Statement from Dr. Jennifer Yttri, senior fellow, at the FDA Public Hearing Establishing a List of Qualifying Pathogens for the GAIN Act

Statement from Dr. Jennifer Yttri

December 18, 2012

I am Dr. Jennifer Yttri and I thank you for the opportunity to speak today on behalf of the National Research Center for Women & Families. Our organization does not accept funding from drug manufacturers and therefore I have no conflict of interest.

Our nonprofit research center includes scientists and medical and public health experts who analyze and review research on a range of health issues. I have a doctorate in immunology from Washington University in St. Louis. In addition to conducting research and publishing our findings in medical journals, we provide objective and understandable information to patients, health care providers, and policy makers through briefings, CMEs, testimony, and other materials and formats.

We have great respect for the FDA, and that’s why our center’s president, Dr. Diana Zuckerman, is on the Board of Directors of 2 nonprofit organizations focused on providing additional resources to the FDA: the Alliance for a Stronger FDA and the Congressionally mandated Reagan Udall Foundation.

The growing risk of antibiotic resistant pathogens and need for development and responsible use of new antibiotics are critical public health concerns that need to be addressed.

There are high-risk patients whose lives depend on effective antibiotics that will help them survive diseases due to multi-drug resistant pathogens. These patients are older, have taken multiple prior antibiotics, and have other health complications. These very sick patients have life-threatening infections and need safe and effective options which clearly decrease mortality in clinical trials.

Antibiotic resistance should be defined by outcomes in patients, such as increased mortality and irreversible morbidity. Often the level of resistance is measured solely by what happens in a test tube. While it is easiest to measure how much drug it takes to inhibit growth of organisms in culture, reliance on bacterial culture or animal models alone loses sight of the real purpose behind these drugs: to help patients feel better, function, and survive. Emphasis should be placed on the patient, not test tube results, when determining which pathogens have a major impact on patient health and which antimicrobials are effective against disease.

For implementation of the GAIN act, determining which pathogens are “qualifying” should be based on which pathogens are actually causing serious and life-threatening disease in these very sick patients who have no other options. So what should the FDA consider in making a pathogen list? Look to your own guidelines.

The FDA’s own regulations (21 CFR Section 312.81) logically states that eligible new drug and biological products for fast track designation and accelerated approval must be for “Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.” By this regulation, the rate of mortality and morbidity in humans needs to be the first and foremost consideration when determining pathogens that pose a serious threat to public health.

Priority pathogens should be defined based on clinical relevance to patients: which are the pathogens CAUSING high rates of death in serious and life threatening disease and in which patients does death occur due to the disease? New qualified infectious disease products are meant to improve the survival of these high risk patients. If these patients are dying for “other reasons,” then the infection isn’t life-threatening, a new drug won’t prolong life, and that pathogen should not be included on the qualifying list. If the infection is life-threatening, drugs need to improve survival in the very sick patient population. The drugs should not be studied in the wider population of patients who are different from those in whom the drugs are intended to be used or who have non-life threatening infection. The drugs need to save lives.

As this list of qualifying pathogens also determines which new drugs are eligible for priority review and fast-track status, the FDA also has the responsibility to ensure that drug trials are performed to show the benefit in survival of very sick patients. By focusing only on which pathogens are involved, we lose sight of the patients. The FDA should require any clinical trial associated with an anti-infective drug for serious and life threatening disease, especially if applying for the added incentives outlined in the GAIN act, to be studied in the right patient population with mortality as the required primary end point.

This is even more important when you consider the last 3 drugs studied for Ventillator Acquired Pneumonia: all 3 had higher mortality than older drugs. New drugs can be worse than old drugs in terms of mortality. Tigecycline was approved because it was active against resistant pathogens in a test tube yet it has higher mortality in exactly the same types of patients whose disease is caused by drug resistant pathogens.

The FDA itself has issued a public health warning regarding tigecycline, yet it is exactly this kind of drug that might qualify for GAIN exclusivity if we focus on organisms alone. When the drug trial data focuses on “minimum inhibitory concentration” test as a predictor of outcome and ignores patient factors, the claim “it is better than nothing” falls apart for lack of evidence since the drug was not studied in these patients. It doesn’t matter if these drugs reduce bacterial growth: the focus needs to be on improvement of patient health. These drugs are failing to save the lives of the intended, treatable population of patients.

One other consideration: in a 2002 review of common risk factors for infection of patients with multidrug resistant pathogens, heavy exposure to antimicrobial drugs was one of the top factors. By considering only the pathogens, priority review of drugs may be exacerbating the drug resistance problem rather than alleviating the impact on public health. The FDA needs to focus on improving patient health rather than reducing bacterial burden alone. Due to the lack of diagnostics, new antibiotics are being widely promoted and used for patients that do not need them. The use of antibiotics in patients without identified infections or with infections in which a new drug is not shown to be safe and effective does more harm than good. There is no benefit of a new antibiotic in these patients and the inappropriate exposure is setting up conditions for increased bacterial resistance. Smart use of current antibiotics will do more to benefit patients and limit antibiotic resistance than expedited review of new drugs. The current paradigm of prescribing antibiotics for “suspected” infections is not sustainable and contributes to the very problem we are trying to address.

As you consider how to generate a list of qualifying pathogens for the GAIN act, remember MRSA defined in a test tube does not kill patients. MRSA VAP acquired in the hospital does. The only way to consistently, and reliably, measure benefit to patients is to measure survival. By limiting qualifying pathogens to those that cause a high rate of death, the FDA can ensure development of anti-infectives of critical need without sacrificing the safety of everyone else who will benefit more from responsible use of older drugs. Without the appropriate studies focused on patient centered outcomes, the GAIN act will fail to live up to the goal of saving the lives of critically ill patients.

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