Overview of Clinical Trial phases
Phase I study – an initial safety trial to determine dosages, involving a small group of adult participants. This is a small-scale trial to assess whether the vaccine is safe in humans and what immune response it evokes. Phase Ia will trial the vaccine in healthy adults in the UK, and Phase Ib will test the vaccine in a more ‘relevant’ target population. For vaccines for infectious outbreak diseases, this will be a country where an outbreak is likely to occur.
Phase II study – a trial to look at safety and immune response (immunogenicity), in a larger group of participants. This group is usually the target group, for whom the vaccine is intended, for e.g. adults, children, and/or infants. The trial will be designed to generate data on the safety and efficacy of the vaccine (the percentage reduction of disease in a vaccinated group of people compared to an unvaccinated group) against artificial infection and clinical disease.
Phase III study – a larger-scale trial on whether the vaccine induces a level of immunity that would prevent disease and provides evidence that the vaccine can reduce disease cases in a given population. This is done in a larger group (many hundreds of trial participants) in order to gain statistically significant safety and efficacy data for the SPC (Summary of Product Characteristics), and may entail conducting trials at several sites to evaluate efficacy under natural disease conditions. If the vaccine shows safety and efficacy over a defined period, the manufacturer can apply to the relevant regulatory authorities to licence the product.
Phase IV - also called post-marketing surveillance, after the vaccine has been licensed and introduced into use, this stage collects data across wide ranging populations that are using the vaccine, in order to detect rare adverse effects and assess long term efficacy.
Support for designing, setting up and running a vaccine clinical trial:
There are many steps involved in running a vaccine clinical trial, with legal and good practice arrangements surrounding setting up and managing a Clinical Trial of an Investigational Medicinal Product (CTIMP).
The Clinical Trials Toolkit was initially developed and launched in 2004 by the MRC and the Department of Health to help clinical trialists and R&D managers understand the regulations and requirements for conducting trials. As the lead organisation for funding clinical trials, the tool is now managed by NIHR.
The Clinical Trials Toolkit is an interactive colour-coded routemap to help navigate through the legal and good practice requirements, and indicates which aspects of these are relevant to wider clinical research in general. It includes an overview of trial practices, along with more detailed information available at ‘stations’ along the route.
Clinical trials - general
- Stringency of requirement to meet GMP threshold- academic design ideas are often difficult to translate into GMP for phase I trials.
- Requirement of GMP at Phase I, rather than GLP; EU Directive in 2003 mandated GMP quality at Phase I, which takes longer to produce than GLP. This is now a major bottleneck and adds time to every single vaccine candidate, as Phase I is a major step in screening promising candidates and getting rid of a large number of candidates that are not taken forward.
- Waiting for “slots” to be considered by ethics committees
- Contract coordination between the clinic, lab, manufacturer etc.
- Patient recruitment- can be very slow and, necessitate outreach to other NHS Trusts/Trials Centres. Bottlenecks for widening participation may include turnaround of contracts if querying trial protocol, however most Trusts should be signed up to HRA (Health Regulatory Authority).
- Limited amount of vaccine to test in Phase I, or slow rate of supply means it can be difficult to open up trails quickly (even if patients are available)
- MHRA regulatory approval for combined approaches. Generally, MHRA turnaround for vaccine approval is reasonable. Vaccines in combination with devices has proven to introduce long delays (e.g. DNA vaccination combined with electroporation).
- Cold chain facilities- avoidable faults with freezer temperatures etc. causing loss of product. Most problematic in UK pharmacies, as overseas storage often better set up for intermittent power.
- Longer, more complex immunisation strategies can be bottlenecks; i.e. trials for prime-boost vaccinations (inc multiple boosts) and longer patient follow up are more challenging to retain patients to.
- Jump from phase II to phase III can be difficult, e.g. starting a trial in a country with different regulatory approval procedures, or where clinical centres or lab processing facilities aren’t available to the same extent.
- Multiple trial sites: same issue as 10 – host country regulatory procedures may take longer (or be so complex they are prohibitive, e.g. India).
- Potential future bottleneck- The EU Portal, to be instated in 2017.
- It would be quicker to make small lots to test for phase I, and discard the (majority) non-viable developments at the earlier stage before investing the time and effort to reach GMP (e.g. pre-2004 practice).
- Identify “fast track” ethics committees for outbreak situations, which are focused solely on relevant applications to speed up the process e.g. Swine Flu 2009
- Promote patient recruitment
- Identify or develop cohorts
- Map volunteers / specific target populations (see example of France, where recruitment pools are used to good effect to enable rapid identification and selection)
- Robust study design for trials going from Phase II to III
- Having clearer direction from manufacturers on stability of product, in case of cold-chain/storage issues – could prevent product wastage (and associated trial delays) if issues encountered.
- Map clinical trial centres for
- methodological competencies
- hospital facilities
- facilities for standardised immune monitoring, functional physiological monitoring imaging, laboratory testing,
- capabilities for human challenge studies, including BSL2 containment
All clinical studies should be underpinned by robust immunology to enable biomarker identification for patient stratification, and biomarkers for follow up of vaccines.