59

Dr. FRIEDMAN. If I might take a page from your book, the short
answer to that question is it’s true in the past we didn’t look at
these data very carefully. It is not true now. Currently we’re en-
gaged in doing exactly what Dr. Epstein said. It’s a little like eco-
nomic modeling. You have to understand not just what’s coming in,
but what’s going out, and we found that a formidable challenge,
but we are committed to doing that.

T’ve made the invitation to Ms. Steinhardt previously, and do so
again here, that if there are any suggestions that they have about
ways we can do this, we’ve called you, we’ve talked, we're com-
mitted to working with them in that regard.

Mr. SHays. We'll be asking the next panel the same questions.

Dr. FRIEDMAN. Fair enough, sir.

As a closing, and I know you want to get on to the next panel,
and we don’t want to keep you, I personally appreciate the chance
to come before this committee. I think that we have focused very
intently on improving standards and making the quality of the
blood supply and the information about the blood supply better and
better. It is a never-ending challenge because of new science and
new information that we learn.

I think it’s fair to say that through the hard efforts of these peo-
ple here and hard efforts in the industry and others outside, and
certainly of this committee, that there’s really been a sea change
in how manufacturing practices have been looked at in this indus-
try over the past several years. We are not satisfied with that.
We're pleased that some progress is being made. We see consider-
able work to do in the future, and we’re committed to doing that.

Thank you, sir.

Mr. Suays. I thank all of you, and I do think we’ve seen signifi-
cant progress, and I do think that we’ve worked well together in
this effort. So I thank you all.

Our second panel is James Reilly, executive director, American
Blood Resources Association; Jan Bult, executive director, Inter-
national Plasma Products Industry Association; Brian McDonough,
chief executive officer, American Red Cross Biomedical Services;
and Dr. John Boyle, Plasma Users Coalition. I think Mr. Boyle is
the only new participant in these hearings. Do we have an initi-
ation in cases like that?

You know, why don’t you stand because I'll swear you in. Is there
anyone that you might turn to as well on your staff that you want
sworn in? If so would you ask them to stand, and they only need
to identify themselves if they are asked to come forward. But if
there’s anyone else, you can sit in the back, you know, or sit up
in the first two seats on the side there or behind, wherever you
want. But I want whoever we need to swear in to swear in now
and not later.

Anyone else? I see others standing and I know they want to be
sworn in, so we'll wait.

I am assuming that whoever is standing is a potential witness
there. If you would all raise your right arms, please.

[Witnesses sworn.]

Mr. SHays. Thank you very much. I appreciate you doing it this
way just so we don’t have to swear in someone later.


123

‘As we noted earlier, the development of plasma products for alpha one, bleeding
disorders, and immune deficiency diseases have dramatically extended the lives and
improved the quality of life for tens of thousands of Americans. However, a
current and ongoing shortage of these products has caused serious adverse
health consequences. For example, in Alpha One Antitrypsin Deficiency, a
congenital emphysema, diagnosis is usually made after 70% of hung function is
gone, the lung deterioration is arrested but not reversed by treatment with plasma
derivatives. Effective augmentation therapy is dependent on regular dosage and
infusion. One study indicates a sixty-percent difference in mortality with treatment.
Unfortunately, the Alpha One community is served by a sole manufacturer who has
been at 50% production for the major portion of 1998. Moreover, even at 100%
production there is not an adequate supply of Protease inhibitor for augmentation
therapy of eligible patients.

Approximately seventy percent of immune deficient patients are treated with
intravenous gamma globulin. For nearly twenty years, IVIG, has been recognized
as a safe and effective treatment for primary immune deficiency diseases. However,
beginning in the fall of 1997, widespread shortages of IVIG developed. Within
this past week, we completed a survey of 100 doctors treating more than 2,000
immune deficient patients to document the current situation. Over ninety percent
of these doctors reported difficulty in obtaining IVIG for their patients since April.
As a result, they report postponing infusions, increasing the intervals between
infusions, and reducing prescribed dosages of IVIG to their patients. How serious
is this for these patients? Well, half of the doctors who have had difficulty in
obtaining IVIG report that the shortage since April has had a negative effect on
the health of their patients. Specifically, patients are suffering from increased
infections that normally would have been checked by recommended [VIG therapy.

It should be clearly remembered that persons with bleeding disorders have been
victims as well as beneficiaries of plasma products. With the introduction of
recombinant alternatives to plasma based clotting factors the treatment of
hemophilia leape into the 21" century, No longer did individuals with bleeding
disorders have to stand in the corridor of fear and pain, deciding to endure painful
bleeds or risk exposure to possible viral contaminants like HIV which devastated
their community. Last week the Surgeon General endorsed the use of recombinant
AHF as the preferred treatment for hemophilia, and recommended accelerated
implementation for all individuals currently using plasma based derivatives to
recombinant usage.


Mr. Chairman and Members of the Committee, I am Dr. Michael A.
Friedman, Acting Commissioner of Food and Drugs (FDA or the
Agency). I appreciate this opportunity to discuss the General
Accounting Office (GAO) report: “Blood Plasma Safety: Plasma
Product Risks Are Low If Good Manufacturing Practices Are
Followed" which reviewed the viral marker rates of paid versus

unpaid donor:

As requested, I also will update the Committee on
the status of FDA's regulatory compliance program which helps
assure the safety of blood and plasma derivatives through the
application of good manufacturing practices (GMP) as well as the
continuing shortage of immune globulin, intravenous (Human)
(IGIV), the subject of the subcommittee hearing on May 7 of this

year.

TI. BACKGROUND

For the millions of Americans with certain medical needs, whole
blood and plasma derivatives are essential for preserving their
life or for maintaining a normal quality of life. ‘These patients
expect that the products will be free of infectious disease and
effective for their intended use. Fundamentally, it is the role

and responsibility of industry to provide adequate and

re
products. FDA has a responsibility to help ensure that these
patients’ expectations of safety and availability are fulfilled


154

Alpha One Foundation

09.07 98
Bard Diecctrn ‘Anne Marie Finley
Mark 1. Reinily. SLD Subcommittee on Human Resources

Nation Insitatesl tests Committee on Government Relations and Oversight
ethesda, Marylaad U.S. House of Representatives

ew Con ft ‘Washington, DC

Sak, Wahington

Sars E, Evert Eun 9

Serta = Trent i
Nya New Yore Dear Anne Marie
Lean Pursuant to our discussion at the CBSA meeting on August 27", I wish to

reiterate my appreciation for inviting the PLC testimony at your upcoming
hearing on the GAO Report on Blood Plasma Safety The members of PUC
have given their input on Dr, John Boyle's testimony and I think his
testimony will make a significant contnbution to the Subcommittee's

Sette Heoitsen + ration
Ves Moines, fons delibe s.

Sree inial ‘As you are aware, the critical shortages of plasma derived products for IGIV
Witlan Ree * and AAT deficiency and recombinant factor product is our primary concern

‘Renae Wain at this time. Pleased find my written testimony for submission to the
tuner A Seadhase. MD... Subcommittee at this hearing attached hereto, { would appreciate it if' you
Natisaal Jewish Mruicat Con could include this testimony with the PUC written testimony for distribution

Dower, Coloemle to Chairman Shays and the members of the Subcommittee.

Garo 1. Snider, M18 +

Thave noted some of our concems regarding the vulnerability of additional

product approval and IND trial design issues at FDA Per my facsimile of

last week, we're still having difficulty wth Dr Ross Pierce t cxpect to see

either Dr. David Feigel or Or Jay Epstein at your hearing and hope that they

SES penn will have an update for us af that time { will keep you advised accordingly
Thank you for your intercst in this issue.

Catneiae Vata *
Merion te _ .

vena w dH € Please advise if you need additional deta! regarding my testimony. { look
freien a O07 forward to seeing you on Wednesday and appreciate your continued

Vartan A. Westra Vigitance on behalf of consumers of blood products With best regards, 1 am
Minn Resi

2997 SW. 27th Avenue, Suite 302, Miami. Florida 331
“‘Fetephone: (205) 567-0888 - (BR8) 825-7421 « Fax: (305) 567-1317 al seftthanthnt


149

Mr. Suays. Is there any comment that any of you want to make,
starting with you, Dr. Boyle? Let me just say I would like you to
state again for the record what your impression of the last hearing
was, and I would like the others to respond to it just to see how
far we are away from living up to that. One, do others agree that
was the understanding of the hearing? And two, are we following
up on it?

Mr. BoyLe. Our understanding from the previous hearing was
that on the industry side there was a commitment to increased pro-
duction, recognizing that one of the things that we still don’t un-
derstand is if industry understood demand was going up by 10 per-
cent per year over a period of time, why production was never in-
creased.

Mr. SHAYS. From your standpoint, I do have a sense that produc-
tion was going to increase. We did have one plant obviously not
producing, and we also had some of the product taken out of the
market, but that has now come back in.

why can’t manufacturers respond to increased demand? You
woul think intuitively profits would increase. Why doesn’t that

appen?

(r. BULT. First of all, manufacturers have participated in in-
creased demands. First, you should realize that the critical short-
age occurred in November 1997, and after that we had a couple of
events that could not be corrected until now. And you may recall
at the May hearing there were three major reasons that contrib-
uted to these shortfalls. One was the increase in clinical use. Sec-
ond was the recall because of Creutzfeldt-Jakob disease-related
issues, and the third was compliance issues.

Since then we have not been able to recover from the shortfalls.
We are working hard to do so.

Mr. Says. Has the production increased?

Mr. Butt. Where possible, production has increased. However,
one company under the consent decree was able to maintain oper-

ing at a 100-percent level. You have heard of the situation with
another member. We have a third member who just got the FDA
approval to increase their capacity at one of the plants, which will
certainly contribute to an increase in supply. And the other com-
pany had a long term commitment to increase production capacity
and they are on track. Increases cannot be done overnight. It takes
about 200 days to manufacture product between collection and fin-
ished product. It is a time-consuming process.

Mr. Suays. I don’t want to labor on this too long, but I do want
to have a better appreciation. 1 am just struck by the fact that if
one company can get more market share, you jump at the oppor-
tunity. With paper mills, if you have a shortage, a whole host will
increase their production and then you have too much because they
each did it thinking they were the only one going to increase pro-
duction. I am still having a difficult time understanding why one
company wouldn’t want to seize that market share.

Mr. McDonoucu. By way of example, in July and August we
worked pretty hard to try to increase our throughput, and that
means increasing the number of donations that ultimately can go
through. Unfortunately, we had a laboratory GMP problem that
held up for 2 months a number of products. We also had two CJD


COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
DAN BURTON, Indiana, Chairman

BENJAMIN A GILMAN, New York

J. DENNIS HASTERT, Illinois

CONSTANCE A. MORELLA, Maryland

CHRISTOPHER SHAYS, Connecticut

CHRISTOPHER COX, California

ILEANA ROS-LEHTINEN, Florida

JOHN M. McHUGH, New York

STEPHEN HORN, California

JOHN L. MICA, Florida

THOMAS M. DAVIS, Virginia

DAVID M. McINTOSH, Indiana

MARK E. SOUDER, Indiana

JOE SCARBOROUGH, Florida

JOHN B. SHADEGG, Arizona

STEVEN C. LaTOURETTE, Ohio
MARSHALL “MARK” SANFORD, South

JOHN E. SUNUNU, New Hampshire
PETE SESSIONS, Texas

MICHAEL PAPPAS, New Jersey
VINCE SNOWBARGER, Kansas
BOB BARR, Georgia

DAN MILLER, Florida

RON LEWIS, Kentucky

HENRY A. WAXMAN, California
TOM LANTOS, California

ROBERT E. WISE, Jr, West Virginia

MAJOR R. OWENS, New York

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

GARY A. CONDIT, California

CAROLYN B. MALONEY, New York

THOMAS M. BARRETT, Wisconsin

ELEANOR HOLMES NORTON, Washington,

Dc
CHAKA FATTAH, Pennsylvania
ELIJAH E. CUMMINGS, Maryland
DENNIS J. KUCINICH, “Ohio
ROD R. BLAGOJEVICH, Iinois
DANNY K. DAVIS, Illinois
JOHN F. TIERNEY, Massachusetts
JIM TURNER, Texas
THOMAS H. ALLEN, Maine
HAROLD E. FORD, JR., Tennessee

BERNARD SANDERS, Vermont
(Independent)

KEvIN BINGER, Staff Director

Dantet R. MOLL, Deputy Staff Director
Davip A. Kass, Deputy Counsel and Parliamentarian
Lisa Siri ARAFUNE, Deputy Chief Clerk
Putt SCHILIRO, Minority Staff Director

SUBCOMMITTEE ON HUMAN RESOURCES
CHRISTOPHER SHAYS, Connecticut, Chairman

VINCE SNOWBARGER, Kansas
BENJAMIN A. GILMAN, New York

EDOLPHUS TOWNS, New York
THOMAS H. ALLEN, Maine
‘TOM LANTOS, California

DAVID M. McINTOSH, Indiana
MARK E. SOUDER, Indiana
MICHAEL PAPPAS, New Jersey

BERNARD SANDERS, Vermont (Ind.)
THOMAS M. BARRETT, Wisconsin
DENNIS J. KUCINICH, Ohio

EX OFFICIO
HENRY A. WAXMAN, California

ab


119

Mr. Suays. Dr. Boyle.

Mr. BoyLe. Can you hear me?

Mr. Suays. I can hear you.

Mr. Boye. Mr. Chairman, members of the subcommittee, I’m
John Boyle. I’m here on behalf of the Plasma Users Coalition. The
coalition includes the Alpha One Foundation, the Alpha One Na-
tional Association, the Committee of Ten Thousand, the Hemo-
philia Federation, the Immune Deficiency Foundation and the Na-
tional Hemophilia Foundation. The coalition represents patients
who depend upon the long-term use of plasma products for their
health and very lives.

As you know, more than 500,000 Americans use plasma products
each year; however, persons with alpha one antitrypsin deficiency,
bleeding disorders and primary immune deficiency diseases must
use plasma products many times each year for their entire lives.
Collectively we represent about 50,000 Americans.

Tm here today speaking on behalf of these individuals who con-
sume plasma-based products repeatedly and in large quantities to
avoid painful, debilitating and life-threatening diseases. My infant
son was diagnosed with one of those disorders nearly 20 years ago.

Four factors influence the Plasma Users Coalition on the issues
before this committee. First, plasma products are essential to the
health and well-being of persons with these chronic disorders. Sec-
ond, there is no medically equivalent product available for alpha
one or primary immune deficiency diseases. Third, the safety of
these products is of utmost concern to chronic users. And fourth,
we are experiencing serious shortages in these products.

Just last week the Surgeon General endorsed the use of recom-
binant AHF as the preferred treatment for hemophilia and rec-
ommended accelerated implementation for all individuals currently
using plasma-based derivatives to recombinant usage. However,
there is a continuing shortage of recombinant AHF, which, along
with prohibitive costs, will keep persons with bleeding disorders
members of the plasma products user community for some time to
come.

The alpha one community is served by a sole manufacturer who
has been at 50 percent production for the major portion of 1998.
Moreover, even at 100 percent production by that manufacturer is
not producing an adequate supply of protease inhibitor for aug-
mentation therapy for eligible patients.

For nearly 20 years IVIG has been recognized as a safe and effec-
tive treatment for primary, immune deficiency diseases. However,
beginning in the fall of 1997, widespread shortages of IVIG devel-
oped. We are here today to report that the product availability has
not improved significantly since the meetings in April or May, and
we are very concerned the situation will get worse in the near fu-

re.

Now to document where we are with IVIG, we have just com-
pleted a survey of 100 doctors treating more than 2,000 immune-
deficient patients. Over 90 percent of those doctors reported dif-
ficulty in obtaining IVIG for their patients since our previous sur-
vey in April. Half of the doctors who have had difficulty in obtain-
ing IVIG report that that shortage since April has had negative ef-
fects on the health of their patients. Specifically patients are suf-


ABRA Statement September 9, 1998
Page 6 of 6 Reference No.GAOC98008

The comparability of these two segments of the industry is not new news. In
terms of viral safety, the comparability of the Source Plasma and whole blood
industries was demonstrated as early as 1985 in an article published in the
journal Transfusion! addressing the prevalence of HIV (know then as the human
T-cell lymphotrophic III virus) in Source Plasma and whole blood donors. In that
article, the repeat reactive rates resulting from nationwide screening of blood and
plasma for antibodies to HTLV-II were 0.34% for whole blood donations and
0.15% for Source Plasma donations.

More recently, a 1993 FDA workshop on the safety of plasma donation
concluded that “plasma pools derived from compensated donors are at least as,
safe as comparable plasma pools recovered from whole blood donations from
volunteer donors.” The viral marker rates reported at that workshop are
strikingly similar. Thus, the comparability of the residual risk rates for whole
blood and Source Plasma donors, as reported in the GAO report, should come
as no surprise.

Given this history of comparable safety profiles, we have begun to question
whether comparisons of viral marker rates between whole blood and Source
Plasma are the best use of limited goverment and industry resources. Source
Plasma donors provide an essential life giving material without which many
Americans would suffer and/or die. Rather than expending valuable resources
comparing one industry segment to another, we are focusing future resources on
striving for continuous quality and safety improvements against our own baseline
of past performance.

In conclusion, | would like to thank the subcommittee again, for bringing these
important issues to light and for giving me the opportunity to address them.
ABRA and its members are committed to continuous improvement of the Source
Plasma industry through the voluntary initiatives outlined previously and a
number of planned enhancements to the QPP. We would welcome an
‘opportunity to discuss our plans for enhancing the QPP and the safety of Source
Plasma with you and the subcommittee.

' Kuritsky et al., Results of Nationwide Screening of Blood and Plasma for Antibodies to Human T-
cell Lymphotropic Ill Virus, Transfusion (1986) 24, 205-7.
" Meeling Report: Workshop on Safety of Plasma Donation, Biologicals (1994) 22, 269-283,


152

say, I didn’t know it, but yes, I did in fact have growth hormone
after some thought and deliberation about it.

That anecdote of information probably is not very helpful, but all
I can tell you is the source of information from our donors which
clearly had an adverse impact on volunteer donors.

Mr. REILLY. We took a look at this issue and had some profes-
sionals, statisticians and so on, try to look at the demographic
issues and figure out why was there such a difference. There really
were two driving factors. One is that it related to age. Age has an
effect related to this, and when you look at the demographics of the
two donor populations, the volunteer sector was a more elderly
group. So that sort of drove the conclusion that you might see the
increases seen here.

The other was simply the size of the donor pool where in the
whole blood sector they deal with the longer duration period, so
consequently they have a larger number of donors contributing to
the pool, if you will. And in the plasma sector we have a smaller
number of donors making more frequent donations.

When you look at those two factors combined, what you found
was that the expected number of recalls or donors that sparked a
recall out of the volunteer sector, and then when you factored in
those two demographic issues, what you would expect out of the
plasma industry was pretty much exactly what we got. So that is
why it looks like it is disjointed.

Mr. HALLORAN. Thank you.

Mr. Suays. Any last comment before we close this hearing?

Sir, if you would just identify yourself. We did swear you in.

Mr. COLLINS. My name is Patrick Collins and I am with the Na-
tional Hemophilia Foundation with Dr. Boyle.

I would just like to bring to the committee’s attention the fact
that in addition to the immune globulin shortage, which is dire,
that there is currently a recombinant factor A shortage, which Dr.
Boyle alluded to. And quite frankly it is rather startling that all
of the manufacturers are rationing their recombinant A product.
For example, Bayer sent out a notice to all of their consumers that
they are rationing at 62 percent of allocation, that Baxter is cur-
rently having Pre lems meeting their supply of recombinant factor
A product, and Centeon, which distributes product made by Baxter
and Bayer, has also resorted to rationing because of a lack of prod-
uct.

This is compiled with the fact that Dr. Satcher, in making his

recommendation, also endorsed the switch to recombinant
product which is in short supply for the population that currently
uses it, let alone the population that will switch as a result of Dr.
Satcher’s recommendation. I just felt that the committee should be
made aware of that, in addition to the alpha I antitrypsin shortage
and the fact that they are relying specifically on one manufacturer
of product and they are having great difficulty in getting that prod-
uct as well.

Mr. Suays. Thank you very much, sir.

Any comments?

Mr. Butt. It night be useful to comment on recombinant factor
8. I want to underline the importance of factor 8 products for hemo-
philia patients, and if we focus on recombinant factor 8 as part of


9

IPPIA Statement Document No. 011218
9 September 1998
Page 9

discussion. We have also enhanced the usefuiness of this information by
collecting actual sales data on a monthly basis, and have data for the first six
months of 1998. This monthly data is an accurate measure of actual U.S.
consumption, and will provide a more timely indicator of changing supply
situations, With the addition of the new participants, we will now allow be able to
see the complete picture for the U.S. supply of IVIG, and changes to that supply
‘on a more timely cycle. We have included a ratio of inventory to consumption
that can be used as an indicator of trends in the balance of supply versus
demand. The following table reflects the newest data:

1998 U.S. Supply of IVIG*

- Ko Jan] Feb | March | April | May | June
Inventory 626 844 585. 478 501 B12
Emergency Supply 75 | 87 | 101 | 121 | 102 | 121
US Consumption 1162 | 1240] 1343 | 1352 | 1326 1822
Ratio Ba | 68] 44 [| 35 | 38 | 45

To date

In ideal situations, manufacturers stock one and a half to two months sales as
minimum inventory in an effort to manage product releases and provide an
adequate supply for distribution. This would show up as 1.5 to 2 on the inventory
to consumption ratio above. Any inventory below one months supply (1.0)
indicates a critical supply situation. The ratios listed here very from .35 to 68,
indicating that the inventory of IVIG is still less than one month's supply.

The good news from this table is that it shows that the supply levels have
remained stable and actually show a slight increase over the six-month period.
Now that we have established the data collection system, we will continue to
monitor this situation and provide monthly updates of this information to this
committee, FDA, consumer groups, and other interested parties.

In addition to the collected data on IVIG, we have also started an initiative to
collect information on the supply of Factor VIII products in collaboration with
Georgetown Economic Services. We will first focus on genetically manufactured
(recombinant) Factor VIII products.

Our members have consistently made additional quantities of recombinant factor
VIII available to the U.S. market as this therapeutic has gained in its use. The
following graph illustrates the increasing U.S. supply for the years 1996-1998:


15

hepatitis B surface antigen (HBsAg), antibodies to hepatitis C (anti-HCV), HIV-1 antigen,
and antibodies to HIV types 1 and 2 (anti-HIV)? Donors with positive test results are
rejected from making further donations. The positive unit and all previously donated
plasma units not pooled for manufacture in the preceding 6 months are retrieved, and
those professional services that receive the plasma products are notified according to
federal regulations (21 CFR 610.46).

RISK OF INFECTIOUS UNITS ENTERING PLASMA
POOLS IS SOMEWHAT HIGHER FOR DONATIONS FROM
PAID PLASMA DONORS THAN FOR DONATIONS FROM VOLUNTEERS

The risk of incorporating a potentially infectious plasma unit into a plasma pool for
HIV, HBV, or HCV is somewhat higher for donations from paid donors than for donations
from volunteer donors. Information we obtained on viral marker rates for volunteer
donors from the American Red Cross and from paid donors from the American Blood
Resources Association (which represents paid plasma collection centers) showed viral
marker rates among individuals who offer donations to paid plasma centers to be one and
a half times higher than rates among those who come to volunteer blood centers." This is
due to higher HCV rates among paid donors.

In addition, incidence rates of HIV, HBV, or HCV are higher among paid donors
than they are for volunteer donors, according to our review. These rates include donors
who pass the initial screening tests and donate but who subsequently seroconvert and
whom a screening test later detects during another donation as being positive.’ Thus,
potentially infectious units from these donors could be incorporated into a plasma pool
for manufacturing. HIV incidence rates are 19 times higher for paid donors than for
volunteer donors; HBV and HCV rates are 31 times and 4 times higher, respectively.

antibody tests detect antibodies that the human body produces in its immune response
to a virus; antigen tests detect a part of the actual virus. Because it takes time for the
body to develop antibodies, antigen tests detect infection earlier than antibody tests.

“In addition, tests are performed to examine the level of the liver enzyme alanine
aminotransferase (ALT). ALT may be an indicator of liver disease or a viral infection.
Units with unacceptable ALT levels are not used. Donors with elevated ALT levels are
also deferred from donating in the future. In addition, whole blood donations are tested
for antibodies to human lymphotropic virus types I and II, but source plasma is not
screened for this because it is cell associated and not found in plasma.

“The term "viral marker rates" refers to the rate at which a particular group has
confirmed-positive tests for particular viruses, in this case for HIV, HBV, and HCV.

‘Seroconverting donors are recently infected donors who test negative on a currently
licensed test.

4 GAO/T-HEHS-242


128

SAMPLING FRAME: DOCTORS, PATIENTS BY DIAGNOSIS

DIAGNOSIS NUMBER OF | NUMBER OF
DOCTORS PATIENTS
REPORTING | REPORTED
ATAXIATELANGIECTASLA 134 558
C1 INH DEFICIENCY 11 41
(D4 LYMPHOPENIA 6 10
cGD 234 841
CHEDIAK HIGASHI SYNDROME 2 3
CHRONIC MUCOCUTANEOUS CANDIDIASIS. 160 1,070
COMPLEMENT DEFICIENCY 273 757
COMMON VARIABLE IMMUNODEFICIENCY 1,039 5,557
DIGEORGE ANOMALY 202 134
HYPER IGD SYNDROME 4 7
HYPER IGE SYNDROME 50 116
HYPER IGM SYNDROME 192 402
igG SUBCLASS DEFICIENCY 799 5,307
LAD 7 30
SCID ADA 16 170
SCID OTHER 120 400
SCID X-LINKED 4 359
SELECTIVE IGA DEFICIENCY 936 5,502
‘WISKOTT-ALDRICH SYNDROME 142 388
X-LINKED AGAMMAGLOBULINEMIA 277 894
X-LINKED LYMPHOPROLIFERATIVE 7 16
OTHER 61 179
TOTAL 1,567 BA

Apsil 1998



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14

IPPIA Statement Document No. 011218
9 September 1998
Page 4

The association is currently developing a comprehensive plan to address
GMP compliance issues, which | will discuss in more detail later.

GAO Report

Both the American Blood Resources Association (ABRA) and the IPPIA provided
extensive assistance to the GAO for the preparation of their report on the plasma
(products) industry. IPPIA agrees with the comments provided by ABRA on the
comparison of volunteer and remunerated donors. Regarding compliance with
current Good Manufacturing Practices (CGMP), we agree with the GAO that
compliance with cGMPs is important to ensure the safety of plasma-based
therapies. We also agree with the GAO that FDA and the plasma fractionation
industry have taken steps to address the concerns related to cGMPs and quality
assurance. At this time, | would like to speak to the compliance history of our
industry and the actions taken to help to ensure continual compliance with
cGMPs.

Industry Compliance with cGMPs.

Mr. Chairman, our industry takes its responsibility to manufacture an adequate
supply of safe products very seriously. Adherence to all regulatory requirements
is a part of this responsibility, and we are continually striving to update our quality
systems and other processes to meet these requirements. An example of our
efforts includes increases in capital expenditures. In the last four years alone,
our members have spent in excess of $380 million on plant upgrades and
compliance enhancements. Details are in the next table:

1994 1995 1996 1997
Capital Expenditures (x1000) | $61,828 | $99,749 | $99,676 | $120,287
% \ncrease = 61.3 oO 20.7

However, as you are aware, recent inspections by the FDA have led to warning
letters and in some cases to consent decrees being issued to our members. |
want to assure you, Chairman Shays, that our members are working around the
clock to institute facility-wide enhancements to quality systems and
manufacturing processes to address these findings, while at the same time
continue to manufacture safe products for patients whose lives depend upon
them. Additionally, the association comprehensive safety plan addresses efforts
associated with cGMP compliance on an industry-wide level. The safety of our
therapies 1s of the utmost importance, and we will take whatever measurers
necessary to continue to assure their continued safety and quality.

With safety as our primary focus, one might be tempted to ask how this current
situation arose. According to the FDA, the agency has placed increased
enforcement scrutiny on the biologics sector, with a primary focus on the plasma


32

previous years' levels. FDA has acted affirmatively to assist
the plasma industry to alleviate shortages and is exploring other
alternatives to address shortages. FDA has continued to expedite
lot release for IGIV; monitored the shortages through data
submissions; and worked with health professionals to identify

needed supplies.

FDA believes that the plasma industry also needs to act more
aggressively to comply with GMP while maintaining adequate
production to meet medical demands. FDA will not and can not
relax GMP standards for this industry. While FDA would prefer
not to allow products manufactured under inadequate GMP to be
distributed in the marketplace, the Agency appreciates the risk
to patients of not obtaining product and, where the safety of the
product can be assured, will exercise enforcement discretion in a

manner that accommodates both priorities.

On April 28, 1998, the DHHS Advisory Committee on Blood Safety
and Availability (Advisory Committee) considered the issue of
shortages of plasma derivatives and issued a number of
recommendations. One recommendation was that FDA and industry
should collect and disseminate standardized information on
production, distribution and demand for a number of plasma
derivatives. FDA has asked industry for monthly data on product
supplies, although there has not been final agreement about the

terms and extent of data collection and sharing. Another


108

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 21

PCR Testing

‘The fourth Voluntary Initiative is the implementation of Genome Amplification
‘Technology, commonly known as Polymerase Chain Reaction (PCR). This
technology can further reduce the window period” by identifying potentially
infectious units which fall below the detection threshold of existing donor
screening and testing technologies. Each of the manufacturers is working
closely with FDA and other affected parties to obtain the required agency
approvals necessary to implement PCR technology as rapidly as possible.

Not only can PCR testing limit the maximum potential viral load to the detection
limit of this sensitive assay, it can also serve to validate the effectiveness of the
previously described standards.

‘SUMMARY

‘The four Voluntary Initiatives, described above, represent a tremendous
cooperative effort between plasma collectors and fractionators, and are expected
to have a significant impact on increasing the margin of safety of all products
derived from human plasma. It should be emphasized, however, that these
standards represent not a final solution, but a dynamic process which will be
continuously evaluated and improved. These Voluntary initiatives discussed
“above are part of a comprehensive package of initiatives put fourth by Industry
to take advantage of new information systems and technology used to
continuously improve the margin of safety in plasma-based therapies.

{tis hoped that the significance of these efforts will be recognized by the
appropriate regulatory agencies, as welll as the consumers of our life-saving
products.


39

donations, These mini-pools are tested with a very sensitive
means of detecting infectious agents -- nucleic acid techniques.
While there are a variety of nucleic acid techniques, the most
promising is PCR testing. This technology can detect very minute
levels of nucleic acids, which are genetic building blocks for
infectious agents such as HIV and HCV and for all organisms. If
this testing detects the presence of an infectious agent in the
mini-pool, the individual positive unit can be identified and
eliminated from further processing. Units that are marker
negative based on testing in mini-pools are then combined into a
larger pool. This larger pool is used as the starting material
which will be separated, or fractionated, into various components
that will eventually become finished products such as albumin,
clotting factors, immune globulins, among others. Because this
technology is more sensitive than some current screening, PCR
testing leads to better detection and elimination of most window
period donations from the plasma pool. This great!y decreases,
if not eliminates, the viral load, or the number of infectious
virus particles, in a plasma pool. Although current viral
inactivation/removal techniques have a capacity that greatly
exceeds the anticipated viral load in a plasma pool, further
reductions in viral load only can be viewed as positive measures,

which add to assurance of safety.

Another means of managing risk is to limit the pool size. The

potential benefit of limiting pool size is that the infectious

15


164

Page 2 -- Rochester Approval

to the theoretical risk of Creutzfeld-Jakob disease transmission; and temporary
reductions in production due to industry efforts to enhance production facilities.

The FDA’s approval will allow Baxter to process an “intermediate” called
fraction 2, which is the main ingredient in IVIG. Baxter will then ship the fraction 2
to its facility in Lessines, Belgium, where the process is completed. IVIG produced
in Lessines is imported back to the United States for patients’ use. Baxter will also
continue to process fraction 2 at its facility in Glendale, California, This facility has
been operating at full capacity.

Additionally, Baxter continues to work with the FDA to license a second
brand of [VIG to import to the United States. This will supplement the current Baxter
brand, which is produced in Lessines. The second brand is processed in the
company’s Vienna, Austria facility. When Baxter receives licensure for its second
brand in the United States, it will increase the company’s supply of IVIG by an

additional 15 to 20 percent.

Hee


ABRA Statement September 9, 1998
Page 2 of 6 Reference No.GAOC98008
. Recommendation on AiDS and Plasma Donor Deferral
(1983)
. Recommendations on Infectious Waste Management (1986)

+ Guidelines for HIV Infection Control at Plasmapheresis
Establishments (1987)

+ Recommendations for Shipment of Biological Samples and
Etiologic Agents (1988)

+ Recommendations for Laboratory Standards (1989)

. Policy Regarding Hepatitis B Vaccine Usage by
Plasmapheresis Establishment Employees (1989)

* Guidelines for anti-HCV Screening in Plasmapheresis
Facilities (1991)

* Guidelines for Training, Supervising, and Evaluating
Physician Substitutes (1991)

* Precautionary Measures to Further Reduce the Possible
Risk of Transmission of Creutzfeldt-Jakob Disease:
Recommendation for Donor Suitability (1995)

Beyond these recommendations and guidelines, one of the most significant
examples of industry self-regulation and commitment to safety is the Quality
Plasma Program (QPP). QPP is a certification program that sets a baseline of
industry standards. The program began in 1991 and today is a de facto
requirement throughout the industry. To maintain certification, Source Plasma
collection facilities must adhere to QPP standards and undergo biennial
inspections by third-party inspectors. Any facility found in non-compliance is
immediately notified and given 60 days to respond with corrective actions or risk
losing its certification.

