# Presentation: 854396

## Proposed guidance:   Clinical trials of empiric antibacterial therapy of febrile neutropenia (ETFN)

- Anti-infective Drug Products
-  Advisory Committee
- July 31, 1998
- David Ross, M.D., Ph.D.

## Outline

- Definition and endpoint issues
- Proposed criteria
- Questions for committee

## Evolution of regulatory definition

- “Immunocompromised patient”
- 
- “Febrile neutropenia”
- 
- Fever/neutropenia (FN)

## Clinical scenario I

- A 24 year old woman with Hodgkin’s disease, an ANC of 0, and a temperature of 39oC is enrolled in a trial of ETFN.  No infectious source is found.  She remains febrile and neutropenic; antibiotics are discontinued after 15 days.  The  patient defervesces two weeks later following bone marrow recovery.  Further chemotherapy results in complete disease remission.
**Is this patient evaluable for efficacy?**

## Clinical scenario II

- A 47 year old man with acute myelocytic leukemia develops fever while neutropenic. He is enrolled in an ETFN trial; study treatment leads to prompt defervescence. No infectious source is identified. Eight days into empiric therapy, the patient becomes febrile and hypotensive; multiple blood cultures grow vancomycin-resistant *Enterococcus faecium*. The patient’s antibiotic regimen is modified, but he dies from sepsis two days later.
**Is this patient evaluable for efficacy?**

## Clinical scenario III

- A 70 year old woman with stage IV rectal carcinoma, receiving irinotecan and 5-fluorouracil, presents with a temperature of 37.1oC while neutropenic. She is screened for an ETFN trial with a inclusion criterion for fever of 38.0oC and is mistakenly enrolled.  Blood cultures drawn at study entry grow *Pseudomonas aeruginosa*.  Repeat blood cultures at end of therapy are sterile and the patient is clinically well.
**Is this patient evaluable for efficacy?**

## Problems in defining disease state

- Fever is an imperfect marker for infection in neutropenic patients.
- Blood cultures are an imperfect marker for infection in neutropenic patients.
- Fever is frequently not associated with positive blood cultures.

## Spectrum of FN

- Microbiologically documented infection
-  MDI with bacteremia
-  MDI without bacteremia
- Clinically documented infection
- Fever of uncertain etiology (FUE)
- Non-infectious fever

## Problems in defining FN for trials

- Lack of consensus on:
- Study population
- Disease definition based on culture results

## Problems in defining FN endpoints

- Lack of consensus on:
- Duration of tx required for assessment
- 1° endpoint:  survival or defervescence?
- 2° endpoints
- bacterial or fungal super-infection
- new episodes of fever
- empiric addition of other anti-microbial agents.

## Different ETFN outcomes

- Outcome I - Resolution; no new infection with susceptible isolate
- Outcome II - Resolution; no new infection
- Outcome III - Survival

## Effect of different ETFN outcomes

- Elliott CR and Pater JL. Clin Invest Med 1988; **11:**327-330

## Trends in ETFN

- Shifts in microbiologic patterns
- Changes in empiric Abx coverage
- Increasing use of growth factors
- Outpatient treatment

## “ . . . the answer to the question, “Which events should be counted and which treatment should be blamed?”  depends on . . . the nature of the question posed.”

- Sackett, DL and Gent M. Controversy in counting and attributing events in clinical trials.  N Engl J Med 1979; **301:**1410.

- “ . . . the answer to the question, “Which events should be counted and which treatment should be blamed?”  depends on . . . the nature of the question posed.”

## Spectrum of FN

- Microbiologically documented infection
-  MDI with bacteremia
-  MDI without bacteremia
- Clinically documented infection
- Fever of uncertain etiology (FUE)
- Non-infectious fever

## Guidance framework for ETFN

- DAIDP Points to Consider
- Adequate, well-controlled multicenter trial
- Effectiveness in 3 specific deep infections
- IDSA guidelines
- study population
- allowable modifications
- endpoints and data analysis

**Notes:**
(24) Empiric Therapy in Febrile Neutropenic Patients

One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product or to a prospectively agreed upon therapeutic regimen is suggested. This trial should use rigorous prospective clinical, radiographic (as appropriate), and microbiologic entry criteria and evaluability criteria. 

