Health Research Associates

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e-mail: kberman@sbcglobal.net

February 24, 2005

Blood Products Advisory Committee - c/o William Freas, PhD

Chief, Division of Scientific Advisors and Consultants

FDA/CBER, 1401 Rockville Pike, HFM-71

Rockville, MD 20852

Subj: **Albumin Safety -- Blood Products Advisory Committee (BPAC) --
3/17/2005**

Dear Blood Products Advisory Committee Members:

Thank you for this opportunity to offer my input on the subject of the
safety of human albumin. BPAC's consideration of this matter is
particularly timely, as there is a particularly high risk of physician
misinterpretation of a recently published prospective trial comparing
fluid resuscitation with albumin and saline in an unusually
heterogeneous study population.

After considering the issues and documentation which follow, I strongly
encourage BPAC to recommend that the FDA take the following measures:

1.  Remove an August 19, 1998 "Letter to Healthcare Providers" from the
    FDA website (http:// www . fda.gov/cber/ltr/albumin.htm), which
    cautions physicians about the safety of albumin administration in
    critical care patients, on the basis of a now-discredited
    meta-analysis by the Cochrane Injuries Group;[^1]

2.  Issue a new "Letter to Healthcare Providers," as well as other
    public communications as the FDA believes appropriate, which informs
    physicians of the following:

> The 1998 Cochrane Injuries Group meta-analysis was undermined by
> several methodological problems raised by a number of experts in the
> field.[^2][^3] The most serious of these, in my view, was the
> injudicious decision to include several highly experimental studies in
> which albumin group subjects were infused with massively higher doses
> of albumin than is standard medical practice; those subjects
> experienced a high associated mortality rate, presumably from fluid
> volume overload.[^4]^,^[^5]
>
> A large prospective randomized trial conducted in Australia and New
> Zealand[^6] clearly demonstrates that administration of human albumin
> in critically ill patients requiring fluid resuscitation is not
> associated with any increased mortality risk over administration of
> saline solutions. This lack of an association between albumin use and
> increased mortality risk was supported by a more carefully conducted
> meta-analysis of 71 patient trials.[^7]
>
> While important for debunking the erroneous conclusions of the flawed
> Cochrane meta-analysis, **the Australian/New Zealander "SAFE" study
> was not properly designed nor adequately powered to provide physicians
> guidance in choosing between the use of albumin or saline in specific
> clinical populations**. In their conclusion, the SAFE investigators
> acknowledged this by concluding that "whether albumin or saline
> confers benefit in more highly selected populations of critically ill
> patients requires further study."^2^
>
> **The SAFE trial documented an important trend towards improved
> survival in severe sepsis patients who received albumin (relative risk
> of death, 0.87; 95% confidence interval (0.74-1.02, *P*=0.09),
> suggesting that albumin may confer survival benefit in this specific
> population**. This finding is consistent with important hemodynamic
> and oxygen transport function advantages seen in critically ill shock
> patients who were administered albumin instead of a lactated Ringer's
> solution.[^8] Moreover, this result is not surprising in light of a
> recent landmark study documenting a dramatic 65% reduction in
> in-hospital mortality in patients with cirrhosis and spontaneous
> bacterial peritonitis who received a total of 2.5 g/kg of human
> albumin in addition to the prescribed antibiotic, compared with those
> who received antibiotic only.[^9]

#### Correcting a misconception: "Albumin and saline should be considered clinically equivalent"

This important albumin group mortality reduction trend is identified in
a paragraph on the sixth page of the SAFE report, under the section
heading "Subgroup Analyses." Unfortunately, the SAFE study
abstract,[^10] *Medscape* reviews[^11] and other "bottom line"
information that reaches thousands of U.S. physicians caring for severe
sepsis patients focus only on *overall* outcome findings that lump
together all clinical populations. These variously include severe
sepsis, postoperative recovery, ARDS and a large, generally much younger
and healthier trauma population \-- for whom [saline
resuscitation]{.underline} is the standard of care in the U.S. (no
published studies have ever suggested a survival or other important
health outcome benefit for albumin in an unselected trauma population).
**There is no specific mention of the important mortality reduction
trend in sepsis in the study abstract or other major communications to
the physician community**.

