Food and Drug Administration

**Center for Drug Evaluation and Research**

# **Anti-Infective Drugs Advisory Committee**

Summary Minutes of the October 16, 2001 Meeting Discussing

Biologic License Application (BLA) 125029

Xigris™ (drotrecogin alfa (activated)), Eli Lilly and Company

## **Members Present Consultants**

L. Barth Reller, M.D. Thomas Fleming, Ph. D.

Alan S. Cross, M.D. Joseph A. Carcillo, M.D.

Joan P. Chesney, M.D. Peter Eichacker, M.D.

Celia Christie‑Samuels, M.D. Craig M. Lilly, M.D.

Steve Ebert, Pharm, D. Robert Munford, M.D.

Gordon L. Archer, M.D. W. Michael O\'Fallon, Ph.D.

Barbara E. Murray, M.D. Leo C. Rotello, M.D.,

James E. Leggett, Jr., M.D. Anthony Suffredini M.D.

Ellen R. Wald, M.D. H. Shaw Warren, M.D.

Julio Ramirez, M.D.

Murray Wittner, M.D.

###### FDA Participants

Jay Siegel, M.D.

Karen Weiss, M.D.

Gibbes Johnson, Ph.D.

Robert Lindblad, M.D.

Lynda Forsyth, M.D.

These summary minutes for the October 16, 2001 meeting of the
AntiInfective Drugs Advisory Committee were approved on October 26,
2001.

I certify that I attended the October 16, 2001 meeting of the
AntiInfective Drugs Advisory Committee and that these minutes accurately
reflect what transpired.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Thomas H. Perez, M.P.H., R.Ph. L. Barth Reller, M.D.

Executive Secretary Chair

> This report contains public information that has not been reviewed by
> the agency or AntiInfective Drugs Advisory Committee. The official
> summary minutes will be prepared, circulated, and certified as usual.
> Transcripts will be available in about 12 days. External requests
> should be submitted to the Freedom of Information office.

The AntiInfective Drugs Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research met on October
16, 2001 at the Hilton Gaithersburg, 620 Perry Parkway, Gaithersburg, MD
20877

The committee considered the safety and efficacy of Activated Protein C
(human, recombinant, human kidney cells, new biologic license
application (BLA) 125029), Eli Lilly & Company, for the treatment of
severe sepsis.

The Committee had received a briefing document from the FDA and a
background document from Eli Lilly.

There were approximately 300 persons present at the meeting. The meeting
was called to order at 8:30 am. by the Chair, Barth Reller, M.D. Thomas
H. Perez, Executive Secretary of the AntiInfective Drugs Advisory
Committee read the Meeting Statement. The Committee members and
discussants introduced themselves. Gibbes Johnson, Chair, FDA Review
Team, provided opening comments.

At approximately 9:00, representatives of Eli Lilly began their
presentation including the following topics and presenters:

> **Introduction** -- Holger Schilske, M.D., Ph.D., Executive Director,
> Eli Lilly and Company\
> **Pathophysiology of Severe Sepsis** **-- Rationale for Drotrecogin
> Alfa (activated)**\
> Steven Opal, M.D., Chief Infectious Disease Division Brown University
> School of Medicine\
> **Efficacy and Safety of Drotrecogin Alfa (activated) in the Treatment
> of Severe Sepsis**\
> William Macias, M.D., Ph.D., Medical Director, Eli Lilly and Company\
> **Benefit-Risk Assessment** **of Drotrecogin Alfa (activated) in the
> Treatment of Severe Sepsis**\
> Jeffrey Helterbrand, Ph.D., Senior Statistical Scientist, Eli Lilly
> and Company\
> **Clinical Experience in** **Pediatric Patients with Severe Sepsis and
> Overall Conclusions**\
> William Macias, M.D., Ph.D., Medical Director, Eli Lilly and Company

FDA's presentation began at 11:30 and included the following topics and
presenters:

> **Summary of Efficacy**
>
> Linda Forsyth, M.D., Medical Officer, Center for Biologics Evaluation
> and Research, FDA

##### Pediatric Data and Summary of Adult Safety

> Robert Lindblad, M.D.**,** Medical Officer, CBER, FDA

The Open Public Hearing portion of the meeting began at 2 p.m. with the
following five participants providing a statement for the record.

> William Lyons, M.D. (*Representing Self)*
>
> Edward Wiginton, Meningitis Foundation of America
>
> Alvin Lever, M.A., American College of Chest Physicians
>
> Curtis Sessler, M.D., American College of Chest Physicians
>
> Thomas Smirniotopoulos M.D., (*Representing Self)*

The Committee began discussion of the questions and vote portion of the
meeting at 4:00 with the following questions.