QPP encompasses a broad range of industry standards including, among other
things:

* use of a National Donor Deferral Registry (NDDR),

* adherence to a viral marker rate standard,

* conformance with additional donor screening, education, and
testing requirements,

+ compliance with forma! employee training requirements.


148

9. DHHS agencies and industry should expand support for research to develop
innovative methods for donor screening and elimination and inactivation of
transmissible agents. The Expert Panel believed that the potential rewards from.
such investments could greatly exceed the incremental gains that may be achievable
with further reductions in donor pool size.

In summary, the Expert Panel: a) emphasized the safety of immunoglobulin products;
b) recommended that regulatory decisions that would cap donor pool sizes below current
manufacturing levels await assurances that-’such reductions would not result in products
with substantially altered biological activities, and c) recommended various additional
measures to improve immunoglobulin safety.


35

Agency generally agrees with the findings relating to the viral
marker rates of donors made by GAO in its report. In particular,
FDA agrees that the data presented demonstrate that the paid and
unpaid donor populations, whose plasma is used for manufacture of
fractionated products, have different viral marker rates. FDA
believes, however, that GAO's analysis shows that within the
error of estimation, the risk of contamination of plasma pools
from paid versus unpaid donors is comparable as a result of donor
screening and testing, and inventory hold procedures implemented

by the source plasma industry.

There have been various studies’ conducted to assess the extent
of the differences in the viral marker rates of paid versus
unpaid donors. As might be expected, the studies show different
results depending upon the design of the study, the region where
the study was conducted and other variables. Various differences
between procedures for collection of source plasma versus
recovered plasma make direct comparison of marker rates

difficult. For example, the differences in frequency of donation

‘ california Department of Health Services, Office of AIDS
(various studies analyzing data from California Blood Banks and
Plasma Centers on HIV-1 and HIV-2 prevalence rates of California
blood donors in 1995 and 1996); Schreiber, Busch, Kleinman and
Korelitz, The Risk Of Transfusion-Transmitted Viral Infections,
The New England Journal of Medicine, Vol. 334, No. 26 (June 27,
1996); Kleinman, Busch, Korelitz and Schreiber, The
Incidence/Window Period Model and Its Use To Assess The Risk OF
Transfusion-Transmitted Human Immunodeficiency Virus and
Hepatitis C Virus Infection, Transfusion Medicine Reviews, Vol.
11, No. 3 (July 1997).

a


67

ABRA Statement September 9, 1998
Page 5 of 6 Reference No.GAOC98008,

met. As such, ABRA believes that data pertaining to viral marker rates among
Applicant Donors are not meaningful in terms of assessing the safety of Source
Plasma for further manufacturing into therapeutic products. Despite this strongly
held belief, ABRA has begun a data collection effort targeting Applicant Donors
to respond to requests for such data. The Applicant Donor data that have been
collected to date are incomplete and thus, inclusion of these data in the GAO
report would have been inappropriate and potentially misteading.

Notwithstanding the current unavailability of the Applicant Donor data, ABRA
provided GAO with the data needed to perform its analyses. These include
prevalence rates for all donors, incidence rates on Qualified Donors, and residual
tisk rates for Qualified Donors. Inclusion of the Califomia Department of Health
Services data in the GAO report was unfortunate, particularly in light of the
significant limitations of the data set and the apparent lack of data verification as
acknowledged by GAO. In contrast, the ABRA-supplied data represent the most
comprehensive, complete, and accurate data available for the Source Plasma
industry.

What the ABRA data show is that Source Plasma is extremely safe. For
example, for the Human Immunodeficiency Virus (HIV), the probability that an
undetectable but potentially intectious (HIV) window period donation may enter a
manufacturing pool is 1.47 per million donations. Moreover, all HIV window
period donations from known seroconverting donors are interdicted under the
inventory hold standard. The 1.47 per million probability of a potentially
infectious window period donation entering a pool represents the remote
likelihood that a non-retuming Qualified Donor’s last donation may be in the
window period despite the fact that it does not test positive using current testing
technologies.

The data for hepatitis C virus (HCV) and hepatitis B virus (HBV) also are
profound. With the promise of PCR testing within reach, the probability of a
potentially infectious window period donation entering a manufacturing poo! will
fall from approximately 36 per million donations to only 3.32 per million
donations. Like HIV, with PCR in place 100% of all HCV window period
donations from known seroconverting donors would be interdicted under the
inventory hold. For HBV, currently 91% of all window period donations are
interdicted under the hold and the probability of a potentially infectious window
period entering a pool is approximately 54 per million donations.

As the GAO report points out, these Source Plasma data are comparable to
those reported for the American Red Cross (ARC). The only discrepancy
between the two data sets exists for HBV and, as the GAO report notes, this is
likely due to the transient detectability of the hepatitis B virus and the fact that
Source Plasma donors donate more frequently than do whole blood donors. The
safety profiles for these two sources of plasma are comparable.


104

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 22

Summary: Douglas Bell, IPPIA

Fractionation Safety

Our commitment to safety is clearly illustrated by the QPP and the voluntary
initiatives. More importantly, what can be seen is that we have responded to the
challenge and the pursuit of making plasma-based therapies ever safer not with
thetoric, but with action.

‘You have heard a detailed discussion of the ABRA Quality Plasma Program and
the IPPIA voluntary initiatives. As you can see, these initiatives are dynamic and
continually evolving in our search for safer therapies. Some of these initiatives
have been in place for years, others are being implemented and we are proud to
announce yet another addition to our safety initiatives.

In our testimony this summer before Congressman Shays Human Resources
subcommittee we outlined seven layers of safety in the manufacture of plasma-
based therapies. The uniqueness of fractionation allows for these additional
layers of safety. We believe that these layers of safety are fundamental to
achieving the level of safety our patients expect and need.


167

FAX werr IN BRIEF

“TO RREMARIE FREY, SHATS FINLEY, SHAYS:

pax. 1000204 1.202 225 2382
FROM: COMMITTEE OF 10,000

PAGES (INCLUDING COVER): 8

Wednesday. September 9, 1998

‘ANN-MARIE-HERE {S$ OUR WRITTEN ADDITION FOR RECORD-ALOT ON ECONOMICS-HAVE A LOOK-ANY
COMMENT ARE WELCOMED-ALL THE BEST AND THANKS FOR THE HAAD WORK-COREY



126

Mr. Chairman, the consumers thank you and your subcommittee for its vigilance in
the oversight of this area. We thank you for the opportunity to comment on these
issues. However, we hope that you will hold both industry and government to
their responsibilities and commitments in this area. In the aftermath of the plasma
product shortages earlier this year, the industry promised increased production.
Based on what we are hearing, we ate likely to see further reductions in production
in the coming months. There will be high human costs if this comes to pass. The
FDA promised to try to address the distribution problems by a more extensive
program of educating providers to the appropriate allocation of these scarce
products. This promise has not been fulfilled.

Please remember we are discussing life-sustaining therapeutics! Twenty years ago,
my wife and I were told that my six-month-old son might not live through the
night. Today, he is a college student with no health impairments o activity
limitations. He has not suffered a hospitalization in nearly twenty years. That is
the difference that a safe, effective and available plasma product can make. We
want to make sure that tens of thousands of other patients will continue to have
that chance in the future.

Six months ago consumer organizations were asking for more information about
the reasons for the shortages. Now, in light of a worsening situation, we want
action. At the May 7 hearing Mr. Bacich of Baxter invited you to point at industry
and challenge them to fix the problem. Did they fail to hear the challenge or ate
they unable to meet it? While we wait to see this action, better information is stil
necessary. The consumer organizations need to be made aware FDA and industry
actions taking place and how these actions will affect the product supply.

In conclusion, we offer the patient notification system as a model for cooperation
and communication. The industry has a consumer advisory panel, all companies
have agreed to participate, and the patient information will be registered with a
neutral third pasty that ensures patient confidentiality. The distribution system
should be approached in the same cooperative manner, by the industry,
government and consumers, assuring that delivery is made to those for whom it is
life sustaining,

‘The consumers wish to commend you, Mr. Chairman for the recent recall
amendment you offered to the appropriations bill. This type of legislation serves to
further patient awareness and education and most importantly safety.


45

within its power to help alleviate product shortages. Unless
industry moves forward aggressively with its quality improvement
and assurance efforts, however, shortages and occasional
disruptions in the distribution of needed products will continue
to occur. We will continue our efforts to assure the safety and
availability expectations of patients who need these critically

important products.

2.


87
IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 5

ABRA and QPP: James Reilly, ABRA

Good aftemoon ladies and gentlemen. Before we move to some of the current
and future initiatives of the plasma and plasma products industry, | would like to
give you a brief overview of our Qualtty Plasma Program (QPP).

The QPP is a series of voluntary standards, that if adopted by an FDA licensed
plasma collection center make them eligible for QPP.

The QPP requires, as a baseline, FDA licensure. From that point, as an industry
we have developed consensus standards which take advantage of unique
‘opportunities in our collection and testing procedures, and donor population to
ensure high quality plasma. One of the most ctitical steps is the aggressive and
targeted recruitment of a community-based donor population.


implemented, these actions by the industry and the FDA should help
alleviate current problems. Mr. Chairman, [ think that your interest in

this area has led to these beneficial changes and ! commend you.

Now, Mr. Chairman, I call upon you to look into another issue
regarding the blood supply. Every year blood centers throw away an
estimated 3 million pints of healthy blood donated by people who have
hemochromatosis, also called iron overload disease. These discarded
units represent almost 20 percent of the entire amount of blood donated
ona yearly basis. The FDA does not prohibit the use of blood with
excess iron content, the blood is not harmful and the condition is not
contagious. Therefore, it is unclear why the industry does not use this
blood. Mr. Chairman, I request that you look into this issue to
determine whether the use of this blood is a way to combat blood supply

shortages.

Again, I want to thank you for holding today’s hearing. I look

forward to the testimony of the witnesses.


BLOOD SAFETY: MINIMIZING PLASMA
PRODUCT RISKS

WEDNESDAY, SEPTEMBER 9, 1998

HOUSE OF REPRESENTATIVES,
SUBCOMMITTEE ON HUMAN RESOURCES,
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT,
Washington, DC.

The subcommittee met, pursuant to notice, at 10 a.m., in room
2247, Rayburn House Office Building, Hon. Christopher Shays
(chairman of the subcommittee) presiding.

Present: Representatives Shays. Snowbarger, and Kucinich.

Staff present: Lawrence J. Halloran, 8 director and counsel;
Anne Marie Finley, professional staff member; Jesse S. Bushman,
clerk; and Cherri Branson, minority counsel.

Mr. Suays. I would like to call this hearing to order. We will
have other Members showing up, but I think we should get started,
and I apologize for being late.

Two wi ago, Surgeon General David Satcher decided to lift
the precautionary hold on blood and plasma from donors who may
have Creutzfeldt-Jakob Disease [CJD]. He did so, in part, because
quarantines of CJD-implicated blood products were reducing al-
ready scarce supplies of lifesaving medicines, and because the prov-
en, negative health effects of shortages far outweigh the theoretical
risk of CJD transmission through blood.

The CJD decision illustrates many of the strengths and weak-
nesses of the system now used to protect an inherently risky but
vital resource. Weighing, and minimizing, the risks of an
uncharacterized threat like CJD challenges each layer of the inter-
locking blood safety complex: donor screening, unit testing,
antiviral technologies and manufacturing standards.

While in place, the CJD exclusion policy had a far greater impact
on those who collect “recovered” plasma from volunteer donors of
whole blood than on those who collect “source” plasma from paid
donors. That unexpected disparity, and contrary suggestions that
the payments lure igher-risk donors, led us to ask the General Ac-
counting Office [GAO] to assess the relative risks of plasma from
paid and volunteer donors.

Three aspects of the GAO findi released today stand out:
First, despite persistent questions whether paid donors have less
incentive to disclose disease risks, neither the Food and Drug Ad-
ministration [FDA] nor the blood industry have much useful data
on the viral marker rates of blood donors. This points to a need for
more effective, more consistent disease surveillance.

q@


150

cases that held up a significant amount of material, which is still
being held up.

In addition to that, our primary fractionator, Baxter Hyland goes
through an annual shutdown to retool the plant, and that hap-
pened in the month of August. Notwithstanding that retooling, our
experience with Baxter is that the compliance issues loom very sig-
nificant here because their total throughput is significantly dimin-
ished while they wrestle with these problems and while they try
to bring the plant back up into full compliance, and that doesn’t
happen very soon, as Mr. Bult said. So despite trying to increase
throughput, it is our impression that these compliance issues,
which are appropriate and significant, are being managed by reduc-
ing the amount of output.

Mr. Suays. Was it your understanding from the hearing that we
would see an increase in production?

Mr. McDonoueHu. It was. And I think everybody anticipated with
Centeon coming back online that more product would be available.
But now with their reclosure, there is some question what the im-
pact will be.

Mr. SHAys. How might Centeon’s current compliance problems
affect the availability of medically necessary products?

Mr. BULT. I would like one of my colleagues to stand up and give
that answer.

Mr. SHays. Sure. You have been sworn in, and if you have a card
we will pass it down.

Mr. DELONGCHAMP. I am Alain Delongchamp, and I am the gen-
eral manager for Centeon North America, and the question dealt
with the near term supply availability of IVIG.

At this point in time, as stated earlier this morning, we are still
discussing the action plan with the FDA to release the existing in-
ventory of our IVIG product we have which is pending release. As
we don’t have a final conclusion on that discussion, I am afraid I
am unable to give you a firm answer regarding the time table re-
garding the release of this product, and I would say that it is prob-
ably premature to speculate about this. We would expect to see
some supply in the near term, although I cannot quantify the
amount at this point.

Mr. SHays. I have no sense what your market share is. What
would that be?

Mr. DELONGCHAMP. Roughly in the order of 12 to 15 percent.

Mr. Suays. Your second part?

Mr. Boye. Since we heard the production difficulties last time
and we knew there were going to be shortfalls, although we hoped
that production was going to be increased, we recognized that not
all patients were going to be able to receive these products, and we
were under the impression from the FDA that there was going to
be an attempt to deal with the distribution problem by identifying
to doctors and hospitals the proper allocation of IVIG in terms of
what was medically indicated. Only 40 percent probably of all IVIG
is used for primary immune deficiency diseases, and it is probably
not a lot more for the other indicated uses. And so our under-
standing was that there was going to be a Dear Doctor letter that
was going to outline——


42

identified emerging infectious agent. The Agency is engaged in
the scientific investigation of -merging infectious agents, which
includes surveillance, methods and standards development and

regulatory controls.

In 1997, DHHS organized a Committee on Emerging Infectious
Diseases (Committee) comprised of representatives of the Centers
for Disease Control and Prevention (CDC), the National Institutes
of Health (NIH), and FDA. The Committee has developed a plan for
evaluating and managing any emerging infection with the potential
to threaten the blood supply. The Committee also has developed a
database of known emerging infectious agents that might threaten
the blood supply. This database is updated as new information is
obtained. The response to a potential threat falls into four
phases. First, epidemiologic characteristics of the agent will
be identified and its transmissibility by blood ascertained.
This process may involve field investigations, seroprevalence
studies (if it is a known agent) using banked and acquired
specimens, literature reviews and consultations with outside
experts. Second, the Agency will undergo extensive laboratory
investigations, including, as necessary, attempts to grow the
agent, to infect laboratory animals, and contribute towards the
development of serologic and gene based amplification assays. In
addition to the laboratories of the PHS agencies, assistance may
be requested from outside laboratories that have the appropriate

expertise either through collaborations or by supplementation of

18


161

America’s Blood Centers
Statement for the Record
September 9, 1998

Page 3

Thus, both the private and the public sectors need to take all practical steps to assure the
continuing improvement of blood and plasma safety. Calls that steps may be too
difficult, too expensive, or not worth the benefit should be carefully evaluated. It was
only 4 years ago that FDA Commissioner David Kessler called for the implementation of

GAT testing for improving blood and plasma safety by closing “the HIV window shut.”
Most experts at the time saw Kessler’s 5-year time frame as impractical and that the costs
‘would be in the hundreds of millions. Less than 5-years later, the plasma sector already
uses that test and the voluntary sector will do so shortly. Costs are about one-tenth of
those estimated just a few years ago. Such visionaries are required to assure that
‘Americans have the safest blood supply available.

In America’s pursuit of an absolute safe blood supply, ABC has the following four
recommendation:

1. Continue Strong FDA Compliance Actions. There is no doubt that FDA action in
the early 1990s to raise the bar on GMP compliance has resulted in a safer blood and
plasma supply. No doubt too, there have been excesses by overzealous inspectors.
Overall, however, these strong actions have been appropriate.

2. Use Negotiated Rulemaking to Promulgate New Standards. In the past 10 years

the number of new blood and safety requirements promulgated by FDA have been
ing. Most have been appropriate. To attain uniform good outcomes FDA

ofien feels compelled not only to state what must be done, but how it should be done.
While this is not always inappropriate, FDA has no operational expertise in most of
the areas it regulates. Thus, and sometimes despite numerous hearings on a subject,
FDA often does not identify the most effective or efficient way to achieve its public
health goals, or necessarily in the most timely or inclusive manner. Other federal
agencies effectively use the consensus process of negotiated rulemaking to achieve
public health goals on controversial and or complex matters. Negotiated Rulemaking
has proven to be an effective way to get consumers and industry to work together for
promulgating effective and efficient regulations in a timely manner. For reasons "wei
do not understand, FDA resists using this inclusive process. Congress should compel
such use for blood safety issues.

3. Justify Not Following More Stringent World Solutions. Blood safety is a global
concer. Thus, countries around the world implement blood safety standards to
address the same problems faced in the US, often with different solutions. *
‘Sometimes those measures are more stringent than those in the US, sometimes less
so, and sometimes just different. Global pharmaceutical companies must meet the
highest standards of all countries. For blood components that are not usually
exported (¢.g., red cells and platelets), FDA should publicly examine new


73

‘PPIA Statement Document No. 011218

Di Patient Notification S
In response to a challenge from you, Chairman Shays, IPPIA promised that
we would investigate a system that would allow plasma-based therapy users
to verify the regulatory status of a particular product lot. | am happy to report
that, in cooperation with patient groups, IPPIA is in the final stages of
developing a system that will do just that.

As you are aware, consumers and other interested parties were not always
notified of recalls or withdrawals through the current regulatory system. Your
‘suggestion to provide an 800 number for patients to verify the recall status of
plasma products provided the encouragement necessary to bring about this
unprecedented achievement. Our new system, when fully operational, will
provide plasma product consumers, health care workers, and parents with the
added piece of mind of knowing that they will receive timely notification in the
event of a plasma product recall or withdrawal.

The industry system being developed, scheduled for release in early October,
will include all major manufacturers and distributors of plasma products. This
system will allow the industry to directly notify end users with a two-fold

|. First, individuals interested in receiving notification will register
with an independent third party administrator of the system. These
individuals are able to choose the method of notification most convenient to
them, such as telephone, fax, e-mail, or overnight package. In the event of a
recall or withdrawal, the individual will be directly notified via their chosen
method. This outbound notification portion of this system will be launched in
early October.

The dial-in section will allow the user to call a toll-free number to hear a list of
the most recent recalls and withdrawals. A second option will allow the user
to verify the regulatory status of a particular lot number before infusing the
We anticipate that this section will be online by the first quarter of
1999. In order to ensure that this system meets the needs of its users, we
have enlisted the help of patient groups in a recently created advisory panel.

Pool Size Limitations
A second part of the industry comprehensive safety plan is the voluntary pool
size limitation announced at the same hearing last year. As we explained
then, IPPIA members pledged to limit the total donor exposure to 60,000 for
the major plasma-based therapies. Our intention to initiate this limitation for
currently U.S. licensed products was communicated to the Food and Drug
Administration (FDA) in January 1998. Our members began constructing
manufacturing poois to meet this standard during the first quarter of this year.
We anticipate that all lots released after January 1999 will adhere to this
limitation.


82

IPPIA Statement Document No. 011218
9 September 1998

Page 12

available supply data on a monthly basis, and we are willing to provide this
information to assist interested parties including government agencies and
consumer groups to understand supply related issues.

Thank you, and | would be happy to respond to any questions from the
committee.


BLOOD SAFETY: MINIMIZING PLASMA PRODUCT
RISKS

HEARING

BEFORE THE

SUBCOMMITTEE ON HUMAN RESOURCES

OF THE

COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES

ONE HUNDRED FIFTH CONGRESS
SECOND SESSION

SEPTEMBER 9, 1998

Serial No. 105-189

Printed for the use of the Committee on Government Reform and Oversight

ae

‘U.S. GOVERNMENT PRINTING OFFICE
82-830 WASHINGTON : 1999

For sale by the U.S. Government Printing Office
‘Superintendent of Documents, Congressional Sales Office, Washington, DC 20402
ISBN 0-16-058382-9



108

{PPIA Voluntary Initiatives Presenation Reference No. 007842
Page 26

As providers of plasma-based therapies we are, and must continue to be. leaders
in the commitment to safety. Itis a responsibility that we take very seriously

‘The message we are sending through these voluntary initiatives and our
‘commitment to this comprehensive plan should be clear: industry is dedicated to
continuous improvement. so that the people who depend upon plasma-based
therapies for their health and their very lives will know that those therapies are

safe, available, and effective.

Finally, we invite you to watch us grow as we reach out to the Internet to
‘communicate our message. Our address is IPPIA.ORG. The web page is a
work under progress right now but will be a critical component in our
comprehensive plan.


181

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159

OUR MEMBERS SERVE COMMUNITIES NATIONWIDE

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‘Testimony of America’s Blood Centers
House Government Reform and Oversight
Subcommittee on Human Resources
September 9, 1998

Mr. Chairman and members of the Subcommittee:

America’s Blood Centers (ABC) appreciates this opportunity to submit a statement to the
Subcommittee on Human Resources Committee on Goverment Reform and Oversight
regarding the US General Accounting Office (GAO) study on Blood Plasma Safety.
From our knowledge of the plasma industry the GAO report is accurate as well as
compelling. We applaud GAO for another good and useful analysis and thank
Congressman Shays for requesting the study.

One important aspect of the study compares safety of volunteer donor plasma with that
from compensated individuals. The members of America's Blood Centers provide nearly
half of the nation’s volunteer donor blood supply. This includes over 10 million blood
components for transfusion and over 900,000 liters of recovered plasma for further
manufacturing into plasma pharmaceuticals. In its 36 year history, ABC has supported
an all volunteer blood and plasma system. ABC endorsed, and continues to support, the
National Blood Policy promulgated by the Federal government in 1974 calling for an all
volunteer blood supply. We also have supported an all volunteer donor plasma supply.
‘Yet we recognize today that this latter goal may be unachievable and potentially
unnecessary.

Less than 25 years after the virtual elimination of compensation to donors who provide »
blood for transfusion and the rise of the commercial paid-plasma donor sector, both the
US blood and plasma supplies are remarkably safe.

For example, in spite of residual risks in the volunteer and paid donor sectors, there have
been no reports of HIV transmission from plasma pharmaceuticals since 1987. This is
due primarily to viral inactivation procedures. Despite the continued lack of such
procedures to apply to blood components, likely less than a handful of HIV transmissions
‘occur annually from the voluntary sector. Early next year, implementation of a powerful
test (Gene Amplification Technology or GAT) in the voluntary sector will virtually
eliminate the transmission of HIV, hepatitis C (HCV), and eventually (we hope) hepatitis
B (HBV).





109

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30

In the case of plasma manufacturers, FDA faces a very difficult
task. In many cases, the plasma industry lags behind the drug
industry in compliance with GMP. As FDA has acknowledged over
the past year, and in testimony before this committee, past
regulatory efforts with the plasma industry were not as rigorous
and exacting as they could have been with respect to GMP. Not
all plasma fractionators have accepted FDA's increased
surveillance and oversight. until the plasma industry accepts
that GMP are essential to safe, high quality products, the
manufacturing operations will continue to be out of compliance,
often necessitating enforcement actions that potentially threaten

product supply.

In May, I testified that FDA anticipated some relief in the
shortage of IGIV based on the assumption that Centeon would
resume production of IGIV at its previous capacity. Centeon is
subject to a court order in the form of a consent decree with FDA
that requires significant improvements in GMP. Pursuant to the
consent decree, the company resumed production based on its
initial efforts to comply with the consent decree, which required
improvements to quality assurance, including the hiring of third-
party consultants to evaluate and improve Centeon's quality
assurance programs. Despite FDA's belief that the company was on
the road to compliance, the first comprehensive inspection of the
company to determine compliance with the consent decree revealed

otherwise. The inspection revealed inadequacies in several


89

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 7

Quality Plasma Program
Standards Upgrade History

+ Employee Education & Training
~ Education added / Training updated
+ National Donor Deferral Registry
= Software Operating improvements
= FDA 510(k) Reviewed
= Tests added (p24 & PCR)
+ Vical Marker Rate Standards
~ HCV Added
= HBV and HIV Lowered

1am going to work backwards a little and quickly review the changes to the QPP
since 1991 and then discuss the current standards in total.

‘The employee training standards have been upgraded once and minimum.
‘educational requirement added.

‘The National Donor Deferral Registry (NDDR) has had several minor software
upgrades since 1992, when it first entered pilot phase usage, and on March 20,
1997, it received FDA 510(k) determination of substantial equivalence allowing
ABRA to market NDDR as a medical device.

‘We have also added additional positive test results as causes for listing a person
‘onthe NDDR. They are HIV p24 antigen and PCR test resutts.

‘The viral marker standard we currently have has been upgraded in two ways, by
adding HCV and lowering the HBV and HIV rates in 1993.


84

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page2

IPPIA is the intemational trade association representing the commercial
producers of plasma-based therapies. IPPIA Members produce approximately
80% of the US market for plasma-based therapies. IPPIA Members include the
four largest commercial fractionators: Alpha Therapeutic, Baxter Health Care,
Bayer Corporation, and Centeon.

ABRA is the trade association representing the US source plasma collection
Industry. Because many fractionators have plasma collection operations, there is.
covertap in the IPPLVABRA membership. Distinct from IPPIA, ABRA members
also include both large and small independent source plasma collectors and
other EuropeanvUS plasma industry related affiliates.

With IPPIA representing the fractionation industry's interests and ABRA
representing the source plasma collaction industry's interests, we represent
Virtually the entire commercial plasma Industry.

Because of the unique way source plasma is collected and our membership
being exclusive to the “commercial” sector, our Voluntary Initiatives and
programs that exceed FDA regulatory requirements do not apply to those that
exclusively collect or fractionate plasma recovered from whole blood collection,

Before | yield the floor to my colleague Jim Reilly, who will discuss the QPP
Program, | would like to provide you with a litte background on the evolution of
the IPPIA Voluntary Initiatives. About two years ago the industry of its own
volition began formal discussions regarding innovative ways on an industry-wide
basis we could improve upon the margin of safety in plasma based therapies.
“These discussions required a significant amount of time, personal commitment,
compromise, and financial investment. The conclusion was that measures.
‘should be developed to reduce the potential that so called window-donations, a
risk factor, could enter the manufacturing process.


12

ae en é
Styyaard
Mr. Chairman and Members of the Subcommittee:

We appreciate the opportunity to be here to discuss blood plasma safety. In the
1980s before the mechanism of human immunodeficiency virus (HIV) transmission was
understood, many hemophiliacs used plasma products made from donations by HIV-
infected individuals, which consequently infected 63 percent of all hemophiliacs in the
United States. Many more such patients contracted hepatitis B (HBV) and hepatitis C
(HCV). Although the introduction of antibody tests and viral inactivation and removal
processes has reduced the number of people contracting these diseases from plasma
products, some safety concerns remain.

One of these concerns relates to plasma donors, who may be paid or unpaid. A
long-standing concern exists that paid donors might have higher infectious disease rates
than those of volunteer donors because paid donors may have a financial incentive to
conceal risk factors that would prevent them from donating. Concerns have also been
raised about the number of donors to whom a recipient is exposed because
manufacturers of plasma products pool donations from many donors. Furthermore, the
efficacy of viral clearance procedures manufacturers use and the manufacturers’ safety
record can clearly affect the ultimate safety of plasma products.

Because of these concerns, you asked us to discuss the results of our recent report
on blood plasma safety.’ In that report, done at the Subcommittee's request, we (1)
compared the risks of incorporating a plasma unit infected with HIV, HBV, and HCV-from
donations from volunteer donors with those from paid donors-into the manufacturing
process; (2) examined the impact on frequent and infrequent plasma users when pooling
large numbers of plasma donations into manufactured plasma products; (3) assessed the
safety of end products from plasma after they have undergone further manufacturing and
inactivation steps to kill or remove viruses; and (4) examined the recent regulatory
compliance history of plasma manufacturers.

In summary, viral clearance techniques have made the risks of receiving an
infected plasma product extremely low when manufacturers follow all the procedures in
place to ensure safety. Although paid plasma donors are over one and a half times more
likely to donate potentially infectious units (1 in every 3,834 units), several recent
irubauves by the paid plasma industry have greatly reduced the chances (to 1 in every
10,959 units) of these units being included in the plasma production pool. These
iniuatives include using only repeat donors (who have been found to have lower rates of
viral infection than first-time donors) and a 60-day inventory hold on all units to allow
manufacturers to retrieve units from donors who subsequently test positive for disease or
are otherwise disqualified. Nonetheless, even with these initiatives in place, plasma units

‘By m ks
Are Followed (GAO/HEHS-98-205, Sept 9, 1998).

GAO/T-HEHS-242


54

a sudden we are measuring these companies against some industry
standards that obviously didn’t come out of this industry, or they
would have been following those kinds of things all along.

I guess I’m trying to figure out where those standards came from
and how we are making that measurement.

Mr. CHESEMORE. There are standards for drug manufacturing,
and there are standards for biological products. Biological products
are considered drug products, and they should follow the GMP’s for

‘s as well as biologicals. The set of standards as published in
the Federal Register have been around probably since the 1970’s.

Mr. SNOWBARGER. But were those for—this is for drugs as a
whole, and then we classified —

Mr. CHESEMORE. And they’re very general, they're very broad.
You should have these types of systems, these types of processes,
you should validate that type of thing. Since that time, since the
1980’s and in the 1990’s, we've added a number of guidances for
the industry, both the blood industry and the plasma fractionation
industry, because the GMP’s are called the current GMP’s, and
things change. We now know about situations in the 1990’s with
HIV, et cetera, that we did not know in the 1970's. So these things
are taken into consideration, and we do provide then updated com-
Pliance guides for the industry to follow.

The other thing I would simply state is that we have changed
our inspectional approach in that the same people who inspect the
drug plants for GMP’s are now inspecting the plasma fractionators
for GMP’s. So from that standpoint, I think we’re getting a more
focused view of how the industry complies with GMP’s.

Mr. SNOWBARGER. When were the biological products brought
under the same standards as the drug manufacturing, or has that
always been the case?

Dr. EPSTEIN. Yes, the biological products are subjeci to the drug
GMP’s and always have been. The issue has been regarding the
inspectional approach. We operate under two acts, and historically
the Public Health Service Act, which governed the biologics, had its
own structure for dealing with inspections.

What has happened since 1996 is a careful merger of the two sys-
tems, taking advantage of the virtues of both, namely the product
expertise in the biologics center and the GMP expertise in the field
force, which historically had the sole role for inspecting the drugs.
So whereas the biologic products were subject to the biologic GMP’s
in the Code of Federal Regulations as well as the drug GMP’s, it’s
the shift of balance and focus that has changed.

The particular points of importance are the fact that the lead re-
sponsibility for the periodic inspecting has been transferred since

tober 1996 to the field, and as Mr. Chesemore stated, that
means that the people who had been doing the pharmaceutical
drug inspecting are doing the fractionation inspecting. So there has
been a shift of orientation, a shift of leadership and a merger of ex-
pertise.

Mr. SNOWBARGER. Not to suggest that we're not using the proper
standards, but when we go back to low compliance rates, how much
of the low compliance rate is attributable to the fact that we’ve
now, in effect, upped the standards by following them more strictly
since 1996 and had the field inspectors—I mean, there was a sig-


1
4

traditional products market which is basically moderated by market
forces and the decisions of given manufacturers? Or, is this a unique
situation due to the nature of the products produced and the life or death
dependence of certain communities on these products?

COTT contends that the medical and social need for plasma
derivative products should impact the way we view and regulate this
marketplace. It is also important to note that the profits incurred by
these particular manufacturers are, in large part, paid for by the society
as a whole. The extreme costs of plasma derivative products are, to a high
degree borne by the states and the federal government, in essence the
taxpayers. From our perspective the social necessity of these products and
the willingness of the public sector to underwrite industry profits in
order to ensure sufficient supply, has resulted in a marketplace that is
essentially sheltered. Normal market forces are not a moderating force on
price in this instance as the four manufacturers have for thirty years
worked in concert to ensure a stable and artificially high price structure.
The federal government has tolerated a situation that raises serious anti-
trust questions and leaves four manufacturers in total control over the
safety and supply of products that represent life or death for the majority
of individuals who depend on plasma derivatives to remain healthy.