A statement in *Medscape Medical News* attributed to a SAFE study
investigator (S. Finfer) also exposes a problematic blurring of the
distinction between safety and efficacy in this study:

> *Dr. Finfer told Medscape that the results provide the first "evidence
> that one fluid is not safer than the other in terms of mortality." Of
> patients who received albumin, 28-day mortality was 20.9% while the
> 28-day mortality in the saline group was 21.1%. "So we can answer the
> question about difference: there is no difference," he said. With
> 7,000 patients, the study was powered at 90% to detect a 3% difference
> in mortality.*

##### In addition to providing evidence that colloids and crystalloids are equally effective...

In evaluating the safety of one anti-inflammatory drug (e.g. a cox-2
inhibitor) against another, mortality is certainly a legitimate
[safety]{.underline} endpoint to evaluate because it is an obviously
[unintended adverse event]{.underline} which is unrelated to the
therapeutic objective. But in this unselected heterogeneous mix of
patients, whose only commonality happens to be that they were admitted
to the ICU, albumin and saline were administered specifically to avoid
complications of hypoperfusion that could lead directly to patient
death.

Just as mortality is not a "safety" endpoint in an assessment of
alternative drug regimens for advanced colorectal cancer, mortality is
clearly not a "safety" endpoint in a randomized trial of albumin and
saline for resuscitation of severe sepsis or ARDS or hemorrhagic trauma.
As in the example of colorectal cancer, mortality is not a unrelated or
unexpected outcome. Mortality happens to be the very outcome the
physician is hoping to avoid by administering resuscitative fluids --
thus the mortality endpoint is properly a measure of the comparative
[efficacy]{.underline} of these two interventions. The same can be said
of end-organ failure, mechanical ventilation days, ICU days and the like
-- all direct measures of efficacy. The SAFE trial evaluated these
efficacy parameters in a number of distinct critically ill populations,
each with distinct baseline patient characteristics and pathophysiology.
Aggregating any of these key health outcome measures across these
populations is not methodologically sound.

Thus, Dr. Finfer's comment to reporters that "our study provides
evidence that albumin and saline should be considered clinically
equivalent treatments...in a heterogeneous population of patients in the
ICU"[^12] is not valid: one cannot reach a single conclusion about a key
efficacy measure [after]{.underline} combining results of a distinct
patient population A (e.g. generally elderly hypotensive patients with
severe sepsis and serious comorbidities), some other *entirely
different* population B (e.g. generally younger, previously healthy
hypovolemic acute trauma patients), a third yet-different population C,
etc. That these very disparate populations all happened to be physically
placed in the hospital ICU is not a justification for treating them as a
homogenous group for purposes of evaluating the efficacy of alternative
resuscitative fluids.

Lumping together findings from such dissimilar populations might be
acceptable if limited to *unexpected adverse events* not associated with
the [intended]{.underline} effect of the treatments. But mortality is a
*common* event whose rate may be *directly* associated with the very
dissimilar physiological effects of albumin and saline. Those dissimilar
effects might be important in one clinical setting, while not in
another. In the SAFE trial, the strong statistical trend toward improved
survival in severe sepsis, but not in non-brain injured trauma patients,
are suggestive of precisely this type of scenario.

###### Making "further study" a reality in our lifetimes -- and the lifetimes of sepsis patients

While the SAFE investigators reflexively call for "further study" to
prove or disprove the strong mortality reduction trend they identified
in sepsis patients resuscitated with albumin, [it is highly unlikely
that such a trial will be completed in the near future]{.underline}.

This is regrettably the case for the same reason that the
"colloid-crystalloid debate" has dragged on for several
[decades]{.underline}: albumin is a very low-priced, costly-to-produce
commodity that yields minimal profitability for manufacturers.[^13]
Individually or collectively, manufacturers of this product simply
cannot justify the cost of sponsoring an adequately designed and powered
trial. Of course, there is also no patient or professional "advocacy
group" to champion more research to resolve this "albumin-versus-saline
in sepsis" question. (The 16-center SAFE trial was realized only through
a remarkable collaborative effort involving the Australian/New Zealand
Intensive Care Society Clinical Trials Group, the University of Sydney,
the Australian Red Cross Blood Service, a large domestic albumin
manufacturer and financial support aggregated from a number of regional
and national health agencies in Australia and New Zealand).

A fast, efficient and relatively inexpensive option is for the SAFE
study investigators -- with support as needed from domestic and/or U.S.
health agencies -- to extend the SAFE protocol itself to specifically
enroll additional severe sepsis patients as required to achieve a
statistically significant result.

