Fall from grace: Is US at risk of becoming second-tier country in vaccine introduction?

by Steven Black, MD

The past 60 years has witnessed an amazing level of new vaccine development and a consequent reduction — or even elimination — of disease due to the major infectious scourges of humanity.

Beginning with polio vaccine introduction in the 1950s, we have seen vaccines developed for hepatitis A and B, new conjugate vaccines developed for Haemophilus influenzae type b, pneumococcus, polyvalent meningococcal conjugate vaccines, a vaccine to prevent varicella, and vaccines to prevent cervical cancer. Because of these vaccines, the number of Hib meningitis cases has been reduced by more than 99% from 20,000 per year to fewer than 50; invasive pneumococcal disease is much less common in children and adults; and varicella and its complications are also less common.

Most of these vaccines were developed and initially evaluated in the US, and all were introduced into widespread use initially in the US. The latter is important because early introduction of these safe and effective vaccines has allowed the US population to reap the public health benefits for years or even decades before other countries. However, the focus on the US as a primary site for vaccine evaluation and introduction appears to be changing.

Trials of two recent rotavirus vaccines were conducted in many countries, and one was introduced outside of the US. Of the two new commercially available pneumococcal conjugate vaccines, only the pneumococcal conjugate vaccine (Prevnar 7, Wyeth) is available in the US, whereas the other vaccine — manufactured by GlaxoSmithKline — is approved in Europe, Latin America and is prequalified by WHO for use globally, but is not available in the US.

A protein-based vaccine against meningococcal type B — the major cause of meningococcal disease in infants — is only now being registered for study in the US, whereas it is already under consideration for licensure in Europe and several other countries, including Canada. Although adjuvant influenza vaccines offer the potential for broader, more effective and longer-lasting coverage against influenza for adults and children, they are licensed only outside of the US.

Finally, even though several polyvalent meningococcal vaccines are under consideration for licensure in the US after as much as a 10-year development program, the Advisory Committee on Immunization Practices may not recommend routine use of these vaccines in infants.

What is driving this change?

Part of this change is due to the emergence of new vaccine markets outside of the US and the ability of the Global Alliance for Vaccines and Immunization and others to pay for vaccine introduction in developing countries. However, although the latter is accelerating introduction of vaccines such as rotavirus and pneumococcal conjugate vaccines into poorer countries, it is not affecting their introduction or use in the US.

As pointed out in a recent article in The New York Times regarding new drug and device introduction, the US is becoming an increasingly expensive and time-consuming place to test and introduce new drugs and vaccines. This article points out that medical device companies routinely seek approval for new devices in Europe first, resulting in some devices being available up to 10 years before their introduction in the US, and more worrisome, some devices not being submitted for review in the US at all.

Reasons cited by manufacturers for this trend include increasing complexity and cost of the review process and the availability of regulatory review and a market overseas. The latter raises an important point. Two decades ago, the FDA was the only option for review of drugs and vaccines, with most countries deferring to their regulatory opinion. Today, with the advent of the European Medicines Agency, manufacturers have access to what they view as a more flexible, consistent, and expeditious regulatory process that also has global acceptance.

Given the global nature of most companies and markets in the 21st century, there is the potential for vaccine manufacturers to make a business decision not to initially target the US market or even not to target it at all. If this were to become common practice, obviously the use of vaccines to prevent disease morbidity and mortality in the US, rather than being at the cutting-edge, could fall behind many countries in the world. In addition, the increasing expense and risk for development programs makes it less likely that manufacturers will risk development or registration of a vaccine for diseases with a small market.

ACIP’s role

There is one other factor that is making the US a more risky place to evaluate and introduce vaccines: After a long evaluation program, recommending agencies such as the ACIP may not recommend a licensed vaccine for routine use, thus making a vaccine commercially unviable in the US. Although vaccines such as varicella and pneumococcal conjugate were both considered very expensive at the time of their introduction, they were recommended for routine use because they were known to be safe and effective, and they were widely accepted as effective public health tools to prevent infectious causes of morbidity and mortality in our population.

If a frame of reference is adopted that requires new vaccines to be cost-saving or “cost-effective” relative to an arbitrary standard in addition to being safe and effective, then this makes the US an even riskier place to introduce new vaccines. This is especially true if, as we have recently seen, such decisions seem to be being made inconsistently. For example, the ACIP has recommended a routine second dose of varicella and adolescent meningococcal vaccine, both of which provide an incremental benefit over a single dose, whereas it does not seem to be prepared to recommend routine use of any of several manufacturers’ approaches for vaccination of infants against meningococcal disease.

If preliminary recommendations could be made earlier on in the development process as to whether the ACIP would be likely to recommend such a vaccine if licensed, manufacturers could adjust their vaccine development programs to be more in line with anticipated final ACIP recommendations. This is important, given that the high cost of investigational new drug registration with the FDA and clinical trial evaluations necessarily limit the number of vaccines that can proceed through this process.

Finally, what needs to be done? Although the FDA regulatory process is recognized globally as being of the highest standard, we now live in a world dominated by global markets and with regulatory alternatives. If the US wants to maintain its pre-eminence in the prevention of disease through the use of vaccines, the functioning of the US regulatory and recommendation framework need to be strategically re-evaluated in the context of what is now a very competitive global landscape.

Pollack A. Medical treatment, out of reach. The New York Times. Feb. 9, 2011. Available at: www.nytimes.com/2011/02/10/business/10device.html?_r=1&pagewanted=1