Blood products are a social utility, a medical product that the
society requires in order to ensure the health of those with clotting
disorder and other diseases such as Alpha-1 and primary immune-
deficiency. The regulation of this industry should reflect the social nature
of the products being produced as well as the public sector’s underwriting
of the costs. Society, the public sector has also borne the human and
financial costs of the industry’s failure during the 1980s regarding HIV
and the blood supply. The medical costs of treating nearly over twenty
thousand Americans who contracted HIV/AIDS through blood/blood
products has been in the hundreds of millions of dollars at 2 minimum.
Now the society will pay for the industry and regulatory failure regarding
the transmission of Hepatitis C to potentially one million Americans.
These “clean-up” costs never appear to be factored into the costs/benefit
equation when assessing the blood/blood products industry and its
regulation. Society has underwritten the costs of the treatment, blood


IPPIA Voluntary Initiatives Presenation
Page 14

96

Reference No. 007842

IPPIA Voluntary Standards
1. Applicant Donor Standard
2. Viral Marker Rate Standard
3. Inventory Hold
4. PCR Testing
=
These Initiatives include:
1. Applicant Donor Standard
2. Viral Marker Rate Standard
3. Inventory Hold
4, PCR Testing

ABRA subsequently has endorsed these Intiatwes and has committed to
incorporating those standards applicable to plasma collection into its QPP. Over
the next few minutes, | will discuss the Voluntary Initiatives in detail

Applicant Donor Standard

te Card

Relative Risk of
Applicant Donor Units

‘Cote Pons Unt



170

3.

It is clear that the violative lipid envelope viruses that we know
about such as HIV, HBV, and HCV can be addressed in an efficacious manner
if viral inactivation technology is applied within a context of vigilant
quality control and regulatory oversight. The GAO report raises serious
questions regarding whether or not this is, in fact, what is currently
occurring. Products considered the safest such as albumin, in one instance
failed existing standards as they were being prepared to be shipped. The
degree of GMP problems currently Identified by the GAO report paints a
troublesome landscape, especially when you consider that half of the
current manufacturers, 50 percent, are currently under consent degrees
due to GMP failures.

While it appears that the FDA has intensified the regulatory climate
in some areas, that intensification has yet to result in what we would
view as an acceptable GMP landscape. Either the agency is not aggressive
enough in its follow through or the manufacturers are not complying at an
acceptable level. Whatever the basis it is clear that GMP failure is a
significant contributing factor in the current shortages of plasma
derivative products. The FDA must use the regulatory authority it
possesses to whatever degree necessary to gain manufacturer compliance
in a timely fashion.

We continue to be appalled by the fact that the FDA Blood Products
Advisory Committee continues to make critical recommendations
regarding safety margin issues without the data necessary to ensure that
the recommendations being formulated are the best possible. Why is the
BPAC not receiving regular updates on the status of the consent decrees
currently in force with Centeon, Alpha Therapeutics and the American Red
Cross? Why are full voting members of the BPAC told that the only way
they can view the consent decrees is through a Freedom Of information
Act petition? Why do senior FDA regulators shrug their shoulders when
queried about why the necessary data is being withheld by the industry?
Why has it taken ten years to begin to get aggregate monthly production
data from the industry?

From our perspective a critical question not being discussed is how
do we view the plasma derivative products marketplace? Is it a


15

IPPIA Statement Document No. 011218
9 September 1998
Page 5

fractionation industry’. As you are aware, the FDA has changed its process for
inspecting biological establishments through the introduction of Team Biologics.
The Office of Regulatory Affairs has taken lead responsibility for these
inspections, emphasizing a complete assessment of cGMP compliance. Under
this new inspectional process, as documented by the Health and Human
Services inspector General (IG)?, the inspections have lasted three times as
long, reported four times as many observations, and resulted in five times as
many enforcement actions as inspections under the old system. It is important to
note that both types of inspections were conducted under the same regulatory
requirements, and while the manufacturers were increasing quality systems and
personnel as discussed earlier.

The IG reported several reasons for these changes, including more inspectors
and longer inspections. Additionally, the reporting system changed. Items that in
the past would only have been discussed with the firm are now reported on Form
483s. Another significant change was the inspectors themselves, scientists
under the old system with primary focus on scientific or technical issues versus
full time inspectors with greater attention to cGMP and documentation issues
under Team Biologics®.

Mr. Chairman, | would like to state for the record that we are proponents, not
critics, of a new approach to enforcement. We agree with the FDA that this
process has led to a greater assurance of quality conditions for product
manufacturing. A larger number of inspectors spending more time on
inspections are more likely to find areas needing further improvement. Our
members are committed to working in cooperation with the FDA to address each
of these issues in order to ensure production under the highest safety and quality
standards possible.

We believe, however, several factors need to be considered to completely
understand the potential implications on safety and supply from this increased
scrutiny.

* Statement by Michae! A. Friedman, M.D., Lead Deputy Commissioner, Food and Drug
Administration, Department of Health and Human Services before the Subcommittee on Human
Resources Committee on Goverment Reform and Oversight, U.S. House of Representatives,
May 7, 1998.

2 “Review of the Food and Drug Administration's Inspection Process of Piasma Fractionators”
Department of Health and Human Services Office of inspector General, June 1997.
® Ronald F. Tetzlaff, “Preparing for Team Biologics Inspection’, BioPharm August 1998, 18-28


36

of whole blood versus plasma affects the calculation of the viral
marker rates. While the various studies are instructive, none
should be interpreted as an absolutely accurate measure of viral

marker rates nationwide.

The implications of viral marker rates in paid donations have
been considered by FDA for a number of years. On June 28, 1993,
FDA sponsored a Workshop on Safety of Plasma Donation as part of
the June 28 and June 29 Blood Product Advisory Committee (BPAC)
Meeting. FDA asked committee members to review whether source
plasma and recovered plasma were comparable with regard to the
safety and efficacy of plasma derivatives produced. The safety
of plasma derivatives also was reviewed at the International
Conference on the Virological Safety of Plasma Derivatives in
November 1996. FDA again brought the issue of viral marker rates
to the BPAC on March 19 and 20, 1998, and asked for a similar
review based upon additional data and changes in the plasma
industry, including implementation of PCR testing and new donor

management practices.

Direct comparison of viral marker rates, therefore, does not
measure either the differences in the underlying donor
populations or the residual risk to plasma pools. FDA concurs
with GAO's models for estimating the incidence of infections in

the populations and the risk after donor selection and screening.

12


48

dustry, for whatever product it is, we think that a collaborative, co-
operative, disciplined, serious relationship is the kind of relation-
ship to have. It is not what has sometimes been described as a cozy
relationship or a blind-eye relationship, but it is not an adversarial
relationship unless it need be. I think the best way that we can ac-
complish what the American public wants is to work cocperatively.

Having said that—and there are dangers in oversimplifying and
generalizing, and I don’t mean to do that—but this is an industry
where we have had difficulty reaching ment on the impor-
tance of good manufacturing practices in the past. What impresses
me is the point Mr. Chesemore made, which is, if you look at par-
ticular firms, you will see that their inspection—that the success
of the inspections has moved up for selected firms; that individuals
have understood the importance of GMP’s, and their subsequent in-
spections have been better and better.

We believe that this is a trend that is moving forward. It is not
moving forward as speedily as you or we would like. It is not as
complete as you or we would like, but we think that there is impor-
tant progress that is made. We accept the word of the companies,
but I don’t think that has diluted at all the intensity of our inspec-
tions.

Mr. SHays. Let me ask GAO’s response to a 50 percent compli-
ance.

Ms. STEINHARDT. Well, I was actually very interested in the
rates. But let me share with you, I read over the inspection reports
which accompanied these findings, the ones that I cited in my
statement, and these were not minor paperwork kinds of infrac-
tions. These were very serious and systemic. They described prob-
lems across the board in manufacturing, in a series of manufac-
turing processes—and these are not the kinds of problems that
could be corrected overnight. I mean, it was not difficult to under-
stand why, following an inspection report like the one that was pre-

ared after the—or during the Centeon inspection—it was not dif-
ficult to understand why the company might choose to shut down
its whole operation to try and address some of those problems. So
it is not just the compliance rate or noncompliance rate. I think it
is important to understand that in this industry, the kinds of viola-
tions that FDA ins rs observed were very, very serious.

Dr. FRIEDMAN. If I may add one other thing, it was very inter-
esting to me that the new chief operating officer of the "Centeon
Corp. came and spoke to us. He described the problem that he was
encountering was a cultural problem. I am reinforcing what GAO
is saying here. It was nonattention to important details.

Mr. Suays. Let me recognize Mr. Kucinich, and maybe he can
ask you that question he asked under his breath.

Mr. KuciNnicu. Thank you, Mr. Chairman. What do you mean by
cultural problem?

Dr. FRIEDMAN. By that I mean it is the—what I understood him
to mean—it was the attention to details, the viewpoint in doing ev-
erything possible to investigate problems, to resolve problems and
to prevent problems from occurring.

If I may give you an example, in a certain piece of equipment,
a residue was found on the bottom of that piece of equipment. That
residue was cleaned up and nobody asked the question, where did


117

NHLBI Retrovirus Epidemiology Study

Three Red Cross Blood Services Regions participate in the National Heart Lung and Blood
Institute (NHLBI) Retrovirus Epidemiology Donor Study, known as REDS. The REDS program
supports a wide range of clinical, laboratory, and epidemiology investigations of infectious
disease agents in blood donors. The regions provide complete donation data and selected blood
samples for repository collection and further testing. REDS continues to provide valuable
information on behavioral risk factors of donors, and the effectiveness of donor screening
measures.

Research Efforts Related to CJD:

To date, the American Red Cross has committed over $1 million to research studying possible
links between CJD and transfusion-- more than any other private organization. We have several
research studies underway at Holland Laboratory, and in collaboration with Dr. Paul Brown at
the National Institutes of Health and Dr. Robert Rohwer at the Veterans Administration. The Red
Cross is also continuing to work with Marian Sullivan, of the American Association of Blood
Banks (ABB), who is directing a CJD “lookback” study, involving recipients of blood
transfusions from donors subsequently diagnosed with CJD. These recipients have been
followed for up to 25 years following transfusion, and none of them has died of CJD or shown
any sign of the illness.

Improvements in Testing

As the Subcommittee heard at its hearing in May, the Red Cross has successfully implemented
Transformation, a seven-year, $287 million program to re-engineer literally every aspect of Red
Cross collection, processing, testing and distribution systems. Transformation has placed the Red
Cross in a leadership position to further enhance the safety of the blood supply by adding
genome amplification technology (GAT) testing to our donor testing processes. GAT employs a
new technology that directly detects the genetic material of viruses that have infected human
cells. This is « distinct improvement over current tests which detect antibodies formed by the
body in response to infection. The result is a significant reduction in the “window period” (the
time between infection and our ability to detect infectivity) for HCV (from the current 82 days to
a projected 23 days), and a further reduction in the already small window period for HIV (from
14 days to a projected 9 days).

We are working with the FDA to secure approval of an Investigational New Drug (IND)
application in order to implement GAT testing for HCV and HIV of plasma to be manufactured
into derivatives later this year, This work is being done in collaboration with GenProbe Inc., the
test kit manufacturer. At present, GAT testing of individual units of transfusable components is
not operationally feasible. We remain committed however, to pursuing this technology for all of
our products.

Patient Notification of Recalls
In response to concerns expressed by patient groups and this Subcommittee, the Red Cross
moved ayyressively to establish a system whereby patients using our plasma derivatives could be

4


53

Mr. SNOWBARGER. Let me go back and kind of followup on a
question that the chairman asked earlier about compliance rates,
and, again, I don’t necessarily need to know the name of the com-
pany, but what’s the highest compliance rate that we have within
the industry, for a company?

Mr. CHESEMORE. Could I address a couple of issues in responding
to this question, and I think perhaps some other issues that Ms.
Steinhardt raised? About a year and a half ago, the agency made
a collective decision to change the way that we would inspect plas-
ma fractionators by having a group of approximately 15 or 16 of
our best investigators who are making these inspections. One of
the reasons we wanted to do this was to better ensure consisten
of our inspectional approach. And I think that’s working quite well.
I think it's also one of the reasons that the compliance rate of the
industry is what it is. One of the comments made was that we’re
taking things for granted. My investigators would be very upset
with me if they didn’t know that just because a firm tells us they
will do something, we want to see the data to show that they did
that. The compliance rate is established really by not just the num-
ber of deviations or violations, but the seriousness of them.

And so there are approximately 26 firms that fractionate prod-
ucts within the United: States and abroad, that produce products,
that ship products to this country. Three foreign firms are not ship-
ping any y products. So that leaves about, you know, 22, 23 firms to
inspect. There are four major manufacturers of plasma fractionated

oducts that produce the most. Two of those, as Dr. Friedman in-

licated, are under consent decree. Very few, I would say maybe 2
of those 20-odd inspections that we made did we find situations so
good that we classified that report as no action indicated, in other
words, that firm was totally in compliance.

Then you have a range of serious violations, some of which the
firm needs to improve, but it’s not serious enough where we're
going to either send the firm a warning letter or we're going to
seek an injunction or some other serious action.

Then at the far end you have these firms that are totally out of
compliance as far as we're concerned. They really have major, seri-
ous violative situations. We either send them a warning letter that
says, basically, if you don’t improve your GMP’s, then we will pos-
sibly seek a court-ordered injunction or perhaps a suspension of
your operations.

The other thing with this particular product is simply that the
features of fractionation are such that the viral inactivation is very
strong. That’s fortunate. But still how you make that product day
in, day out, lot by lot, that’s the thing that our investigators loo!
at, and that’s what the GAO has described in their report.

That’s a little bit of a long answer. I apologize.

Mr. SNOWBARGER. There ought to be a longer way to ask this
question, but I'll ask it very shortly, and if you’re not addressing
it the way I had in mind, I'll let you know.

Where are we getting the GMP’s? I guess I need a little history.
I mean, this is an industry that has a history, that’s been around
a while, that’s been making blood products, and I presume that as
we got into an era where there seems to be more blood-borne
pathogens, that we began to look at it more seriously, and all of


138

In other words, I don’t get the sense that there is this kind of
competition. I get the sense that old practice has stayed on too
long. Maybe somebody can tell me if I am way off on that. If I am

“ie

Mr. Butt. If I may respond first, Mr. Chairman, I don’t know
where this feeling is coming from. What we have to realize, and we
really want to work and cooperate with all agencies to work on a
model if that is a possibility and provide the data.

Mr. SHays. Let me say that I think there has been some signifi-
cant ss made in the last few years. I ask myself why didn’t
that happen sooner? What was wrong with the system that didn’t
make that happen earlier?

Mr. REILLY. I think competition has driven a number of improve-
ments over the years. The drive within the group Mr. Bult rep-
resents toward monoclonals and ultimately recombinants for AHF
is clearly competitive.

On the source materials side, issues like RQPP have been driven
in large measure by competition. When we first initiated it, the
NHF took a look at the program and endorsed it, and that was a
major factor in a drive toward it being what I reference as a de
facto requirement for source material. So there is substantial com-
petitive pressure to improve products and maintain a safety and
compliance record.

Mr. Suays. It seems to me that the competition might make you
want to come to the marketplace and have larger lots and so on.
There is not as much—it seems to me that the safety area, you
don’t have as much of an incentive unless the FDA does shut you
down. And I get the sense that sometimes the FDA is not going to
shut you down because they simply need your supply.

Mr. REILLY. The improvements that I just discussed were all
largely around safety initiatives.

. SHAYS. That is in the last 2 years.

Mr. REILLY. No, those thing s that I described were over the past
15 years. The speed at which we are adopting them, I think the
committee deserves a great deal of credit for. These hearings have
brought a lot of focus on the aggressiveness of compliance and the

we are at looking at new initiatives, and they have focused
in the it several years much more specifically than in the past.
Mr. Suays. Let me invite the minority staff to ask a few ques-
tions.

Ms. BRANSON. There has been quite a bit of discussion about 40
percent of the industry being under consent degree. I am won-
dering what percentage of the product that represents?

Mr. BULT. It is difficult to make an accurate number. I have not
made a calculation. We have two companies who are working on
the consent decree. I don’t know exactly what the total percentage
of product is that is affected.

Is. BRANSON. There was a discussion earlier about lipid envel-
oped viruses versus nonlipid enveloped viruses and the effective-
ness of viral inactivation. First of all, what does the FDA require
you to test for, and are those particular infections, viruses, what-
ever you choose to call them are lipid enveloped or nonlipid envel-
oped? Anybody on the panel can answer that.


49

it come from? Did a vial break? Is there something wrong with this
uipment?
it is the sort of cultural issue. You don’t want somebody to
just clean it up. You want somebody to ne did a problem occur?
How did it arise? How can I prevent it and how can I fix it?

It is a more sive, overall commitment to quality. This
chairman gave us his personal commitment to wanting to instill
that sort of a culture. We told him that we thought that was en-
tirely appropriate. But until that is done, the kinds of issues that
GAO is talking about won't be addressed. We are not talking about
a paper checklist.

ir. KUCINICH. Thank you, Doctor. I am just wondering, since
this shockingly low rate of compliance is at issue here, it occurs to
me that in order to come to compliance, it would be expensive for
these companies. I just wonder if profit motive is one of the cul-
tural roblems that we are talking about here.

Dr. FRIEDMAN. I can say that I think the most ay propriate thing
for me to say is that is a question that you should address to the
industry. That concern has not escaped us. We have been told that
considerable investments have been made, but the thing that influ-
ences me in this, sir; is that these are products that we are talking
about that are in sometimes desperately short supply, where the
price has risen Progressivel , where if a company were motivated

y profit, then having the largest production because the need is
a very substantial one——

Mr. Kucinicu. I can see that the FDA is concerned about ad-
dressing supply issues. I looked at your statement. Centeon is out
of compliance despite repeated efforts. They keep operating. You
relaxed restrictions on CJD, so obviously you are very concerned
about supply. I congratulate you about your concern about supply.

I do not congratulate you about your concern about safety, be-
cause it seems when you decouple the issues about safety, the pub-
lic has plenty of reasons to be concerned about the blood supply.

Dr. FRIEDMAN. I don’t think any of our actions have compromised
safety. We have carefully looked at all of the products currently
being released. If we have any concerns about the safety of those
products, those products are withdrawn and not released.

Mr. Kucinicu. I wish you would have footnoted your testimony
with respect to the statement that says, “More importantly, epide-
miological studies of humans over the past few decades have failed
to demonstrate a single case of blood transfusion causing CJD in-
fection.”

That is a remarkable statement because it suggests a pathway
for a cure for CJD. Whose studies were they? When were they
done? Who did them? I would be very interested.

Dr. FRIEDMAN. I will be happy to supply that. That is informa-
tion which comes to us from Dr. Schoenberg and others at the Cen-
ters for Disease Control. These are studies which have been pre-
sented nationally and internationally. If I may, I would be very
happy to have them provide to you those data.

‘ay I add one other thing, sir; and that is, we take no comfort
from an individual point analysis such as that, and the commit-
ment that we all have made is that we will continue to scrutinize
very carefully the people who receive the most blood donations to


78

IPPIA Statement Document No. 011218
9 September 1998
Page 8

cGMP Element of industry Safety Plan

As | stated earlier, our industry is committed to providing an adequate supply of
safe products. Part of this commitment includes the assurance of quality
conditions for product manufacturing by strict adherence to cGMP guidelines. To
this end, IPPIA has initiated several activities under the overall heading of the
GMP compliance element of the IPPIA Strategic Safety Plan. | would like to
outline these activities for the committee at this time:

Process Validation

Our members are working as members of a task force from the Parenteral
Drug Association (PDA) to develop process validation guidelines for the
plasma fractionation industry. The purpose is to evaluate the appropriate
approaches to develop and implement process validation in an industry where
many processes have been is use for many years. The task force plans to
establish guidelines on what constitutes an acceptable level of
documentation, and establish guidelines on how to obtain that level of
documentation for our existing fractionation processes. Several meetings
have already taken place on these issues.

cGMP Workshops

IPPIA, in cooperation with Pharma Conference Arrangements, is working to
develop cGMP workshops for the fractionation industry. These workshops
will provide an open forum where industry and our regulators can discuss
strategies for enhancing compliance with cGMPs. The first workshop is
tentatively scheduled for Spring 1999. We anticipate that the program will
include issues on environmental monitoring and quality systems.

Industry Response to Product Shortages

| would like to focus my remaining testimony on the industry response to
shortages of plasma products and their recombinant analogs. During a hearing
of this committee on May 7, 1998 to discuss a shortage of Intravenous Immune
Globulin (IVIG), IPP1A provided data from our members in an effort to quantify
available supplies and determine the causes of the shortage. We also committed
to providing updated data on a quarterly basis to better understand the supply
situation as the shortage evolved. The data we supplied in May showed IVIG
supply on a yearly basis, with a preliminary forecast for 1998. The data was also
limited to IPPIA members only.

| am happy to announce here today that we have expanded this effort to include
data initiatives that will provide this committee, FDA, patients, and other
interested parties with more sensitive indicators of the U.S. supply situation.
First, through Georgetown Economic Services we have expanded our data
gathering effort. Now, we have included data from the American Red Cross and
Novartis, the two major distributors of IVIG not accounted for in our last


{PPL Voluntary Intetives Presenation Reference No. 007842

Quality Plasma Program
Facts & Figures

+ Eatsbtahed 1991
+ 300.0410 Centers Cortted

12m of 13 m Donations Certied
‘mm 102m Donors
{11m Liters of Source Ptaums
+ NHF Support by Resohion & Leer
+ Wertwide Recognition

Before | go into the standards themselves and some of the changes we have
made to the program over the years, it would be useful to review a few basic
facts about the industry and QPP.

QPP began in 1981 with the first center being certified. Today, 372 of the eligible
413 commercial plasma centers are QPP certified. To place this in a more
meaningful context, roughly 1.5 millon donors donate approximately 13 million
times annually. About 12 million of those donations are at a QPP certified center.
‘These donations produce about 11 milion liters of plasma.

‘This program is supported by the National Hemophilia Foundation by Board
Resolution and subsequently by @ letter to all of the U.S. fractionators
encouraging them to make it a requirement in their plasma collection
specification.

Over the years, it has in fact become a requirement of all the U.S. plasma
fractionators and most of the fractionator world-wide, To put the world market
into perspective, the 11 million liters produced here in the U.S. is about 60% of
the entire world supply of plasma for further manufacture.


43

existing grants. Third, FDA will issue recommendations to blood
establishments for donor screening and deferral. Fourth, PHS
will establish emergency communications to enhance coordination
and interact with State and local health departments and blood

organizations.

The Committee has been holding regular quarterly teleconference
meetings and ad hoc meetings. The FDA BPAC and PHS Blood Safety
Committee have been informed on a regular basis of updates and
initiatives undertaken by this Committee. FDA also regularly
interacts with patient groups, academicians and industry
scientists to remain current with outstanding issues of concern

and technological advances.

There are a number of examples of emerging threats for which FDA
has been actively involved in developing a response. For
example, Chagas disease, caused by the parasite Trypanosoma
cruzi, while endemic in South and Central America, has become an
emerging threat in North America. This parasite is transmitted
through blood transfusion, although fortunately there only have
been four cases of this disease caused by transfusions in

North America. FDA is monitoring several large-scale clinical
trials being conducted in blood banks in the United States using

experimental assays to detect infection of the parasite.

19


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113

First, the Red Cross research and surveillance program, known
as ARCNET, researchers at the Holland Lab and in Red Cross re-
ions throughout the country monitor the epidemiol. of trans-
sion-transmitted diseases. ARCNET investigators work with our
current and deferred volunteer blood donors to gather information
critical to disease surveillance. Through an Internet-based commu-
nication system, ARCNET allows speedy exchange of the latest sci-
entific information about existing and emerging infectious diseases.
The system maintains a cent repository for epidemiologic data
used to support research studies unde n at Hyland and at a
number of our regions. At present the Red Cross is studying the
possible impact of Chagas’ disease and a number of tick-borne in-
fections on the safety of the blood supply through this mechanism.

Next, Red Cross is a key participant in the National Heart Lun;
and Blood Institute retrovirus epidemiology study known as REDS.
The REDS program supports a wide range of clinical, laboratory
and epidemiology investigations of infectious disease agents in
blood donors.

Mr. Says. Mr. McDonough, I’m trying to follow you. I admit I
should have had more sleep. I should have had some sleep. But I
want to know the relevancy of what you're testifying now to the
issue at hand. What’s the bottom line point that you want me to

ow?

Mr. McDonoucu. The bottom line point is that we are workin;
in several different avenues to identify risk associated with bl
transfusion, emerging risks such as Chagas’ or other tick-borne dis-
eases which could or certainly may impact the safety of both whole
blood and components and plasma derivatives, and a point that I
would conclude on is that we’re also implementing new testing
technology for the same purpose.

Mr. Suays. I had a sense that this is all happening, and what
I would love you to address, and then we'll get to Dr. Boyle, is the
issue of the standard that exists now throughout the industry, the
good manufacturing practices that take place and the issue of com-
pliance versus noncompliance. Those would be the issues that I
think that this committee has a sense that there has been tremen-
dous progress and the desire to improve systems, but that’s

Mr. McDonoucu. Mr. Chairman, with that comment I'd be glad
@ conclude my remarks and defer comments about compliance on

Mr. Suays. If there’s anything else that you want to cover in that
statement, I’m happy to give you a second just to look at it.

Mr. McDonouGu. No, I think I’ve covered it adequately, Chair-

man.
[The prepared statement of Mr. McDonough follows:]


122

Ms. Chairman and members of the Subcommittee, I am John Boyle and I am here
today on behalf of the Plasma Users Coalition. The Coalition includes the Alpha
One Foundation; the Alpha One National Association; the Committee of Ten
Thousand; the Hemophilia Federation; the Immune Deficiency Foundation; and
the National Hemophilia Foundation.

‘The Coalition represents patients who depend on the long-term use of plasma
products for their health and very lives. As you know, more than 500,000
‘Americans use plasma products each year. However, persons with alpha one
antitrypsin deficiency, bleeding disorders and primary immune deficiency diseases
must use plasma products many times each year for their entire lives. There are
approximately 4,000 alpha one plasma users, 15,000-18,000 bleeding disorder users,
and 20,000-30,000 immune deficient plasma users. Collectively, we represent about
50,000 Americans. The Coalition exists so that we may exchange information and
support the needs of individuals dependent on frequent and life long usage of
plasma based products. Hence, Mr. Chairman, I am here today speaking on behalf
of the 50,000 to 60,000 individuals who consume plasma-based products repeatedly
and in large quantities to escape suffering from painful, debilitating and life
threatening diseases. Personally, I am here today because my infant son was
diagnosed with one of these disorders nearly twenty years ago.

First, it is very important to note that plasma products are essential to the
health and well being of persons with these chronic disorders. For example,
before the introduction of gamma-globulin for the treatment of immune deficient
patients nearly fifty years ago, persons with these disorders could expect to suffer
repeated infections until one finally killed them. Today, many immune deficient
Patients can be expected to live long and relatively asymptotic lives, thanks to
intravenous gamma globulin. Second, there is currently no medically equivalent
product available for alpha one or primary immune deficiency diseases. ‘The
bleeding disorders community docs have a recombinant option, however,
recombinant products are in short supply, and more expensive than some patients
can afford.

Mr. Chairman, you requested that the Coalition address the following issues; the
GAO report comparing viral marker rates of paid versus volunteer donors, the
regulatory compliance of plasma manufacturers; current and chronic shortages of
plasma products and finally the Department of Health and Human Services efforts
to address product availability. Given our limited time and urgency of the latter
issues I will focus my remarks on GMPs, product availability and efforts to address
those issues.


127

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151

Mr. SHays. FDA is not here, but could someone from this el
respond to that? OK, that is something we will followup on. re
was a sense that we did want to make sure where there were high
priorities that the high priorities received the product.

Is there anyone else who was raising their right arm who could
jump in?

Mr. BULT. Mr. Chairman, I think one of the initiatives that the
industry has taken to buildup an emergency supply, we have made
a prediction that for year 1998 we will have 400 kilograms avail-
able for emergency supply. Up to now the first half year we made
available already about 500 kilo; s which means that companies
have made an attempt to have higher numbers of emergency sup-
ply available for critical patients such as pediatric AIDS patients,
HIV patients and other patients in critical need.

Mr. SHAYS. We need to get the word out though, don’t we.

Mr. BoyLe. Of the doctors that we have spoken to, 90 percent
said that they have been having difficulty in getting IVIG, and of
those who say that they have had difficulty, 50 percent say their
patients have had health problems as a result.

Mr. SHays. You are using percentages in a congressional hear-
ing. Are you comfortable with those percentages?

Mr. Boye. Yes. There are only approximately 200 physicians
who see 25 or more immune deficient patients. Of those 200 and
some, we have received responses from approximately 100. There
is not much sampling error about that type of response. It would
probably be improper to take the 40 percent and try to project it
onto all patients.

Mr. SHays. The danger is that the people who contact you are
the ones who are not getting the supply.

Mr. BOYLE. For doctors who respond, there may be some likeli-
hood if you are having a problem, you are more likely to respond.
So 50 percent. Mm

Mr. SHAYS. So I will take the numbers based on that.

Mr. BOYLE. The issue is that there is a health problem out there
that is affecting patients right now.

Mr. Suays. I am going to conclude this hearing. Are there any
additional questions?

Mr. HALLORAN. I just wanted to touch on CJD with Red Cross
first. Why do you think that CJD has such a far greater impact on
the volunteer sector than the paid? As a tracer for some future
uncharacterized agent, it kind of worked against expectations or
type there.

Mr. McDonoucu. I am not sure that we know or understand;
and, frankly, there is probably some disagreement. There is some

ent that the demographics of volunteer donors lend them-
selves more to people who either have had dura mater transplants
or have taken pituitary growth hormone. There are arguments that
say voluntary donors know how to answer the question.

I don’t think that we can honestly say with accuracy why the im-
pact. The majority of our donors identified to us their risk status
almost on all occasions by being asked the question, have you ever
had a dura mater transplant or growth hormone. They would go
home and interact with a family member and then call us back and


155

Mr. Chairman and members of the Subcommittee, the Alpha One Foundation and Alpha,
National Association would like to formally endorse the testimony presented by Dr. John
M. Boyle, on behalf of the Plasma Users Coalition (PUC). As Dr Boyle has testified, the
Coalition represents over 50,000 chronic consumers of plasma derivatives. The critical
shortages of plasma derived products is of the utmost importance to us at this time. We
appreciate Chairman Shays’ and the Subcommittee on Human Resources’ continued
interest in addressing these critical shortages and including this issue in your
deliberations on the GAO report on Blood Plasma Safety.

‘As stated in our testiomony before this Subcommittee on May 7, 1998, the Alpha One
community embraces those families that are affected by the IVIG shortage. Similar to
those afflicted by primary immune deficiency, individuals with alpha 1-antitrypsin
deficiency depend on alpha-l-protease inhibitor (IPI) to prevent lung damage from
infection that causes the loss of lung function, disability and ultimately death. In addition
we embrace the Hemophilia Community challenged by the current shortage of
recombinant factor products for clotting disorders

The Alpha One community has experienced a severe shortage of Prolastin® (h-c1PI) and
has been on an allocation of only 50% most of this year. Our product shortage was the
result of having a single manufacturer decreasing production to respond to the
recommendations of the FDA waming letter regarding GMP improvements. Although
Bayer has made every effort to increase supply and production levels at both their
Clayton, NC and Berkeley, CA facilities; they will not be able to meet current demand
when they reach 100% of their production capability. The shortage of product will
continue until another manufacturer's product and manufacturing facility is approved.

Throughout this shortage numerous inequities in the distribution process were identified.
The Alpha One community has presented testimony at this Subcommittee's hearing last
May, at the DHHS Advisory Committee on Blood Safety and Availability (ACBSA)
meeting, and the FDA Blood Products Advisory Committee (BPAC) meetings calling for
the immediate development of a direct consumer allocation program and evaluation of
the current distribution process. The precedent established by the development of the
national notification program may well serve as a blueprint for a consumer allocation
program. The collaboration of the PUC, FDA, IPPIA, Novartis and the ARC made it
possible to work through the issues of notification of withdrawals and recalls wand
collectively contract with a third party to maintain consumer confidentiality. This
collaboration provides for input from all stakeholders and gives the industry the ability to
share the cost of operating this system, while providing a central platform for all
consumers.

As referenced in the GAO Draft Report on Blood Plasma Safety, 50% of the plasma
derivative manufacturers were shut down last year because of consent decrees.
Additionally, our community was severely impacted by a warning letter to the sole
producer of our h-c:IPI for augmentation therapy. Our community remains vulnerable to
the potential of delays in the approval of the BLA for a second manufacturer of an
ha. PI product and the immediate possibility that a third manufacturer may be delayed in
producing product to complete phase I/II trials.