Of approximately 750,000 sepsis cases each year in the U.S., an
estimated 225,000, or roughly one in three, are fatal.[^14] The SAFE
study identified a very important potential survival benefit associated
with albumin resuscitation in the severe sepsis population. Remarkably,
this potential mortality reduction benefit is on a similar order to the
much-heralded benefit of a newer and significantly more costly
intervention: recombinant activated protein C (drotrecogin alfa
activated; *Xigris*^®^).[^15]

If we assume that the sepsis mortality reduction trend documented by the
SAFE investigators is eventually borne out, a comparison with findings
from the 1,690-subject, Eli Lilly-sponsored PROWESS trial of drotecogin
alfa activated should awaken the interest of critical care specialists,
federal health and research officials and other healthcare policy
makers:

+--------+------------+-------------+--------------+-------+---------+
| ##     | ##         | *Mortality  | *Risk        | *Trea | *       |
|  Study | # Randomiz | (%)*        | reduction    | tment | Nominal |
|        | ation -- n |             | per 100      | cost* | cost    |
|        |            |             | patients     |       | per     |
|        |            |             | treated*     |       | life    |
|        |            |             |              |       | saved*  |
+--------+------------+-------------+--------------+-------+---------+
| P      | *Xigris*   | *Xigris* -- | **6.1        | *     | **\$16  |
| ROWESS | -- 850     | 24.7%       | lives**      | *\$9, | 0,000** |
|        |            |             |              | 800** |         |
|        | Placebo -- | Placebo --  |              |       |         |
|        | 840        | 30.8%       |              |       |         |
+--------+------------+-------------+--------------+-------+---------+
| SAFE   | 4% albumin | Albumin     | **4.6        | *     | **\$    |
|        | -- 603     | (30.7%)     | lives**      | *\$15 | 3,300** |
|        |            |             |              | 0**\* |         |
|        | 0.9%       | Saline      |              |       |         |
|        | saline --  | (35.3%)     |              |       |         |
|        | 615        |             |              |       |         |
+--------+------------+-------------+--------------+-------+---------+

\*Assumes a mean of approximately 2 liters of 5% albumin at a
hospital-level cost of \$75/liter

I believe it would serve the public health interest for the SAFE
investigators to extend their trial specifically to address the severe
sepsis population in the ICU, and resolve this unanswered "safety"
question.

Failing that, BPAC should urge the FDA and the National Institutes of
Health to orchestrate and finance a well-designed and adequately powered
"Albumin vs. Saline Resuscitation in Severe Sepsis" trial.

"Further study" is needed urgently for the sake of many thousands of
patients worldwide at risk of death from severe sepsis.

Sincerely,

![](media/image1.png)

Keith Berman, MPH, MBA

*Disclosure*: I consult for FFF Enterprises, a leading U.S. distributor
of plasma products and other biotherapeutics.

Appendix 1

**New Engl J Med 2004 May 27; 350(22):2247-56**

**A comparison of albumin and saline for fluid resuscitation in the
intensive care unit.**\
\
**Finfer S, Bellomo R, Boyce N, et al; SAFE Study Investigators.**\
\
ANZICS CTG, Level 3, 10 Ievers St., Carlton, VIC 3053, Australia.
ctg@anzics.com.au\
\
BACKGROUND: It remains uncertain whether the choice of resuscitation
fluid for patients in intensive care units (ICUs) affects survival. We
conducted a multicenter, randomized, double-blind trial to compare the
effect of fluid resuscitation with albumin or saline on mortality in a
heterogeneous population of patients in the ICU.

METHODS: We randomly assigned patients who had been admitted to the ICU
to receive either 4 percent albumin or normal saline for
intravascular-fluid resuscitation during the next 28 days. The primary
outcome measure was death from any cause during the 28-day period after
randomization.

RESULTS: Of the 6997 patients who underwent randomization, 3497 were
assigned to receive albumin and 3500 to receive saline; the two groups
had similar baseline characteristics. There were 726 deaths in the
albumin group, as compared with 729 deaths in the saline group (relative
risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09;
P=0.87). The proportion of patients with new single-organ and
multiple-organ failure was similar in the two groups (P=0.85). There
were no significant differences between the groups in the mean (+/-SD)
numbers of days spent in the ICU (6.5+/-6.6 in the albumin group and
6.2+/-6.2 in the saline group, P=0.44), days spent in the hospital
(15.3+/-9.6 and 15.6+/-9.6, respectively; P=0.30), days of mechanical
ventilation (4.5+/-6.1 and 4.3+/-5.7, respectively; P=0.74), or days of
renal-replacement therapy (0.5+/-2.3 and 0.4+/-2.0, respectively;
P=0.41).

CONCLUSIONS: In patients in the ICU, use of either 4 percent albumin or
normal saline for fluid resuscitation results in similar outcomes at 28
days.