Questions for AIDAC - Drotrecogin alfa (activated) for the treatment of
severe sepsis

**I. Patient Entry Criteria**

Data supporting the efficacy of drotrecogin alfa (activated) were
derived from a single phase 3 randomized, placebo controlled trial of
nearly 1700 adult patients with severe sepsis. Treatment with
drotrecogin alfa (activated) resulted in a significant reduction in 28
day all cause mortality compare to placebo treated patients (25% vs 31%,
respectively, p= 0.005). Eligibility required meeting three or more SIRS
criteria, at least one of five organ failure criteria, and with evidence
of infection. Midway through the trial, the eligibility criteria were
modified to more clearly exclude patients who had a high probability of
dying from an underlying non-sepsis related condition within the 28-day
study period. As a result of the modifications, fewer patients with
malignancy, chronic APACHE II health points, who were immunocompromised,
etc. were enrolled.

1.  Please comment on the entry criteria, and the implications of the
    modified criteria. Do the entry criteria define a population
    appropriately described as having severe sepsis?

> **The panel discussed this question and generally felt that the
> definitions were reasonable, but that the population studied after
> modifications was narrow. Many concerns were voiced including,
> difficulty in establishing criteria for patients that might benefit
> from the therapy, broad exclusion criteria, the combining of the two
> studies, why there was a difference between them, and how to asses the
> changes between the two groups.**

**II. Treatment effect in subgroups defined by disease severity**

The reduction in mortality was not consistent across all prospectively
defined patient subgroups. The data suggest there may be a different
mortality effect in less severely ill patients with better survival
prognosis. Mortality in patients in the lowest APACHE II quartile was
higher in the drotrecogin alfa (activated) group compared to placebo
patients, and a smaller treatment benefit was observed in those in the
second APACHE II quartile compared to patients who were in the 3^rd^ and
4^th^ APACHE II quartiles as shown in the table and figure below.

+-----------+-------+-------+-------+---------+---------+----------+
| **APACHE  | rhAPC |       | Pl    |         | R       | 95% CI   |
| II        | (850) |       | acebo |         | elative |          |
| Q         |       |       | (840) |         | Risk    | for RR   |
| uartile** | Total |       |       |         | (RR)    |          |
|           | N N   |       | Total |         |         |          |
| **        | (%)   |       | N N   |         |         |          |
| (score)** |       |       | (%)   |         |         |          |
+-----------+-------+-------+-------+---------+---------+----------+
| **1       | 218   | 33    | 215   | 26 (12) | 1.25    | 0.78,    |
| ^st\ ^**\ |       | (15)  |       |         |         | 2.02     |
| (3-19)    |       |       |       |         |         |          |
+-----------+-------+-------+-------+---------+---------+----------+
| **2^nd^** | 218   | 49    | 222   | 57 (26) | 0.88    | 0.63,    |
|           |       | (22)  |       |         |         | 1.22     |
| (20-24)   |       |       |       |         |         |          |
+-----------+-------+-------+-------+---------+---------+----------+
| **3^rd^** | 204   | 48    | 162   | 58 (36) | 0.66    | 0.48,    |
|           |       | (24)  |       |         |         | 0.91     |
| (25-29)   |       |       |       |         |         |          |
+-----------+-------+-------+-------+---------+---------+----------+
| **4^th^** | 210   | 80    | 241   | 118     | 0.78    | 0.65,    |
|           |       | (38)  |       | (49)    |         | 0.96     |
| (30-53)   |       |       |       |         |         |          |
+-----------+-------+-------+-------+---------+---------+----------+

![](media/image1.wmf){width="4.8in" height="2.7in"}

2.  Please comment on the implications of the analysis of treatment
    effect and disease severity (i.e., mortality by APACHE II quartile
    subgroup analysis). Should the sponsor conduct further controlled
    studies of the effects of drotrecogin alfa (activated) in patients
    with severe sepsis and more favorable prognosis (e.g., lower APACHE
    II scores)?

> **Vote: Yes 14 No 6**
>
> **The committee member's responses provided many comments qualifying
> their votes. The complete details of the responses are recorded on the
> meeting transcripts to which those interested are referred.**

3.  If licensed, should the indication for drotrecogin alfa (activated)
    be limited to the subset of patients with severe sepsis who have a
    poorer prognosis?

> **Vote: Yes 13 No 7**
>
> **The complete details of the responses to question 3 and its subparts
> are recorded on the meeting transcripts to which those interested are
> referred.**

a.  If so, how might the indicated population be described?

b.  If not, will an indication for severe sepsis without such
    limitations adversely impact the ability to conduct a placebo
    controlled trial in the population with less poor prognosis?