CONTENTS

Hearing hela on September 9, 1998 . -
Statement of:
Reilly, James, executive director, American Blood Resources Association;
Jan Bult, executive director, International Plasma Products Ih
ition; Brian McDon , CEO, American Red Cross Biomedical
Services; and John Boyle, Ph.D., Plasma Users Coalitiot
Steinhardt, Bernice, Director, Health Services Quality ‘and Public Health
Issues, Health, Education and Human Services Division, General Ac-
counting Office, accompanied by Marcia Crosse and Kurt Kroemer,
and Michael Friedman, M.D., lead Deputy Commissioner, Food and
Drug Administration, accompanied by David Feigal, M.D., Jay Epstein,
M.D., Center for Biologics, and Ronald Chesemore, Associate Commis-
sioner of Regulatory
Letters, statements, etc., submitted for the record by:
Boyle, John, Ph.D., Plasma Users Coalition, prey statement of ...........
Jan, executive director, International Plasma Products Industry
‘Association, repared statement of ..
Friedman, el, M.D., lead Deputy Commissioner, Food and Drug
Administration, pre statement of ..
McDonough, Brian, , American Red Cross Biomedical Services, pre-
pared statement of
Reily, James, executive director, American Blood Resources Association,
repared statement of ...
nya, Hon, Christopher, Representative in Congress from the State
of Connecticut:
statement of ..
of the Expert Pans

Steinhardt, Berni ices Quality th
Issues, Teal, eae. ‘and Human Services Division, General Ac-
counting OFF pared statement of
fon. Baas, oes a Representative
TOE Ne New ‘York, prepared statement of ...

122


145

The Expert Panel was asked to address these issues in the context of current medical
indications for immunoglobulin products, including intravenous and intramuscular
immunoglobulins and hyper-immune globulins”. In the absence of data to form
evidence-based recommendations, the Expert Panel was asked to address the feasibility,
design, and advisability of additional studies that could form the basis for such
recommendations. The findings and recommendations of the Expert Panel are
summarized in this report.

FINDINGS and RECOMMENDATIONS

1, Based on the available data, it is not possible to establish minimum donor pool
sizes needed for optimal efficacy of immunoglobulin products. This is particularly
true of IVIG, the product with the broadest range of medical uses. Recent
recommendations concerning donor pool size deserve comment. In 1997, the source
plasma industry’ proposed that IVIG donor pool size be limited to 60,000. The FDA
is now considering lower limits, i.¢., ~15,000 donors per lot’, Both recommendations
appear to be based less on published evidence concerning the effects of donor pool
size on efficacy of immunoglobulin products than on estimates of “tolerable” risks of
transmitting infectious agents. In the absence of scientific data to establish minimum
donor pool sizes, the Expert Panel recommended that the FDA ensure that donor pool
sizes do not exceed current manufacturing levels. In considering this topic, the
Panel's deliberations touched on many of the issues considered earlier by the Institute
of Medicine:

“The management of a public health risk requires an evolving process of decisionmaking
under uncertainty. It includes interpretive judgement in the presence of scientific
uncertainty and disagreement about values. Public health officials must characterize and
estimate the magnitude of the risk... They must also develop and test public health and
clinical care strategies, and communicate with the public about the risk and strategies for
reducing it. .... Lack of scientific consensus becomes a kind of amplifier for the usual
discord and conflict that can be expected whenever an important science-based public
policy decision ~ one profoundly affecting lives and economic interests — must be made.
First, uncertainty creates opportunities for advocates of self-interested and ideological
viewpoints to advance plausible arguments that favor their desired outcome. Second,
uncertainty intensifies bureaucratic cautiousness."*

2. Evidence is accruing that antibody dimerization may contribute to the biological
activity of [VIG in immune-mediated diseases. Modeling studies and laboratory

? Immunoglobulin products considered by the panel included intravenous and intramuscular
immunoglobulins, and hyperimmune globulins (anti-Rh immune globulin, anti-RSV immune globulin, anti-
CMV immune globulin, Hepatitis B immune globulin, Varicella-Zoster immune globulin, rabies immune
globulin, and tetanus immune globulin)

Immunoglobulin product ar curently manufacture from plasma recovered from whole blood
ined by plasmapheresis (designated “source plasma”).

Stoto, eds. National Academy Press, Washington, D.C. (1995); p209-21


106

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 24

component parts. Yet, all of these parts must be strong in order to provide the

best assurance of safety.

What we are pursuing — and what we committed to at Chairman Shays oversight
hearing — is a comprehensive pian that builds upon the seven layers of safety. A
comprehensive plan that will review the existing initiatives to measure their
progress, assess the need for new initiatives, and communicate to key
individuals our objectives and the progress we have made. In a staged-process,
we are assessing our existing voluntary initiatives, our commitment to reduce
pool size, and the need for new programs. In the context of this examination we

will determine accurate forms of measurement to quantify our progress.

As IPPIA Executive Director Robert Reilly stated “That is our goal, our challenge,
and our commitment — and we will verify the success of our efforts through

accurate measurements.”

RE

If you examine the QPP certification standards and the four voluntary initiatives
at the macro-level, each is an important piece of the safety puzzle. Each has its



ABRA Statement September 9, 1998
Page 4 of 6 Reference No.GAOC98008

based donor population by accepting only those donors that have shown a
commitment to repeat participation in the program.

The Qualified Donor standard was implemented in July 1997. Concurrent with its
implementation, ABRA began collecting data on the prevalence of positive viral
marker test results among the Qualified Donor population. {t was anticipated that
these data would form the basis of the revised viral marker rate standard. While
this remains true, in the year since the implementation of the Qualified Donor
standard, we have leamed a great deal about the resources needed to effectively
collect, manage, maintain, and analyze data on roughly 1 million Source Plasma
donations per month. As a result of these data collection efforts, we believe we
now have the data necessary to proceed with the establishment of a revised viral
marker rate standard. We anticipate that the revised standard will take effect
during 1999.

It is also worth noting that the data collected in connection with the Qualified
Donor standard forms the basis of the GAO report insofar as it pertains to the
Source Plasma industry. However, before moving ahead to discuss ABRA's data
collection activities in greater detail and viral marker rates in general, | would like
to briefly outline the Inventory Hold standard. Implementation of the Inventory
Hold began in July 1997 and was phased-in over a six-month period. This
standard requires that each individual unit of Source Plasma be held in inventory
for a minimum period of 60 days from the date of collection before it is used for
further processing. This hold period provides a large window of opportunity to
retrieve previous donations if a Qualified Donor seroconverts on a subsequent
donation or if new health history information is discovered. The Inventory Hold is
a powerful tool in terms of preventing so-called “window period donations”
(potentially infectious but nonreactive) from entering a manufacturing pool.

Over the past year ABRA and its member companies have committed extensive
resources to the collection of data to accurately and meaningfully characterize
the safety of Source Plasma. Although ABRA initially believed that it would
manage the data collection and analyses in-house, the sheer volume of data and
the complexity of statistical assessments made this impracticable.
Consequently, one of the milestones in the process was the retention of an
independent research organization to assist with data collection and
management activities and to ensure objective data analyses. Now, with the first
round of data collection and analyses behind us, ABRA is committed to continue
sound scientific assessment of the Source Plasma industry. This includes
continued data collection and ongoing evaluation of statistical models to
accurately depict our industry.

To date, ABRA’s data collection has focused on viral marker rates among
Qualified Donors. This is because, as noted, only donations from Qualified
Donors are used for further processing. Donations from Applicant Donors are
not used for further manufacture unless and until the Qualified Donor criteria are


52

spection, not by the company, but by consultants that they must
hire that we will then inspect.

I do appreciate your concern, but I think it is very important to
understand how committed we are to good manufacturing practice
and that we are putting considerable pressure on the industry
right at this time.

Mr. Kucinicu. Thank you, Mr. Chairman.

Mr. SHays. Mr. Snowbarger.

Mr. SNOWBARGER. I want to go back to the original topic of the
report. Ms. Steinhardt, you keep saying that these are not just pa-
perwork kinds of mistakes, and Dr. Friedman indicated they are
not that serious because they are paperwork kinds of mistakes.

Dr. FRIEDMAN. If I said that, it was not my intention.

Mr. SNOWBARGER. I didn’t think it was, but you said it.

Dr. FRIEDMAN. These are serious mistakes. I said this is not
merely a checklist. I think GAO and FDA are in exactly the same
place here. These are serious concerns, and I apologize for inter-

rupting.
ir. SNOWBARGER. That is fine.
Dr. FRIEDMAN. This is so important, I wanted to make it clear.
Mr. SNOWBARGER. Ms. Steinhardt, I would like to know the kinds
of violations that were found. I don’t care that you identify them
with a particular company or anything of that nature. We heard
about the residue problem that no one had traced the source for.
What are the kinds of issues that to a layman are going to be real

gnif icant?

's. STEINHARDT. Right. And I read them as a layman. While our
report gives the kinds of problems in general terms, I want to give
you a flavor of reading a whole inspection report that is not cap-
tured in just a summary.

There could be hundreds of different processes that are used to
produce a final finished product; am I right? These are hundreds
of processes. There were inspection reports that looked at every
single one of these processes, and in every single one or at least
many of them—I don’t know whether it was the universe of proc-
esses—there were problems with how well tested those processes
were, how well qualified the personnel were who were operating,
who were conducting those processes, how well trained they were
to carry them out, whether they had ever been validated and prov-
en effective to do what they were supposed to be doing.

And they’re—you know, some of the inspection reports are this
thick, and they were very to the point. These weren’t sort of ram-
bling inspection reports. They weren’t about, you know, something
that hadn’t been checked off. I mean, they were very focused, very
disciplined, very structured, and they covered dozens and dozens
and dozens of problems, and it was the total effect of these prob-
lems that I think is—you know, rather than what each one was,
but the total effect of all of these problems that I think led to the
kinds of concerns that led FDA to seek court orders for fixes.

Dr. FRIEDMAN. If I may? One of the things Mr. Snowbarger—I’d
like to correct a mistake that I made. I said there were two consent
decrees. In fact, my staff has correctly pointed out to me there are
currently three consent decrees for fractionation facilities. We take
these very, very seriously.


173
6.

donors per plasma pool. We were shocked at a minimum to learn that, in
fact, our risk factor had consistently been five times that number and that
the industry had been outright lying to us, their customers, for twenty-
five years.

Since 1993 the Committee Of Ten Thousand has been calling for a
new paradigm in blood/blood products. We have worked to develop
relationships with industry and government, in part, to ensure that this
nightmare we have been subjected to does not occur again and, in part, to
attempt to develop relationships of trust between industry, government.
and consumers. However without significant change in the regulatory
decision making process and a new willingness on the part of the industry
to not continue with “business as usual” this new paradigm will never
evolve and we will certainly continue to place the users of blood products
in harms way.


101

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 19

anti-HCV 0.0112%

This retrospective data was collected to obtain an immediate glimpse of where
‘our prospectively determined rates are likely to be. ABRA will publish data
collected during the July 1 - December 31 period, as well as that collected on an
annual basis. Viral reactive data collected from all participating centers will be
evaluated on a routine basis so that meaningful "cut-off" limits can be maintained.

Inventory Hold
The third Voluntary initiative is the institution of an inventory hold for units of

plasma prior to pooling for further processing. A minimum 60-day hold will be
implemented on all units collected by January 1998.

‘The inventory hold program takes full advantage of the frequent and repeated
Participation of source plasma donors. As can be seen in this example, if a
donor becomes infected with a given virus (e.g. HIV or HCV), a “window period”
‘exists, during which time he/she is potentially infectious, but is not detected as
such by current screening tests which measure antibody response to the viruses.
By hokding all seronegative units in an inventory hold, this standard provides
manufacturers with the opportunity to retrieve units from previously qualified


26

by our oversight of blood and plasma collection, processing and

manufacturing facilities, as well as through product approvals

and surveillance.

While the United states is recognized as having one of the safest
blood supplies in the world, assuring the safety and availability
of blood products still poses formidable challenges. While
humans are the source of plasma, humans also are potential
carriers of many transmissible diseases. From the collection of
source and recovered plasma from donors, through the
fractionation and manufacturing process, to the quarantine and
retrieval process, there are numerous points at which safety
measures are in place to minimize the risk of exposing recipients
of blood products to infectious agents. FDA views the entire
process as a continuum of interrelated steps. At each one of
these steps, the Agency has recommended or required safety
mechanisms to decrease the risks associated with the use of blood

products.

The technology associated with disease detection in blood and
plasma donors is continually improving, but is not perfect. The
number of blood and plasma donors, while adequate to meet present

needs, is not unlimited. Further improvements in efficiency,

capacity and quality in the manufacturing process are possible,

but often take significant time to accomplish and the commitment


22

Mr. Suays. Thank you.

Doctor? You don’t always wear your uniform. What is going on?

Dr. FRIEDMAN. Two things. It is Wednesday; and the second is,
since I have accompanied Dr. Satcher last time in uniform, it
seemed consistent.

Mr. SHays. I treated you better, that is what happened.

Dr. FRIEDMAN. Mr. Chairman and members of the committee,
with me today is Mr. Ron Chesemore, our Associate Commissioner
of Regulatory Affairs; Dr. David Feigal and Dr. Jay Epstein from
our Center for Biologics Evaluation and Research.

We appreciate this opportunity to once again come here and dis-
cuss these important issues. We are prepared today to focus on
three main topics.

First, the serious issue of continuing shortages of immune glob-
ulin, intravenous preparation, IGIV; and second, to update the
FDA compliance program, that program that helps assure the safe-
ty of blood and plasma derivatives; and, third, to cooperate with
the General Accounting Office in discussing their report on blood
plasma safety and plasma donors. These are all important and
complex issues, issues which have garnered the attention of this
committee on previous occasions.

As you well recognized in your opening remarks, FDA must bal-
ance the need to assure the quality of blood and plasma products
with a need to maintain an adequate supply of these life-sustaining
therapies. The tension created by these two interests can be a for-
midable challenge, and while I recognize at this time there con-
tinues to be shortages, I believe very strongly that the agency must
maintain a comprehensive regulatory approach that assures that
the industry follows the good manufacturing practices that are nec-
essary to produce high-quality products. Only in this way can fu-
ture supplies of high-quality products be assured.

There is a shortage of a number of plasma derivatives, particu-
larly IGIV, but not exclusively IGIV. A contributing factor has been
the production problems encountered by several plasma manufac-
turers that have resulted in the compliance actions that we have
just heard about.

One of the more recent and concerning problems has been with
Centeon Corp., headquartered in Pennsylvania, a major manufac-
turer of plasma products. In a consent decree last year, Centeon
agreed to sharply curtail production and distribution of most of its
plasma products until it came into compliance with good manufac-
turing practice.

This spring, FDA testified that it expected the shortage of IGIV
to be alleviated once Centeon resumed full production at its pre-
vious capacity. Despite the agency’s belief that the company was
making important steps on the road to compliance, the latest com-
prehensive FDA inspection revealed concerns that have just been
enumerated. The company failed in several critical GMP areas, in-
cluding quality assurance investigations, laboratory controls, equip-
ment and process validation and. production and process controls.

Consequently on August 13, 1998, FDA presented to Centeon a
letter requiring it to take specific action under the consent decree
to correct these violations. We met with the company leadership in
a very serious and sober and I think a very thoughtful discussion.


IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 23
{a Fe
= a
= ee _)
—S- aA
=! 2- Ea
=—2- =—_s
L == be SS
Donor Screening
Donor Deferral
Donor Testing
Inventory Hold

Quality Assurance & Good Manufacturing
Viral Inactivation/Removal

RecalUNotification

‘As you have just heard, industry has for years actively and methodically
undertaken a series of voluntary initiatives to address these opportunities for
defense. These industry initiatives serve to compliment the individual efforts
made by each manufacturer to safeguard against impurities. Together, these
efforts form a protective safety barrier that is far stronger than each of the


162

‘America’s Blood Centers
Statement for the Record
September 9, 1998

Page 4

requirements implemented by other countries to determine whether and how those
measures should apply in the US. For example:

‘* Britain and Canada now filter all red cell products. Should the US? If not, why
not?

‘© Why does FDA allow up to 2,500 donations to be pooled for solvenvdetergent
treated plasma, but France has a standard of 200 donations?

‘* Germany and Switzerland have just approved the use of methylene blue treated
plasma, yet no clinical trials for this product are underway in the US. Why not?
Should FDA facilitate the introduction of this viral inactivation method?

* Next year the FDA will approve the first fully automated blood testing
technology. Yet this technology, which was invented in the US, has already been
in use in Europe for over two years. Why?

4, Implement a no-fault compensation system for blood injuries. Two years ago the
Institute of Medicine made many sweeping recommendations to assure no repeat of
the AIDS tragedy. Nearly all of IOM’s highest priorities have been addressed, except
for the implementation of a no-fault compensation system for blood injuries. There
needs to be a program that would respond to blood-related injuries, in a manner such
that the National Childhood Vaccine Injury Act has responded to vaccine injuries.
Congress should commission an HHS or GAO study now for recommendations on
this issue with a report back next year in time for the possible passage of enabling
legislation.

ABC thanks the Chairman and members of the Subcommittee for this opportunity to
present our views.


165

Bayer ¢B

Fax Cover Sheet

Date: ‘September 8, 1988 No. of Pages (Inctuding this page): 2
To: ‘Anne Marie Finley From: ‘Greg Lane

‘Company: Office of Christopher Shays DiiDept: Pharmsceutical Division
Fax 202/228/2382 Fax 1-203-812-6478
Phone: 202-225-2548 Phone: 4-203-812-3283

Dear Anne Marie:

Further to our earller conversation, we have undertaken an assessment of the anticipated
shortfall of Bayer-produced IGIV in 1998 versus 1997. The following summarizes the
situation as we see It today:

1. The 1998 estimated releases of IGIV now appear to be 22% less than 1997 total
releases. Mr. Jan Turek estimated this figure at 50% of 1997 performance at the May
hearing based on the latest information available at that time.

. CJD has had no impact on 1998 IGIV releases to date.

}. HVAC: Unanticipated problems with the heating, ventilation and air conditioning system
(HVAC) in our liquid fill area, required replacement and validation of the unit. The
‘submission of this change, affecting Line 1 and 2, ‘esutted in a delay in production unti
June.

4. FDA Compliance: As a result of the FDA review, it was necessary to review production

processes to assure the quality and safety of all plasma-derived products, including IGIV.
It is difficult to separate out the effects of the FDA review from the impact of the HVAC
Brabiems, asthe ltr required equipment replacement, validation and FDA approval of

wR

NOTICE OF CONFIDENTIALITY


169
2.

hemophilia, the usage of recombinant factor has resulted in a higher
degree of individual security regarding the margin of safety and the
dangers associated with the usage of clotting factor in general. This
becomes even more critical for an individual who has already been
subjected to the nightmare of the AIDS and hepatitis C epidemics that
have ravaged the hemophilia community. For these individuals, a return to
human product can have intense psychological and emotional
repercussions.

This situation is exacerbated by the industry's lack of candidness
regarding why this shortage is occurring. Individual companies continue to
be secretive and vague about the specific causes of a given shortage. Our
inability to ascertain the reason for this current recombinant shortage
leaves us, at times, suspicious and distrustful regarding our overall
relationship with the manufacturers of the products we depend on.

An adequate supply of plasma derivative and recombinant products is
obviously a shared goal of the consumers, manufacturers and the federal
government. However, we certainly are tired of the sometimes overt and
sometimes more subtle connection made by industry between safety
margin and adequate supply. We continue to reject the bipolar graph that
places supply at one pole and safety at the opposite pole. A safe and
adequate supply should be the attainable goal that the industry and the
government work together to reach.

Simultaneously, the federal government must ensure that good
manufacturing practices and standard operating procedures are strictly
and vigilantly enforced in order to guarantee that current safety margin
technologies are, in fact, effective.

The recent Government Accounting Office, GAO, report, “Plasma_

painted a distressing picture of the current GMP landscape. It chronicled a
fairly lengthy list of violations by certain companies involved in the
manufacture of plasma derivative products. Violations that could
potentially result in end user harm if not substantively addressed in a
timely fashion.


34

derivatives has caused harm to the public health due to product

shortages.

FDA's policy regarding CJD has been a contributing factor to the
shortage of IGIV. Multiple IGIV lots have been quarantined or
withdrawn because of donors who, after donation, were identified
as being at risk of, or as having developed, CJD. Substantial
amounts of intermediate product, not yet processed into final
products, also were affected by the withdrawals and placed in

quarantine.

The Agency anticipates that this new recommendation, once
implemented by industry, should help minimize the present
shortages of IGIV and other plasma derivatives, although the

change will not resolve the shortage situation.

rrr. VIRAL MARKER RATES/DONOR SCREENING

Although the final safety step of viral inactivation/removal is
the most important mechanism which assures the safety of plasma
derivatives, the initial step in the process, namely donor
collection, also plays a critical role in product safety. GAO
evaluated this first step to determine the risk of infectious
agents including human immunodeficiency virus (HIV), hepatitis B
virus (HBV) and hepatitis ¢ virus (HCV) from unpaid versus paid

donors being incorporated into the manufacturing process. The

10


5

The GAO, and others, faced several challenges in attempting to compare the safety of plasma
derivatives from volunteer recovered plasma with those using source plasma from paid donors.
Several distinctions between recovered plasma and source plasma needed to be taken into
account to assure that the study accurately compared apples with apples. First, the length of time
between donations as regulated by the FDA, is significantly different between the two groups.
Volunteer blood donors are allowed to donate every 56 days, with an average time between
donations of 154 days. Paid plasma donors may retumn every 48 hours, not to exceed two
donations per week, and have an average time between donations of 5.3 days.

Second, the GAO was also asked to look at the effect of plasma pool size on safety. Therefore it
was necessary to take into account the fact that a unit of recovered plasma is significantly smaller
than that of source plasma -- an average 250 ml compared with 825 ml. The result is that an
initial pool of recovered plasma incorporates plasma from more than three times the number of
donations as the same size pool made exclusively from source plasma. Both of these factors --
time between donations, and the lumber of donors included in a plasma pool -- have a distinct
impact upon the chance of incorporating a window period unit into the pool from which the
plasma product is derived.

We believe that the GAO report offers an accurate assessment of the comparative viral marker
rates between the two donor populations, and the possibility of incorporating a unit of plasma
within the infectious window period into plasma pools. Further, GAO cites viral inactivation as,
a “more significant step in reducing the risk of infection.” Indeed, the efficacy of viral
inactivation techniques is such that there has been no reported transmission of infectious disease
through plasma derivatives since the introduction of viral inactivation techniques.

Red Cross Efforts to Improve Safety

The American Red Cross remains committed to ensuring that an ample supply of transfusable
‘components and plasma derivatives derived from voluntary donations of whole blood by healthy
individuals is available for patients in need. The remainder of my comments today will focus on
efforts undertaken by the American Red Cross to continuously improve the safety of transfusable
blood components and plasma products distributed under our label. These efforts include:

> improved viral inactivation methods;

» continuous surveillance of blood donors to identify potential emerging infections;
> improved testing methods; and
» the role of the Red Cross in developing an system to notify patients in the event of a

withdrawal or recall.

Viral Inactivation Methods

Plasma Derivatives

Researchers at Holland Laboratory are investigating methods to inactivate all viruses in plasma
derivatives. Current virus inactivation procedures work most effectively on lipid-enveloped

2


136

Mr. Suays. Thank you very much. Let me just say, Dr. Boyle, we
sometimes have the consumers speak first when we have our hear-
ings because it gives a little reality to what we are doing.

low as an individual patient in the consumer groups, how would
you learn of a regulatory or production problem affecting the sup-
ply of product? How do you find out about it?

ir. BOYLE. As an ave! consumer with a primary immuno-
deficiency disease, you wouldn’t. If you were aggressive and were
on the mailing list of a consumer organization, you would look for
some description in newsletters, but they do not come out all that
often. You might call the consumer organization, you might get on
the Web and try to get it. But the bottom line is that most con-
sumers have little or no access to information about the types of
things that you are talking about.

For many years, even when we started the IDF 20 years ago be-
fore we actually became involved in the regulatory arena, we had
no idea that there were any problems. We had no idea of any issues
because we had no information about that. And we were informed
consumers.

Mr. SHays. Do you get sent some of the information—do
have access to the information that would be provided to the FDA?
Is that on the Internet?

Mr. BoyYLe. Can I ask our staff representative to speak to that?

Mr. Says. I think you were sworn in?

Ms. O'Day. Yes, I was.

Mr. SHays. Do you have a card?

Ms. O'Day. Yes. My name is Miriam O’Day, vice president of the
Immune Deficiency Foundation.

The question is how easy is it for us to access information from
the FDA?

Mr. Suays. Right. Is that on the Internet?

Ms. O’Day. Some materials are on the Internet and they are
available under Freedom of Information. But again, you have to be
savvy enough to know what you are looking for and how to access
it.

Mr. Suays. If the FDA does not have the resources or the focus
to take some of this information and maximize its use, the con-
sumer groups sometimes can provide a significant amount of re-
sponse to it. Maybe I can ask the industry the same question.

ere would be nothing inconsistent with making this information
available, or would some of this be proprietary information?

Mr. Butt. I think you are touching on a very important issue.
Some information is propriet

In an initiative that we took, we invited IDF to come to one of
our board meetings, and we did that as an initiative for them to
have a better understanding what is going on.

Mr. BoyLeE. Could we use perhaps recall notices of something
that would obviously be of great interest to consumers, and Miriam
can you tell how the recall notices come to us?

Ms. O'Day. Oftentimes individual companies will contact the na-
tional organization and we will do distribution. But in the case of
the CBER recall notices listed on their Web site, the individual
consumer has to be the one to seek the information. They do not
contact you and outreach that information.


58

isn’t available even though the risk of some contamination would
be fairly minor. But I want to thank the panel.

Dr. EDMAN. Thank you, sir.

I would like to respond to your point, Mr. Chairman. I'll ask Dr.
Epstein to please begin, and then let me add just a couple of words
at the end if I may.

Please go ahead.

Dr. EPSTEIN. Yes, Ms. Steinhardt correctly states that there is
product distribution information which comes into the agency rou-
tinely as required by regulation, however we get that at all times
on all products, and I think that there has been a need for the FDA
to focus its fairly limited resources wisely and to try to do further
analyses where we think the problems lie.

Now, the problem with respect to the immune globulin shortage
really was recognized only late in 1997. Since that time we have
mounted a very focused effort to, first of all, improve the informa-
tion coming into the agency, namely reporting monthly instead of
6-monthly data. The first monthly reports were, in fact, received
only in the last 2 months. Industry periodically provided us month-
ly data prior to that reporting, but the ongoing reporting on a
monthly basis is, in fact, new.

The second point is that the modeling process itself is quite com-
plex, and it has taken the agency some time to figure out just how
to model these data. Let me just say that there are a lot of param-
eters. It could be presumed, for example, that since we have lot re-
lease data, we should know what product is going out there, but
it’s, in fact, not so. Not every product is under lot release. The lot
release report may not contain the production size of the lot, only
the vial size, et cetera, and products that are lot-released may not
always be distributed for a plethora of reasons.

So we've recognized, first of all, the need to focus on distribution
data. Second, distribution data doesn’t tell you the whole story, be-
cause there’s supply and demand factoring into shortage. We do not
have data coming into the agency regarding demand, and we are
only now trying to figure out ways to create surveillance systems
that could bring that information to light.

So I would answer Ms. Steinhardt that whereas it’s correct that
data were available to the agency which had not yet been utilized,
it’s because of the fact that we have needed to create systems to
look appropriately at data where needed and then to try to model
the data in a constructive way. And this we are doing now very ag-
gressively, and we are expanding our scope of activities to look at
other plasma derivatives, again judiciously. We're trying to look at
where the problems are.

And let me just make one final point which is that the data that
you look at retrospectively are not always predictive. If you look at
month-by-month trends, you find that there can be very erratic
swings, and you can be grossly misled thinking that you can trend
past data. Furthermore, it requires an effort on top of that to try
to figure out what’s in the pipeline, not just to look at what was
previously distributed.

So all I can say is that the apparent lag or lapse in analyzing
available data is really due to mounting the appropriate effort; that
we are attempting this now for the appropriate plasma derivatives.


112

blood donors are allowed to donate every 56 days with an average

time between donations of approximately 154 days. Paid plasma

donors may return every 48 hours, not to exceed two donations per

week, and have an average time interval between donations of 5.3
lays.

Second, the GAO was asked to look at the effect of plasma pool
size on safety. A unit of recovered plasma is significantly smaller
than that of source plasma, an average of 250 milliliters compared
with 825 milliliters. The result is that an initial pool of recovered

lasma incorporates plasma from more than three times the num-

r of donations as the same size pool made exclusively from source
plasma. Both of these factors, time between donations and the
number of donors included in the plasma pool, have a distinct im-
pact on the chance of incorporating a window period unit into the
pool from which the plasma product is derived.

The remainder of my comments today will focus on efforts under-
taken by the Red Cross to continuously improve the safety of trans-
fusable blood components and plasma products distributed under
our label. These efforts include improved viral inactivation meth-
ods, continuous surveillance of blood donors to identify potential
emerging infections, improved testing methods, and our role in de-
veloping a system to notify patients in the event of a withdrawal
or recall.

Researchers at the Red Cross Holland Laboratory are inves-
tigating methods to inactivate all viruses in plasma derivatives.

e current virus inactivation procedures work most effectively on
lipid-enveloped viruses, that is those which incorporate the fatty
coats of cells in their structure, such as HIV and HCV, and they
do not work as well on nonenveloped viruses.

One method of pathogen inactivation under study involves the
use of iodine to inactive viruses and bacteria in plasma products.
In this method iodine is chemically linked to a resin called
Sephadex.® The resulting product is used in a filtration system
which inactivates the pathogenic organisms. So far the use of this
process is focused on IGIV, but we are also investigating the use
of iodine with Sephadex® in the purification of other plasma prod-
ucts.

Promising efforts are also underway at our Holland Laboratory
to identify methods of inactivating viruses in traditional trans-
fusable blood components. To date it has been impossible to virally
inactivate red or platelets without destroying their efficacy.
Red Cross is investigating the use of a light-activated dye, dimethyl
methylene blue, called 491. With this process a light-activated mol-
ecule, 491, binds to the nucleic acids of viruses and, when activated
by light, causes the viral nucleic acids to break thereby destroying
the infectivity of the virus. This type of system is feasible for use
in red blood cells, because they contain no nucleic acids of their
own. Preliminary studies show that the process successfully inac-
tivated viruses without damaging the quality of the cells.

As Red Cross has previously shared with this subcommittee, we
are actively engaged in several surveillance initiatives and remain
vigilant in monitoring for emerging infectious diseases. There are
three efforts which I would like to highlight for you.


76

IPPIA Statement Document No. 011218
9 September 1998.
Page 6

1. One must understand the nature of cGMPs, and how the FDA
enforces these ever-changing requirements.

2. 483 observations need to be viewed in a proper context:
observations may reflect a range of seriousness.

3. Assignificant amount of resources, including personnel, capital, and
time, may be necessary to meet the challenges of operating in this
evolving regulatory environment.

4. An increased focus on compliance has an effect on supply of these
products

Plasma fractionators must conform to cGMPs as defined under 21 CFR parts
210-211. These regulations are not static, rather they require a firm to maintain
good manufacturing practices in light of current technology and other capabilities.
What is considered current tomorrow will be different than what is considered
current today. As technology and information capabilities change, so do the
requirements for maintaining good manufacturing practices.

The FDA has varied and potentially significant authority to ensure compliance
with these regulations and protect the public health. Following an inspection, the
inspectors report observations of objectionable conditions and practices on the
Form FDA 483, Inspectional Observations. The agency classifies observations
as Voluntary Action or Official Action Indicated. Under official actions, the FDA
may take advisory actions, such as issuing an untitled or warning letter. An
untitled letter notifies the firm of circumstances that do not violate FDA
regulations, but may nonetheless call for corrective action. Waming letters, a
more severe regulatory action, notify a firm that a product, process, or other
activity violates FDA regulations, but there is not an imminent public safety threat
as a result of the violation. In certain circumstances, the FDA may seek to have
a firm operate under a consent decree to ensure that products continue to be
manufactured under quality conditions and that corrective actions are undertaken
within an agreed timeframe.

Form 483 observations noted in the plasma fractionation industry have risen over
the previous five years due to intensified inspectional practices by the FDA. This
is indicative of the change in the direction and emphasis of FDA inspections in
recent years

Once a 483 observation is communicated to the firm, the observation is analyzed
to determine how to address it. It is important to note that 483 observations may
reflect a range of seriousness. Regardless of the significance of the observation,
all are treated very seriously. Some observations reflecting noncompliance may
represent minor deviations, such as a simple error in documentation. Many
observations such as these can be addressed immediately. For the more
significant observations, those that could represent a serious systemic deviation
in GMP compliance, a corrective action team comprised of individuals familiar


28

(manufacturers who further process plasma and other blood
derivative products) from The Center for Biologics Evaluation and
Research (CBER) to the Office of Regulatory Affairs (ORA) in
1996. Along with that transfer of the lead responsibilities in
inspections and field emergency response, FDA also adopted a new
model and approach, called Team Biologics, to the inspection of

plasma fractionators.

Under Team Biologics, FDA hai ablished a partnership between
ORA and CBER which utilizes the diverse skills and knowledge of
both ORA and CBER staffs to focus Agency resources on inspection
and compliance issues in the biologics area. The goal of Team
Biologics is to assure the quality and safety of biological
products and bring product manufacturers into compliance. To
accomplish this a cadre of investigators has been created that is
more specialized and technically prepared to inspect fractionated
product facilities and other biologics establishments. This
specialized investigator cadre has access to a similarly
specialized group of compliance officers for guidance, support
and counsel on evidence development and assistance in drafting
any required administrative or regulatory action documents.

Likewise, a specially trained cadre of investigators has been

established to inspect blood banks and plasma collection
facilities.


94

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 12

Next, Dr, Waytes will describe several new industry-wide voluntary standards.
‘The two of these that are related to the plasma collection portion of plasma
product manufacturing have and will become QPP standards. They are a
Qualified Donor Standard or the exclusion of the use of plasma from non-
returning applicant donors from further manufacture, which became effective in
July of this year, and a new viral marker rate standard based on the confirmed
positive viral marker tests in qualified donors.

