Friday, December 18, 2020

How can policymakers encourage COVID-19 vaccine trials for children?

By Jacob S. Sherkow, Lisa Larrimore Ouellette, Nicholson Price, and Rachel Sachs

The past two weeks have been full of exciting COVID-19 vaccine news, including the FDA’s emergency use authorizations (EUAs) for the Pfizer–BioNTech and Moderna vaccines and the nationwide rollout of Pfizer’s vaccine. Choosing how to allocate access to vaccine doses has been left to individual states, leaving policymakers with difficult decisions about how to prioritize their populations, complicated in part by the federal government’s reduction in some vaccine shipments

With a limited supply of doses, who should get the first shots? Some commentators have suggested prioritizing children early for a host of reasons, including hope about children returning to school. Last month a New York Times column asserted that “saving the most lives could mean prioritizing the vaccination of children and young adults.” But there is an important reason that kids can’t be part of the vaccine line yet: we don’t know whether these vaccines work for them. In this post, we explain why COVID-19 vaccines are only just starting to be tested in children and what policymakers can do to spur pediatric vaccine trials.

When will COVID-19 vaccines be tested in kids, and why haven’t they been already?

So far, most of the vaccine clinical trials have enrolled adults age 18 or older. Pfizer’s EUA includes 16- and 17-year-olds, although three of the FDA Advisory Committee members voted against granting an EUA because of the scant data in this population: out of over 18,000 people who received the vaccine in Pfizer’s phase 2 and 3 trials, only 138 were under 18. (Moderna’s EUA is limited to individuals 18 and older.)

This is not unusual. Children are commonly excluded from early clinical trials for a host of reasons. As medical schools emphasize: “Children are not little adults.” They are a vulnerable, wildly heterogeneous population. Pediatric doses cannot be calculated simply by scaling by weight, and some drugs that are safe in adults may have surprisingly adverse effects in children. Pediatric studies also involve greater ethical challenges, including the involvement of parents in the informed consent process. In this case, the exclusion of most children from trials means that—barring off-label administration, unlikely en masse given the shortage of doses—kids won’t have access to COVID-19 vaccines for quite a while.

This paucity of evidence in children is concerning because one of the biggest challenges the pandemic has caused is school closures. Children are less likely than adults to develop severe COVID-19, but they are still at risk, including for complications like multisystem inflammatory syndrome and respiratory failure. And the racial disparities in the impact of COVID-19 are as tragic for children as for adults. The CDC has documented that Black, Hispanic, and Native youths accounted for 78% of COVID-related deaths in persons under 21 from February to July. In addition, the indirect costs are staggering. For example, students of color are much more likely to be in online-only school districts and to have fallen further behind educational goals—sometimes because they lack the resources to attend online school. And this gap isn’t just educational. For many students of color, schools provide social welfare services, physical and mental therapy, and even meals. Schools also inculcate “social–emotional learning, formative relationships with peers and adults, opportunities for play, and other developmental necessities . . . . Children living in poverty, children of color, English language learners, children with diagnosed disabilities, and young children face especially severe losses.” The ability to vaccinate children would greatly aid in school reopenings and reductions of the current devastating toll the pandemic has taken on children.

Fortunately, pediatric clinical trial data is coming. The Pfizer trial was expanded to include 12- to 15-year-olds in late October, and Moderna recently announced that it will soon expand its trials to include children as young as 12. After Pfizer analyzes data from trials in children 12 and older, it apparently plans to start trials in 5 to 11 year olds in April 2021, with trials in kids under 5 after that. How long will it take to complete trials and authorize a vaccine for use in children? Expert predictions range from “many months” to “not in time for the new school year.” Of course, if the Pfizer and Moderna clinical trials reveal substantial safety concerns with their vaccines in pediatric populations, it could be even longer.

What innovation incentives are there for pediatric vaccine development?

A number of policy levers encourage pharmaceutical companies to develop vaccines approved for children. Congress has passed laws providing additional six-month periods of FDA exclusivity (on top of baseline exclusivity periods already granted by the agency) for companies choosing to conduct pediatric testing for their drugs and biological products (including vaccines). This exclusivity is granted whether or not these trials are successful so long as they are conducted.

Congress subsequently chose to add an innovation “stick” to the six-month exclusivity “carrot,” giving FDA the authority to require pediatric studies for certain drugs and biological products. Additional incentives exist for innovators to develop products in the area of rare pediatric diseases, but these are less likely to be used for vaccines. These programs have succeeded in greatly increasing the number of pediatric clinical trials, although pediatric drug development still lags behind studies in adults.

Where pediatric studies have not been completed (or have not led to changes in the FDA labels for a product), physicians are still likely to prescribe new products to children off-label. This prescribing may serve itself as an incentive for companies to develop new products if they contemplate a substantial amount of pediatric off-label prescribing.

