18th April 2025

healio.com/news/hematology-...

Data derived from Ouimet C, et al. J Natl Cancer Inst. 2025;doi:10.1093/jnci/djaf013.

Kimmelman and colleagues — including Charlotte Ouimet, MSc, PhD candidate in experimental medicine at McGill University — aimed to address the risk and benefit of phase 2 clinical trials

Several published studies have evaluated the risk-benefit balance of phase 1 cancer trials.

Research has shown objective response rates typically range from 3.8% to 13.2%, according to study background. Life-threatening adverse events occurred at rates between 10% and 19%.

They identified 1,154 eligible phase 1, phase 1/phase 2, or phase 2 trials initiated between Nov. 1, 2012, and Nov. 1, 2015. They then randomly sampled 400 of those trials, which included 25,002 participants and assessed 332 drugs.

- In all, 16.2% (95% CI, 10.3%-22.7%) of patients in the sample group received one of 71 treatment regimens that garnered FDA approval.

- Results showed 19.4% (95% CI, 14.1%-25.8%) of therapies evaluated received off-label recommendations based on NCCN guidelines, and 9.3% (95% CI, 4.7%-14.6%) produced substantial clinical benefit based on ESMO-MCBS.

- Nearly one-third (32.5%; 95% CI, 26%-38.8%) of patients participated in a trial in which the treatment advanced to phase 3 testing.

- Therapeutic response did not vary significantly by trial sponsorship, drug phase or trial characteristics.

- The results demonstrate phase 1 trials help filter out unsafe or ineffective drugs, investigators concluded.

Added 21st March 2024

Randomised controlled trials—the gold standard for effectiveness research

healthunlocked.com/cllsuppo...

Observational Studies vs Randomised Clinical Trials

healthunlocked.com/cllsuppo...

Neil

[Jm954 Administrator]

Really good articles.

The only thing I would add is that, in the type of clinical drug trials that we take part in, the randomisation of a single, individual patient may influenced by several factors.

It's imperative that the various treatment 'arms' of a trial are balanced so that true comparisons can be made about a drug's effectiveness and the various characteristics of each arm are usually reported when the trial results are published. For example - the range of age and mean age in each arm, ratio male:female, stage of disease, number of previous treatments etc etc.

For leukaemias this will also include the genetics and they will want the same number of, for example, 11q- patients in each arm. So, if I'm going to be randomised and the person before me got arm A then I should get arm B but if arm A is unbalanced in terms of 11q- patients then I'll get arm A too. This ensures the arms are not negatively weighted by the 'random allocation' of too many patients with poor genetics to one arm which could affect the results.

The better that treatments get, the harder it is to detect the difference between them and so hundreds, sometimes thousands, of patients are needed to 'power' the trial. The data analysis of the results will also look at various subsets of patients and that goes on for many years after the trial is complete, with some studies following up all the patients until death.

Jackie