**III. Treatment effect in patients with disseminated intravascular
coagulation**

Drotrecogin alfa (activated) has anti-thrombotic and pro-fibrinolytic
properties that may contribute to its mortality effects in patients with
severe sepsis. Thus, one might see different effects in patients with
sepsis who have DIC from those who do not. The majority of patients in
the trial (\> 90%) had laboratory evidence of DIC at study entry, as
defined by the presence of 2 or more of the following laboratory
findings:

1.  platelet count \<100,000/mm^3^ or 50% decrease in the past three
    days

2.  PT or APTT \>1.2 x ULN

3.  D-dimer \>ULN (0.4 ng/ml)

4.  Protein C, Protein S or Anti-thrombin \<LLN

Of note, in 2 individuals who did not have DIC at baseline and 113
patients in whom insufficient laboratory data were available to
determine DIC, there was little suggestion of a treatment effect.

+---------+---------+---------+---------+---------+---------+---------+
| DIC     | RhAPC   |         | Placebo |         | R       | 95% CI  |
| Status  |         |         |         |         | elative | for RR  |
| at      |         |         |         |         | Risk    |         |
| B       |         |         |         |         |         |         |
| aseline |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         | Total N | Mo      | Total N | Mo      |         |         |
|         |         | rtality |         | rtality |         |         |
|         |         |         |         |         |         |         |
|         |         | N (%)   |         | N (%)   |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Present | 800     | 196     | 774     | 243     | 0.78    | 0.67,   |
|         |         | (25)    |         | (31)    |         | 0.92    |
+---------+---------+---------+---------+---------+---------+---------+
| Absent  | 49      | 14 (29) | 66      | 16 (24) | 1.18    | 0.65,   |
| or      |         |         |         |         |         | 2.16    |
| unknown |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

4.  Should drotrecogin alfa (activated) be further evaluated in
    controlled studies in patients with severe sepsis who do not have
    laboratory evidence of DIC?

> **Vote: Yes 1 No 18 Defer 1**

5.  Given the limited information available about treatment effects in
    patients not diagnosed with DIC, if licensed, should the indication
    for drotrecogin alfa (activated) be limited to those patients with
    severe sepsis who have laboratory evidence of DIC?

> **The complete details of the responses to this question are recorded
> on the meeting transcripts to which those interested are referred.**

**IV. Treatment effect and heparin use**

A.  **[Low Dose Heparin]{.underline}**

Many patients received low dose heparin for prophylaxis of deep venous
thrombosis. Both heparin and drotrecogin alfa (activated) have
anti-thrombotic effects. Mortality was lower in patients who received
drotrecogin alfa (activated) than in those receiving placebo regardless
of whether low dose heparin was used, but the treatment effect was
several fold greater in patients not on low dose heparin, as seen in the
table below.

+--------------+----+--------+-------+----------+-------------------+
| ###          | r  |        | Pl    |          |                   |
| # On Heparin | hA |        | acebo |          |                   |
|              | PC |        |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
|              | N  | Mor    | N     | M        | Mortality         |
|              |    | tality |       | ortality | difference %      |
|              |    |        |       |          |                   |
|              |    | N (%)  |       | N (%)    |                   |
+--------------+----+--------+-------+----------+-------------------+
| At baseline  | 5  | 138    | 559   | 170 (30) | 4                 |
|              | 32 | (26)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| During       | 6  | 158    | 637   | 179 (28) | 3                 |
| infusion     | 34 | (25)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| By day 1\*   | 5  | 134    | 578   | 154 (27) | 3                 |
|              | 67 | (24)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| #### No      | r  |        | Pl    |          |                   |
| t on Heparin | hA |        | acebo |          |                   |
|              | PC |        |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
|              | N  | Mor    | N     | M        | Mortality         |
|              |    | tality |       | ortality | difference %      |
|              |    |        |       | %        |                   |
|              |    | N ( %) |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| At baseline  | 3  | 72     | 281   | 89 (32)  | 9                 |
|              | 18 | (23)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| During       | 2  | 52     | 203   | 80 (39)  | 15                |
| infusion     | 16 | (24)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+
| By day 1\*   | 2  | 45     | 222   | 65 (29)  | 11                |
|              | 52 | (18)   |       |          |                   |
+--------------+----+--------+-------+----------+-------------------+

**\***pts who died by day 1 are excluded from this analysis

If the differences between drotrecogin alfa (activated) effects in
patients on low dose heparin (3-4%) and patients not on low dose heparin
(9-15%) are real, then the question of whether to administer low dose
heparin when using drotrecogin alfa (activated) could be very important.
Potential mechanisms by which low dose heparin might influence the
drotrecogin alfa (activated) effect include: low dose heparin may
provide some benefits, leaving less residual benefit for the addition of
drotrecogin alfa (activated), and low dose heparin use might abrogate
some of the benefits from drotrecogin alfa (activated), perhaps through
synergistic toxicity.

