The infectious disease community has mixed feelings about the 21st Century Cures Act, a new health care bill that is supposed to revolutionize health care in this country. The bill (H.R. 6) was approved by the House but is just beginning to make its way through the Senate.
If the Senate approves the measure and it is signed into law, proponents claim it will create a 21st Century health care infrastructure that emphasizes innovation, funding new cures for rare and fatal diseases. Opponents claim it will lower the standards for new drug and device approvals, potentially enabling ineffective or harmful products to come to market.
Nearly everyone supports the measures that will increase general funding for the stagnating National Institutes of Health (NIH) budget, which has suffered from sequester and other cuts, and a separate allocation of $1.86 billion a year for five years to create an NIH Innovation Fund. The monies would be dedicated to innovative research for rare and fatal diseases with a medical need for better and more innovative treatments. As always, however, the devil is in the details
Many in the infectious disease community support this much-needed funding for research, as well as the efforts that will be made to find new antimicrobials and promote antibiotic stewardship to fight the development of resistance. However, they are less enamored by the provisions in the act that cover how vaccine recommendations are made in this country.
Section 2141 of H.R. 6 states that the Advisory Committee on Immunization Practices (ACIP), which sets the U.S. vaccination schedule, must review any vaccine or new indication for a vaccination at its next regularly scheduled meeting. The ACIP meets three times a year.
“For the first time, the ACIP has been provided a countdown, basically, that has a maximum of 120 days from licensure to recommendation,” said Jon Temte, MD, MS, PhD, former chair of the ACIP.
“We are charged with making the best recommendation for application of vaccines and other associated biologics for use in the civilian population based on a number of different issues, specifically, the effectiveness of a vaccine, the safety of a vaccine, some consideration of costs, and also implementation issues, equity and so on,” said Dr. Temte, a professor in the Department of Family Medicine and Community Health at the University of Wisconsin-Madison School of Medicine and Public Health. “That is a lot of information to consider.”
Typically, the ACIP forms a working group to start considering a vaccine about the same time when the company applies for licensure, he explained. Although individuals are looking at many of the above issues before a vaccine is approved, the ACIP is statutorily required to make a recommendation only after that vaccine has been licensed.
“Although we will hear about the vaccine prelicensure, we don’t really start considering all the issues until licensure has occurred [and they have all the data about the vaccine and its potential effect on millions of individuals],” he said.
Amanda Jezek, the vice president of Public Policy and Government Relations at the Infectious Diseases Society of America (IDSA), in Arlington, Va., said there is concern that this push to recommend a vaccine before the ACIP has reviewed the evidence would completely “jeopardize the integrity of ACIP’s recommendations.”
Most of the vaccinations given in this country are received by those younger than 2 years of age, so assuring the safety and efficacy of vaccines is paramount. Every year, more than 40 million vaccines are given to children younger than 1 year of age, usually between 2 and 6 months of age, Dr. Temte said. At this age, infants are at greatest risk for certain serious medical adverse events, including high fevers, seizures and sudden infant death syndrome, according to the U.S. Vaccine Adverse Event Reporting System. Therefore, it is important for the ACIP to consider carefully the risks versus the benefits before making a recommendation rather than be on a forced schedule that suits the manufacturer as opposed to the patient.
In addition, the ACIP is tasked with choosing the components of the annual influenza vaccination, which changes every year as the virus mutates throughout the season. Experts around the world track these mutations to predict which flu strains will be predominant in the following season. The ACIP makes recommendations about the strains to include in next year’s flu vaccination. Just under 1 million U.S. infants, children and adults received the influenza vaccine during the 2012-2013 flu season.
Every situation surrounding a recommendation is different, Dr. Temte said. For instance, the pneumococcal conjugate vaccine (Prevnar 13, Pfizer) is recommended to protect against pneumococcal disease. The vaccine has been indicated for children for some time, but received a new indication for adults older than 50 years of age in December 2011.
The vaccine received accelerated approval by the FDA for the adult indication without clinical data to show efficacy in adults. Those data did not come until the company conducted a postlicensure trial involving 84,000 individuals. It was almost two years after the new indication was granted before the ACIP had the safety and efficacy data to make a good recommendation about the vaccine.
“I’d like to get some explanation about how we can compress the acquiring of information into a very limited time frame,” Dr. Temte said.
