Adaptive design (medicine)

In an adaptive design of a clinical trial, the parameters and conduct of the trial for a candidate drug or vaccine may be changed based on an interim analysis.[1][2] Adaptive design typically involves advanced statistics to interpret a clinical trial endpoint.[1]

Schematic block diagram of an adaptive design for a clinical trial[1]

Characteristics

Traditionally, clinical trials are conducted in three steps:[1]

  1. The trial is designed.
  2. The trial is conducted as prescribed by the design.
  3. Once the data are ready, they are analysed according to a pre-specified analysis plan.

Modifications using an adaptive design may include:[1][3][4]

  • refining the sample size
  • abandoning treatments or doses
  • changing the allocation ratio of patients to trial arms
  • identifying trial participants most likely to benefit and focusing recruitment efforts on them
  • stopping the whole trial at an early stage for success or lack of efficacy.

Usage
See also: Phases of clinical research

The adaptive design method developed mainly in the early 21st century.[1] In November 2019, the US Food and Drug Administration provided guidelines for using adaptive designs in clinical trials.[2]

See also: COVID-19 vaccine § Adaptive design for the Solidarity trial
See also: COVID-19 drug development § Adaptive designs for COVID‑19 trials

In April 2020, the World Health Organization published an "R&D Blueprint (for the) novel Coronavirus" (Blueprint). The Blueprint documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3-6 months of it being made available for the trial." The Blueprint listed a Global Target Product Profile (TPP) for COVID‑19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID‑19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks.[5]

The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development;[6] 3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international randomized controlled trial – the "Solidarity trial" for vaccines[5][7] – to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID‑19 disease, ensuring fast interpretation and sharing of results around the world.[5] The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage.[5]

The global "Solidarity" and European "Discovery" trials of hospitalized people with severe COVID‑19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge.[8][9][10][11] The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID‑19 people at 100 sites in multiple countries.[12]

See also

References
  1. Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, et al. (February 2018). "Adaptive designs in clinical trials: why use them, and how to run and report them". BMC Medicine. 16 (1): 29. doi:10.1186/s12916-018-1017-7. PMC 5830330. PMID 29490655.
  2. "Adaptive designs for clinical trials of drugs and biologics: Guidance for industry". U.S. Food and Drug Administration (FDA). 1 November 2019. Archived from the original on 13 December 2019. Retrieved 3 April 2020.
  3. Van Norman GA (June 2019). "Phase II trials in drug development and adaptive trial design". JACC. Basic to Translational Science. 4 (3): 428–437. doi:10.1016/j.jacbts.2019.02.005. PMC 6609997. PMID 31312766.
  4. Sato A, Shimura M, Gosho M (April 2018). "Practical characteristics of adaptive design in Phase 2 and 3 clinical trials". Journal of Clinical Pharmacy and Therapeutics. 43 (2): 170–180. doi:10.1111/jcpt.12617. PMID 28850685. S2CID 3704071.
  5. "Update on WHO Solidarity Trial – Accelerating a safe and effective COVID-19 vaccine". World Health Organization. 2020-04-27. Archived from the original on 30 April 2020. Retrieved 2020-05-02. It is vital that we evaluate as many vaccines as possible as we cannot predict how many will turn out to be viable. To increase the chances of success (given the high level of attrition during vaccine development), we must test all candidate vaccines until they fail. [The] WHO is working to ensure that all of them have the chance of being tested at the initial stage of development. The results for the efficacy of each vaccine are expected within three to six months and this evidence, combined with data on safety, will inform decisions about whether it can be used on a wider scale.
  6. "Draft landscape of COVID 19 candidate vaccines". World Health Organization. 2020-09-03. Retrieved 2020-09-03.
  7. "An international randomised trial of candidate vaccines against COVID-19: Outline of Solidarity vaccine trial" (PDF). World Health Organization. 2020-04-09. Archived (PDF) from the original on 12 May 2020. Retrieved 2020-05-09.
  8. COVID-19 Clinical Research Coalition (April 2020). "Global coalition to accelerate COVID-19 clinical research in resource-limited settings". Lancet. 395 (10233): 1322–1325. doi:10.1016/s0140-6736(20)30798-4. PMC 7270833. PMID 32247324.
  9. Li G, De Clercq E (March 2020). "Therapeutic options for the 2019 novel coronavirus (2019-nCoV)". Nature Reviews. Drug Discovery. 19 (3): 149–150. doi:10.1038/d41573-020-00016-0. PMID 32127666.
  10. Dhama K, Sharun K, Tiwari R, Dadar M, Malik YS, Singh KP, Chaicumpa W (March 2020). "COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics". Human Vaccines & Immunotherapeutics. 16 (6): 1232–1238. doi:10.1080/21645515.2020.1735227. PMC 7103671. PMID 32186952.
  11. "Launch of a European clinical trial against COVID-19". INSERM. 22 March 2020. Retrieved 5 April 2020. The great strength of this trial is its "adaptive" nature. This means that ineffective experimental treatments can very quickly be dropped and replaced by other molecules that emerge from research efforts. We will therefore be able to make changes in real time, in line with the most recent scientific data, in order to find the best treatment for our patients
  12. Clinical trial number NCT04280705 for "Adaptive COVID-19 Treatment Trial (ACTT)" at ClinicalTrials.gov
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