6.  Should more studies be done addressing whether and how low dose
    heparin should be used in patients receiving drotrecogin alfa
    (activated)?

> **Vote: Yes 20 No 0**
>
> **The Committees vote included a sense of consensus that although more
> studies should be done, the heparin issue alone should not be a
> deciding factor in product approval.**

[B. Therapeutic Heparin]{.underline}

The role of therapeutic doses of heparin (i.e., high dose, intravenous)
in sepsis-related DIC is controversial. There have been no adequate
controlled trials of therapeutic heparin in this setting. However, some
clinicians favor its use there is high concern about thrombotic
complications. Clearly, therapeutic heparin and drotrecogin alfa
(activated) should not be administered simultaneously because of
bleeding risks. In the phase 3 trial, therapeutic heparin use was an
exclusion criterion. If any patient subsequently required therapeutic
heparin, the protocol specified that the drotrecogin alfa (activated)
(or placebo) infusion be discontinued.

Were drotrecogin alfa (activated) approved, clinicians treating patients
with severe sepsis and DIC will face a choice of therapy with
drotrecogin alfa (activated) or therapeutic heparin, but not both due to
bleeding risks.

7.  Please discuss how such a choice might be made. Are there situations
    in which heparin use rather than drotrecogin alpha (activated) might
    be appropriate? Is there need for further studies and, if so what
    types of studies would best address this question?

> **The Committee's responses generally indicated a need for further
> study, since data were not available. Generally it was felt that
> heparin therapy is controversial in DIC, that in instances where
> heparin is controversial RhAPC could be used, and in those instances
> where heparin therapy is needed RhAPC would need to be stopped. The
> complete details of the responses to this question are recorded on the
> meeting transcripts to which those interested are referred.**

**V. Safety of drotrecogin alfa (activated)**

Patients with severe sepsis who were at increased risk for bleeding were
excluded from the phase 3 trial, including:

-   Any patient who had undergone major surgery[^1], any postoperative
    patient who demonstrated evidence of active bleeding; or any patient
    with planned or anticipated surgery during the study drug infusion
    period[^2],

-   History of severe head trauma that had required hospitalization,
    intracranial surgery, or stroke within 3 months of study entry, or
    any history of intracerebral arteriovenous malformation, cerebral
    aneurysm, or central nervous system mass lesion. Patients with an
    epidural catheter or who anticipated receiving an epidural catheter
    during study drug infusion

-   History of congenital bleeding diatheses, such as hemophilia.

-   Gastrointestinal bleeding within 6 weeks of study entry that
    required medical intervention unless definitive surgery had been
    performed.

-   Trauma patients at increased risk of bleeding[^3],

-   Patients taking the medications with known bleeding risks[^4]

The number of patients experiencing serious bleeding adverse events[^5]
(AEs) during the phase 3 study was 3.5% (30/850) in those receiving
drotrecogin alfa (activated) and 2% (17/840) in those receiving placebo.
20 of the 30 bleeding events in the drotrecogin alfa (activated) group
occurred during days 1-5 (during or immediately after the infusion) for
a rate of 2.3% (20/850) compared to a placebo rate of 1% (8/840). Of
these, 12 occurred during days 1-2 and the rest days 3-4(or 5). Four
patients receiving drotrecogin alfa (activated) in the phase 3 study
were recorded by investigators as having died from bleeding
complications (intracranial, pulmonary or intra-thoracic related bleeds)
attributable to study drug, while no patients receiving placebo in this
study were thus identified. In the uncontrolled studies, where
monitoring and or entry criteria may be somewhat different from the
phase 3 trial, 13 of 520 patients have developed intracranial bleeds
while on study, 8 of whom had the bleed during the infusion or within
one day of stopping the infusion.

8.  Given that the bleeding events are greatest during the drotrecogin
    alfa (activated) infusion, should further dose optimization studies
    be conducted, for example of infusion duration, with the goal to
    minimize major bleeds while preserving efficacy?

> **Vote: Yes 0 No 20**
>
> **The Committee generally felt that a study would be useful but not
> necessary for optimization with appropriate exclusions. In children it
> needs to be studied because of the relative greater risk.**

9.  If licensed, should drotrecogin alfa (activated) be contra-indicated
    in patients with conditions that led to exclusion from the phase 3
    trial because of high risk for bleeding? What, if any other,
    characteristics of patients at high risk for bleeding (e.g.,
    thrombocytopenia) should be specifically identified in product
    labeling?