Additional incentives exist to help ensure children have access to approved vaccines in particular. After a large measles outbreak between 1989-1991, Congress created the Vaccines for Children (VFC) program, aiming to provide free vaccinations to children who otherwise would not receive them for financial reasons. The CDC purchases the relevant vaccines at a discount and ensures their dissemination nationwide to tens of thousands of VFC providers. Tens of millions of children may be vaccinated under the VFC each year, at a cost of a few billion dollars. By federally supporting the purchase and distribution of these products, the VFC program creates a reliable, regular market for producers of pediatric vaccines.

The 1997 creation of the Children’s Health Insurance Program (CHIP) helped support this goal of VFC. CHIP enabled states to expand access to health insurance to uninsured children in families who are not able to obtain private insurance, but whose incomes are too high to qualify for Medicaid. Medicaid-eligible children were already eligible for VFC, as were uninsured or underinsured children, but CHIP provided additional opportunities for children in low-income families to obtain necessary childhood vaccinations. The Affordable Care Act further expanded access by requiring that private insurers cover recommended vaccinations with no cost-sharing.

Finally, Congress has spurred pediatric vaccine development not only by increasing the expected return but also by decreasing expected liability costs through the 1986 National Vaccine Injury Compensation Program (VICP). For vaccines designated by the CDC for “routine administration to children,” VICP provides a no-fault injury compensation program that largely bars civil lawsuits.

As we have previously explained, these kinds of changes to expected healthcare markets serve as important innovation incentives. In fact, the first empirical demonstration of this effect was in the vaccine context: Professor Amy Finkelstein showed that the VICP combined with expansions in vaccine recommendations and coverage in 1991 and 1993 led to a 2.5-fold increase in vaccine trials for affected diseases.

What can policymakers do to support pediatric COVID-19 vaccine trials?

Acquiring good pediatric safety and efficacy information is a persistent problem in biopharmaceutical development, and substantial evidence suggests that existing incentives aren’t sufficient. In the vaccine context, this problem is compounded by the problem of insufficient incentives, even for adults. As we have discussed in prior posts, policymakers could draw from the innovation policy toolkit to advance the goal of acquiring better information.

Because information about pediatric safety and efficacy is largely nonexcludable on its own, patents provide little incentive; instead, pediatric trials can result in additional FDA-mediated exclusivity on the underlying product itself, as noted above. Policymakers could increase the strength of that incentive by lengthening the 6-month period of additional exclusivity granted for pediatric vaccine trials, although this will do little, if nothing, to speed up the development of pediatric COVID-19 vaccine information.

If the potential incentive/access tradeoff of further exclusivity is practically or politically problematic (though the tradeoff can be illusory), other incentives that do not rely on exclusivity could be increased. The government could fund pediatric vaccine trials directly via grants or decrease their cost via targeted tax incentives such as the existing 25% credit for clinical trial expenses for orphan drugs (including vaccines). Such changes would likely take congressional effort, though, which would take time and bipartisan support, both of which appear to be in short supply.

In the absence of such congressionally driven expenditures, the FDA could conceivably link pediatric evidence to the authorization requirements of an EUA or to the eventual requirements for approval of a vaccine. Such trials could include similar diversity requirements as those for adult trials, to ensure that safety and efficacy data for kids are also representative. And the FDA does currently have, and exercises, authority to require EUA applicants to collect and provide to the FDA information “on the safety and effectiveness of the EUA product during the period when the authorization is in effect and for a reasonable time following such period.” 

But in the middle of a public health emergency like the current pandemic, requirements linked to approval rather than EUAs seem more politically feasible, as the agency would not face criticism of keeping essential vaccines off the market. Such requirements might face some ethical difficulties; since children’s reactions to COVID-19 are generally mild, the risk-benefit calculus is somewhat skewed, and enrollment might be more difficult than normal. Nevertheless, the regulatory imposition of pediatric trial requirements as a precondition for approval seems a promising possibility.

The problem of pediatric evidence is not unique to vaccines, of course; many treatments, including treatments for COVID-19, also lack good evidence about their safety and efficacy in children. A similar range of policy options is available for treatments. But another step is simply making sure that when kids are treated off label—as they likely will as dosage supply increases—information is appropriately gathered, whether by enrolling them in clinical trials or by methodically collecting their information, to sufficiently analyze outcomes. Implementing such suggestions will ultimately depend more on the physicians and health-care workers on the ground than on legislative action.

Ultimately, getting pediatric safety and efficacy information for COVID-19 vaccines and treatments is doable; policymakers must simply decide it is a goal worth fighting for.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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