Another example was Sanofi’s high-dose influenza vaccine for seniors. The company had every intention of doing a postlicensure study in a large group of seniors, but that flu season was pretty mild and there were little data—for another year—for which the ACIP could base its recommendation.
Other recommendations can be quite rapid, Dr. Temte noted. In the case of the meningococcal B vaccines, they received a category A recommendation for a limited high-risk population right after they were approved.
“Sometimes, the ACIP can be quite fast,” he said. “At other times, we require more information to make a good recommendation, and that more information could be issues dealing with safety; it could be clinical efficacy. The process really does involve having good information.”
In addition, the bill takes exception to the grading recommendations that the ACIP uses and wants the Centers for Disease Control and Prevention to conduct a review of the process to ensure it is consistent. The ACIP uses the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to review and analyze scientific data, Dr. Temte said. “GRADE was brought in to have a well-accepted, uniform and very transparent methodology for making recommendations,” he said.
“There are individuals who do not like the GRADE, but I think the problem is that people do not understand it. The legislation talks about grading economic, as well as scientific, evidence. We have not applied GRADE to economic data,” he said. The GRADE system classifies the scientific evidence that supports a recommendation, he explained. For example, low-quality evidence would be expert opinion; high-quality evidence would be a randomized clinical trial. However, the ACIP considers all the evidence, he said.
When the ACIP made the recommendation for the meningococcal B vaccine, it received a category B recommendation, which meant that the ACIP recommended the vaccine “for anyone for whom the clinician and the patient, through discussion, determined it was appropriate.”
He explained: “That’s a little cumbersome, but it is a recommendation for individual clinical decision-making, not for universal use.”
When making the recommendation, the ACIP not only considered all the science, but also heard from many individuals and associations that provided anecdotal evidence, personal history, values and preferences before making a recommendation. “That is part and parcel of what we do,” Dr. Temte said. “I think it is very important that our stakeholders and the American public know that we take safety as a paramount issue in terms of vaccines. I think the ACIP does a very good job of coming up with good recommendations on a timely basis,” he said.
The antibiotic proposals will help expedite the development and availability of much needed antimicrobials, IDSA’s Ms. Jezek said. “We have a lot more positive things to say about these provisions [than the vaccine proposal],” she said.
The IDSA and others said that the bill will complement the president’s National Action Plan for Combating Antibiotic-Resistant Bacteria that was released earlier this year, which calls for increased investing in research and development, as well as antibiotic stewardship and surveillance to reduce resistance.
“One of the biggest challenges that we are seeing—the greatest unmet need—are for serious life-threatening infections that are still occurring in a relatively small number of patients,” Ms. Jezek said.
Because the number of patients is small, it is difficult to hold large, clinical trials. Therefore, using nonclinical susceptibility and pharmacokinetic data, which the 21st Century Cares Act supports, is important. However, under Cures, new antibiotics would still need data from human clinical trials in order to be approved by the FDA. The bill just allows the trials to have fewer patients, which is important because that is all that is feasible.
Elizabeth Jungman, the director of public health programs at The Pew Charitable Trusts, reiterated the need for new and better antimicrobials. “With infections, if you stand still you lose ground,” she said. “So, there is this constant arms race between the ability to develop new drugs and the bugs’ ability to develop resistance to them.
“We need a robust pipeline.”
She said that on the one hand, there is a 30-year gap in the development of new classes of antibiotics, and many companies have pulled away from this area of new drug development, and on the other, infectious disease physicians with a number of patients who have no options. “We are particularly concerned about the need for antibiotics to treat resistant infections,” Ms. Jungman said.
There is concern that the accelerated antibiotic development pathway will lead to an increase in medication safety errors, according to Thomas J. Moore, a senior scientist of Drug Safety and Policy at the Institute for Safe Medication Practices, in Horsham, Pa., and lecturer in the Department of Epidemiology and Biostatistics at The George Washington University, Milken Institute School of Public Health in Washington, D.C.
However, Ms. Jezek said that the new antimicrobials will be indicated and labeled for a small, specific group. In addition, the use of the drugs will be closely monitored by the Department of Health and Human Services.
“The FDA provided a lot of technical assistance for the development of this particular piece of the bill,” Ms. Jezek said.
“The issue of antibiotic resistance includes the need to develop new drugs as well as to appropriately steward these resources,” said Ms. Jungman.