> *The Committee generally felt that exclusions should be the same.*

VI\. Overall benefit/risk assessment

10. Do the available safety and efficacy data support an indication for
    use of drotrecogin alfa (activated) in adult patients with severe
    sepsis (with any of the limitations discussed above)?

> **Vote: Yes 10 No 10**
>
> **The committee member's responses provided many comments qualifying
> their votes; the yes votes had limitations attached to them as noted
> in the full record. The complete details of the responses are recorded
> on the meeting transcripts to which those interested are referred.**

**VII. Pediatric Studies**

The sponsor is seeking an indication for use of drotrecogin alfa
(activated) in pediatric patients, and cites the regulations which state
"that the FDA may approve a drug for pediatric use based on adequate and
well-controlled studies in adults, with other information supporting
pediatric use...(when the agency has) concluded that the course of the
disease and the effects of the drug, both beneficial and adverse, are
sufficiently similar in the pediatric and adult populations to permit
extrapolation from the adult efficacy to pediatric patients". The
sponsor asserts that sepsis is sufficiently similar in pediatric and
adult patients and that similarity of effects between pediatric and
adult patients could be sufficiently demonstrated by studying
pharmacodynamic parameters, primarily D-dimer formation, following
drotrecogin alfa (activated) treatment.

Limited pediatric data are available, all uncontrolled. The majority of
the data are derived from a safety and pharmacokinetic/pharmacodynamic
(PK/PD) study in patients age 0 to 18 years with sepsis. Additional
small numbers of pediatric patients with sepsis and/or purpura fulminans
were enrolled in other studies. The dose and duration selected for
pediatric patients was based on the ability of dotrecogin alfa
(activated) to reduce D-dimer levels to a similar degree as was found in
the studies in adult patients. In general, the pediatric experience
indicated similar PD effects with respect to the adult experience but
the absence of controlled data and the small numbers of pediatric
patients studied preclude meaningful conclusions. Of note, mortality in
the pediatric study was 10%, lower than the overall mortality in the
adult study. As discussed, data from the adult study suggest the
possibility that the drug effect is absent in the subpopulation with
most favorable prognosis and lowest mortality.

11. Is severe sepsis in children sufficiently similar to severe sepsis
    in adults such that it would support extrapolation of the efficacy
    of drotrecogin alfa (activated) from adults to children based on PK
    and PD data in lieu of adequate and well-controlled efficacy data in
    pediatric patients?

> **Vote: Yes 0 No 16 Defer 4**
>
> **The committee member's responses provided many comments qualifying
> their votes. The complete details of the responses are recorded on the
> meeting transcripts to which those interested are referred.**

12. If the answer to the above is yes, then is D-dimer formation an
    appropriate PD marker to indicate a similar drug effect? If D-dimer
    is not an appropriate PD marker, please discuss other potential
    PK/PD markers that could establish similarity of effect between
    adult and pediatric populations.

13. If the answer to #11 is no, please discuss the types of additional
    clinical data that should be generated to support an indication for
    pediatric sepsis.

> **The Committee generally felt that studies are needed to assess the
> benefit risk in this population. The complete details of the responses
> to this question are recorded on the meeting transcripts to which
> those interested are referred.**

[^1]: defined as surgery that required general or spinal anesthesia that
    was performed within the 12-hour period immediately preceding study
    drug infusion;

[^2]: such as patients with staged surgeries or burn patients with
    planned excisions and grafting during the study drug infusion
    period.

[^3]: for example: flail chest; significant contusion to lung, liver, or
    spleen; retroperitoneal bleed; pelvic fracture; or compartment
    syndrome.

[^4]: Therapeutic heparin (Note**:** Prophylactic unfractionated heparin
    up to 15,000 units/day was permitted), Warfarin, if used within 7
    days of study entry and if prothrombin time was prolonged beyond the
    upper limit of normal for the institution, Acetylsalicylic acid
    (ASA) \>650 mg/day or compounds that contain ASA \>650 mg/day within
    3 days of study entry, Thrombolytic treatment within 3 days of study
    entry, Glycoprotein IIb/IIIa antagonists within 7 days of study
    entry.

[^5]: Bleeding events defined as serious adverse events included any
    intracranial hemorrhage, any life threatening bleed, any bleed that
    required 3 or more transfusions of PRBCs on 2 consecutive days, or
    was reported as a bleeding event and met SAE reporting criteria
    (prolonged hospitalization, etc.)