US Capitol Capsule: IOM analysis finds little evidence of vaccine harm, debunks autism link

In the midst of the US focused last week on disaster preparedness – with an earthquake rattling the nation's capital, followed by a hurricane ravaging much of the East Coast – a new report from the Institute of Medicine (IOM) again brought attention to the havoc communicable diseases also can wreak, especially when parents fail to have their children vaccinated.

But while the proliferation of vaccines has lessened the susceptibility of infectious diseases, the shots also have come under fire for causing serious harm – most notably, accusations of a link between the measles-mumps-rubella (MMR) vaccine and autism.

But after analyzing 22 research articles – part of a broader review of more than 1,000 studies – an IOM committee again debunked the claims that the MMR shot causes autism.

"The committee has a high degree of confidence in the epidemiologic evidence" based on the studies that there is a "null association" between the MMR vaccine and autism, the experts concluded. "The evidence favours rejection of a causal relationship between MMR vaccine and autism," they added.

The notion that the MMR vaccine was behind the surge in autism cases first gained steam when UK researcher Dr Andrew Wakefield and his colleagues published a study in the Lancet in 1998, which linked the disease to the immunization in children. The Lancet, however, retracted the article last year, and Dr Wakefield was later struck off the UK medical register for serious professional misconduct (scripintelligence, 25 May 2010).

While the IOM committee cleared the MMR vaccine of any links to autism, it did, however, conclude that the evidence convincingly supported a causal relationship with the immunization and febrile seizures, a type of seizure that occurs in infants and young children in association with a fever. The panel could not, however, make that same conclusion about afebrile seizures.

The committee also said the evidence sustained a causal link between the MMR vaccine and measles inclusion body encephalitis, which in very rare cases can affect people whose immune systems are compromised and usually occurs within a year of acute measles infection or vaccination.

But the IOM experts said the evidence was inadequate to accept or reject a causal association between the vaccine and encephalitis or encephalopathy.

While the IOM's literature review, which involved research about the MMR, varicella zoster, influenza, hepatitis A and B, meningococcal, human papillomavirus and the tetanus-toxoid vaccines, found no autism link, it did, however, reveal some other rare adverse events.

In a minority of patients, the varicella vaccine against chickenpox induced brain swelling, pneumonia, hepatitis, meningitis, shingles and chickenpox in immune-compromised patients but also in some who had competent immune function, the IOM reported.

But the analysis deflated claims that flu shots cause Bell's palsy or exacerbate asthma. The committee also said the evidence showed no link between the tetanus or MMR vaccines and Type I diabetes.

Overall, the panelists determined that the eight vaccines involved in the analysis were generally safe.

"The findings should be reassuring to parents that few health problems are clearly connected to immunizations, and these effects occur relatively rarely," said Ellen Wright Clayton, director of the Center for Biomedical Ethics and Society at Vanderbilt University in Nashville, who served as the IOM panel chairwoman.

The IOM's analysis was requested by the US Health Resources and Services Administration, which sought a review of the epidemiologic, clinical and biological evidence of adverse events linked to the vaccines covered by the US National Vaccine Injury Compensation Program (VICP), a no-fault compensation programme created to protect vaccine makers against large judgments that could put companies out of business, while providing compensation to those who are injured from vaccines.

The IOM said its report's findings could be useful to all stakeholders involved in decisions for VICP awards, which are paid out of a fund created by an excise tax on each vaccine dose.

Under the VICP, manufacturers enjoy significant tort-liability protections. The law provides that a party alleging a vaccine-related injury may file a petition for compensation in the court of federal claims, naming the Health and Human Services secretary as the respondent. The vaccine court must resolve the case by a specified deadline. The claimant can then decide whether to accept the court's judgment or reject it and seek tort relief from the vaccine manufacturer.

Last February, the US Supreme Court in a 6-2 decision upheld rulings from lower courts that the National Childhood Vaccine Injury Act of 1986, which created the VICP, preempts all design-defect claims against manufacturers brought by plaintiffs in court cases seeking compensation for injury or death caused by vaccines outside the government programme (scripintelligence, 22 February 2011).

Super Congress takes flight

Although the House and Senate have been in recess since early August, the 12 members of the so-called "Super Congress" have been holding conference calls over the past few weeks, Representative Fred Upton (Republican-Michigan) revealed last week.