Let me now introduce to you Dr. Thomas Waytes who will describe in more detail
the new voluntary standards and provide you with some data in support of the
standards and from our intial experience with these standards.


9

Mr. Says. It is wonderful to have both of you with your staff.
Ms. Steinhardt, you may begin.

STATEMENTS OF BERNICE STEINHARDT, DIRECTOR, HEALTH
SERVICES QUALITY AND PUBLIC HEALTH ISSUES, HEALTH,
EDUCATION AND HUMAN SERVICES DIVISION, GENERAL AC-
COUNTING OFFICE, ACCOMPANIED BY MARCIA CROSSE AND
KURT KROEMER; AND MICHAEL FRIEDMAN, M.D., LEAD DEP-
UTY COMMISSIONER, FOOD AND DRUG ADMINISTRATION,
ACCOMPANIED BY DAVID FEIGAL, M.D., JAY EPSTEIN, M.D.,
CENTER FOR BIOLOGICS, AND RONALD CHESEMORE, ASSO-
CIATE COMMISSIONER OF REGULATORY AFFAIRS

Ms. STEINHARDT. Thank you.

As you pointed out, our report to you discusses the risk of infec-
tion associated with plasma products. To sum it up, the risk of re-
ceiving a potentially infectious plasma product is extremely low if
manufacturers follow all of the safety assurance procedures that
they have put into place.

It is very important to stress the “if” here, though, because if
these critical steps are not taken, the risks can be considerably
higher, and this caution is especially important today in light of
the recent performance of the industry.

Let me describe what our analysis found and what it means for
the industry and FDA. The risks of infection in plasma products
start out higher than where they ultimately wind up. About 85 per-
cent is collected from paid donors who are more than 1¥2 times
more likely to donate potentially infectious plasma than volunteers.
About 1 in 3,800 units collected from paid donors is potentially in-
fectious for hepatitis B, C or HIV, but particularly for hepatitis C
where the rate of infection among paid donors is twice as high as
among volunteers. Some of the recent initiatives that the plasma
industry has adopted helped to lower this risk considerably. By
using donations only from repeat donors which helps to reduce the
likelihood of infected donors and by putting a 60-day hold on dona-
tions before using them to—

Mr. Suays. Ms. Steinhardt, if I may interrupt. I have no problem
with the first three chairs being used. I don’t want—if we have
paid lobbyists here, I think it is more appropriate if we do have
students. Do we have anyone who has no vested interest—someone
like the press, they can sit up here. I would like to free up some
chairs.

Thank you. Why don’t you sit in one of the first three there? Ei-
ther side. Does anyone else want to? Do we have any witnesses in
our next group who are here? Why don’t you—if yn don’t mind
coming up front. I am sorry to delay the hearing a bit, but I would
like everybody to be comfortable. Any witnesses sitting in the front
row, maybe they can sit up here and we can free up some seats.

You can’t say I didn’t try. I am sorry. We have three chairs on
this side also. OK.

Sorry.

Ms. STEINHARDT. That is OK.

I started to explain that the risks of infection in plasma products
have been lowered considerably because of some recent initiatives
that the industry has taken. By using donations only from repeat


TW

IPPIA Statement Document No. 011218
9 September 1998
Page 7

with the area of concern will be assembled. Depending on the nature of the
issue, extemal consultants may be employed to provide additional expertise.

Following an analysis of the affected process or product, the team will formulate
a plan to correct the deviation and submit the plan, with suggested timetables, for
FDA review. In some circumstances the corrective action team may conclude
that the nature of the deviation will require a temporary shutdown of part or all of
the facility to implement the necessary corrective action. In many instances,
personne! normally involved in manufacturing must be shifted to other areas in
order to address these issues. Both of these actions have an impact on the
firm’s ability to produce these products. For these more serious observations, a
significant amount of time may be required to develop and implement this
corrective action plan.

The production of plasma derivatives is a very complex process and
manufacturers recognize the importance of cGMP compliance. Therefore, to
ensure product safety, purity and effectiveness, each company has put in place a
robust Quality Program comprised of a number of complementary systems which
are designed to provide control over all elements of the manufacturing process.
This Quality Program is a key component of the multiple layers of safety that
protect patients by providing a system of control for assurance of the quality of
personnel, facilities, equipment, raw materials, manufacturing procedures and
processes and final product. Surveillance also extends past the point of
manufacture as quality systems also monitor product quality after distribution.
The intense focus on quality and the cross checks that the Quality Program
provides is a critical mechanism which works to mitigate the adverse impact of a
potential lapse in GMP.

The summary table of these systems (Attachment 2) represents a sampling of
some of the quality system check points that control each element of
manufacturing. These quality systems of multiple tests and reviews provide a
redundancy of systems to check and crosscheck that any released product
meets its approved safety, purity, and potency.

In the end, we want to assure this committee that we continue to provide very
safe products. Shifting regulatory emphasis from a scientific review of the
process to a focus on cGMP compliance has resulted in increased 483
observations. However, the products we produce continue to be safe and
effective. In the short term, this evolving regulatory environment has affected our
members’ ability to provide an adequate supply of several products. Consistent,
‘stable and well-communicated requirements, with reasonable timetables for
implementation, will help our industry to meet the expectations of this committee,
the FDA, and the general public to further ensure adequate supplies of safe
products. Our members have made and will continue to make the necessary
investments in capital, personnel, and training to meet this obligation.


I P I International Piasma Products Industry Association

4
1100 New York Avenue « Suite 1080 + Washington, DC 20005 USA.

‘Telephone: (202) 789-3100 « Telefax: (202) 789-4197
‘e-mail: 75424.1742@compuserve.com

Attachment 1
007842

IPPIA Voluntary Initiatives Presentation

Blood Products Advisory Committee

‘56th Meeting ~ 18-19 September 1997
‘Quality Suites Hotel — Rockville, MD 20850

Introduction: Douglas Bell, IPPIA

Good afternoon. My name is Douglas Bell . | am Director of Public Affairs for the
International Plasma Products industry Association or IPPIA. | will serve as
‘moderator for our presentation regarding the ABRA Quality Plasma Program and
IPPIA's Voluntary Initiatives. Immediately following me will be James P. Reilly,
President of the American Blood Resources Association (ABRA) to discuss the
background and history of QPP. Following him will be Dr. Tom Waytes for IPPIA.
who will outline the IPPIA Voluntary Initiatives and the scientific reasoning and
data supporting their implementation. Finally | will return to summarize.

Before the technical presentations begin | would like to briefly outline for you the
role of the IPPIA and its relationship with ABRA. It is also worth noting that IPPIA
is affiliated with the European Association of the Plasma Products industry which
represents the vast majority of the commercial fractionation industry in Europe.


5

Mr. SNOWBARGER. All I have to say is welcome, because you left
that out. Of course, I wasn’t here when you left that out.

Mr. Suays. If we don’t have some good laughs today, we are in
trouble because there is lots going on in this place and we need
something to make us feel good, about the world.

I will swear in a host of people, two of whom will address us: Ms.
Bernice Steinhardt, Director, Health Services Quality and Public
Health Issues, Health, Education and Human Services Division, ac-
companied by Marcia Crosse and Kurt Kroemer.

Did FDA just get the chairs first, is that what happened?

. FRIEDMAN. We had a drawing and we lost.

Mr. Suays. I will ask ou a fo be ete inDr Michael Fried:
man is accompani yy Dr. David Feigal and Dr. Jay Epstein an
Mr. Ronald Chesemore.

And I will ask all to stand and we will administer the oath.

[Witnesses sworn.]

Mr. Suays. The record should reflect that everybody has been
sworn.

I ask unanimous consent that all members of the subcommittee
be allowed to place any opening statement in the record, and the
record remain open for 3 s for that purpose, and also that wit-
nesses be permitted to include their opening statements in the
record, and without objection so ordered.

[The prepared statement of the Hon. Edolphus Towns follows:]


111

Mr. SHays. Mr. McDonough.

Mr. McDonoueu. Chairman Shays, thank you and members of
the House Human Resources Subcommittee. I’m Brian McDonough,
the chief operating officer and responsible head of the American
Red Cross Blood Services, and I thank you for the opportunity to
respond to the report by the General Accounting Office on the safe-
ty of plasma derivatives.

By way of background, the American Red Cross Blood Services
is the Nation’s largest supplier of transfusable blood components,
serving more thau 3,000 hospitals across the country. We collect al-
most 6 million units of whole blood through the generous donations
of nearly 4¥2 million volunteer donors. The Red Cross provides
both transfusable blood components and plasma derivatives. Con-
sistent with the needs of transfusion medicine, units of whole blood
are separated into specific components following donation, those
being red blood cells, platelets and plasma. Due to the relatively
limited need for plasma for transfusion, most of the plasma Red
Cross recovers from whole blood donations is fractionated into the
various plasma derivatives.

The Red Cross plasma derivatives account for approximately 15
to 20 percent of the Nation’s supply; however, the Red Cross does
not fractionate its own plasma products. Rather, we contract with
Baxter Healthcare’s Hyland Division and the Swiss Red Cross to
manufacture AHF, IGIV, and albumin products under FDA li-
censes.

Mr. Suays. That’s done in Europe.
pv McDonouceu. In Switzerland at the Baxter plant, Hyland in

Approximately 80 percent of the plasma the Red Cross recovers
is fractionated by Baxter. As a distributor of plasma derivatives
fractionated under the FDA licenses of other companies, the Red
Cross is not directly responsible to the FDA for the compliance of
these firms. We do, however, exercise great diligence to ensure the
products distributed under our label are manufactured in compli-
ance with cGMP’s and FDA regulations. We have worked with Bax-
ter and the Swiss Red Cross to support them in their compliance
efforts and continue to monitor and. evaluate these compliance ac-
tions undertaken by both fractionators. Further the Red Cross is
responsible for maintaining its own good manufacturing procedures
during the processing of blood donations from the time of collection
through distribution to hospitals or the fractionators.

We were pleased to work with the GAO staff on the study, and
commend them for their diligence in assuring that the study accu-
rately compared differing data sets presented by the Red Cross and
the American Blood Resources Association. We believe that the
GAO report offers an accurate assessment of the comparative viral
marker rates between volunteer blood donors and pad plasma do-
nors and the possibility of incorporating a unit of plasma within
the infectious window period into plasma pools.

The GAO faced several challenges in attempting to compare the
safety of plasma derivatives from these two donor populations and
insuring that the study accurately compared apples with apples.
First, the length of time between donations as regulated by the
FDA is significantly different between the two groups. Volunteer


81

IPPIA Statement Document No. 011218
9 September 1998
Page 11

A tight supply to demand margin of recombinant factor VIll may have an impact
‘on consumption of the plasma-derived factor VIII. As with the other products we
have started to look at this ratio as well

1998 U.S. Supply Ratio of Plasma Derived Factor FVIII*

Ratio Jan |Feb |March | April | May | June
Ratio 33 38 25 3.0 37 1.4
‘To date

The ratio indicates that changes occur throughout the year and went down in
June. We will continue to monitor this situation very closely on a monthly basis.

Our industry is taking several actions to address any potential supply issues for
factor VIII, similar to those taken to address the IVIG supply. Short term, our
members are working with FDA to ensure quick lot releases for products as they
become available. Additionally, an emergency supply of recombinant factor VIII
is being developed for patients in critical need. More long-term, our companies
are investing hundreds of millions of dollars to expand overall capacity to
manufacture the needed therapies.

Conclusions

In conclusion, | would like to reiterate that our members are working in
cooperation with the FDA to address issues associated with continued cGMP
compliance. At the same time all of us are committed to continuing to provide
access to adequate supplies of these life-saving therapies. At times, this can be
a delicate balance. Our commitment here today is to make sure that by working
with the FDA, this and other govemmental bodies, and patient groups, this
balance is reached. We will continue our constant efforts to provide a safe and
adequate supply of these products.

The IPPIA members Alpha Therapeutic, Baxter Healthcare Corporation, Bayer
Corporation, and Centeon, together with the American Red Cross and Novartis
have already started to collect data on plasma products to better understand
current and potential future shortages. The collection of actual consumption data
gives an accurate picture of the current supply for our industry, and we believe
that our newly developed model for collecting and sharing this data will be a good
indicator of the current supply of our products. However, the use of this data for
making accurate predictions is problematic due to unknowns, such as changes in
clinical demand, the unexpected-nature of technical manufacturing problems, and
‘a changing regulatory environment including but not limited to the cGMP
compliance issues discussed earlier. We will continue to collect and make


107

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 25

critical role in maximizing safety. Each has its critical time in the process.
Finally, each has its critical place in the system.

What is evolving ~ and what industry has committed to develop -- is a keystone
to these programs that will be the glue bringing all of the pieces of the puzzle
together.

IPPIA over the next several months will be examining the key elements of this
plan. We will share those key elements with Congress, the FDA and Consumer
‘groups for feedback and comment. After receiving comment from interested
parties, the industry will then finalize the details.

‘The seven layers of safety are the foundation upon which we are building in our
‘on-going commitment to making plasma-based therapies safer stil. The basis of
‘our strategic plan should then be no surprise. The industry has a long history of
multi-faceted voluntary initiatives that address the seven layers of safety. We are
looking toward expanding those voluntary initiatives to include a keystone or
comprehensive plan that will help interlock the existing voluntary initiatives
together with the seven layers of safety into one unified program.


92

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 10

| would like to describe the viral marker rate standard in a little more detail
because we are developing a significant change to this standard this year. In
1991, we established a standard for HIV and HBV. At that time, and until very
recently, plasma products were manufactured from plasma obtained from both
applicant donors and qualified donors. With this in mind, we set the standard
based on the mean industry average of all positive tests per center plus two
standard deviations.

In 1993, we added a standard for HCV and lowered the acceptable standard for
HIV and HBV by 19% and 32% respectively. The rates for HIV and HBV were
lowered because we were seeing steady improvement in the industry mean as a
result of the overall affect of the QPP.

In 1997, we are making an even more substantial change based on the
imposition of an applicant donor exclusion standard which Dr. Waytes will
describe in just a moment.


60

We have four people who will be giving testimony, and we'll just
go right down the list: Mr. Reilly, Mr. Bult, Mr. McDonough; is
that how we say your name? Thank you. And John Boyle. OK,
thank you.

STATEMENTS OF JAMES REILLY, EXECUTIVE DIRECTOR,
AMERICAN BLOOD RESOURCES ASSOCIATION; JAN BULT,
EXECUTIVE DIRECTOR, INTERNATIONAL PLASMA PROD-
UCTS INDUSTRY ASSOCIATION; BRIAN McDONOUGH, CEO,
AMERICAN RED CROSS BIOMEDICAL SERVICES; AND JOHN
BOYLE, Ph.D., PLASMA USERS COALITION

Mr. REILLY. Thank you, Mr. Chairman.
My name is James Reilly. I’m the president of ABRA, the trade
association representing the Nation’s source plasma collection in-

lustry.

Th eek —I will summarize our written testimony in the interests
of time and would ask that the complete testimony be entered into
the record.

ABRA members collect roughly 11 million liters of source plasma
annually.

I appreciate the opportunity to speak to the subcommittee re-
garding the GAO report on plasma safety. I believe the message
that can be taken from the report and today’s testimony, and what
we would like to reinforce, is that sound scientific analyses dem-
onstrate the overall safety of source plasma.

Almost since its inception, ABRA served as a vehicle for in-
dustry self-regulation through publication of industry guidelines
and recommendations that go over and above existing Federal,
State and local requirements. In the written testimony are several
examples from our past experience.

One of the most significant examples of industry self-regulation
is the Quality Plasma Program. QPP is a certification program that
sets a baseline of industry standards. The program began in 1991,
and today is a de facto requirement throughout the industry to
maintain certification. To maintain certification, facilities must ad-
here to QPP standards and undergo inspections by third-party in-
spectors. Any facility found in noncompliance is immediately noti-
fied and given 60 days to respond with corrective actions or risk
losing its certification.

QPP has had a dramatic affect on source plasma safety. Stand-
ards put in place through the program have resulted in more effec-
tive selection of low-risk donors, more skilled collection center per-
sonnel, better facilities and lower marker rates among the donor
population. However, one of the greatest benefits of QPP is that it
has served as a vehicle for effecting continuous improvement
throughout the industry.

In 1997, the source plasma industry publicly committed to four
voluntary initiatives. Two of these initiatives, the qualified donor
stan and the inventory hold, have already been implemented,
and are having a positive effect on plasma safety. Two oft the initia-
tives are by necessity still work in progress. The initiatives that
are still work in progress include viral testing and a revised
viral marker rate standard. We anticipate that the revised viral
marker rate standard will take effect during 1999. PCR testing is


56

industry produces, I think it’s really important to note the salutary
effect that oversight has played here.

And I admit to having an institutional bias. I am the GAO, and
we are the watchdogs, so we believe in oversight. But when we first
testified on the safety of the blood supply before you in this room
1 year ago in June, we talked about risks associated with the plas-
ma products industry specifically, and we had—there were a lot of
unknowns. I mean, there was very little known about it then. And
if we had—and that was in part why you asked us to do the study
that we have just completed. If we had done that study, if we had
done the analysis right then in June 1997, we would have had dif-
ferent numbers to report to you, because right after that hearing,
the industry adopted two very important practices which reduced
the risk of potentially infectious agents sixfold. The 60-day hold, in-
ventory hold, alone has—plays a very big part in reducing the risks
associated with plasma products.

The next big—the layers of safety that Dr. Friedman talked
about, which we discussed at great length in the whole blood indus-
try, there were no layers of safety or very few layers of safety at
the time of that hearing. The industry adopted them voluntarily,
but I think in large part because of concerns that were raised,
practices, to help reduce the risks.

The residual risks, the risks of infectious agents that now go into
the pool, are reduced dramatically by the viral inactivation and
elimination processes associated with manufacturing, but it’s be-
cause of the increased attention that FDA has paid to safety prac-
tices, to the integrity of the manufacturing processes and the in-
dustry—the increased attention of the management of the industry
to those practices that I think changes are now coming about. I
think that’s undeniable, and I think all of those things together,
the result of oversight, will have contributed to a safer product all
around.

That same kind of oversight—and this returns to your question—
that same kind of oversight also has to be paid to the consequences
of these safety concerns for the supply of what is indeed a very crit-
ical material to many people whose lives depend on it, and I think
there we are still concerned about the amount of attention that’s
paid to the consequences of all these actions on supply, too.

When we testified before you last May, we were trying to
gauge—at your request we were trying to gauge the impact of with-
drawals on the amount of intravenous immune globulin supply,
and doing that we tried to get from FDA information about the
amount of product that was actually in distribution. And when we
asked for it, we were able to get information actually, although it
came a little too late for us, but we were able to get information
on immune globulin. But FDA told us that they couldn’t give us
any information on any of their other plasma products because
even though the information was reported to them every 6 months
by manufacturers, they hadn’t analyzed the data.

Now those same manufacturers who have shut down production
and whose compliance situation raises concerns about immune
globulin supplies, those same manufacturers produce other plasma
products. And so it remains a concern to us, the extent to which
FDA is looking at the data it has and keeping an eye on the con-


18

In addition, risk of exposure does not always equate with risk of infection. In fact,
risk of exposure is always greater than or equal to risk of infection. For example, the
recent transmission of HCV by a plasma derivative that had not undergone viral
inactivation procedures showed that the risk of seroconversion for recipients of this
product increased with the number of positive HCV lots infused and the quantity of HCV
viral material infused. Not all recipients were infected, however, because the highest
percentage of seroconversions seen with the highest levels of HCV virus infused did not
exceed 30 percent. Not all recipients experience seroconversions because of two factors:
() each recipient's dose and (2) the reduction of infectiousness due to steps in the
manufacturing process in addition to viral removal and inactivation.

RISK OF INFECTION REDUCED THROUGH
‘VIRAL INACTIVATION AND REMOVAL TECHNIQUES

‘As mentioned, certain infectious units could make it through the donor screening,
deferral, and testing process. Manufacturers have, therefore, introduced additional steps
in the fractionation process to inactivate or remove viruses and bacteria that may have
gotten into plasma pools. These techniques virtually eliminate enveloped viruses such as
HIV, HBV, and HCV. They are only partly effective, however, against nonenveloped
viruses such as HAV and human parvovirus.”

All types of plasma derivatives undergo viral inactivation or removal." The two
main methods of inactivation are heat treatment and solvent-detergent treatment. To be
effective, inactivation techniques must disrupt the virus, rendering it noninfectious. Heat
treatment is accomplished either by exposing the freeze-dried product to dry heat or
suspending it in a solution. Another technique heats the completely soluble liquid product
with the addition of various stabilizers such as sucrose and glycine. The second
technique, solvent-detergent washing, exposes the product to an organic solvent to
dissolve the lipid coat of viruses, rendering them inactive without destroying the plasma-
derived products. The lipid membrane contains critical viral proteins needed for infection
of host cells. Disrupting the viral lipid envelope renders the virus noninfectious,
Solvent-detergent inactivation is only partly effective, however, in eliminating
nonlipid-coated viruses such as HAV or human parvovirus.

the amount of viral clearance obtained through a particular inactivation
or removal process determines the effectiveness of these different procedures. This

"Parvovirus is the cause of Fifth disease, a common childhood illness, which is usually
mild and brief. Approximately 50 percent of the population has been infected by
parvovirus at some time.

“Currently, only two immune globulin intramuscular products are manufactured without
the use of viral inactivation procedures.

7 GAO/T-HEHS-242


47

Dr. EPSTEIN. I am not sure that I should be answering that. Per-

haps Dr. Zavagno can.

fe are in the process of developing a proposed rule that will
have to be cleared by the Department, by 0! before it can be
published for comment, and we would follow with a final rule. We
are trying to achieve a timeframe of publishing a final rule within
about a year’s time.

Dr. FRIEDMAN. That formal rulemaking process is necessary, but
we are moving forward with other parts of the Department and
with the industry to identify these individuals, to begin the edu-
cational effort, because this notification doesn’t need to wait for
that scictivity. It is my estimation that that will begin relatively
quickly.

Mr. Suays. Has any blood recipient yet received a letter inform-
ing him or her of possible infection?

r. FRIEDMAN. Not that I know of, sir.

Mr. SHays. It seems to me that we are moving rather slowly.

Dr. FRIEDMAN. I would like to take that as a question that we
will respond to you with. I will have the Department provide an
overview of that.

Mr. Suays. To move on, what is the current compliance rate of
the plasma fractionation industry with what we call the good man-
ufacturing practices requirements? What is the compliance rate?
era FRIEDMAN. I would ask Mr. Chesemore to please respond to

at.

Mr. CHESEMORE. Mr. Chairman, this fiscal year the compliance
rate of those firms which we have inepected, which is approxi-
mately 20 firms at this time, has been—55 percent have been with-
in compliance; 45 percent we would classy as out of compliance.

Mr. Suays. That seems like a low compliance rate and a high
noncompliance, but are we straightening out gnats and swallowing
camels? If it is a technicality, is that led noncompliance?

Mr. CHESEMORE. I would say two things, Mr. Chairman. One is
if you look at a similar percen! in fiscal year 1997, the out-of-
compliance rate was approximately 60 percent. So now it is 45 per-
cent. That is an improvement.

The other thing is, we are talking here about what I would char-
acterize as serious deviations from good manufacturing practices.
They are not small, technical violations.

- SHAYS. With the drug industry, what would your compliance
rate be expected, what would you expect it to be?

Mr. CHESEMORE. I would like to provide a more accurate state-
ment for the record, but it is approximately, I would say, about 15
percent out of compliance.

Mr. Suays. So 85 Percent in compliance?

Mr. CHESEMORE. Kighty-five percent in compliance.

Mr. Suays. I just get the feeling that the relationship with
FDA—the way that it comes across to me is that you all seem to
have a lot of confidence in the industry, and so if they say they are
doing something, even if it is not in writing, you accept it, and I
don’t know why.

Dr. FRIEDMAN. If I may respond, I am not sure that is an entirely
accurate portrayal. I do think—and there is a tension that I would
like to describe. The tension is that working with the regulated in-


51

Mr. KUCINICH. You have a fact of noncompliance and sloppy
manufacturing techniques. How can the public be assured that
there is not symmetry between that and the practices which inves-
tigate the transmission of viruses such as C.

Dr. FRIEDMAN. Your question is a really good one and it is a little
complicated, so let me break it into two parts. The first is the con-
fidence that the public should have in the manufacturing processes
that exist now. As the chairman has pointed out and as GAO has
pointed out and as we agree with, the safety that accrues to the
American public is built upon multiple layers of different activities
beginning with the screening of individuals who donate the mate-
rial to the very finished end product. Any one of these steps may
be flawed, and yet the overall product may be entirely safe because
there is considerable redundancy and fail-safe mechanisms put in
place. I am not comfortable with that and you are not comfortable
with that.

Mr. Kucinicu. Let me tell you further why I am not comfortable,
because you testified earlier about what you called a collaborative,
cooperative, disciplined, not adversarial relationship. Now, there is
a certain logic that flows from that, Mr. Chairman, a concern logic
which suggests that the regulators and the community being regu-
lated may be too cozy; that in effect the one p: ‘aph in your tes-
timony, “Although Centeon continued to be out of compliance, FDA
has advised Centeon they can continue to produce medically nec-
essary products for the time being, including IGIV under certain
conditions. At this time FDA is still working with the company.”

Now, it seems to me that if you have a consistent lack of compli-
ance—excuse me, I am not a doctor, I am not a scientist, just a
public servant from Cleveland, OH—why don’t you shut them

lown?

Dr. FRIEDMAN. I think, sir, that it is a question that we have se-
riously considered. If we believed that the product that was bein;
produced was risky or harmful, if we had evidence of that, it woul
not be released. There are patients, ill, sick, and dying because of
lack of material. For the theoretical risk of a patient receiving
something which may not have been produced under the highest
quality, to say to that patient, “You will die because we believe
that it is more important to keep records straight than it is to care
for you,” I think fundamentally moves away from our public health
mission.

Mr. Kucinicu. I am touched by your concern for dying people,
but I would be more touched if there was a stronger statement
from the FDA in support of blood safety.

Dr. FRIEDMAN. Sir, I think it would be a misstatement to say
that the agency is anything less than committed to full GMP com-
pliance. We are currently engaged in two consent decrees. These
are court orders where we have gone to court to make sure that
companies don’t do this voluntarily, but that we have the power of
the legal system behind us to order third-party inspections, them
to hire consultants and do extra special checks.

The reason that we are permitting Centeon to release some ma-
terials that are medically necessary is because we have imposed
upon them extra layers of inspection, extra layers of third-party in-


80

U.S. Consumption Recombinant Factor VIII

1996-1998"
(Miu)

350

300

250

200.

150.

100.

50.

0
Jan July- Jan- July- Jan
June Dec June Dec June
1996 1996 1997 1997 1998
*Todate

In a further effort to monitor available supplies for these products, IPPIA initiated
a data gathering effort similar to that for [VIG. The vast majority of hemophilia A
patients use either recombinant or high purity plasma derived factor Vill for their
treatment, consequently, we focused our data collection to these products.

1998 U.S. Supply of Recombinant FVIII*

Mio Units Jan [Feb [March |April |May | June | Jul
Inventory 140.6 | 145.6 | 132.1 | 134.3] 97.5] 99.8[ 75.1
Emergency Supply 15 18
US Consumption 481) 451 488] 528] 508] 65.4 48
Ratio 29 3.2 27 25 13 1S 16
“To date

The trend from this data shows a decreasing inventory to consumption ratio. A
factor to be taken into account is the fact that one of the manufacturers of
recombinant factor VII! has announced that production problems have
temporarily limited its ability produce this therapeutic. Given this, one could
expect tight supply versus demand margins in the near future. The ratio
calculated from the gathered data seems to be a good indicator for this. We will
continue to closely monitor the supply situation. As you can see on this chart, an
‘emergency supply of this therapeutic is beginning to be developed in response to
this situation.


142

REPORT OF THE EXPERT PANEL ON
DONOR POOL SIZE OF IMMUNOGLOBULIN PRODUCTS

National Institute of Allergy and Infectious Diseases

National Institutes of Health

September, 1998


135

NATIONAL INSTITUE OF HEALTH
REGISTRY OF U.S. RESIDENTS AFFECTED
BY
SEVERE COMBINED IMMUNODEFICIENCY DISEASE
COMMON VARIABLE IMMUNODEFICIENCY DISEASE
CHRONIC GRANULOMATOUS DISEASE
X-LINKED AGAMMAGLOBULINEMIA
WISKOTT-ALDRICH SYNDROME
LEUKOCYTE ADHESION DEFICIENCY
HYPER IGM SYNDROME
DIGEORGE ANOMALY
CONTRACT #NO1-A1-75328
$1,236,478
Awarded 10/01/97
to the Immune Deficiency Foundation
25 West Chesapeake Avenue, Ste. 206
Towson, MD 21204


13

donated by paid donors pose a somewhat higher risk of infection than those from
volunteer donors (in which 1 in every 15,662 units are potentially infectious).

Limiting the number of donors whose plasma is pooled for production into plasma
products helps to reduce the risks of viral transmission for recipients of these products.
Currently, the industry has a limit of 60,000 donors for each finished plasma product.
This effort has minimized infrequent users’ exposure to a certain number of donors for
the few times they would receive a plasma product. For frequent users of plasma
products, such as hemophiliacs, however, this donor limit has little impact because such
patients receive a large number of infusions and are therefore exposed to a large number
of pools during their lifetimes.

‘A more significant step in reducing risk of infection tales place in manufacturing,
during which all plasma products undergo viral removal or inactivation procedures, which
virtually eliminate enveloped viruses such as HIV, HBV, and HCV. Epidemiological data
on the transmission of viruses through plasma products since the introduction of viral
removal and inactivation procedures in the late 1980s support the value of these
procedures as do laboratory data characterizing the effectiveness of viral clearance
through these procedures. The effectiveness of these processes is limited, however, in
reducing transmission of nonlipid enveloped viruses, such as hepatitis A (HAV), and
human parvovirus.

Voluntary initiatives by the commercial plasma industry, technological advances
from increasingly sophisticated screening tests that close the "window period’ (the
interval between when a donor becomes infected and when a particular laboratory test
becomes positive), and viral removal and inactivation procedures are only effective if
manufacturers of finished plasma products adhere to current good manufacturing
practices. Not all of the major manufacturing companies producing plasma products
adhere to these practices, however. In fact, recent FDA inspection reports highlight many
instances of noncompliance with current good manufacturing practices, This has led to
consent decrees between FDA and two manufacturing companies, temporary suspensions
of production at one manufacturing company's facility, and shortages of some plasma
products. Although no known cases of HIV, HBV, or HCV from plasma products have
been transmitted during the time FDA identified these problems, instances of companies’
noncompliance with current good manufacturing practices have been many. A lack of
strict adherence to these practices related to viral removal and inactivation procedures
could compromise the safety of plasma products. Actions being taken by FDA and the
plasma manufacturers since these problems were identified should help to alleviate some
of these problems.

BACKGROUND

Plasma is the liquid portion of blood, containing nutrients, electrolytes (dissolved
salts), gases, albumin, clotting factors, hormones, and wastes. Many different parts of

2 GAO/T-HEHS.242


137

Mr. SHays. Mr. McDonough, I want to make sure since I did in-
terrupt you, if there was anything in your statement that you feel
that you need to bring up, I will welcome you to jump in.

Mr. McDonoucu. There is one thing relative to this and that is
through the National Notification Center we have established an
800 number and a registry that patients can sign up for and learn
the status of any recall identified Red Cross lot numbers, and we
keep that posted on a daily basis. We are just beginning to roll that
out, but referenced in his comments that we are working with them
to extend this to modify it industry-wide. As we sit here today, I
am aware only that the Red Cross system has this number.

Mr. SHays. What is the best way—Mr. Bult, you addressed
this—to predict shortfalls. Is there a model that the industry is
working on?

Mr. BULT. Yes, this is a difficult question because if you want to
have a reliable model, some of the issues raised this morning in the
questions to FDA, it is very difficult to predict clinical demand.

Mr. SHays. Predict what?
Mr. BULT. Clinical demand. You don’t know exactly what the use

is ing to be.
. SHays. Why is that, because there are new uses? I don’t
know why that would be difficult.

Mr. BULT. You can look at historical data and see that there is
a trend of immune globulin use, an increase of 9 percent per year,
but it is not worthwhile for all indications and it depends from
plasma product to plasma product.

The second is if you have technical problems, nobody knows
when these will occur.

The third is if you live in the current regulatory environment, we
see the impact of current compliance issues. There may be others
that do occur. So there is not a reliability to work on the model.

What we can do, and I think that is important, is to collect ac-
tual data, and that is what we have provided to you in our testi-
mony, and provide that data to consumers, FDA and GAO and
work on the model.

Mr. Suays. I am going to have staff jump in here in a second,
but one of the things that we learned from the previous hearing
was that there were contracts out. The industry has long-term con-
tracts so that gives us a sense of demand on the individual compa-
nies; isn’t that true?

Mr. BuLT. I remember from the previous hearing one company
stated they were the sole supplier of immune globulin in Canada,
for example, but that is not true for the whole capacity that is
available nowadays. In addition to the data that we provided to you
in May, we have data now available for six companies, and that
does not take into account all of these parameters. So we are focus-
ing on domestic supply and what we can do to increase that supply.

