July 30, 2013
Docket No. FDA-2013-N-0556
As members of the Patient, Consumer, and Public Health Coalition, we recognize the need for new drugs to reach patients with serious or life-threatening diseases. The pipeline for new antibacterial drugs is shrinking. However, we have grave concerns about proposals to change the standards for meeting FDA’s requirement of two “adequate and well controlled” trials. While the draft guidelines developed by FDA for bacterial indications clearly outline appropriate ways to test new antibacterial drugs, a review of those that have been considered in the past 10 years reveals that the clinical trials that are performed do not adequately measure efficacy. Unfortunately, physicians, patients, and reviewers are left with incomplete information about when it is appropriate and safe to use these new antibacterial drugs. If this trend continues, using new antibiotics will increase the problem of antibiotic resistance and leave us with a pool of ineffective drugs.
Study Design Considerations
One commonly cited reason for the low development of new antibiotics is the cost associated with conducting large clinical trials. This misses the point: large, phase III trials are often ineffective at measuring the efficacy of new antibiotics. Our own research evaluating the recent drug trials for new antibacterials show efficacy differences between experimental drugs and controls are close to zero. We believe that this is because larger trials do not target the patients that have susceptible organisms and disease for which a new drug is intended. Without clear benefits, it would be unethical to expose patients to unnecessary risks from these drugs. Clinical trials targeted to patients that most need new antibiotics would greatly reduce the number of patients needed per study, would mean that studies are more sensitive to changes in efficacy, and would not expose patients to unnecessary harm.
Another critical component of trial design for antibiotics is the choice of efficacy outcome measures. Suggestions have been made that using surrogate markers of disease or pharmacokinetic measurements are appropriate. Of the new antibacterial drugs reviewed in the past 10 years, 85% used clinical response as an endpoint.[i] This is an arbitrary measurement based on a physician’s (or sponsor’s) subjective judgment. These types of surrogate endpoints fail to reflect patient outcomes of mortality and morbidity, which are the most important reasons for developing new antibacterial drugs. If patients are dying from infections, new antibiotics should save their lives. If they die because of other comorbidities, then FDA should make drug development in those arenas a higher priority than antibacterials. Surrogate endpoints that are affected by antibiotics in the same way that survival and morbidity are affected could be appropriate[ii] but these are often difficult to identify because the mechanisms influencing efficacy and the relationship between microbial measurements and patient survival are not clear.
Finally, because the goal is to support development of new antibiotics to replace older ones which are not working well, all new antibiotics should be superior to ones to which resistance is developing. Why consider a new drug that works no worse than one that “doesn’t work”? That mindset only puts patients at risk for side effects without any hope of getting better.
Guidance for Bacterial Indications
The current guidance documents published by the FDA concerning trials for priority infections are well written and clearly outline appropriate ways to test new antibiotics.[iii] If these were finalized and NDAs were required to meet these guidances, patients and medical professionals could be assured of the rigorous standards to which new drugs were tested prior to being marketed. FDA should, however, avoid any changes to draft guidance that potentially lower safety and efficacy standards. FDA approvals should still be based on adequate and well-controlled trials.
We need to better preserve antibiotics as effective therapeutics. Strategies such as labeling antibiotics to ensure compliance with indications have not worked well. We need stronger support for stewardship in medical practice and for reporting and measuring rates and sources of antibiotic resistance.
One problem with appropriate use of antibiotics is that medical professionals (and researchers) lack the diagnostic capabilities to quickly identify patients who would benefit from a new antibiotic. Incorporating R&D on diagnostic tools into antibacterial NDAs would be a way to get these new tools, which could in turn benefit those designing clinical trials: the better a target population can be identified, the fewer patients a trial needs to enroll.
Development of less effective new antibiotics will increase, not decrease, the problem of drug resistance, both to the new drug and co-resistance to existing therapeutics.[iv] Unless new antibiotics clearly show a survival benefit to patients, the FDA should not consider approval. Otherwise, efforts to stimulate antibacterial drug development will exacerbate the problem we all are trying to address—growing antibiotic resistance.
There is clear evidence that the incentives FDA is considering to foster antibiotic development will put patients at risk and contribute to the problem of antibiotic resistance. New approaches to drug development should not provide less information about how well these antibiotics work, how safe they are, and how they compare to current products. This knowledge is critical for understanding when these antibiotics should be used. The burden of proof should be put on the manufacturers not on the FDA, physicians, or consumers. We agree that new antibiotics are needed, but these need to be high quality products, proven to significantly improve quality of life or survival. Antibiotics that are less safe or less effective than those currently available will not help vulnerable patients and will do little to address the need for new therapeutics.
American Medical Student Association
Annie Appleseed Project
Center for Science and Democracy at the Union of Concerned Scientists
Connecticut Center for Patient Safety
National Research Center for Women & Families
For more information, contact Paul Brown at firstname.lastname@example.org or (202) 223-4000.
[i] Yttri, J., Field, E., and Powers, J. Systematic Review of Antibacterial Drugs Reviewed by FDA from 2002-2012. unpublished findings.
[ii] Fleming and DeMets. Surrogate End Points in Clinical Trials: Are We Being Misled? Ann Intern Med. 1996;125(7):605-613.
[iii] US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry. FDA website [online].
[iv] Powers, J., Phoenix, J., and Zuckerman, D. Antibiotic Uses and Challenges — A Comprehensive Review From NRCWF. Medscape. Jun 16, 2010.