The special panel of lawmakers is charged with finding at least $1.2 trillion and up to $1.5 trillion in additional cuts beyond the $917 billion in initial reductions enacted by President Obama on 2 August under the debt ceiling bill, known as the Budget Control Act Amendment of 2011 (scripintelligence, 8 August 2011, 15 August 2011).

The Super Congress is under a 23 November deadline to submit its recommendations to Congress for the cuts, with Medicare, Medicaid and other health care spending expected to be in the crosshairs (scripintelligence, 18 July 2011).

Mr Upton said the committee plans to hold at least one public hearing, although much of the deliberations are expected to be behind closed doors.

FDA tests 'mini me' Sentinel network

The US FDA last week said it has taken the first step towards building its Sentinel system – a nationwide electronic medical product safety network – by launching its "Mini-Sentinel" pilot programme.

The Sentinel network, launched under a 2008 initiative, is a collaborative project between government agencies and the private sector aimed at using existing and planned databases to track, collect and analyze adverse event reports about drugs, vaccines and medical devices.

The FDA said the Sentinel system will help it actively query diverse automated health care data holders, such as electronic health record systems, administrative and insurance claims databases and registries, to evaluate possible medical product safety issues quickly and securely.

The Sentinel network, which is being developed and implemented in stages, is envisioned to be a system in which data would continue to be managed by its owners, with questions sent to the participating data holders, who would evaluate their information and send summary results to the FDA. The system is expected to give scientists the ability to get responses to their questions in a matter of weeks versus the several months it usually takes using traditional surveillance methods, the agency said.

Regulators said the Mini-Sentinel pilot is providing the agency with a working laboratory for developing and evaluating scientific methods that might be used in its planned fully-operational system and is expected to help the FDA identify the barriers and challenges in building a viable and accurate system for monitoring regulated medical products.

With 17 data partners across the US and data encompassing nearly 100 million patients, the FDA said the pilot, which took two years to develop, is "not so mini".

Indeed, the pilot also includes information on 2.9 billion prescription drug dispensings and 2.4 billion unique medical encounters, including 38 million acute inpatient hospital stays, regulators said.

FDA issues neglected tropical disease drug guidelines

The FDA last week issued a new draft guidance document intended to aid manufacturers developing drugs to treat or prevent neglected diseases of the developing world, such as malaria, dengue hemorrhagic fever, leishmaniasis and human African trypanosomiasis.

The document outlines the agency's expectations about clinical trial designs and clarifies the regulatory requirements for drug approval and internal review standards to support approval of drugs.

The FDA noted that adaptive clinical trial designs may be appropriate to consider for clinical studies of some neglected tropical diseases (NTDs) drugs.

"Clinical trials can be designed with adaptive features that may enhance the efficiency of the trial," the agency said.

For example, regulators said, the adaptive design might result in a shorter overall duration of the trial, a fewer number of patients enrolled or a greater likelihood of showing an effect of the drug if one exists.

But the FDA emphasized that drug makers considering adaptive trial designs should consult with the agency before starting those studies to seek regulators' advice.

The FDA noted that most of the supporting safety and efficacy data for drug development programmes for NTDs are likely to be generated from outside the US, and while US regulations permit the acceptance of foreign studies in support of approval not conducted under an investigational new drug application (IND), "we strongly encourage submission of an IND so that the development programme will be sufficient" to support future new drug or biologic license applications.

The FDA urged manufacturers interested in developing NTD drugs to seek the agency's feedback for proposed content of IND submissions.

Public Citizen petitions for strong PPI warnings

The US public consumer advocacy group Public Citizen asked FDA Commissioner Margaret Hamburg in a 23 August petition filed with the agency to require black-box warnings in the labeling of proton pump inhibitors (PPIs) used to treat gastroesophageal reflux disease, such as AstraZeneca's Nexium (esomeprazole) and Takeda's Prevacid (lansoprazole), alerting prescribers about the risks of rebound acid hypersecretion, fracture, serious infections and magnesium deficiency.

The group also wants the FDA to require other warnings in the labeling, including alerts about drug-drug interactions between PPIs and the heart-protective drug clopidogrel, the potential for vitamin B12 deficiency with long-term use and the possibility for patients to develop acute interstitial nephritis.