Mr. SHAYS. Before we go to staff, I tried to have a sense—I hap-
pen to think that competition in most cases allocates resources
well, not in every instance, obviously, but logically it should make
for a more efficient operation. I get the sense that this isn’t true
in this industry, and I am trying to figure out why.


55

nificant drop from 1997 to 1998. I think—I can’t remember who
mentioned it, but what, a 60 percent noncompliance in 1997 and
45 percent noncompliance in 1998, and how much of this is a mat-
ter of the industry catching up to at least new enforcement if not
new standards?

Dr. FRIEDMAN. I think a lot of it has to do with the industry’s
more serious attention to the standards. I think that the stand-
ards—in addition to what’s been said, the standards were not as
clearly defined and articulated for the biologic products as they
have been over the past several years. We’ve changed our means
of checking and enforcing compliance. We've put new emphasis on

at.

I think that the question that you're really asking is are these
the right standards. We constantly re-evaluate them based upon
new emerging scientific information. We strongly believe and have
advisory committees that have told us that these are the right
standards, that this is what the American public expects in terms
of a quality product. We know that in the 1970’s, for example,
there were similar problems with drug manufacturers, where it
was difficult to ratchet up their compliance, but they have done so
very successfully.

We have seen movement on the part of this industry. We have
heard a commitment on the part of this industry. We're going to
keep up the strong discipline, the clear message here, and we ex-
pect that there will be the same high level of compliance not to our
standards, but what the right standards should be.

Mr. SNOWBARGER. I’m not so sure that I’m questioning changes
in standards which may be occurring, but it sounds like there has
been a significant change in enforcement.

Dr. FRIEDMAN. There has been.

Mr. SNowBARGER. We allow the industry to get lax, and then all
of a sudden we decide to enforce it pretty stringently, and all of a
sudden they’re surprised that very few are in compliance. I mean,
it’s the way my kids treat me all the time if I don’t make them toe
the line, they’re going to get away with as much as they can and
then move on. And if I say, no, you can’t do that, they won’t do it.

Dr. FRIEDMAN. I think it’s fair to say we paid much more atten-
tion over the past 2 years, that we have been much clearer, that
we have been much more consistent about this, and that does con-
tribute to the out of compliance rate, you’re correct.

Mr. Suays. If the gentleman would yield?

The one challenge though is that you’re kind of between a rock
and a hard place because you need the product, I don’t know—well,
you do need your kids, but——

Mr. SNOWBARGER. Only for 1 more year.

Mr. Suays. I’d like to get to the next panel, but I would like, Ms.
Steinhardt, to ask you the question of how the GAO views FDA’s
information collection practices with regard to the availability of
critical plasma products. What’s your take on their process today?

Ms. STEINHARDT. I want to answer that question. I want to say
something more generally, though, on the way to the answer to
that question which struck me in the line of questioning here, and
that is that in the risks, looking at the overall risks presented to
the product that this industry produces—in the product that this


2

Second, while paid plasma donors are 1¥2 times more likely to
donate potentially infectious units, recent safety initiatives by the
fractionation industry greatly reduce the chance that an infected
unit will be pooled for use in making a final product. This sustains
our heavy reliance on source plasma from paid donors for most
plasma-derived therapies.

Third, the success of those industry initiatives to inactivate or re-
move viral agents depends heavily on consistent compliance with
strict regulatory standards governing manufacturing practices and

lures. In view of recent FDA inspections citing numerous vio-
lations of good manufacturing practices [GMP’s] at plasma fraction-
ation facilities, this GAO finding compels us to ask: What is bein;
done to minimize the risks to blood product safety and blood prod-
uct supply posed by widespread failure to comply with good manu-
facturing practices?

In May, we heard testimony that compliance-related production
shortfalls, along with surging demand, have created chronic, crit-
ical shortages of immune globulins, the plasma-derived antibodies
needed by some to fight disease. Both the FDA and the plasma in-
dustry described ambitious plans to strengthen regulatory policy
and company compliance without compromising blood product safe-
ty or supply. Today we look to both for word of progress, not more
plans, toward full regulatory compliance and timely production of
needed plasma-derived products.

Our 3-year investigation of blood safety issues has included
seven prior hearings, and full committee adoption of specific find-
ings and recommendations to protect the safest blood supply in the
world from emerging infectious agents. Our , shared by pa-
tients, regulators and the blood products industry is a vigilant,
comprehensive, science-based system of safeguards that yields nec-
essary medicines while avoiding the need to make false, potentially
deadly, tradeoffs between product safety and adequate supply.

Toward that goal, we asked the GAO, the FDA, and representa-
tives of blood banks, the plasma industry, and plasma patients to
help us address the risks of paid versus volunteer donors and the
importance of GMP compliance in minimizing those risks.

We welcome today’s testimony. Mr. Snowbarger, the vice chair of
this subcommittee has arrived, if he has an opening statement.

(The prepared statement of the Hon. Christopher Shays follows:]


174

International Plasma Products Industry Association

1950 I Street, NW ° Suite 1020 * Washington, DC 20005 USA
‘Telephone: (202) 789-3100 + Telefuxc (202) 799-4197

‘You requested an update on the commitments that IPPIA member companies made at the
May 7, 1008 hearing before the aubcommittee. The companies have supplied us the
following information:

Alpha

$75 milion to expand manutacturing capacity funding approved

40-50% increase In IVIG production by 2003 on eck

Operating at 100% capacity in 1908 unchanged

‘Alpha-1 submission in progress

Bayer

Double IVIG emergency supply ‘accomplished

Boost IVIG production over next few years 1h process, on track

‘GCentean

‘Achieve full production in 1908 affected by recent inspection

Baxter

Increase IVIG production at Rochester, Mi FDA _ approved addtional
‘capacity 8/10/28

Import new form of IVIG (ENDOBULIN) ‘Submission completed. FDA
Priory sttention. Possible action
by end of yr.

‘All companies checked their distributors for anomalies as committed,
Plepse let me know If you have any further questions.

—

Vice nt, North America


163

Baxter

FOR IMMEDIATE RELEASE

Media contact: Mary Thomas, (847) 948-2815

FDA APPROVAL OF BAXTER’S ROCHESTER FACILITY TO INCREASE,
PRODUCTION OF MUCH-NEEDED MEDICAL THERAPY

Company Makes Progress with FDA on Licensing a Second Brand of IVIG

DEERFIELD, Ill., September 9, 1998 -- Baxter Healthcare Corporation
announced today that it has received approval from the U.S. Food and Drug
Administration (FDA) to process an intermediate form of intravenous gamma
globulin (I'VIG) at its facility in Rochester, Michigan. The approval will enable
Baxter to increase by 15 to 20 percent its production of IVIG, which will help to
alleviate an industrywide shortage of the therapy

IVIG, which is derived from human plasma, is prescribed for patients
suffering from deficiencies in their immune systems, cancer, and other often life-
threatening conditions. For many years, there have been periodic shortages of IVIG
throughout the world. Most recently, the shortage has been the result of a several

factors including: better diagnosis and treatment of patients; product withdrawals due


12

IPPIA Statement Document No. 011218
9 September 1998
Page 2

Good morning Chairman Shays and other distinguished committee members.
My name is Jan Bult, and i am Executive Director of the International Plasma
Products Industry Association (IPPIA), the trade association representing the
commercial producers of plasma-based therapies. IPPIA members produce
approximately 80% of the plasma products for the U.S. market, and include the
four largest commercial fractionators: Alpha Therapeutic Corporation, Baxter
Healthcare Corporation, Bayer Corporation, and Centeon. | would like to thank
the committee for inviting us here today to discuss the General Accounting Office
(GAO) report on the safety and supply of plasma-based therapies.

Our member companies are deeply aware of the critical role that the plasma
derivatives we manufacture play in the lives of patients who depend upon them.
We applaud the efforts this committee has made in helping to ensure the
continued safety and availability of these therapeutics. Your efforts have
assisted us in achieving the highest levels of safety for the plasma derivatives
that we manufacture.

Our industry takes pride in the current safety record of our therapies, and we
appreciate the opportunity to discuss our efforts to continually increase the
margin of safety for these therapies. While the progress in further developing
‘safer plasma therapeutics has been remarkable, we recognize that improving
quality is a continuous process. We are also aware that there are compliance
issues that need to be addressed.

My testimony today will focus on four areas:

 Anupdate on previous commitments from our industry;

Our comments on the GAO report;

* Adiscussion of the compliance history of our industry; and

* Our efforts to understand and respond to shortages of plasma

products.

{will summarize my written testimony and request that a copy of my entire
testimony be included for the record.

Industry Update

During testimony before this committee on July 31, 1997, the IPPIA announced
‘our commitment to develop a comprehensive safety plan for the plasma products
industry. As you may recall, our plan was based on the multiple layers of safety
in the fractionation process, with an industry action plan to enhance the margin of
safety for each of those layers. We presented a more detailed discussion of this
plan to the FDA's Blood Products Advisory Committee in September 1997, and a
copy of that presentation is included with my written testimony as Attachment 1.
| would like to give you an update on the considerable progress we have made
‘on several fronts of this plan.


27

of major resources by an industry that often is resistant to

change.

In this process, the Agency deals with competing interests in

effecting its regulatory compliance program. Product safety must
be maximized, but an adequate supply of lifesaving blood products
needs to be available. The balance of these two interests can be

very difficult to achieve and is often precarious at best.

There is no question that a shortage of plasma derivatives still
exists, particularly of IGIV. This shortage situation was
described in detail this past May 7 before the Committee by

Dr. David Satcher, Assistant Secretary for Health and surgeon
General, Department of Health and Human Services (DHHS) and
myself. Since that hearing, FDA has taken a number of actions to
try and alleviate the shortage. Simultaneously, however, FDA
continues to demand the highest level of compliance from the
plasma industry. Actions taken by the industry have had, and

will continue to have, an impact on product availability.

III. UPDATE OM FDA INSPECTIONS AND REGULATORY OVERSIGHT

Since 1996, FDA has strengthened its oversight of the
fractionation industry. As elaborated upon last year in the June
1997 hearing held by your subcommittee, FDA transferred lead

responsibility for periodic inspections of fractionators


70

As you are aware, the FDA has changed i ts process for inspecting
biological establishments through the int: ction of team bio-
logics. Recent inspections by the FDA have led to warning letters
and in some cases to consent decrees being issued to our members.
I want to assure this subcommittee that our members are working
around the clock to institute facilitywide enhancements to address
these findings.
ir. Chairman, I would like to state for the record that we are
pro nents, not critics, of a new approach to enforcement. We agree
the FDA that this is process has led to a greater assurance of
quality conditions for product manufacturing.

We believe, however, several factors need to be considered to

completely understand the potential implications on safety and
supply. One must understand the nature of GMPs and how the
enforces these ever-changing requirements. Four hundred
a hy three observations need to be viewed in a proper context.

Observations may reflect a range of seriousness. A significant
amount of resources, including personnel, capital and time, may be
necessary to meet the challenges of operating in this evolving regu-
latory environment. And 4, an increased focus on compliance has
an effect on supply of these ’ products.

CTMP’s regulations are not static. Rather, they require a firm to
maintain in good manufacturing practices in light of current tech-
nology an other capabilities. Being current tomorrow is different

eing current today. As technology and information capabili-
ties change, so do the requirements for maintaining good manufac-
turing practices.

We want to assure this committee that the products we produce
continue to be safe and effective. Quality systems of multiple tests
and reviews provide a redundancy of systems to check and
crosscheck that any released product meets its approved safety, pu-
rity and tency. An In the short term this evolving regulatory envi-
ronment Pas d our members’ ability to provide an adequate
supply of several products. Consistent, stable and well-commu-
nicated requirements, with reasonable timetables for implementa-
tion, will help our industry to meet the expectations of this com-
mittee, the FDA and the general public. Our members have made
and will continue to make the necessary investments in capital,
personnel and training to meet this obligation.

I would like to focus my remaining testimony on the industry re-

mse to shortages of plasma products. First I would like to say
t it we recognize the importance of our products to those patients
who depend on them to live healthy and productive life. We are
doing everything we can to resolve the shortage as quickly as pos-
sible.

During this subcommittee’s M: earing, IPPIA provided IVIG
data. We also committed to re May be updated data on a quarterly
basis. I’m happy to report today that together with the American
Red Cross and Novartis, we have been able to expand this effort
to include data initiatives that will contain even more timely indi-
cators of the U.S. supply situation. We will now be able to see the
complete picture for the U.S. supply of IVIG and changes to that
supply.


146

observations suggest that donor pools >10,000 may be needed to support a high level
of dimerization. However, the published studies are not sufficient to form the basis
for regulatory decisions. Therefore, the Expert Panel recommended that agencies of
the Department of Health and Human Services (DHHS) including the FDA, Centers
for Disease Control and Prevention (CDC), and NIH support: a) additional
independent, peer-reviewed modeling studies; and b) laboratory research to test
hypotheses generated from such studies,

. The Expert Panel did not recommend clinical trials to explore the effects of
donor pool size on safety and efficacy of IVIG. Instead, the Panel recommended
careful clinical monitoring and continued vigilance with any further reductions in
donor pool size. In drawing this conclusion, the Expert Panel considered the
multiplicity of off-label uses and the paucity and speculative nature of the available
information on the mechanisms of action of [VIG in autoimmune and immune-
mediated disorders. In the absence of more precise information on mechanisms of
IVIG action, it is neither possible to establish minimum donor pool requirements, nor
to design clinical trials, the results of which could be broadly applied.

In particular, the Expert Panel felt strongly that the conclusions of individual trials
would not necessarily apply to the use of IVIG in other diseases or in different
clinical settings Furthermore, because there are manufacturing and end-product
differences among commercially manufactured IVIGs, panel members voiced
concerns that conclusions drawn from individual clinical trials might not necessarily
apply to the clinical uses of different commercial preparations of IVIG.

A stronger argument could be made for trials to assess minimum donor pool needs for
the hyperimmune globulins, due to their more narrowly focused clinical indications.
However, the Expert Panel noted that these products are currently manufactured using
relatively smal! donor pools. In addition, at least one product, Rho (D) immune
globulin, is licensed not only to prevent hemolytic disease of the newborn, but also
for idiopathic thrombocytopenic purpura. Because it is likely that different
immunological mechanisms account for the activity of Rho (D) immune globulin in
these two disorders, panel members expressed concems about the interpretation and
broader applicability of disease-specific trials of this agent.

|. Among all blood derivatives, immunoglobulin products stand out for their
extensive record of safety. Advances in donor screening, viral detection, and viral
inactivation have resulted in plasma derivatives that appear safer than ever, relative to
known viruses. Current screening and manufacturing procedures incorporate multiple
“layers of protection,” which were not in place in the 1980s and early 1990s, when
the transmission of hepatitis and AIDS was linked to blood products. Of note, the
transmission of Hepatitis C virus (HCV) by intravenous immunoglobulin (IVIG),
occurred prior to the industry-wide use of solvent-detergent treatment, a viral
inactivation procedure effective against all lipid-envelope viruses (e.g., Human
Immunodeficiency Virus [HIV], Hepatitis B virus (HBV), and HCV).


63

A B R A The International Authority for the
Source Plasma Collection Industry
-

Statement of James P. Reilly, President

September 9, 1998

Good moming, my name is James Reilly. | am the president of the American
Blood Resources Association (ABRA). ABRA is the trade association
representing the nation’s Source Plasma collection industry. ABRA members
include approximately 375 community-based Source Plasma collection centers
across the United States. These centers collect roughly 11 million liters of
Source Plasma annually from approximately 1.5 million donors. Source Plasma
donors are valued members of society whose donations provide the raw material
used to manufacture an impressive list of live saving and life enhancing medical
products. These donors make an important contribution to the healthcare
community in the form of the products manufactured by the member companies
of the Intemational Plasma Products Industry Association (IPPIA).

| appreciate the opportunity to speak to the subcommittee regarding the General
Accounting Office (GAO) report on plasma safety. | believe the message that
can be taken from the report, and what we would like to reinforce today, is that
sound scientific analyses demonstrate the safety of Source Plasma. ABRA and
its members are committed to continued science-based analyses of the Source
Plasma industry and its many voluntary safety initiatives.

This hearing and the GAO report represent the latest chapter in the
subcommittee’s oversight of the blood and plasma industries. We welcome this
oversight and recognize the important role the subcommittee serves in
maintaining the safety of the nation's supply of blood and blood products. We
view ourselves as working in partnership with the subcommittee to provide the
greatest possible assurance of Source Plasma and plasma product safety to the
public and patient communities we all serve. Safety is not the responsibility of
‘one subcommittee, one company, or one regulatory agency -- it is the collective
responsibility of us all.

Before tuming to specific aspects of the GAO report, | would like to take just a
few minutes to describe how ABRA meets its responsibilities in assuring Source
Plasma safety. Almost since its inception, ABRA has served as a vehicle for
industry self-regulation through publication of industry guidelines and
tecommendations that go over and above existing federal, state and local
tequirements. The following are just a few examples of these industry policies
and practices:


20

either mandates corrective actions that must be taken or prohibits the firm's operation
unless and until such actions are taken. FDA may pursue an action to suspend a facility's
license if the agency has documented deficiencies that constitute a danger to health,
necessitating immediate corrective action. In such instances, the manufacturer would not
be conforming to the standards in its license or the regulations.

Recent FDA inspections conducted at the four major fractionation companies
found many potential deviations in each company's adherence to current good
manufacturing practices. A recent inspection by FDA of Alpha Therapeutic’s facility
observed 139 potential deviations from current good manufacturing practices or standard
operating procedures; this has recently resulted in a consent decree with FDA. An FDA
inspection of Baxter Healthcare's fractionation facility observed 96 potential deviations.
Bayer Corporation's Berkeley, California, facility was cited for 30 potential deviations, and
an inspection of Bayer’s Clayton, North Carolina, facility observed 77 potential deviations.
Finally, an inspection of Centeon's facility observed 87 potential deviations, which
resulted in a consent decree filed in January 1997. The consent decree required Centeon
to cease distribution of all but two of its products, while it brought its
‘standards into compliance with FDA statutes and regulations. In May 1997, FDA
authorized the distribution of Centeon's products from the facility, but, in a subsequent
inspection completed in July 1998, FDA found that Centeon had failed to fully comply
with the consent decree, and the company was notified to immediately cease
manufacturing, processing, packing, holding, and distributing all biological and drug
products manufactured at that facility. The company may, however, manufacture
products deemed medically necessary.

Examples of potential deviations from current good manufacturing practices found
by FDA inspectors include the following:

- in-house-developed software that had not been validated being used for
performance of finished product testing;

- often incomplete and sometimes inaccurate calibration and preventive maintenance
records;

reports of problems with plasma products after distribution not being
reviewed and investigated in a timely manner;

- undetected or not corrected deviations found in viral inactivation processes used
on several lots of factor VIII,"

“Factor VIII is the antihemophilic factor concentrate used to treat hemophilia A bleeding
episodes.

9 GAOVT-HEHS.242,


37

It needs to be recognized, however, that these calculations have

a wide margin of error.

The Agency believes that management and analysis of viral marker
rates should be considered in the broader context of implementing
strategies for reducing risk, including developing improved donor
screening processes, additional and more sensitive testing
methods, improved viral clearance procedures, and reducing pool
size. If an opportunity exists to make the ultimate product
safer by addition of tests in the initial stages of plasma
collection these tests should be utilized. More importantly,
plasma fractionators must adhere to GMP to ensure the safety of
products. Presently, however, it makes no sense to further
restrict the donor pool to unpaid donors given the need for
plasma for manufacturing needed products when there is no
evidence that safety of the products would be enhanced. This
same conclusion was reached independently by experts in 1993 and

1996 at national and international workshops.

It is, of course, highly desirable to collect plasma from
disease-free individuals, whether paid or unpaid. Collection
establishments assess for risk factors for blood borne diseases
by interviewing potential donors for high-risk behavior and for
symptoms of disease. Based on this information, donation
facilities eliminate individuals with higher risks for disease,

although this process also eliminates many healthy potential

13


157

IT would also encourage the committee to support more collaboration between industry
and the FDA and provide the resources necessary for the FDA to assume more regulatory
responsibilities in the distribution of products in short supply.

On behalf of the Alpha One community, I wish to reiterate our appreciation for your
continued vigilance on these issues and commend the Subcommittee for your efforts in
ensuring 8 safe and available supply of life saving plasma derivative products.

‘Thank you for your consideration.


57

sequences of changes in production for the supplies of other impor-
tant plasma products.

Mr. Suays. Mr. Snowbarger asked his point, but let me just state
to you I stayed up all night last night wall-boarding my recreation
room to get it ready for the tapers today, so I’m going to ask the

uestion and then I’m going to give the answer that’s shorter than

e one you gave me and ask you to tell me if my answer is accu-
rate or not.

Ms. Steinhardt, how does the GAO view FDA’s information col-
lection practices with regard to the availability of critical plasma
products? GAO, this is your answer, I want to know, GAO believes
the FDA receives important information about supply of plasma-de-
rived therapies in quarterly reports submitted by manufacturers to
the agency. GAO has found that FDA does not review these data
in a timely manner, resulting in lost opportunities to identify po-
tential product shortages in advance of critical impact on patients
who need these products.

Would that be an answer you would give in the shorter version?

Ms. STEINHARDT. Yes.

Mr. Suays. Thank you.

Mr. SNowsarcer. Mr. Chairman.

Mr. Suays. We’re going to allow you to respond, and I also say,
Dr. Friedman, you have been a wonderful participant in a whole
host of our hearings, blood supply and others, and I’ve always, in-
cluding today, found you to be very forthright and frank and thor-
ough and thoughtful, and appreciate that you came today because
you do have—Dr. Henney is close to a confirmation and it’s just
nice that you’re here. And so I do want to make sure that you all
have a chance to respond to that.

But on the table right now is a concern that for whatever reason,
the FDA may have information that it’s just not—maybe staff or
whatever taking advantage of the information. That’s the thing
that’s on the table. And notwithstanding my love and affection for
you, I wanted to make sure that that was on the record.

Mr. Snowbarger.

Mr. SNOWBARGER. Do you want him to answer now or respond?

Dr. FRIEDMAN. I’d like to bask in that for a few moments.

Mr. Snowbarger, please go ahead, sir.

Mr. SNOWBARGER. Well, Mr. Chairman, I want just to comment,
and that is that any time that we have found a problem and are
moving toward solutions, you can write reports in two different
ways. One can be a report that says we're not there yet, and cer-
tainly we want to get to 100 percent compliance; where the other
way you can write the report is, look how far we’ve come in a few
short years, and it seems to me that we have a little bit of both
of it.

We don’t want to get complacent about things, but it’s not like
we're sitting still and that things haven’t happened, that the indus-
try is not responding. Again, we can all wish for more speed in the
process and obviously are concerned about the quality of the prod-
uct they put out, but I appreciate the fact that it’s a difficult bal-
ance trying to make sure quality and availability mesh and in some
degree, and I appreciate your statement earlier, Dr. Friedman,
about that patient that may lose their life because the product just


23

The agency is now evaluating the company’s response. We are
permitting the company to continue producing, on a selective basis,
medically necessary products, including IGIV. This action is con-
sistent with FDA’s policy of carefully considering the impact of its
regulatory actions on product availability. We will exercise the dis-
cretion, balancing all of the factors, permitting the manufacturer of
a medically necessary product to continue manufacturing.

Under some circumstances, the FDA will permit the continued
manufacture of the critical product even while regulatory action
against the firm proceeds. And again I want to stress the serious-
ness of the commitment that was given to us by the leadership of
the Centeon company.

Despite this exercise of discretion, FDA is aware of IGIV short-
ages as well as possible future shortages with several other plasma
derivatives. FDA anticipates that the IGIV shortage will continue
as Tong as production levels do not meet or exceed previous years’

levels.

Since May, when Dr. Satcher and I described the IGIV shortage
as it existed at that time, FDA has taken a number of actions to
try and address and, if Rossible, alleviate it. FDA is working with
the plasma industry to alleviate shortages, including expediting lot
release for IGIV, monitoring the shortages, working with health
professionals to identify needed supplies. We continue to feel that
the plasma industry needs to aggressively comply with good manu-
facturing practices standards in order to meet the medical de-

mands.

In April the department’s Advisory Committee on Blood Safety
and Availability made several recommendations that may help al-
leviate the shortages.

You, sir, have discussed the impact of the Creutzfeldt-Jakob Dis-
ease restrictions that had been in place. Those restrictions Dr.
Satcher announced will be relaxed in the future. We are also look-
ing at ways in which we can work with the industry to better foster
the necessary supplies.

On August 27, Dr. Satcher made his announcement concerning
CJD. We hope to see the effects of that in the future. This policy
change was deliberated very carefully and extensively within the
Health and Human Services, and was the subject of two meetings
of the Public Health Services Blood Safety Committee. Epidemio-
logic studies of humans over the past two decades have failed to
demonstrate even a single case of blood transfusion causing CJD
infection. Based upon that, the risk is thought to be very low and
possibly even nonexistent.

Conversely, we recognize that removing plasma products because
of CJD has caused shortages with real medical consequences. Our
policy regarding CJD has been a contributing factor to the shortage
of IGIV. ‘Wtultip le lots have been quarantined or withdrawn because
of donors who, after donation, were identified of being at risk of or
having developed CJD. This new recommendation, once fully imple-
mented, should help the present supplies of CJD and other deriva-
tives.

Let me briefly turn to the GAO report. There has been concern
that there may be an increased risk of infection from plasma col-
lected from paid donors compared to unpaid donors. GAO evaluated


144

ECUTIVE SUMMARY
INTRODUCTION

Antibodies have been used to confer passive humoral immunity since the early 1900s.
Intravenous immunoglobulin (I'V1G) to prevent serious bacterial infections in antibody-
deficient individuals became available in the U.S. in 1981. It soon became apparent that
IVIG possessed immunomodulatory, as well as immunoprotective properties, leading to
clinical trials in a wide range of non-infectious, immune-mediated diseases. In the late
1980s and throughout the 1990s, utilization of IVIG grew rapidly, fueled largely by
increasing off-label use.

In the face of rapidly increasing demand, manufacturers of IVIG “scaled up” production,
increasing the numbers of plasma units pooled during the manufacture of IVIG. With
some donor pool sizes! reported to be in excess of several hundred thousand, public
attention focused on the potential effects of large donor pools on the risks of transmitting
infectious agents, In 1997, growing shortages of a number of plasma products raised
concerns that steps to limit the size of plasma pools might further reduce availability of
IVIG.

In 1997 and 1998, the shortage of IVIG and the topic of donor pool size were discussed at
meetings of the Public Health Service Advisory Committee on Blood Safety and
Availability, the Blood Products Advisory Committee of the U.S, Food and Drug
Administration, and the Subcommittee on Human Resources of the House Committee on
Government Reform and Oversight.

In the fall of 1997, the Subcommittee requested assistance from the National Institute of
Allergy and Infectious Diseases (NIAID), a component of the National Institutes of
Health (NIH), to determine the minimum donor pool size needed for safety and efficacy
of immunoglobulin products.

In April 1998, the NIAID convened an Expert Panel of federal and non-federal
physicians and scientists to review published data and other information pertinent to the
issue of donor pool sizes for immunoglobulin products. The panel included experts in
science and public health policy, adult and pediatric medicine, infectious diseases,
rheumatology, immunology, transfusion medicine, epidemiology and statistics, and
medical ethics. The Expert Panel reviewed information presented by medical experts,
professional societies, patient advocacy organizations, and representatives of the U.
Food and Drug Administration and the plasma products industry.

‘Donor pool size” refers to the total number of individual donors contributing source or recovered plasma
to a product lot. Because multiple plasma units from a given individual may be pooled during manufacture
‘of plasma products. the donor pool size may be smaller than the number of plasma or blood donations/units
‘comprising each product lot



90

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page &

Quality Plasma Program
‘Standards Overview

‘With the changes behind us, now let me describe in a little more detail all of the
QPP standards. If you have any specific questions | would be happy to answer
them at the conclusion of our overall presentation.

First, facilities must have @ formal employee training program. The QPP
provides guidance by dictating the components of the program such as initial,
annual and interim training; documentation; retraining; and that all functions in
the center are covered.

‘Some of the ways we create a community based donor population are through
requirements for donor identification with a local address as an example. This
criteria actually serves as a useful function on the rare occasions when we have
positive viral marker test results, by improving our ability to contact the donor and
‘appropriately counsel and refer those donors for further medical evaluation and
treatment.

‘We have very rigid criteria intended to ensure that each location maintain their
facility as a professional medical operation. These include criteria related to
‘signage, cleaning, storage facilities, donor flow, lavatory facilities, etc.


172

5.

products, and then also had to shoulder the costs when the system failed
and the treatment became the transmitter of a deadly virus. Taken as a
whole, we can only conclude that this is a unique marketplace where the
relationship between government regulation and industry cannot be left to
the traditional accepted norms. It is a marketplace where government.
regulation must be rooted in an understanding of the unique situation and
the role of the public sector in underwriting the costs and profits of the
four major corporations involved in the manufacture of plasma derivative
products.

Yet the federal government continues to regulate through so-called
consensus building and recommendations rather than wielding the power it
possesses in order to ensure a safe and sufficient supply of plasma
derivative products. Why does the regulatory system for blood/blood
products not reflect the social value placed on these products? Why does
the federal government continue to allow these four manufacturers to
collectively control critical data and information? Information that is
crucial to the development and implementation of sound regulatory and
safety standards. Why does the FDA continue to operate as if these four
manufacturers have the right to withhold critical safety and supply data?

Have we not yet concluded that the self-regulation that has
prevailed since the introduction of factor concentrates has failed? Why
has the hemophilia holocaust and the transfusion associated HIV infection
of thousands of Americans not resulted in substantive changes in the way
we approach regulating this essential industry? It is past due the time
when the federal government reassesses the regulation of the blood
products industry and begins to regulate these manufacturers within the
context of the social utility of these products. Consensus building has
obviously failed and must be abandoned. The regulatory “culture of
decision making” Is not only fiawed in terms of the financial costs to the
public sector it is also flawed in terms of protecting the health and well
being of the end users, consumers, of blood products. Was it not a vivid
and disturbing lesson when we leamed from the earlier hearing before the
Subcommittee on Human Relations the truth regarding the pool sizes the
manufacturers had been employing over the last 25 years. Persons with
hemophilia had believed that their risk factor was based on 20 thousand


44

Some emerging threats do not come from newly characterized
infectious agents, but rather from variations of well known
infectious agents. An example of this is HIV-1 Group 0 that was
identified for the first time in 1996. In July 1996, FDA
requested manufacturers of HIV test kits to modify their kits for
enhanced sensitivity to Group 0. Later that year, FDA advised
blood and plasma establishments to add to their donor deferral
criteria histories of risk factors associated with geographical

areas in which Group 0 is endemic.

Identification of a new emerging infection will depend heavily on
the recognition by the epidemiology community of new trends in
data. While it is possible that viral marker rates may assist in
identifying certain trends there is no present identifiable
correlation that will assure that certain viral marker rates will
lead to the identification of presently unknown infectious
agents. It is just as possible that there will be no
correlation. Populations at increased risk for known agents,

however, are appropriate to monitor for emerging agents.

VII. CONCLUSION

FDA maintains as one of its highest priorities assuring the
safety of the blood supply and blood and plasma derivatives,
including vigilant oversight of GMP compliance by the plasma

fractionators. The Agency also will continue to do everything

20


85

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 3

‘As a result, industry drafted four voluntary initiatives that focus on minimizing the
risk of “window units.” We determined that there were three primary
opportunities for window units to enter the manufacturing process:

‘+ Units of plasma from previously untested one-time donors;

‘+ Previously collected negative units of plasma from repeat donors who
‘subsequently seroconvert; and

‘* Units of plasma collected from repeat donors who have tested negative but
do not retum after their last donation; and

We have developed an industry initiative to address each of these theoretical
threats from window units and also developed a standard to institute new, more
sensitive testing technology to further close the window period. More broadly,
we believe that these initiatives address three fundamental risks: that of the
known pathogens; that of the unknown or emerging pathogens; and that of
limited access to plasma-based therapies. Dr. Tom Waytes wil alk in more
depth about each of the four voluntary initiatives.

During 1997 IPPLA member companies, as well as the European members of the
European Association of the Plasma Products Industry (EAPPI), in cooperation
with ABRA, have been implementing these standards one by one as technology
‘and regulatory approval will allow. We have started the collection of data to
measure the progress and effectiveness of the program. Our objective is to
continue to collect more data to validate the program and subsequently report
publicly on the progress that we have made. These efforts will be a component
part of an additional comprehensive initiative that we are in the process of
developing.


62

the journal Transfusion. In that article the repeat reactive rates
from nationwide screening for blood and plasma for antibodies to
HTLV-III, currently known as HIV, were 0.34 percent for whole
blood donations and 0.15 ‘percent for plasma donations.

More recently, as Dr. Friedman noted, a 1993 FDA workshop on
the safety of plasma donations concluded, “Plasma pools derived
from compensated donors are at least as safe as comparable plasma

ls recovered from whole blood donations from volunteer donors.”

‘he viral marker rates reported at that workshop were strikingly
similar. Thus the comparability of residual risk rates for whole
blood and source plasma donors reported in the GAO report should
come as no surprise.

Given this history of comparable safety profiles, we have begun
to question whether continued comparisons of viral marker rates
between whole blood and source plasma are the best use of limited
government and industry resources. We are focusing future re-
sources on continuous quality and safety improvements measured
against our own baseline of past performance.