Appendix 2

**\[Medscape -- Critical Care Medpulse\]**

**Albumin, Saline Comparable for Fluid Resuscitation in ICU**

NEW YORK (Reuters Health) May 26, 2004 - Whether saline or albumin is
used for fluid resuscitation in the ICU setting seems to have no effect
on survival or other clinical endpoints, according to a report published
in the May 27th issue of The New England Journal of Medicine.

The best fluid to use for resuscitation has remained unclear due in
large part to a lack of adequately powered randomized trials examining
this topic. In the absence of such trials, clinicians have relied on
evidence from meta-analyses, which have yielded conflicting results.

To hopefully settle this issue, Dr. Simon Finfer, from the ANZICS
Clinical Trials Group in Carlton, Australia, and colleagues conducted a
randomized trial involving nearly 7000 patients in 16 ICUs in Australia
and New Zealand. Known as the Saline versus Albumin Fluid Evaluation
(SAFE) study, subjects received either 4% albumin or normal saline for
fluid resuscitation in the ICU.

During the 28-day study period, mortality in each group was nearly the
same\--726 deaths in albumin group compared with 729 in the saline
group. Moreover, the proportion of patients who experienced organ
failure in each group was similar.

The groups were also comparable in terms of length of ICU and hospital
stay, days of mechanical ventilation, and days of renal-replacement
therapy.

\"[Our study provides evidence that albumin and saline should be
considered clinically equivalent treatments for intravascular volume
resuscitation in a heterogeneous population of patients in the
ICU]{.underline},\" the authors state. However, further studies are
needed to determine if either might be advantageous in a highly selected
patient subgroup, they add.

In a related editorial, Dr. Deborah Cook, from McMaster University in
Hamilton, Canada, comments that authors\' \"study has raised the bar for
future trials by using multidisciplinary implementation strategies and
Web-based management and by demonstrating excellent protocol adherence
in thousands of patients. The SAFE study is not only a landmark trial;
it is also a milestone for the discipline of critical care medicine.\"

*N Engl J Med* 2004;350:2247-2256,2294-2296.

Appendix 3

**\[Medscape Medical News\]**

No Difference in Mortality Between Colloid, Crystalloid IV Fluid
Resuscitation

Feb. 24, 2004 (Orlando) --- Fluid resuscitation is a cornerstone of
intensive care therapy, yet for years there has been little agreement
about the best fluid to use --- crystalloid or colloid. Now, results of
a 7,000-patient placebo-controlled study suggest that there is no
difference in 28-day mortality between patients resuscitated with
albumin or saline.

Simon Finfer, MBBS, MRCP, FRCA, is a senior staff specialist in
intensive care at Royal North Shore Hospital in Sydney, Australia, and
lead investigator of the Saline versus Albumin Fluid Evaluation (SAFE)
trial. He presented the study results at a late-breaking clinical trials
session here at the 33rd Critical Care Congress, the annual meeting of
the Society of Critical Care Medicine (SCCM).

Dr. Finfer told Medscape that the results provide the first \"evidence
that one fluid is not safer than the other in terms of mortality.\" Of
patients who received albumin, 28-day mortality was 20.9% while 28-day
mortality in the saline group was 21.1%. \"So we can answer the question
about difference: there is no difference,\" he said. With 7,000
patients, the study was powered at 90% to detect a 3% difference in
mortality.

J. Christopher Farmer, MD, professor of medicine, pulmonary, and
critical care medicine at the Mayo Clinic in Rochester, Minnesota, told
Medscape that the \"crystalloid-colloid debate has been going on for
three or four decades\...but nobody has been able to do a study that is
this large and this well designed so that it weeds out bias. What is
really different about this trial is that it is so well done that it is
amazing --- to meet the enormous logistical challenge of running a
7,000-patient trial at so many ICUs and collect all the data in just 18
months. The bottom line is that this is a very clean set of data.\"

Dr. Farmer was not involved in the study, but he chaired the
late-breaking clinical trials session and he is a cochair of this
year\'s congress. He is also the series editor of supplements to
*Critical Care Medicine*.

In addition to providing evidence that colloids and crystalloids are
equally effective, the study also \"debunked another myth: the
three-to-one ratio,\" said Dr. Farmer. He said it has been universally
accepted that it takes three times as much crystalloid volume to
resuscitate. But Dr. Finfer said that the actual ratio was 1.38 L saline
to 1 L albumin. \"On average, the patients received an average of 1,200
mL albumin/day and 1,600 mL saline during the initial four days,\" Dr.
Finfer said.

