How are Vaccines Assessed in Clinical Trials?

1

The vaccine testing paradigm

Advances in biotechnology and knowledge of ways to enhance immune responses and immunologic memory have revolutionized the field of human vaccine development, resulting in a vaccine “pipeline” that in recent decades has led to the licensure of many new and improved vaccines. However, a candidate vaccine faces a long, arduous, and expensive road, replete with obstacles, as it commences the journey toward becoming a licensed product that can protect individuals from disease and serve as a public health tool. The step-wise process that involves a series of sequential clinical vaccine studies that must be properly executed to advance a vaccine candidate, incrementally, toward licensure is based on proof of the vaccine’s safety, immunogenicity, and efficacy in target populations, and is divided into “Phases”. The early phases of the vaccine clinical testing paradigm are associated with the highest risk of failure and consequently the vaccine pipeline rather more resembles a funnel in which many products enter into Phase 1 but the winnowing of candidates results in fewer advancing to Phase 2, even fewer to Phase 3 and only a handful achieving licensure. Thus, the chance of success for a vaccine candidate to become a licensed product and thereupon a potential public health tool increases as each phase in the vaccine development paradigm is successfully achieved. In general, in industrialized countries where mortality from infectious diseases is low and age expectancy is high, safety is the key parameter of selection. For vaccines largely targeted for populations in developing countries where young child mortality remains high and morbidity from infectious diseases remains an important public health burden, a somewhat different risk:benefit ratio operates such that efficacy in preventing the target disease is key and milder forms of adverse reactions can be tolerated if accompanied by high efficacy.

Phase 1 trials undertake the initial careful assessment of the safety and clinical acceptability of the candidate vaccine in small numbers of healthy individuals (usually tens or scores of subjects). Such early dose/response tests can only detect common adverse reactions (some of which may be unacceptable) and provide an initial glimpse of whether relevant immune responses can be generated.

Phase 2 trials evaluate the candidate vaccine in increasingly larger numbers of subjects (typically hundreds) and are usually placebo-controlled to measure better the rate of adverse reactions versus background rates of symptoms and complaints. The level of shedding of a live viral or bacterial vaccine is intensively examined in Phase 2 trials, as is the propensity of the live vaccine to be transmitted to household contacts and to survive in the environment. For vaccines that will ultimately be used in infants and toddlers, Phase 1 and 2 trials must be undertaken in progressively younger subjects (age deescalation) until the target age group is reached. The immunization schedule and dose of vaccine to be used in a Phase 3 trial is identified in Phase 2 trials.

A vaccine candidate that has proven to be well tolerated in Phase 2 trials involving hundreds of persons of the target population group (and often in participants in several different geographic sites to document broad relevance) can progress to evaluations of the vaccine’s efficacy in preventing disease. Assessments of efficacy in large-scale Phase 3 trials whenever possible follow a randomized, placebo-controlled (or active agent-controlled), double-blind design. Large clinical trials must also document that different lots of the vaccine have been manufactured in a consistent manner such that the clinical tolerability and immune responses elicited by three different lots of vaccine are similar. These important large safety/immunogenicity studies are termed “lot consistency” trials.

When sufficient evidence of the vaccine’s safety, ability to elicit relevant immune responses and efficacy in preventing disease has been assembled and there is documentation of consistent manufacture of the vaccine in an approved manufacturing establishment, a Biologics License Application (BLA) can be submitted for review by a national regulatory agency such as the US Food and Drug Administration (FDA). If approved, the vaccine will become licensed.

The clinical trials that assess the vaccine at each Phase of development are performed according to clinical protocols that must undergo prior review by ethics committees [called Institutional Review Boards (IRBs) in the USA] and particular attention is paid to the informed consent methods and the documentation of informed consent. Moreover, before a clinical trial of a new vaccine can be initiated, a submission must be made to the national regulatory agency (eg, the US FDA) where the clinical protocol and detailed information about the vaccine, its components, method of manufacture, formulation, results of prior animal tests and animal toxicology tests, and other relevant information are included. In the United States such submissions to the Center for Biologics Evaluation and Research of the FDA are in the form of a New Drug Application (IND). The FDA has up to 30 days to review an IND and to request additional information and clarifications or to request modifications. Sometimes the request for modifications or collection of additional information does not delay initiation of the clinical trial. However, should the FDA have substantial concerns about some aspect of the proposed vaccine trial, the FDA can apply a “clinical hold” that prevents the clinical trial from commencing until it receives satisfactory responses that address the concerns raised; at that point if the concerns have been addressed, approval will be given to initiate the clinical trial. If 30 days pass after the FDA-confirmed date of submission of an IND and no comment has been forthcoming, investigators may initiate the clinical trial.