In conclusion, I would like to thank the subcommittee for bring-
ing these important issues to light and for giving me the oppor-
tunity to address them. ABRA and its members are committed to
continuous improvement of the industry through the voluntary ini-
tiatives outlined previously and a number of planned enhance-
ments to the QPP. We would welcome the opportunity to discuss
our plans for enhancing QPP and the safety of source plasma with
you and the subcommittee at any point in the future.

Mr. Suays. Thank you.

[The prepared statement of Mr. Reilly follows:]


86

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 4

I would ask that you hold any questions until the end of our presentation. Each
of our speakers will remain at the front to answer any of your questions.


121

coming months rather than increases. If this is true, there will be
high human costs.

'e also thought we heard a promise from the FDA to try to ad-
dress the distribution problems by a more extensive program of
educating providers to the appropriate allocation of scarce re-
sources, particularly in the area of IVIG. We don’t think that prom-
ise has come to pass.

Please remember we are discussing life-sustaining therapies.
Twenty years ago my wife and I were told that our 6-month-old son
might not live through that night in the hospital. Today he is a col-
lege student, he has no health impairments, he has no activity lim-
itations, he has not suffered a hospitalization in nearly 20 years.
That’s the difference that a safe product can make. We want to
make sure that tens of thousands of other patients will continue to
have access to safe plasma product.

Six months ago consumer organizations were asking for more in-
formation about the reasons for the shortages. Now in light of what
we think is a Worsening situation, we want to see more. We would
like to see action. At the May 7 hearing Mr. Bacich of Baxter in-
vited you to point at industry and challenge them to fix the prob-
lem. Did they fail to hear the challenge, or are they unable to meet
it? We will wait to see action—while we wait to see action, better
information is still necessary. The consumer organizations need to
be made aware of FDA and industry actions taking place and how
these actions will affect their product supply.

In conclusion, we offer the patient notification system as a model
for cooperation and communication. While trying to fix the produc-
tion problems, the plasma product distribution system should be
approached in the same cooperative manner by the industry, gov-
ernment and consumers, assuring that delivery is made to those for
whom it is life-sustaining.

Finally, the consumers wish to commend you, Mr. Chairman, for
the recent recall amendment you offered to the appropriations bill.
This type of legislation serves to further patient awareness, edu-
cation and most importantly safety. The Plasma Users Coalition
have a series of recommendations which are presented in my writ-
ten testimony, but with the time limit, I haven’t presented it here.

Thank you.

[The prepared statement of Mr. Boyle follows:]


124

However, there is a continuing shortage of recombinant AHF, which along with
prohibitive costs will keep persons with bleeding disorders members of the plasma
products users community for some time to come.

The Department of Health and Human Services Advisory Committee on Blood
Safety and Availability reviewed the chronic product availability problems at its April
meeting followed by the attention of this subcommittee in May. At both of these
meetings short and long term recommendations were made. We are here today to
report that the product availability has not improved significantly since those meetings
and we believe that the situation will get worse in the near future. May I repeat, we
believe that a very bad situation is getting worse, not better, despite the recognition of
the seriousness of the problem by both government and industry.

This brings us to the substance of the GAO report. The GAO teports numerous
deficiencies in adherence to good manufacturing practices in recent inspections of
four major fractionation companies. These deviations led to two consent decrees,
including one requiring a company to cease distribution of its products. This shut
down was one of several factors in the IVIG shortage.

At first glance, the GAO report suggests a manufacturing industry that has significant
problems with the production of plasma derivatives, with over 50% of the
manufacturers under consent decree. I can tell you as a parent of a plasma user that
the 429 deviations from good manufacturing practices cited in the report scares me.
A few months ago my wife and I were pulled off a plane because my son could not
get his gamma globulin, which is equally scary. At the same time, none of us want
bathtub plasma products carrying infectious agents that kill rather than cure.

The GAO report, however, does not evaluate the state of manufacturing and
specifically, the safety of manufacturing at these plants. The 429 deviations could
represent a broken industry, which as a result of old plants, low investment, and
company indifference to the product and customer, is unable to manufacture a safe
product. Or, the same numbers could represent too much of a meter-maid mentality
on the part of the regulatory agency. A better understanding of the true situation 1s
critical because it tells us about the future availability of safe plasma products for
persons whose lives depend upon them. If the industry is currently unable to produce
enough products according to reasonable manufacturing guidelines, we need to decide
how to address the long term production issues while trying to redirect the
distribution system to get the available product to the patients for whom it is live
saving. For example, less than half of all IVIG produced in the United States goes to
immune deficient patients ot other on label uses.


31

critical areas including: quality assurance, failure
investigations, laboratory controls, equipment and process

validation, and production and process controls.

Consequently, it was necessary for FDA to require Centeon, by
notice dated August 13, 1998, to take specific action under the
consent decree to correct these violations. As this testimony
was being prepared, the Agency was evaluating the company's
response to FDA's August 13 letter and the plans to address the

specified violations.

Although Centeon continued to be out of compliance, FDA has
advised Centeon that it can continue to produce medically
necessary products for the time being, including IGIV, under
certain conditions. At this time, FDA is still working with the
company to determine the company's final response to FDA's
August 13 letter and the ultimate impact on the availability of

the products it produces.

B. IGIV SUPPLY

At the present time, FDA continues to be aware of IGIV shortages
as well as shortages and possible shortages of several other
plasma derivatives, including albumin and clotting factors. FDA
anticipates that the IGIV shortage will not be alleviated and

will continue as long as production levels do not meet or exceed


156

We, by no means, want to sacrifice safety or compliance of GMP; however, we ask that
every consideration be given to manufacturers to make corrections without affecting
production and product releases. It is imperative that the FDA and industry work in
concert to resolve GMP issues without impacting the production of these life saving
plasma derived therapies.

‘We are extremely concerned about the continued delays in the approval of final trial
design for phase I1/1M for the third manufacturer. This IND and trial has been delayed for
more than a year. The current delay appears to be the result of a proposed requirement to
divert an excessive amount of product, already in short supply, to conduct a randomized,
prospective comparison trial. This is contrary to the BPAC's recommendation not to
change clinical trial design and the ACBSA's recommendation, through Secretary
Shelala, to expedite the availability of additional c11PI products.

It is significant that Secretary Shalala and the Surgeon General have both called for the
increasing efforts to transition plasma derivative consumers to recombinant products. We
encourage the Subcommittee to support these recommendations. I have been assured by
the Director of the Office of Technology Transfer that there will be no delays in
responding to the multiple applications for licensure of the patent for the aerosilization of
protein therapeutic agent (patent no.5,618,786). The Alpha One Foundation has also
requested that Chiron, the co-owner of this patent, cooperate with industry to license this
patent without further delay. The technology to transition people afflicted with alphal-
antitrypsin deficiency from plasma based augmentation therapy to recombinant has
existed for over 10 years and we must support manufacturers’ interest in developing these
products. There are ongoing trials for aerosolized delivery of a transgenic recombinant
form of a1PI (tg-hAAT) as a therapy for treating cystic fibrosis patients and this same
company is designing a trial for alpha l-antitrypsin deficiency. This effort will be delayed
if patent licensure and/or trial design is delayed. We also ask this Subcommittee to
support current initiatives to accelerate the development of gene-based products and
‘gene-directed therapies for alpha 1-antitrypsin deficiency and other rare disorders.

We ask that the Subcommittee review the progress in the issues that we addressed in our
testimony at the IGIV shortage hearings in May. We are still concerned about
dependence of plasma derivatives as the sole option for life saving therapy and the
importance of constant vigilance by government, industry and the consumer
communities. We still recognize that the timely application of new therapies can only
‘occur in an environment that promotes the close collaborative effort of the NIH, FDA and
‘the pharmacet industry. The leadership and vigilance of this Subcommittee has
brought attention to the impact of shortages, initiated some response by industry and
supported more collaboration between the FDA and industry. We encourage the
Subcommittee to take the next step and support the recommendations of the PUC,
address the delicate balance of GMP compliance and product availability and move to
correct the inequities in the distribution process,

‘As a member of the DHHS Advisory Committee on Blood Safety and Availability and a
plasma derivative consumer, I ask that the Subcommittee support Secretary Shalala's
policy initiatives to transition to recombinant technologies and respond to the critical
shortage of IGIV, aIPI and recombinant factor products.


1 am encouraged by a number of recent initiatives by the industry
that have greatly reduced the chance of using infected blood or plasma.
These initiatives include the use of only repeat donors and a 60 day
inventory hold on all units. The GAO found that viral inactivation
techniques significantly lower the risk of receiving an infected product
when manufacturers follow all the procedures in place to ensure safety,

quality and effectiveness.

Good manufacturing practices require that plasma manufacturers
operate in compliance with applicable regulations and principles of
quality assurance. Good manufacturing practices must include standard
industry-wide operating procedures, effective donor education and
screening; and maintenance and consultation of donor deferral registries.
Most importantly, GMP must include high quality viral testing and
inactivation techniques and procedures that assure that products are held

in inventory until they have been found to be safe.

In the previous year, the industry has increased quality assurance,
quality control and production staff training. Additionally, they have
undertaken capital investments to improve equipment. FDA has also
taken several actions to ensure manufacturer compliance. Under a new
program, FDA has designated two groups of specialized investigators for
plasma fractionation and blood banks. GAO found that if properly


139

Mr. BuLT. Maybe we can divide the question to the collection
side first and then continue with manufacturing.

Mr. REILLY. Maybe you can repeat the question.

Ms. BRANSON. it does the FDA require you to test for as far
as viral markers are concerned? The second part of the question is,
are those particular viruses lipid enveloped or non-lipid enveloped?

The concluding part of the question is whether inactivation tech-
niques are effective against t! particular viruses that you are
required to test for?

. SHays. Sir, if you would identify yourself and also give a
card to the transcriber.

Mr. Dopp. I am Roger Dodd, head of the American Red Cross
Transmissible Diseases Department, Holland Laboratory.

Currently all blood donations are required or recommended to be
tested for antibodies to HIV 1 and 2, for the P 24 antigen of HIV,
for antibodies to hepatitis C virus, for hepatitis B surface antigen.
And additionally, all donations are tested for syphilis.

For the voluntary sector, there is also testing for HTLV-I and II.
That is the human T-cell lymphotropic retroviruses I and II, and
also antibodies for hepatitis B core. And some locations also test for
alanine amino transferase, which is an additional indicator of po-
tential liver damage.

_Hepatitis B, hepatitis C, HIV, and HTLV are all lipid enveloped
viruses.

Ms. BRANSON. Thank you, Mr. Chairman.

Mr. Suays. Thank you.

I invite the majority staff, Anne Marie Finley, to ask a question
or two.

Ms. FinLEY. Mr. Reilly, how can your members be certain that
the qualified donor program reduces viral marker rates in collected
plasma if your organization does not collect and maintain records
of viral marker rates for applicant donors?

Mr. REILLY. I think through the data that has been provided to
GAO and I believe even your office as well. In the past we made
pools of plasma, if you will, out of all of the donations. So the com-
parable viral marker rate was the viral marker rate of the entire
Population or the prevalence rates as compared to the qualified
q lonor only rates. So that is the way that we are able to establish
So when you look at the overall rate, all donors, applicant and
qualified, that was the pool of product before and that would be the
risk assessment, and tl you take that against the comparative
qualified only rate.

Ms. Finury, I am not sure that I understood you. Let me ask
again an haps you can explain it.

The GAO t requested applicant donor information, specifically the
viral marker rates for individuals walking into a plasma collection
center who had not donated before, in comparison to the individ-
uals who have fone through the qualified donor program. Is it true
that ABRA and your members do not collect viral marker data for
individuals who come in for the first time to donate?

Mr. REILLY. Late in the preparation of the report GAO did come
back and ask for applicant only donor data. Let me go back and
address your initial question, how to compare the past situation


47

Reducing the number of donors contributing to plasma pools is one important
measure to decrease the risk of exposure to infectious agents, especially for
infrequent users of plasma products. However, for patients requiring repeated or
continuous treatments, the risks of exposure would be reduced to a lesser extent, even
by large reductions in donor pool size. Therefore. in addition to efforts to reduce pool
size, the Expert Panel stressed the need for continued vigilance and further
improvements in donor screening and in procedures for viral inactivation and
elimination.

The federal government should evaluate claims that reductions in donor pool
size will decrease product availability. The government should provide a
mechanism (e.g., a General Accounting Office review) to guarantee that the analysis
is comprehensive, credible, fair, and in the public domain. Expert Panel members
emphasized that neither they nor the FDA staff had sufficient information or the
capacity to evaluate claims that reductions in donor pool size would have such an
effect.

. The panel strongly supported the development of recombinant therapies to
replace plasma-derived products. The purification of non-immunoglobulin
derivatives (e.g.. clotting factors, a1 antitrypsin) consumes source plasma and may
necessitate donor pool sizes that exceed those most appropriate for IVIG. Therefore,
the panel supported the development of recombinant products in order to: a)
minimize overall dependence on plasma derivatives; b) diminish “competition”
among different products for source plasma; and e) assure that all plasma derivatives
are manufactured. to the extent possible, from donor pools of optimal size.

DHHS agencies and industry should support research to develop a variety of
recombinant plasma proteins and monoclonal antibodies for clinical use.
Furthermore, federal agencies and third party payers should make such agents
available to all patients who need them.

. Industry should collect, and make available to DHHS agencies, information on
donor immunization status and the potential value and costs of measures to
improve donor immunization. Efforts to improve donor immunization could
potentially contribute to a reduction in the risks of viral transmission (e.g., hepatitis A
and B) and to improved antibody profiles of IVIG (i.e., IVIGs that would provide
broader humoral immunity to common pathogens, including influenza viruses,
Hemophilus influenza type B, and pneumococci).

. Federal agencies should assist in the development of patient databases for
comprehensive surveillance and longitudinal monitoring of recipients of IVIG.
Such databases would allow IVIG treatment records to be correlated systematically
with information on immune function, seroconversion, and prevalence of chronic
infection. Certain patient advocacy groups (e.g., the Immune Deficiency Foundation)
currently support databases that could facilitate the collection and analysis of such
information.


153

the testimony, we are able to show that over the last 2¥2 years,
there has been a constant increase in supply of recombinant factor
8 for the American hemophilia patients. At the same time, we are
starting an initiative to look closely on a monthly basis with a re-
combinant factor 8. What we see at this moment is a decrease in
ratio, which tell us that inventories are going down. We developed
a ratio which is inventory divided by consumption. If you have a
ratio of 1 equal to a 1 month supply, what we see is that the ratio
is going down so we feel there is a reason to closely monitor recom-
binant factor 8, and that is what we are doing at this moment.

Mr. SHays. Well, with that, I thank you, all of our participants,
and thank you for coming forward.

This hearing is closed.

[Whereupon, at 12:38 p.m., the subcommittee was adjourned.]

[Additional information submitted for the hearing record follows:]


46

Mr. Suays. Thank you.

Dr. Friedman, the first hearing I think we had on blood safety
dealt with HIV and an infectious agent that we really didn’t know
much about at the time, but we all realized that once we had indi-
cations that we had a problem, we didn’t deal with it quick enough,
and a number of people became infected. In the process of that
hearing, we also learned about concern about hepatitis B and this
hepatitis strain that we now name C.

At one of the hearings, we thought there were 400,000 that were
infected with hepatitis C, and now we know it is somewhere close
to a million, through the blood.

I feel like in the 3 years, that there has been movement but rath-
er slow. And I am just interested, since you brought hepatitis C up,
before I get to my other questions, if you would tell me where we
are at.

Dr. FRIEDMAN. I will be happy to. I will ask my colleagues to
help me address this as well.

As you recall the commitment given by Dr. Satcher, not just on
the part of FDA but on the part of the entire Department of Health
and Human Services, indicated a serious organization-wide com-
mitment and a look-back campaign.

Mr. Snays. Is that sputtering?

Dr. FRIEDMAN. No. If I implied that——

Mr. Suays. I am not aware, after the major announcement by
Dr. Satcher, what we have been doing since then.

Dr. FRIEDMAN. I can say that he has assigned several activities
to different portions of the Department of Health and Human Serv-
ices. I can’t speak definitively about all of that, but let me give you
a sense of the global nature of that. For example, there is a serious
effort ongoing, which I believe is more than halfway complete, of
providing physicians in the United States with educational mate-
rials about hepatitis C and activities associated with the diagnosis
and treatment. If I am correct, roughly half of the physicians have
been mailed a full educational packet.

Mr. Suavs. That part was done. What about the hospitals? What
information—are they going over their records?

Dr. FRIEDMAN. Yes, sir. My understanding, and I will ask Dr. Ep-
stein to please fill in on this, is that medical facilities have largely
completed record reviews to identify the banks of patient names
who would be considered for the look-back policy. Maybe I can ask
you to elaborate.

Dr. EPSTEIN. FDA published a guidance in March of this year
which directed the blood organizations to identify the units where
the donor subsequently was learned to seroconvert to hepatitis C.
The process of tracing those records, we believe, has been ongoing
since that time. The notifications to the recipients——

Mr. SHays. Why do you believe that?

Dr. EPSTEIN. We have been told that by the industry.

Mr. Suays. What documentation have they provided?

Dr. EpsTEIN. I don’t believe that we have any such statement in
writing. We will follow with enforcement oversight after we publish
regulations. In the meantime, we have issued a guidance.

Mr. Suays. When will regulations be published?


OPENING STATEMENT

REP. EDOLPHUS TOWNS
RANKING MINORITY MEMBER

BEFORE THE
SUBCOMMITTEE ON HUMAN RESOURCES

SEPTEMBER 9, 1998

Mr. Chairman, thank you for holding this hearing on the safety of
the blood supply. Today, we will hear the results of a new GAO report
examining the effect of volunteer and paid donors on the blood and
plasma industry. Additionally, we will hear the results of GAO’s
overview of industry compliance with current Good Manufacturing
Procedures in the collection, processing and distribution of blood and
plasma products. I want to commend you on your long-term interest and

commitment to this issue and your efforts to keep the blood supply sate.

It is my understanding that the GAO found that paid plasma donors
are one and a half times more likely to donate potentially infectious
blood and plasma. Hopefully, these findings will not lead to a call for
the elimination of paid donors. Such an action would further reduce

critical supply without increasing overall safety.


40

risk for infrequent users would be reduced in instances where the
prevalence of the infectious agent is low. Reduction in pool
size also might lessen the impact of recalls and withdrawals on
supply of the products. In setting upper limits on pool size,
however, potential adverse consequences also must be considered.
With small size batches, quality monitoring and release testing
could consume a large portion of the batch. smaller pool size,
and therefore smaller batch size, in existing plants may result
in sub-optimal processing and decreased overall product

availability.

This Committee has considered issues related to plasma pool size
in its ongoing oversight activities concerning blood safety
issues and recommended limitations on pool size. FDA is now
developing guidance on limitations to plasma pool size which is

expected to be issued in the near future.

‘V. VIRAL INACTIVATION

Since the initial safety steps of eliminating blood possibly
contaminated with infectious agents is imperfect, the most
critical safety step remains viral inactivation. The risk to a
patient from any particular agent may vary with the particular
plasma derivative. Thus, FDA believes that all human plasma
derivatives should undergo viral inactivation or removal

procedures to ensure safety. FDA has been moving progressively

16


120

fering from increased infections that normally would have been
checked by the recommended IVIG therapy.

Mr. SHays. Given that there’s just one member here right at the
moment, would you say that we need to take a look at this a few
weeks from now or months from now after—with the ban lifted by

r——

Mr. BoyLe. Personally I don’t think that lifting of that ban is
going to have that much effect on the shortage. It certainly would
be useful. We intend to continue monitoring the situation on a
quarterly basis. But there are a number of factors that contribute
to the shortage. I’m not aware of all of them.

Mr. SHays. OK. We'll come to that then.

Mr. Boy.e. This brings us to the substance of the GAO report.
The GAO reports numerous deficiencies in adherence to good man-
ufacturing practices in recent inspections of the four major
fractionating companies. These deviations led to two consent de-
crees, including one which required a company to cease distribution
of its products. This shutdown was one of several factors in the
IVIG shortage.

The GAO report su; a manufacturing industry that has sig-
nificant problems with the production of plasma derivatives, with
over 50 percent of the manufacturers under consent decree. I can
tell you as a parent of a plasma user that the 429 deviations from
good manufacturing practices cited in that report scares me, and
T have to wonder is my son getting bathtub gamma globulin. At the
same time, a few months ago my wife and I were pulled off a plane
and told that my son had a medical emergency. It turned out that
he and his medical center could not get gamma globulin through
any mechanism at the moment, and that was quite scary.

jo are plasma product users truly faced with a choice between
safety and availability, or is neither of them possible? The GAO re-
port unfortunately does not evaluate the state of manufacturing
and specifically the safety of manufacturing at these plants. The
429 deviations could represent a broken industry which is the re-
sult of old plants, low investment and the company’s indifference
to the product and consumer, and it’s inability to manufacture safe
product. Or the same number could represent too much of a meter-
maid mentality on the part of the regulatory agency. A better un-
derstanding of the true situation is critical because it tells us about
the future availability of safe plasma products for persons whose
lives depend upon them. If the industry is currently unable to
produce enough products according to reasonable manufacturing
guidelines, we need to decide how to address the long-term produc-
tion issues while trying to redirect the distribution system to get
the available product to those patients for whom it is lifesaving.

Mr. Chairman, the consumers thank you and your subcommittee
for its vigilance in oversight of this area. We thank you for the op-
portunity to comment on these issues. However, we hope that you
will hold both industry and government to their responsibilities
and commitments in this area. In the aftermath of the plasma
product shortages earlier this year, we thought we had a promise
from the industry for increa: Production. Based upon what we're
hearing, we are likely to see further reductions in production in the


19

assessment is based on the amount of virus that is killed or removed and therefore the
extent to which these processes eliminate viruses through manufacturing. Individual
manufacturing steps can be specifically designed for viral clearance, or they may be
intended primarily as a purification process that will also help in killing or removing viral
agents. To meet FDA approval of their particular inactivation or removal technique,
manufacturers must separately validate each clearance step.

‘The viral inactivation and removal steps now in use have all been demonstrated to
reduce the levels of virus and, in many cases, most likely eliminate them. Even if the
virus is not completely eliminated, reducing it significantly is of value. Although
theoretically even a single virus can cause infection, research has shown that infection is
much more likely to occur with higher concentrations of virus. Proper viral inactivation
and removal steps have resulted in no documented cases of HIV, HCV, or HBV
transmission from plasma products since 1988.

RECENT NONCOMPLIANCE WITH CURRENT GOOD
MANUFACTURING PRACTICES COULD JEOPARDIZE
PLASMA PRODUCTS’ SAFETY

Although viral inactivation and removal techniques have proven to be highly
effective, they are only useful if the steps in the manufacturing process are carried out
Properly. Recent FDA inspections of plasma fractionation facilities have found many
violations of current good manufacturing practices. The lack of strict adherence to these
practices could compromise the safety of plasma products.

The objective of good manufacturing practices is to ensure that plasma products
are safe, effective, adequately labeled, and possess the quality purported. Plasma
manufacturers should operate in compliance with applicable regulations, which require
adherence to current good manufacturing practices and quality assurance principles. In
addition, each manufacturer must adhere to the standard operating procedures it has
established for its facilities,

To ensure that manufacturing processes, including inactivation procedures, follow
current good manufacturing procedures, FDA is authorized to inspect plasma
fractionation establishments. If the inspectors identify problems, FDA has a range of
actions it may take. For violations deemed serious, these actions can include issuing
wamning letters, seeking a consent decree, or suspending a facility's license.

‘When an inspection reveals deficiencies, FDA may issue a warning letter to the
facility, which does not suspend operations but gives the facility an opportunity to correct
deficiencies. A warning letter notifies a firm that FDA considers its activities to be
violating statutory or regulatory requirements and that failure to take appropriate and
prompt corrective action may result in further FDA action. For some serious violations,
FDA may seek a consent decree against a firm or individual-a court-ordered action that

8 GAO/T-HEHS-242,


14

plasma are used in treating the trauma of burns and surgery and for replacing blood
elements that are lacking due to diseases such as hemophilia. According to estimates,
each year about one million people in the United States receive products manufactured
from human plasma

Plasma-derived products are purified from plasma pools by a process known as
fractionation. This procedure involves a series of steps so that a single plasma pool
yields several different protein products such as albumin end immune globulins.

Plasma used for plasma-derived products manufactured and distributed in the
United States may only be collected at facilities licensed and registered with the FDA.
Centers require donors to provide proof that they are in the United States legally and
have a local permanent residence. About 85 percent of plasma comes from paid donors
in a commercial setting and is known as source plasma. The remaining 15 percent of
plasma comes from volunteer donors and is known as recovered plasma. Units of plasma
collected as source plasma contain approximately 825 milliliters; recovered plasma from
whole blood donations contains approximately 250 milliliters. Thus, more than three
times as many donated units of recovered plasma are required to make up a plasma pool
equal in volume to one comprising only source plasma.

Approximately 370 paid plasma collection centers collect about 11 million liters of
plasma from 1.5 million donors annually, involving a total of approximately 13 million
separate donations each year. Four companies process the vast majority of source
plasma: Alpha Therapeutic Corporation, Baxter Healthcare Corporation, Bayer
Corporation, and Centeon LLC.

An additional 1.8 million liters of plasma are collected from approximately 8
million volunteer (not paid) donors, who contribute 12 to 13 million whole blood
donations each year. These donors give blood at American Red Cross blood centers and
independent blood centers represented by the trade group, America’s Blood Centers, and
the plasma is recovered for further manufacturing. Plasma collected by the American Red
Cross is fractionated under contract by Baxter Healthcare and the Swiss Red Cross and
returned to the American Red Cross for distribution. Plasma collected at centers
represented by America's Blood Centers is sold only to the Swiss Red Cross, which
manufactures the various plasma products and sells them through U.S. distributors.

Paid donors typically receive between $15 and $20 for the 2 hours of time required
to remove whole blood, separate the plasma from the cells and serum, and reinfuse the
latter back into the donor. Source plasma donors may donate once every 48 hours but no
more than twice a week. Whole blood donors may only donate once every 56 days
because their red cells are not reinfused as they are with paid donors.

All donors are tested for certain viruses known to be transmitted through blood,
including HBV, HCV, and HIV. The specific screening tests check for the presence of

3 GAO/T-HEHS-242


(ONE HUNDRED FIED CONGRESS.

Congress of the United States

Bouse of Representatives
‘COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
2187 Ravaur House OFFie Bukone.
Waspancon OC 20515-6148

‘SUBCOMMITTEE ON HUMAN RESOURCES
‘Christopher Shays, Connecticut

‘Washigion 0.6. 20815)
“Tet 202 725.2508
Fax: 202 228.2382
Mas: hr gtee@mat Movte gor

Statement of Rep. Christopher Shays
September 9, 1998

‘Two weeks ago, Surgeon General David Satcher decided to lift the precautionary hold on
blood and plasma from donors who may have Creutzfeldt-Jakob Disease (CID). He did so, in
part, because quarantines of CJD-implicated blood products were reducing already scarce
‘supplies of life-saving medicines, and because the proven, negative health effects of shortages far
‘outweigh the theoretical risk of CJD transmission through blood.

‘The CJD decision illustrates many of the strengths, and weaknesses, of the system now
used to protect an inherently risky, but vital, resource. Weighing, and minimizing, the risks of
‘an uncharacterized threat like CJD challenges each layer of the interlocking blood safety
‘complex: donor screening, unit testing, anti-viral technologies and manufacturing standards.

‘While in place, the CJD exclusion policy had a far greater impact on those who collect
“recovered” plasma from volunteer donors of whole blood, than on those who collect “source”
plasma from paid donors, That unexpected disparity, and contrary suggestions that payments
lure higher-risk donors, ted us to ask the General Accounting Office (GAO) to assess the relative
risks of plasma from paid and volunteer donors.

Three aspects of the GAO findings released today stand out: First, despite persistent
questions whether paid donors have less incentive to disclose disease risks, neither the Food and
Drug Administration (FDA) nor the blood industry had much useful data on the viral marker
rates of blood donors. This points to a need for more effective, more consistent disease
surveillance.

‘Second, while paid plasma donors are one and a half times more likely to donate
potentially infectious units, recent safety initiatives by the fractionation industry greatly reduce
the chance an infected unit will be pooled for use in making a final product. This sustains our
heavy reliance on source plasma from paid donors for most plasma-derived therapies.



182

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69

Mr. Suays. Jan Bult, please.

Mr. Butt. Thank you very much.

Good morning, Chairman Shays and honored distinguished com-
mittee members. My name is Jan Bult, and I’m executive director
of International Plasma Products Industry Association, IPPIA.

Mr. SHays. Where are you based?

Mr. Butt. I’m based in Washington, DC, sir.

Our members include the four largest commercial fractionators,
Alpha Therapeutic Corp., Baxter Healthcare Corp., Bayer Corp.
and Centeon. I would like to thank the committee for inviting us
here today to discuss the safety and supply of plasma-based ther-
apy.

Our industry is committed to producing safe, high-quality lasma
products, which are used by millions of people each year in fighting
diseases and treating a variety of medica) conditions. IPPLA mem-
bers are working to continuously improve the safety of our prod-
ucts, and we appreciate the opportunity to brief the committee on
our efforts. My testimony today will focus on three areas, an up-
date on previous commitments from our industry, a discussion of
the compliance issues and how we are addressing those issues, and
our efforts to understand and respond to shortages of plasma prod-
ucts.

During testimony before this committee on July 31, 1997, the
IPPIA announced a commitment to develop a comprehensive safety
plan for the plasma products industry. We have made considerable
progress in this area.

First, in response to a challenge from you, Chairman Shays,
IPPIA promised that we investigate a system that would allow con-
sumers to verify the regulatory status of a particular product lot.

Mr. Suays. Sorry to interrupt you. If you just put that mic a lit-
tle closer.

Mr. BULT. Is this better, sir?

Mr. Suays. Yes, a little closer, too. I realize it gets in the way
of your talking, but that will help.

ir. But. OK, thank you.

In response to a challenge from you, Chairman Shays, IPPIA
promised that we would investigate a system that would allow con-
sumers to verify the regulatory status of a particular product lot.
IPPIA is in the final stages of implementing a system that will do
just that.

A second part of the industry comprehensive safety plan is the
voluntary pool size limitation announced at the same hearing last
year. We anticipate that all lots released after January 1999 will
adhere to this limitation.

The association is currently developing a comprehensive plan to
address current good manufacturing practices, compliance issues,
which I will discuss in more detail later.

Our industry is continually striving to update our quality sys-
tems and other processes so that we can provide an adequate sup-
ply of safe products. In the last 4 years our members have spent
in excess of $380 million of planned upgrades in compliance en-
hancements. Spending for these improvements increased by more
than 20 percent in 1997 alone.


24

the risks of infectious its, including human immunodeficiency
virus, hepatitis B and C, and found that paid and unpaid donor
populations have different viral marker rates. We generally agree
with these findings. As the GAO has shown, viral marker ratios for
both paid and unpaid donors are such that some viral contamina-

tion is possible with all plasma lots, both from paid and unpaid do-

nors.

We believe that GAO’s analysis shows that the risk of contami-
nation of plasma pools from paid versus unpaid donors is very simi-
lar, although there is a slight increased risk from the paid donors.
The implications of viral marker rates in paid donations have been
considered by FDA for a number of years. We believe that direct
comparison of viral marker rates does not adequately or fully meas-
ure the risk of contamination in the final product since, as was just
discussed, the techniques for clearing these products of infectious
units can be enormously effective.

In the end, it is critically important that plasma fractionators ad-
here to good manufacturing practices, for exactly the reasons that
have been mentioned by both previous speakers, that eliminate or
inactivate viruses. In addition, we believe that it would be counter-
productive to further restrict the donor pool to unpaid donors en-
tirely when such a restriction would unlikely improve the safety or
even the availability of products. This same conclusion was reached
independently by experts in 1993 and 1996 at national and inter-
national workshops.

The safety of the blood supply and products from blood and plas-
ma remains one of FDA’s highest priorities. Working with this com-
mittee, Mr. Chairman, the agency has significantly improved and
continues to address the need for increase in its vigilant oversight
of good manufacturing compliance by the plasma fractionators, and
the agency is doing everything within its power to help alleviate
product shortages.

As the industry moves toward aggressively implementing the
quality improvement and quality assurance programs, shortages
and occasional disruptions may continue to occur but will, I think,
be addressed ultimately when these good manufacturing practice
are completely complied with.

We appreciate being here again, sir, and I look forward to an-
swering your questions.

[The prepared statement of Dr. Friedman follows:]


143

TABLE OF CONTENTS.

Executive Summary
Introduction
Findings and Recommendations

Appendix A:
Appendix B:
‘Appendix C:
‘Appendix D:

Appendix E:

Appendix F:

Appendix G:
ix H: Presentation of Mary Ann Lamb

Meeting Agenda
Panel Members

Pane] Member Biographical Sketches
Professional Societies and Patient Advocacy
Groups Invited to Submit Written Comments
Summary and Individual Responses from
Interested Groups

Presentation of Rebecca H. Buckley
Presentation of Thomas J. Lynch

Presentation of Fred Feldman
Presentation of Donald Baker

: Presentation of Sue Preston

Presentation of Jean-Jacques Morgenthaler

|: Presentation of Chris Lamb
|: Presentation of Paul R. McCurdy
: Donor Pool Size for IGIV: Safety and Efficacy

Considerations, Donald L. Tankersley


10

donors which helps to reduce the likelihood of infected donors and
by putting a 60-day hold on donations before using them to make
sure that they don’t subsequently turn out to test positive for infec-
tion, the risk of pooling an infectious unit is reduced to 1 in 11,000.
This is still higher than the risk from volunteer donors which is
roughly 1 in 16,000.