Prior to approval for this entity, the compound should also have established effectiveness in at least three of the following infections: nosocomial pneumonia, complicated intra-abdominal infections, complicated urinary tract infections, complicated skin and skin structure and soft tissue infections, acute osteomyelitis, or acute bacterial arthritis. 

## Inclusion criteria

- Fever
- 38.0°C x 2, or 38.3°C x 1 (oral)
- Neutropenia
- ANC < 500 cells/μL within 48 h of entry
- Underlying cancer or recent chemotherapy

## Additional data

- Age
- Severity and depth of neutropenia
- Underlying disease and disease status
- Use of hematopoetic growth factors
- Presence of indwelling catheter
- Use of prophylactic ABx
- History and type of bone marrow Tx

## Exclusion criteria

- Abx within 72 hours of study entry
- Exception:  If oral ABx prophylaxis used
- Specify regimen prospectively
- Use same regimen for all patients
- Stratify prospectively
- Parenteral prophylaxis discouraged

## Additional exclusion criteria

- (HIV infection)
- Low risk syndromes
- Impending mortality
- Pathogen identified prior to entry

## Assessments

- History
- Relevant review of systems
- Physical examination
- BCx, other Cx as indicated
- CXR
- Other diagnostic tests as indicated

## Timing of Assessments

- Pre-therapy
- Initial efficacy assessment at 72 h
- Subsequent assessments
- Inpatient - daily
- Outpatient - discuss with division
- End of therapy assessment
- Test of cure at 7 days post-therapy

## Analysis considerations

- Blinded assessment
- ITT and per protocol analyses
- Consistent application of objective criteria
- Analyze all episodes and first episodes

## Evaluated populations

- All randomized patients
- MITT population
- (Exclusions based on pre-randomization characteristics)
- Per protocol population
- (Least heterogeneous population)

## MITT population

**	****All enrolled patients who:**
- receive at least one dose of study drug
- are febrile at entry
- are neutropenic within 2 d of entry
- do not have non-infectious fever

## Per protocol population

- MITT criteria
- At least seven days follow-up
- Original regimen given for 72 h; modified only for persistent or new symptoms
- If FUE, no anti-fungal, anti-viral, or anti-parasitic prior to defervescence
- Absence of nonbacterial infection at entry
- Death before TOC due to infection

## “It is optimal to use multiple parameters for the assessment of patients, including clinical response to therapy, evidence of microbiologic efficacy, and survival.”

- “It is optimal to use multiple parameters for the assessment of patients, including clinical response to therapy, evidence of microbiologic efficacy, and survival.”

- Hughes, WT *et al*. Evaluation of new anti-infective drugs for the
- treatment of febrile episodes in neutropenic patients.  Clin Inf Dis
- 1992; **15 (Suppl 1):**S206-15.

## Efficacy assessments

- Examination of different endpoints:
- Size of analyzed population kept constant
- ‘Success’ corresponds to specific goals:
- Survival
- Clinical and microbiologic response
- Need for Abx modification
- Effect of sequential IV-oral therapy

## Definitions of response

- I - 1° episode resolved without modification, no new febrile episodes or infection
- II - 1° episode resolved without modification
- III - Survival of infection, modification allowed

## Other study considerations

- Discuss with division in advance:
- Comparator
- Treatment modifications
- Use of oral Abx to complete therapy
- Outpatient treatment
- Planned* *subgroup analyses

## Questions for committee

- Are these entry criteria appropriate for study of ETFN?
- How should protocols incorporate
- Different analyses?
- Different endpoints?