Certain clinical trials, such as any Phase 2 or Phase 3 vaccine trial in the United States and Phase 1 pediatric vaccine trials within the European Union, must be registered in a clinical trials registry. The International Committee of Medical Journal Editors requests that all clinical trials of products be registered. Examples of clinical trials registries include ClinicalTrials.gov (maintained by the National Library of Medicine, Bethesda, MD, USA), the Pan African Clinical Trials Registry [( www.pactr.org ) managed by the South African Cochrane Centre at the South African Medical Research Council], and the European Union Clinical Trials Register. Registration of clinical trials increases transparency for the general public (who can access the websites) as well as for health professionals. It allows interested parties and stakeholders to assess rapidly the landscape of trials ongoing with particular types of vaccines. It also allows the contents of scientific publications about a vaccine to be compared with what was proposed to be studied in the summary of the clinical trial contained in the register.

The stepwise process vaccine development paradigm continues even after a vaccine becomes licensed, as there must be a post-licensure surveillance plan to monitor the safety profile of the newly licensed vaccine and its impact on the target disease once it is in large-scale use. Only post-licensure, when very large numbers of individuals of the target population have received the vaccine in numbers far exceeding the numbers of participants in Phase 3 trials does one have the possibility through Phase 4 surveillance to detect rare but severe adverse events. Similarly, Phase 4 post-licensure trials and surveillance methods of different types allow an evaluation of how the vaccine is protecting under real-life conditions and constraints.

2

Ethical issues

Ethical Committees such as the IRBs in the United States are responsible for overseeing the health and satisfactory clinical condition of participants involved in clinical trials. US regulations instruct that the board includes at least five members, at least one who is not a scientist, and one who is not affiliated with the institution. The IRB reviews protocols, investigator’s brochures, consent forms, recruiting materials, and additional safety information.

WHO guidance recommends that Ethics Committee members should include individuals with relevant scientific knowledge, expertise in legal matters and/or ethics and lay people whose primary role is to share their insights about the communities from which participants are likely to be drawn. To enhance independence, WHO suggests that the Research Ethics Committee should include members who are not affiliated with organizations that sponsor, fund, or conduct research reviewed by the Research Ethics Committee. Since committees should be large enough to ensure that multiple perspectives are brought into the discussion, quorum requirements provide that at least five people, including at least one lay member and one nonaffiliated member, be present to make decisions about the proposed research.

3

Good Clinical Practices

Good Clinical Practices, “GCP”, refers to the comprehensive regulations and guidelines for conducting clinical trials that must be followed for results of those trials to be contained within an application requesting licensure of the vaccine. GCP covers items such as protocol design, informed consent, record keeping, data reporting, laboratory standard operating procedures (SOPs), adverse event reporting, among others. GCP is intended to assure the integrity and quality of clinical data and to protect the rights and safety of study participants.

4

Phase 1

If the vaccine candidate is based on a technology that has been previously utilized to make other vaccines that ultimately proved to be safe, immunogenic, and efficacious, that generally facilitates the initiation of Phase 1 trials and allows them to be performed at an accelerated pace. For example, conjugate vaccines consisting of polysaccharides from pathogenic bacteria covalently linked to carrier proteins have led to multiple successful vaccines including several Haemophilus influenzae type b (Hib) conjugates (Hib capsular polysaccharide linked to tetanus toxoid, CRM ₁₉₇ genetically detoxified mutant diphtheria toxin, or outer membrane protein of Group B Neisseria meningitidis ), multivalent pneumococcal conjugate vaccines (capsular polysaccharides of 10 or 13 serotypes of Streptococcus pneumoniae linked to carrier protein), quadrivalent meningococcal conjugate vaccine (capsular polysaccharides of Neisseria meningitidis Group A, C, W135, and Y linked to carrier protein) have all proven to be well-tolerated, immunogenic, and efficacious vaccines in children, including young infants. Thus, a new bivalent conjugate vaccine to prevent invasive disease due to nontyphoidal Salmonella should be able to enter Phase 1 clinical trials and progress through stepwise age deescalation to infants without generating undue anxiety.

Certain target populations and types of vaccines require that they be evaluated in Phase 1 clinical trials of special design and performed with caution. Examples are given later:

5

Phase 2

The Phase 2 vaccine trials that pave the way for pivotal Phase 3 field trials that assess the efficacy of a vaccine, are typically less visible than the latter. Ideally the sites and populations for Phase 2 trials will be representative of the ultimate target population. However, for various reasons, sometimes Phase 2 and 3 trials are carried out in parallel in other populations. During Phase 2 trials, it is important to select and validate the assays that measure immune response(s) to the vaccine. It is also critical that before the Phase 2 trials begin (or as soon as possible after they begin), the final method of manufacture and the formulation be finalized as this is what must be utilized in the future pivotal Phase 3 efficacy trial and will be commercialized for post-licensure use.