Regulation of Vaccines: Strengthening the Science Base

Journal of Public Health Policy,  2004  by Milstien, Julie B

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Clinical trials. In the US, all products for trials in humans fall under the IND (Investigational New Drug) provisions, which means that there is an approval process for each trial. The system is flexible, allowing maximal control where there are questions, but with the ability to abbreviate the process in some cases. The US IND system is generally considered a good one for products in clinical trial. Phase 4 trials, which are done after licensing, post-marketing, constitutes a useful concept. Sometimes a phase 4 trial is designed to allow definition of potential safety issues in a large monitored population under actual use conditions.

For rotavirus vaccine, postmarketing monitoring detected intussusception associated with its use-a rare event (one case per 10,000 recipients) which could not have been definitively documented in smaller phase 3 trials. For new candidate rotavirus vaccines, regulators are now recommending extremely large phase 3 trials (27) (>70,000). In the US, this number of trial participants may be feasible, but for other countries, trials of this size may approach that of an entire birth cohort, and multi-center trials may be necessary, thus adding to the expense and complexity. Moreover, as phase 2 trials are generally much smaller, this requirement could imply a large increase in the number of recipients of an unlicensed product-a situation not necessarily safer than if the product were licensed on the basis of smaller phase 3 trials and subject to careful phase 4 monitoring.

GMP. GMP compliance, characterized by a new concept-current GMPs (cGMPs)-is an ever changing target. Although various GMP codes do not differ much, their interpretation and enforcement by GMP inspectors in different countries does. In August 2002, the FDA announced an initiative "Pharmaceutical cGMPs for the 21st Century," a risk-based approach designed to:

- Enhance the focus of the agency's cGMP requirements on potential public health risks;

- Help ensure that FDA's work does not impede innovation in the industry;

- Enhance the consistency of the FDA approach across its different centers and field components (28).

Perhaps such an approach will provide some balance to the current cGMP escalation.

Product decisions. Decision making based on a theoretical risk rather than solid scientific evidence is a regulatory practice that carries global implications. The decision to require removal of thimerosal, a mercury-containing preservative, from vaccines for use in the United States, because of concern about exposing infants to mercury compounds constitutes a recent example (26,29). The action, based on a perceived risk which has not been demonstrated to exist (30), cost manufacturers dearly and created a vaccine shortage in the US. (The decision threatened the global supply of vaccine had it been implemented in additional countries). Moreover, much of the developing world depends on use of thimerosal, to preserve vaccines in multi-dose vials, that help keep down the cost of vaccination programs (31).