Letter to Dr. Janet Woodcock (FDA), expressing concern about the Anti-Infective Drugs Advisory Committee (AIDAC) meetingts regarding clinical trial designs for antibiotic treatments for community-acquired pneumonia (CAP)

May 12, 2008

Dr. Janet Woodcock, Director,
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Parklawn Building
5600 Fishers Lane
Rockville, MD  20857
Via Fax: (301) 847-8752

Dear Dr. Woodcock:

The undersigned members of the Patient and Consumer Coalition write to express our concerns about the April 1 and 2 meetings of the Anti-Infective Drugs Advisory Committee (AIDAC) regarding clinical trial designs for antibiotic treatments for community-acquired pneumonia (CAP).

Pneumonia is the seventh leading cause of death in the U.S.[1] At least 4 million cases of CAP occur annually in this country.[2] Approximately 5-10% of all children under 5 years-old in developing countries suffer from pneumonia each year.[3] Nearly one-third of seriously ill people who contact the disease die from it.[4] The annual health care cost of CAP is estimated at nearly $10 billion.[5]

The FDA must respond to the gravity of CAP.  One critical strategy is to ensure that clinical trials for antibiotics to treat CAP are based on not only a solid scientific method but, equally as important, evidence that will provide patients and clinicians with accurate information to make informed decisions.

Antibiotics are effective in decreasing mortality in pneumonia in older, sicker patients and those who have bacteria in their blood regardless of age.  Antibiotics are also effective in decreasing deaths in younger populations.  Nevertheless, conducting a valid non-inferiority trial in a younger population is not the most appropriate approach.  Younger populations experience smaller differences between antibiotics and placebos.  This clinically relevant reality challenges the validity of conducting non-inferiority trials in this population.[6]

Clinical trials on CAP should focus on the population with documented disease and the population more likely to have the serious form of the illness, such as infants under one year-old and adults over 50 years of age.  However, the prescription drug industry wants to study antibiotics in non-inferiority trials in healthy 18 year-olds.  This could lead to approval of potentially ineffective antibiotics when those antibiotics are studied in non-inferiority trials.  Approval of ineffective antibiotics can lead to unwarranted adverse events without benefit to patients.  Ineffective antibiotics can also lead to increasing antibiotic resistance, which is a real and growing public health crisis that the FDA acknowledges is “due largely to the increasing use of antibiotics.”[7]

The Patient and Consumer Coalition is concerned that the pharmaceutical industry is promoting use of inappropriately designed and analyzed non-inferiority trials to obtain FDA approval for new antibiotics to treat CAP.  A new drug might be deemed adequate in a non-inferiority trial, and yet be less effective than older drugs that are already available and have an established safety record.  Moreover, at the Advisory Committee meeting, industry representatives stated that current drugs cannot demonstrate superiority to older drugs.  This seems inconsistent with the idea that older drugs are no longer effective due to the increase in antibiotic resistance.

Patients need more effective antibiotics; they should not pay more for a new antibiotic that is less effective or less safe than older, less expensive antibiotics on the market,  That it why the use of non-inferiority trials harms rather than helps patients.

Instead of only non-inferiority trials, FDA should also ask sponsors for superiority trials for new antibiotics to treat CAP caused by resistance pathogens.  Superiority trials would be more fair to both patients and research subjects.  Otherwise, research subjects might be exposed to potential risks in non-inferiority trials of antibiotics that researchers conclude “are not as credible as those from a superiority trial.”[8] And, ultimate, patients will be spending more for less effective medications.

Endpoint standards in CAP trials also need to be improved.  The current endpoint standard in CAP trials is based on clinician judgment that the subject is better. This is an imprecise and unclear endpoint.  Industry-proposed endpoints, such as the product “reduces fever,” are inadequate because they do not address all the important outcomes that matter to patients.   Since antibiotics to treat CAP are supposed to be life-saving drugs, one endpoint should be mortality.  Quite simply:  Do the new antibiotics reduce deaths from CAP?  FDA should help develop other endpoints for CAP trials such as resolution of patients’ symptoms, but currently there is no basis for these endpoints in non-inferiority trials.

The AIDAC meeting was disappointing, because almost all of those testifying were from the pharmaceutical industry, and their views dominated the meeting.  In addition, several of the clinicians participating seemed to have a very limited understanding of the questions that FDA was posing.  Unfortunately, the pharmaceutical industry said at the AIDAC meeting that it does not want to use mortality as an endpoint.  One industry representative cavalierly stated that endpoints do not have to be valid before their use in clinical trials.  This violates FDA regulations that require well-defined and reliable outcome measures in clinical trials for new drugs.

The bottom line: inappropriately designed non-inferiority trials that are incapable of separating effective from ineffective drugs and that have inappropriate endpoints are a huge step backwards to the FDA’s pre-1938 standards, where new drugs did not have to prove their safety and effectiveness.

The Patient and Consumer Coalition strongly urges that the FDA not approve antibiotics without credible proof of their effectiveness.  FDA should use solid, scientific rationales for conducting clinical trials for antibiotics to treat CAP.  If the FDA permits an inferior clinical trial alternative, patients will suffer more adverse reactions and antibiotic resistance will increase.

We specifically recommend that the FDA:

  • use appropriately designed non-inferiority trials based on data and with mortality as the endpoint and superiority trials for other endpoints;
  • seek more input from patients and patient and consumer groups; and
  • select members for AIDAC with appropriate expertise to address the questions about which FDA needs advice.


Center for Medical Consumers
Government Accountability Project
National Research Center for Women & Families
Our Bodies Ourselves
Title II Community AIDS National Network

For more information, contact Paul Brown, National Research Center for Women & Families and liaison for the Patient and Consumer Coalition, at (202) 223-4000 or at pb@center4research.org

1701 K St. NW, Ste 700, Washington, DC  20006

cc: Robert Temple, Director, Office of Medical Policy
Edward M. Cox, Director, Office of Antimicrobial Products
John K. Jenkins, Director, Office of New Drugs
Sandra L. Kweder, Deputy Director, Office of New Drugs

[1] National Vital Statistics Reports, Vol. 55, No. 10, March 15, 2007, Table C. Deaths and percentage of total deaths for 10 leading causes of death: United States, 2002-2003, http://www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_10.pdf.

[2] Harrison’s Practice  (McGraw Hill), http://www.harrisonspractice.com/practice/ub/view/Harrison’s_Practice/Community-Acquired_Pneumonia/141119/0.

[3] Center for Disease Control and Prevention, Pneumonia Among Children in Developing Countries, http://www.cdc.gov/ncidod/dbmd/diseaseinfo/pneumchilddevcount_t.htm.

[4] Fine MJ, Auble TE, Yealy DM et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia. New England Journal of Medicine 1997;336:243-50.

[5] Harrison’s Practice  (McGraw Hill), http://www.harrisonspractice.com/practice/ub/view/Harrison’s_Practice/Community-Acquired_Pneumonia/141119/0.

[6] Dowling HF, Lepper MH. The effect of antibiotics on the fatality rate and incidence of complications in pneumococcic pneumonia. American Journal of the Medical Sciences 1951;222:396-403.

[7] U.S. Food and Drug Administration, “Facts About Antibiotic Resistance,” http://www.fda.gov/oc/opacom/hottopics/antiresist_facts.html.

[8] Steven M. Snapinn, Merck Research Laboratories, PubMed Central, “Noninferiority trials,” http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=59590.