Data were available on 3,473 patients randomized to albumin and 3,460
patients randomized to saline. Dr. Finfer noted that the 16-center study
had \"closed the books\" in October so \"we have only completed the
analysis to answer the mortality question.\"

Nonetheless, he did note that while there was no overall difference in
survival, there was a slight difference in trauma and head trauma
patients that favored saline. Trauma patients resuscitated with albumin
had a 1.36 risk for death, so \"there was a slight excess death.\"

The average age of patients in both groups was 58 years; 1,424 of the
albumin-treated patients were female as were 1,376 of the saline
patients.

Dr. Finfer said an essential part of the study was the use of specially
designed packaging and tubing. Both albumin and saline were packaged in
cardboard sleeves that disguised their contents and the intravenous (IV)
tubing was tinted green so that it was impossible to detect a color
difference. Dr. Farmer agreed that this unique blinding technique
successfully eliminated bias.

Timothy G. Buchman, MD, PhD, professor of surgery, anesthesiology, and
medicine and chief of the burn, trauma, and critical care section at
Washington University School of Medicine in St. Louis, Missouri, told
Medscape that \"perhaps the most common therapy we deliver in intensive
care --- more common than vents, more common than antibiotics --- is the
administration of IV fluids.\"

The results of the SAFE trial indicate that \"a caring and competent
clinician can make a good choice using either albumin or saline as he or
she thinks appropriate,\" Dr. Buchman said. Dr. Buchman, who was not
involved in the study, is the president of SCCM.

But Dr. Farmer said that he thinks most clinicians will opt for
crystalloid fluids since \"they cost just pennies compared to colloids,
which are purified human protein products and thus carry some antigenic
risk.\"

The study was supported by the Australian and New Zealand Intensive Care
Society Clinical Trials Group, the Institute for International Health at
the University of Sydney, the Australian Red Cross Blood Service, and
CSL Limited of Melbourne, which manufactured the IV fluid products used
in the study.

SCCM 33rd Annual Congress: Late-Breaking Topics --- \"Does Albumin Kill?
Results of a Randomized Control of 7,000 Patients.\" Presented Feb. 22,
2004.

*Reviewed by Gary D. Vogin, MD*

[^1]: Cochrane Injuries Group Albumin Reviewers: Human albumin
    administration in critically ill patients: systematic review of
    randomized controlled trials. *BMJ* 1998; 317:235-40.

[^2]: Erstad BL. Concerns with defining appropriate uses of albumin by
    meta-analysis. *Am J Health Syst Pharm* 1999; 56:1451-4.

[^3]: Horsey P. Albumin and hypovolaemia: is the Cochrane evidence to be
    trusted? *Lancet* 2002; 359:70-2.

[^4]: Lucas CE, Weaver D, Higgins RF, et al. Effects of albumin versus
    non-albumin resuscitation on plasma volume and renal excretory
    function. *J Trauma* 1978; 18:564-70. Investigators infused 150
    g/day x 5 days.

[^5]: Goodwin CW, Dorethy J, Lam V, et al. *Randomized trial of efficacy
    of crystalloid and colloid resuscitation on hemodynamic response and
    lung water following thermal injury. Ann Surg* 1983; 197:520-31.
    Albumin group patients received 300-350 g albumin in first 24 hours;
    equates with an isooncotic load of 6.0-7.0 L.

[^6]: SAFE Study Investigators. A comparison of albumin and saline for
    fluid resuscitation in the intensive care unit. *N Engl J Med* 2004;
    350:2247-56.

[^7]: Wilkes MM, Navickis RJ. Patient survival after human albumin
    administration: A meta-analysis of randomized, controlled trials.
    *Ann Intern Med* 2001; 135:149-64.

[^8]: Shoemaker WC.and Wo CC. Circulatory effects of whole blood, packed
    red cells, albumin, starch, and crystalloids in resuscitation of
    shock and acute critical illness. *Vox Sang* 1998; 74(Suppl
    2):69-74.

[^9]: Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin
    on renal impairment and mortality in patients with cirrhosis and
    spontaneous bacterial peritonitis. *New Engl J Med* 1999; 341:403-9.

[^10]: Transcribed verbatim in Appendix 1.

[^11]: Transcribed verbatim in Appendices 2 and 3.

[^12]: Appendix 2.

[^13]: The current retail price per liter of 5% albumin is less than
    \$75 (source: FFF Enterprises, Temecula, CA;
    [www.fffenterprises.com](http://www.fffenterprises.com/))

[^14]: Linde-Zwirble WT, Angus DC, Carcillo J, et al. Age-specific
    incidence and outcome of sepsis in the U.S. *Crit Care Med* 1999;
    27(Suppl 1):A33.

[^15]: Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety
    of recombinant human activated protein C for severe sepsis. *New
    Engl J Med* 2001; 344:699-709.