Another practice which has been adopted by the industry that
helps to reduce the risks of infection for some users has been the
limits placed on pool sizes. Larger pools mean that someone who
receives the product is exposed to more donors and consequently to
more potentially infectious units. For an infrequent user of plasma,
somebody who is being treated for a burn, for example, lower pool
size can significantly reduce the risk of receiving an infected unit.
But for frequent users, like hemophiliacs, the decrease winds up
making little difference.

By far the most important safety assurance is in the manufac-
turing process itself. We know that the viral inactivation and re-
moval techniques that are used in manufacturing virtually elimi-
nate enveloped viruses such as hepatitis B and C and HIV, and
any other type of lipid-enveloped virus that hasn’t been identified
yet. These techniques are only partially effective against nonlipid-
enveloped viruses like hepatitis A and human parvovirus, so it is
important to recognize that manufacturing practices are much less
of a safeguard.

But the promise of eliminating or reducing potentially infectious
agents is only meaningful if manufacturers adhere carefully to good
manufacturing practices. And recent experience tells us this hasn’t
been the case. In fact, we know that FDA inspections at the four
major fractionation companies found numerous deficiencies in each
company’s adherence to these good manufacturing practices. Let
me just run down the list.

At Alpha Therapeutic’s facility, FDA ing rs observed 139 in-
stances of potential problems, a finding that resulted in a recent
consent decree. At Baxter Healthcare’s facility, inspectors flagged
96 potential problem areas.

At one of Bayer’s facilities they had 30 observations, and at an-
other, 77.

Finally, an inspection of Centeon’s facility last year found 87 ob-
servations and resulted in a consent decree that ordered the com-
pany to cease distributing all but two of its products while it
brought its plant up to standards. Last month, after FDA rein-
spected the plant, the company was ordered to cease manufac-
turing most products because it was still out of compliance.

What are the kinds of problems FDA ins; rs found? In a num-
ber of instances, manufacturers were relying on processes that
hadn’t been validated or fully tested to make sure that they per-
form predictably. In one case the company wasn’t co! ly fol-
lowing its viral inactivation processes and hadn't detected or cor-
rected the problem. In some cases, the final product did not meet
specifications. More than half of one company’s albumin lots failed
final container inspection because they were contaminated.

Since these deficiencies were found, the manufacturers have all
taken some corrective actions, in many cases slowing production in
order to address problem areas. Undoubtedly this is playing some


141

cused effort or limited resources into figuring out what we have al-
ready screened out because we have already screened it out.

Ms. FINLEY. What Percentage of ABRA members are QPP, quali-
fied plasma program, certified?

Mr. REILLY. Nearly 100 percent.

Ms. FINLEY. And all plasma collected that goes into further frac-
tionation of IVIG, and some of those other products would
come only from QPP certified donors?

Mr. REILLY. I believe the four major fractionators in this country
have all committed that they would only distribute AHF, and I
don’t know if the commitment has extended to immune globulins,
although you would assume that it would, from QPP certified facili-
ties.

Mr. BULT. I can confirm that statement.

Ms. FINLEY. OK, thank you.

Mr. Suays. I want to make sure I put in the record and ask
unanimous consent that a copy of the National Institutes of Health
document Report of the Expert Panel on Donor Pool Size Immune
Globulin Products be inserted into the record of this hearing. I
probably should have done that a little earlier, but we will do that
without objection.

(The information referred to follows:]


29

This new approach emphasizes a more complete assessment of
compliance with GMP. In addition, the approach includes a more
detailed assessment of the manufacturer's procedures in handling
and investigating reports of adverse experiences and subsequent
FDA notification of these adverse experiences. FDA has taken
strong steps to assure compliance of the plasma industry with GMP

through court injunctions and warning letters.

A. PRODUCT AVAILABILITY /SHORTAGES

As part of the FDA enforcement program, FDA carefully considers
the impact of regulatory actions on product availability. FDA
takes regulatory action when it believes that products are
violative and could compromise the public health. FDA will
exercise enforcement discretion when appropriate. For example,
if the Agency determines, after balancing all the factors, that
halting the manufacture of a “medically necessary product” could
cause harm to patients, FDA can permit continued manufacture of
the critical product even while regulatory action against the
firm proceeds. Each case has to be evaluated on its own merits
weighing the need for the medical product versus the risk of use
of a product manufactured outside the parameters of GMP. In no
instance, however, would FDA authorize release of a product known

to be contaminated or potentially unsafe.


166

Anne Marie Finely
September 8, 1998.
Page 2

5. Capacity: As Bayer worked through completion and validation of these improvements,
capacity was adjusted to reflect the status of these changes. We are now operating at
‘our current optimum capacity with plans to increase fractionation capacity utilization in
the 1999 fractionation year by up to 22% over 1998 production.

| regret that | have not been able to provide a more detalled breakdown of the impact of the
various issues on total production, however the overlap of factors (Le, HVAC and
compliance) makes it difficult to precisely segment their individual effects.

{hope that this addresses your questions regarding Bayer's production of IGIV.

Sincerely,

Lip lal

cc: Jan Turek


98
IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 16

‘STANDARD:

Individuals will be considered Applicant Donors until such time as they have
successfully passed the following two-stage minimum donor screening process:

Persons presenting themselves for donation initially will be screened
‘according to all applicable government and QPP screening and testing
criteria. This applies whether a complete plasma unit or sample only is
collected. At this stage the person will be considered an Applicant Donor.

Reclassification of a person from Applicant Donor to “Qualified Donor’ is
achieved by passage of a physical examination as required by
government regulations and either:

a) Subsequent donation of a complete unit, and acceptable donor
screening and testing based on all applicable govemment and QPP
requirements, of

b) Subsequent donation of a sample only for the purposes of viral
marker testing and successful passage of the complete medical
history screening questionnaire.

The subsequent screening of Applicant Donors must occur no less than
the minimum time interval allowed by applicable government requirements
and no greater than six (6) months.

Testing and donor screening to classify a person as a Qualified Donor must be
administered by collection centers operated by the same company.

‘No units of plasma from Applicant Donors will be acceptable for the manufacture
of therapeutic plasma products until the person has become a Qualified Donor.


140

and an assessment of its risk versus with the qualified donor proc-
ess in place.

The pool that you would manufacture from included all donors,
applicant and qualified. So the rate—the way to assess that risk
is by looking at the combined rate of all of those Positive donations,
and that was the prevalence rate, which we did provide to GAO.

If you want to compare that against the new pool, the new pool
would be created from qualified donors only. And so you would look
at it and com it against the overall rate, and that assessment
was made and we did provide GAO prevalence rates for the overall
group as well as the rate for the qualified only.

The request that came late in the process for applicant only data,
we have attempted to comply with. Our problem is simply around
timing. Many of the companies did collect it, but they all had a dif-
ferent mechanism to collect it and the data sets were not compat-
ible. We have gone back to the companies and we are right in the
middle of beginning to collect that data in a standardized format
so it is usable and validated data. The problem was meeting the
timeframe.

Ms. FINLEY. As you assess the efficacy of the qualified donor pro-
gram, isn’t it necessary to compare the data collected from appli-
cant donors to that data collected from donors who successfully
complete the qualified donor program?

ir. REILLY. No.

Ms. FINLEY. Can you explain that?

Mr. REILLY. Let me try this again.

When you look at the plasma that is used—that was used before
ut the qualified donor standard in place, the plasma that was
was from all donors, applicants and qualified. You would look

at the rate for all of those donors because that was what we made
the product out of.

Subsequent to the qualified donor standard being in place, we
now use the plasma only from qualified donors. So we now look at
that rate, and we would compare it against what we used to do.

Ms. FINLEY. I see the point that you are making, but wouldn’t
it be necessary as you evaluate the viral load for individual collec-
tion centers to evaluate the people that come through the door
versus those that you actually want as continuous donors?

Mr. REILLY. The load in the pool is only related to those that we
retain as continuous donors. .

Ms. FINLEY. I think the question that I am trying to get at is not
necessarily the load in the pool but rather the confidence that you
would have in the qualified donor program. Isn’t that in fact a re-
flection of the improvement in the viral marker rate in qualified
donors versus the applicant donors who have not been qualified?

Mr. REILLY. We are looking at or we are in the middle of estab-

ing a viral marker rate of qualified donors that each facility
would be measured against so that the facility can see how they
measure against an industry-wide viral marker rate standard. And
the objective is continuous improvement over that baseline.

Rather than look at the applicant donor data and say that is
what we screened out and then look at the qualified donor that is
what we retained, we focused on what do we retain and how do we
continuously improve what we retain, and have not put a lot of fo-


91
IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 9

Donor screening criteria include a variety of additional standards. Each is
designed to focus on the retention of qualified donors and the exclusion or
deferral of donors at increased risk of known and possibly unknown viral
transmission. As you know, the unknown is very difficult, if not impossible, for us
to quantify until it becomes the known, The additional screening criteria we
require include increased emphasis on donor education of high risk activities,
exclusion for incarceration, and drug testing.

We are particularly proud of the next requirement. It is participation in the
National Donor Deferral Registry. We have successfully developed a national
computer system capable of capturing the name and a donor identification
‘number for any plasma donor who tests positive for any viral marker test. The
donors are listed on the NDDR by industry testing laboratories utilizing a secure
private computer network. Collection facilities can instantaneously check donors
against the Registry utilizing an 800 telephone number and a series of location
‘specific identification numbers and passwords. All of the QPP centers and
associated laboratories are required to participate in the NDDR.

One of the more creative of the standards is the application of a viral marker rate
standard to all locations. | will describe this standard in more detail in just a
minute.

Finally, each facility is required to submit specific documents and data for review
‘and they are subject to both bi-ennial scheduled and random unannounced
inspections by third party inspectors.


ll

part in current plasma product shortages. In fact, at this commit-
tee’s hearing last May, FDA estimated that over 60 percent of the
IVIG shortage was attributable to the GMP problems.

FDA has also made some changes in its inspection practices, fol-
lowing recommendations that we and the IG’s office made last
year, but the key will be sustaining the commitment to improve-
ment on the part of both the industry and the FDA. On that note
I will conclude my remarks, and I look forward to your questions.

[The prepared statement of Ms. Steinhardt follows:]


7

IPPIA Voluntary initiatives Presenation Reference No. 007842
Page 15

A recent investigation has shown that, although only a small percentage of
source plasma units are collected from first time donors, or “donor applicants,”
these units account for approximately 95 percent of all positive viral marker test
results.

The first of the Voluntary Initiatives, implemented in July 1997 as an element of
QPP, requires that no units of plasma be accepted for further processing unless
the donor has successfully passed at least two health history interviews and two
panels of all required screening tests. This standard takes advantage of the
tepeat donor population unique to the source plasma industry, to further reduce
the risk of undetected infectious units of plasma being manufactured,

e e
ater

DEFINITIONS:

Applicant Donor- All individuals presenting themselves who have not
been previously qualified as a donor in the past six
(8) months.

Qualified Donors - All individuals who have been qualified for continued

donations by successfully passing two donor
screenings and viral testing.


102

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 20

‘donors who seroconvert on a subsequent donation, or are otherwise disqualified
‘Thus, “window period” units, as those shown in the cartoon, can often be
prevented from entering the manufacturing pools.

Data have been obtained over a five-month period from an IPPIA member
company incorporating an inventory hold program. During that time over
300,000 units of plasma were entered into the inventory hold. Its important to
note that approximately 97% of these units were followed by a subsequent
donation by the same donor. A total of 2555 units were removed fram the
inventory hold as the result of 331 donors being identified by subsequent
seroconversions, other surrogate testing, or post-donation information. As a
result, these units were prevented from entering the manufacturing pools.

The voluntary inventory hold identifies units obtained from seroconverters for
HIV, HCV, and HBV. It also has the capacity of removing units that may contain
‘any known or unknown virus of which transmission may be associated with the
potential high-risk behavior identified by the current testing methods or post-
donation information.


118

notified as soon as possible in the event of a withdrawal or recall. Working with the National
Notification Center, the Red Cross established an 800# and registry in which patients could
voluntarily enroll to be notified in a confidential manner of any actions related to products in
their possession. This system was developed with input from patient groups, including the
National Hemophilia Foundation, Immune Deficiency Foundation, Committee on Ten Thousand
and the Alpha One Foundation. Red Cross has made this system available to the International
Plasma Products Industry Association for implementation of an industry-wide system.

Conclusion

State-of-the-art safety and consistent availability of plasma derivatives and transfusable
components for patients in need remains the highest priority of the American Red Cross
Biomedical Services. We commend you Mr. Chairman, Representative Towns, and Members of
the Subcommittee for continuing your review of issues related to plasma safety, and thank you
for the opportunity to take part in today’s hearing.



ABRA Statement September 9, 1998
Page 3 of 6 Reference No.GAOC98008

. maintenance of certain facilities standards, and

* fostering community based donor groups (through the
exclusion of individuals who do not have a local address).

A few of these standards deserve special attention. The NDDR, for example, is a
nation-wide computer database that allows Source Plasma collection facilities to
instantaneously check donors to assure that they have not previously tested
positive on a viral marker screening test. The viral marker rate standard was
established in 1991 and set an upper limit for the number of positive donations at
any given collection center. In 1993 the standard was revised downward and is
currently under revision once again to reflect recent industry safety initiatives.
The QPP donor screening criteria include, among other things, an increased
emphasis on donor education of high-risk activities and drug testing. In fact, QPP
was instrumental in establishing FDA criteria for exclusion of donors for
incarceration.

Since its implementation, QPP has had a dramatic effect on Source Plasma
‘safety. The standards put in place through the program have resulted in more
effective selection of low risk donors, more skilled collection center personnel,
better facilities, and lower marker rates among the donor population. However,
one of the greatest benefits of QPP is that it has served as a vehicle for effecting
continuous improvement throughout the Source Plasma industry. This has been
bome out by a number of recent voluntary industry initiatives.

in 1997 the Source Plasma industry publicly committed to four voluntary
initiatives or standards. Two of these initiatives, the Qualified Donor standard
and the Inventory Hold, already have been implemented and are having a
demonstrable effect on Source Plasma safety — two of the initiatives are by
necessity, still work in progress. The initiatives that are still work in progress
include polymerase chain reaction (PCR) viral testing and the previously noted
revised viral marker rate standard. PCR testing is still under development and is
being performed pursuant to the Food and Drug Administration (FDA) regulations
for Investigational New Drugs (IND). With respect to the revised viral marker rate
standard, we had hoped to sit before you today and explain the full impact of an
already implemented revised standard. However, after attempting to revise the
standard, we quickly feared that a revised standard could not be established
without first assessing the impact of the Qualified Donor standard.

The Qualified Donor standard takes advantage of the repeat donor population
that is unique to the Source Plasma industry. Under the standard, no unit of
plasma may be accepted for further processing unless the donor has
successfully passed at least two health history interviews and two panels of all
required screening tests within a six-month period. Thus, even regular donors
that go for a period of six months without donating must once again become
Qualified Donors. In this way, the Qualified Donor standard fosters a community-



71

The good news is that the supply levels have remained stable
and actually show a slight increase over the 6-months 8 period. We
will continue to monitor the situation and provide monthly updates
of this information to this committee, FDA, consumer groups and
other interested parties.

In addition to the collected data on IVIG, we have also started
an initiative to collect information on the supply of Factor VIII.
Our members have consistently made additional quantities of re-
combinant Factor VIII available to the U.S. market as this thera-
peutic has gained in its use.

The trend from the recombinant data factor shows a decreasing
inventory-to-consumption ratio. One could expect tight supply
versus demand margins in the near future. The tight supply-to-de-
mand—tight supply-to-demand margin of recombinant Factor VIII
may have an impact on consumption of the plasma-derived Factor
VIII. As with the other products, we have started to look at this
ratio as well, and we will continue to monitor the situation very
closely, again on a monthly basis.

Our in ustry is taking several actions to address any potential
supply issues for Factor VIII similar to those taken to address the

supply. Short term our members are working with FDA to ex-
pedite lot releases for products as they become available. Addition-
ally, an emergency supply of recombinant Factor VIII is being de-
veloped for patients in critical need.

In conclusion, I would like to reiterate that our members are
working in cooperation with the FDA to address issues associated
with continued cGMP compliance. All of us are committed to con-
tinuing to rovide access to adequate supplies of these—therapies.

The IPPIA members together with the American Red Cross and
Novartis have already started to collect data and plasma products
to better understand current and potential future shortages. We
will continue to collect and make available supply data on a month-
ly basis. We look forward to working cooperatively with patient
groups, Government agencies and others to develop workable solu-
tions to this critical shortage.

Thank you, and I will be happy to respond to any questions from
the committee.

Mr. Suays. Thank you very much.

[The prepared statement of Mr. Bult follows:]


16

Finally, the residual risk of incorporating an infectious plasma unit into a plasma
pool is somewhat higher for donations from paid donors than for donations from
volunteer donors, according to our review. The residual risk represents the incidence
rate and other factors that, in the final analysis, could result in a potentially infectious
unit being incorporated into a plasma pool. The overall residual risk of incorporating an
infectious HIV, HBV, or HCV plasma unit into a plasma pool is about 43 percent higher
for donations from paid plasma donors than for donations from volunteer donors (1 in
every 10,959 donations compared with 1 in every 15,662 donations, respectively). This
difference is statistically significant. Thus, we calculated that about 3.8 infectious units
would be included in a plasma pool of 60,000 donations if the pool were made exclusively
from donations from volunteers; however, 5.5 infectious units would be included in that
poo! if it were made exclusively from donations from paid donors.

FREQUENT USERS

Concerns have been raised about the size of plasma pools because larger pools
expose recipients of plasma products to more donors, raising the risk of infection.
Manufacturers have recently taken steps to reduce the size of the plasma pools they use
for producing plasma derivatives. Modeling techniques indicate that this effort can affect
infrequent users of these products by minimizing their exposure to a certain number of
donors. Frequent users of plasma products, such as hemophiliacs, however, tend not to
benefit from these techniques because of the large number of different pools to which
they are exposed during their lives.

As recently as a year ago, FDA believed that initial fractionation pools contained
1,000 to 10,000 source plasma units or as many as 60,000 recovered plasma units. In
response to inquiries from your Subcommittee, however, FDA obtained information from
plasma manufacturers showing that after adjusting for the combination of intermediates,
pooling of material from several hundred thousand donors for single lots of some
products sometimes took place. For example, albumin can be added during intermediate
processing steps or to a final product, such as factor VII, for use as an excipient or

“The calculations for the volunteer sector are based on the possibility that donors infected
with HBV may have transient antigenemia, of which a portion would be found positive by
the HBsAg test. If this calculation is not made, the risk of incorporating an infectious
HIV, HBV, or HCV unit into a plasma pool becomes 1 in 20,872. This would mean that
donations from paid donors would be about twice as likely to be potentially infected with
HIV, HBV, or HCV and incorporated into a plasma pool as units from volunteer donors (1
in 10,959 compared with 1 in 20,872, respectively).

5 GAO/T-HEHS-242


160

America’s Blood Centers
Statement for the Record
September 9, 1998

Page 2

Indeed, the US blood and plasma supplies are very safe. Few people are harmed each
year by their appropriate use, while many millions of American lives are saved by their
therapeutic value.

Yet history has some important lessons:

© No other step has improved blood safety more than the elimination of paid
individuals as donors of blood for transfusion

+ The rates of HIV in persons with hemophilia, who were treated in the early 1980s
with multiple single-donor products from volunteer donors (i.e., cryoprecipitate),
were far lower than those of patients treated with pooled pharmaceuticals.

The GAO report confirms that paid donations still represent significant risks over
volunteer programs. For example, despite all the safety measures in place (many that
cannot be applied practically to blood for transfusion), paid plasma donations that are
used to make pharmaceuticals still have a two-fold residual risk for HBV when
compared with volunteer donors. (The risk for HIV and HCV are roughly equivalent.)

‘* In spite of proven and overlapping safety measures, breakthrough infections can still
occur when mistakes are made.

‘+ Emerging infectious agents, such as avCJD, may be resistant to the viral inactivation
processes already in place.

In the 1970s and 80s, the US voluntary sector tried but failed to establish volunteer donor
plasma programs that would meet the needs for plasma pharmaceuticals. Other countries
have recently had similar experiences. This has given rise to the worldwide dominance
of the commercial paid donor sector in providing plasma pharmaceuticals.

Although volunteer donor plasma is potentially a superior starting material, it remains
doubtful that the voluntary sector could ever supply all the plasma required to meet
patient needs for plasma pharmaceuticals. It is equally doubtful that the voluntary sector
will be able to supply the large numbers of red cells soon to be required by
pharmaceutical companies for manufacturing hemoglobin solutions.

With the emergence of more and better synthetic substitutes (ie., genetically engineered
products), itis likely that within 20 years most simple human plasma products will be
replaced by biotechnology. Cells, tissues and organs will remain the final frontier, but
eventually the synthetic biotech products will dominate there as well. Good estimates do
not exist for when the need for volunteer donors of blood, tissue, marrow and organs will
eventually dissipate. Despite rapid advances in biotech, the tasks to find effective and
safe substitutes for human products are very complex.


99

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 17

‘What this accomplishes, is that no plasma will be used for manufacture that has
come from a donor who has not shown a commitment to repeat participation at
the plasma centers. This markedly reduces the probability of using plasma from
unacceptable populations such as persons who appear primarily for free viral
testing, oF those in immediate monetary need. This standard also ensures that at
least two acceptable virus screening panels are performed on each prospective
donor, which reduces the probability of testing error, and, to a lesser of greater
degree (depending on the intervat between samples), reduces the ‘window
period” for each virus.

In summary, the use of plasma from one-time donors is completely eliminated
through this initiative. Through this standard, Industry is also able to
retrospectively assess the acceptability of initial donations with subsequent
interviews and test resutts.

Viral Marker Rate Standard

‘The second Voluntary Initiative will redefine the existing standards to re-establish
a maximum allowable viral marker rate for incidence of anti-HCV, anti-HIV, and
HBsAg in qualified donor populations. It was agreed by the members of IPPIA
‘and ABRA that the quality of plasma from a given center is best determined by
measuring the confirmed reactive rates of all plasma units obtained from the
Qualified Donors of each center. Because the donor population and testing
requirements are precisely defined, this standard will provide an ability to monitor
and assess the overall quality of the repeat donor population at each center.

‘All participating centers are committed to have begun to perform confirmatory
testing of anti-HCV, anti-HIV, and HBsAg as of July 1987. From this date, the
confirmed reactive rates of Qualified Donor units obtained at each center will be


21

- no validation of reprocessing steps used for repooling of albumin product lots that
failed final container testing for sterility;

~ no validation of the cleaning process and removal of cleaning agent residues from
fractionation kettles, bulk tanks, buffer tanks, or centrifuge bowls; and

~ no validation of albumin manufacturing processes and final products that did not
consistently conform to the release specifications. In 1997, 54 percent of
albumin lots for one company failed final container inspection because of visible
evidence of protein material.

To overcome these problems, the major fractionation companies have taken certain
steps, such as increasing quality assurance and quality control and production staff and
training, implementing capital investments at the fractionation facilities, and validating
equipment processes. Many of the facilities slowed production as the firms reallocated
Tesources to work on their corrective actions.

In addition, FDA has taken several actions within the last year to better ensure
manufacturer compliance with current good manufacturing practices. In a previous study
examining the safety of the blood supply, we found inconsistencies in FDA's inspection
practices. As a result of this and an Office of Inspector General study examuning FDA's
regulatory role in the field of biologics, FDA adopted a new inspection program Under
this program, FDA has designated two groups of investigators: one to focus on blood
banks and source plasma collection centers and another to focus on plasma fractionation
and manufacturers of allergenic products, therapeutics, licensed in vitro diagnostics, and
vaccines. This approach is intended to ensure that all FDA current good manufacturing
practice inspections are conducted by a single agency unit using a similar approach. If
Properly implemented, these actions by plasma manufacturers and FDA should help
alleviate the problems related to adherence to current good manufacturing practices and
quality assurance.

‘This concludes my prepared statement, Mr Chairman. I will be happy to respond
to any questions that you or Members of the Subcommittee may have.

(108384)

10 GAO/T-HEHS-242


50

see whether any illness, either CJD or some other illnesses, oc-
curred. This is a commitment that Dr. Satcher has made, and one
that we strongly agree with.

Mr. KucinicH. That is interesting. I want to go back over that
statement, Mr. Chairman. “More importantly, epidemiological stud-
ies of humans over the past few decades have failed to demonstrate
a single case of blood transfusion causing CJD infection.”

I just wonder what part of the curve you are looking at because,
Doctor, as you well know, this particular disease has not been a
matter of major public health concern except for the last few years.
And for you to talk about the last few decades, I am just wondering
how aggressively the medical community and the scientific commu-
nity was pursuing studies of that, because if you are comparing the
last few decades as opposed to perhaps a curve that may not have
even begun to peak, you may be looking at the wrong part of the
study projectory.

Dr. (EDMAN. I think your concerns are very appropriate, sir.
Let me answer, and then I will ask Dr. Feigal to amplify.

First of all, there has been real scrutiny of Creutzfeldt-Jakob
Disease for a considerable period of time because unfortunately the
injection of human pituitary growth hormone did result in cases in
people both in the United States and abroad. Additionally,
neurosurgical procedures done with the lining of the brain from do-
nors who had CJD have resulted in other countries of Creutzfeldt-
Jakob Disease. Luckily in the United States we had good manufac-
turing practice in place for dura mater. Those have not occurred
here. There was a tragic outbreak of more than 60 cases in Japan.

But our Centers for Disease Control have been carefully tracking
this for close to two decades. We have looked carefully at those pa-
tients with HIV disease and with classic fact rate hemophilia be-
cause those individuals received large amounts of blood donations
to see if there were any illnesses detected there.

Dr. FEIGAL. I would. add to that, the other way that they have
looked at this, they have worked backwards. They have taken a
look in many countries at patients who have had CJD disease to
see if they were more likely to have any type of blood exposure. So
the combination of not finding frequent or excessive blood use in
patients with CJD, of not finding the disease in patients who fre-
quently get blood products, and the knowledge that we have been
able to detect it when it has been transmitted through medical
problems in the past, at this point leads to the overall statement
that we are unable to find documented cases despite a fairly inten-
sive effort.

Dr. FRIEDMAN. We are committed to continue to look for this, and
I can’t adequately portray to you the soberness and the intensity
of discussions which have taken place within our Department and
at various Blood Committee meetings dealing with exactly the kind
of concerns that you raise. We do not have all of the information
about oP. and the responsibility that we bear is to be especially
careful.

Mr. Kucinicu. I yield back to the Chair but I would like to con-
tinue this line of questioning when we come back.

Mr. Suays. You can finish up.


95

IPPIA Voluntary initiatives Presenation Reference No. 007842
Page 13

IPPIA and Voluntary initiatives: Dr. Thomas Waytes, Immuno-US, inc.

Good afternoon, my name 1s Tom Waytes, and today | am representing the
IPPIA. The member plasma fractionators of the IPPIA have continuously sought
to improve the quality of their therapies by increasing the theoretical “margin of
safety,” the difference between the maximum potential viral load of the
manufacturing plasma pools and the sum of the virus removalinactivation steps.
incorporated into the manufacturing processes.

My presentation will focus on industry initiatives to increase the safety of the
plasma starting material.

‘To address further the issue of reducing the potential maximal viral load in
manufacturing pools, the IPPIA took the historic step of implementing what are
now known as the four “Voluntary Initiatives.”


33

Committee recommendation was for FDA and industry to explore the
possibility of importing supplies of IGIV and Immune Globulin
Intramuscular (IGIM). FDA has explored this issue and various
concerns need to be resolved involving GMP and plasma collected

abroad.

The most important action, however, has been the recommended
change in policy on plasma derivative product withdrawals because
of concern regarding transmission of Creutzfeld-Jakob (CJD)
disease. On August 27, Dr. Satcher announced at the DHHS
Advisory Committee that he supported a modification of the
current recommendation on quarantine and withdrawal of blood and
plasma derivatives due to the theoretical risk of CJD. The new
policy recommends withdrawal of plasma derivatives only if the
blood or plasma donor develops new variant CJD (nvCJD). FDA
presently recommends the withdrawal of blood and plasma
derivatives when there is any evidence in a donor of classical
CJD or CJD risk factors. The policy change was deliberated
carefully and extensively within DHHS and was the subject of two
meetings of the Public Health Service (PHS) Blood Safety
Committee. The scientific deliberations considered a number of
factors before recommending the policy change. Most importantly,
epidemiological studies of humans over the past few decades have
failed to demonstrate a single case of blood transfusion causing
CJD infection. Based upon that, the risk is thought to be very

low, and possibly non-existent. Conversely, withdrawal of plasma


168

1

On August 27, 1998 the US Surgeon General, Dr. David Satcher,
stated that for persons with clotting disorders Recombinant Factor
Concentrates shall become the standard of care. He also stated that for
other plasma derivative dependent communities, the usage of recombinant
products, when and where available, should be the product of choice. Dr.
Satcher also cited the need or developing and bringing to market
recombinant products for diseases such as Alpha-1 Deficiency and others.

Two years ago the Committee Of Ten Thousand called for the
establishment of a new standard of care for the treatment of hemophilia
and other bleeding disorders. We asserted then and now that recombinant
factor concentrates provided bleeding disorder clients with the highest
degree of safety possible. This call came subsequent to our earlier push In
1994 for the usage of recombinant factor in all persons with hemophilia
whose immune systems were compromised by HIV and HCV. This was based
‘on our reading of the 1993 Swedish study which demonstrated a higher
degree of CD4 count stability in HIV immune-compromised hemophilia
clients who only treated with recombinant factor concentrates.

During that historical period we found a serious lack of
understanding by American hemophilia doctors regarding the relationship
of product purity and immune system stability. The issue still has not
been given the attention it deserves, however, a greater clarity on the
part of clients themselves has led to much more widespread usage of
recombinant factors in immune compromised hemophilia clients.

While we all agree that moving all persons with clotting disorders
to recombinant factor usage is a desirable goal and does represent a
safety margin increase, the current discussion and proposal is occurring
in @ vacuum as there currently not a sufficient supply of recombinant
factor to reach the desired goal.

In fact, we are facing a degree of shortage that will not only
prevent the expansion of recombinant usage, but will require some current
users to return to the infusion of human derived factor concentrates. It is
important to understand at this juncture, that for 2 person with


133

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17

stabilizer.’ This albumin often comes from another plasma pool containing donations that
are not in the original pool.

Because of concerns about poo! size, the four major plasma fractionators
voluntarily committed to reducing the size of plasma pools, measured by total number of
donors, to 60,000 for all currently licensed U.S. plasma products, including factor VII,
factor IX, albumin, and immune globulin intravenous. This measurement takes into
account the composition of starting pools, combining of intermediates from multiple
pools, and use of plasma derivatives as additives or stabilizers in the manufacturing
Process. Prior production streams are still being processed and distributed, however, 50
that products distributed through the end of 1998 may still be produced from pools that
exceeded the 60,000-donor limit.

‘The American Red Cross has also voluntarily reduced the size of the plasma pools
from which its products are manufactured. As a policy, the American Red Cross has a
60,000-donor limit for plasma products that are further manufactured by Baxter
Healthcare. Seventy-five percent of all American Red Cross plasma manufactured by the
Swiss Red Cross is now at the 60,000-donor limit, with plans for all production to adhere
to the limit in the near future.

In a study employing the modeling technique noted above, researchers found that
limiting the number of donors in a pool may only be marginally beneficial for infrequent
recipients, who might be exposed to an emergent unknown infectious agent with a low
prevalence in the donor population, which current manufacturing processes did not
inactivate or remove.' As an example, the researchers calculated that for an agent with a

of 1 in 500,000 (for example, a rare or emerging virus), a pool comprising
10,000 donations would yield a 2 in 100 chance of exposure to that agent for a one-time
recipient. For frequent users of plasma products (that is, 100 infusions during a lifetime),
however, this same pool size of 10,000 would yield an 86 in 100 chance of exposure to
that agent, assuming that the products would come from different pools. Reducing the
number of donors in a poo! does not significantly decrease this effect. Thus, these
modeling data suggest that smaller plasma pool sizes will reduce the likelihood of
transmission of viral agents to infrequent users of plasma products but will have only a
minor impact on frequent recipients of such products.

"Excipients are additives, other than the active ingredient of a drug, that confer a desired

property on the final dosage form. This may include a preservative to prevent microbial

growth ora stablizer that maintains potency. A stabilizer maintains the integrity ofthe
active ingredient against chemical degradation or physical denaturation.

“Thomas Lynch and others, ‘Considerations of Pool size in the Manufacture of Plasma
Derivatives," Transfusion, Vol. 36, No. 9 (1996), pp. 770-75.

6 GAO/T-HEHS-242


61

still under development, is being performed pursuant to Food and
Drug Administration regulations for investigational new drugs.

Over the past year ABRA and its member companies have com-
mitted extensive resources to the collection of data to accurately
characterize the safety of plasma. To date, ABRA’s data collection
has focused on viral marker rates among qualified donors. This is
because only donations from qualified donors are used for further
processing.

Donations from applicant donors are not used for further manu-
facture unless the qualified donor criteria are subsequently met. As
such, ABRA believes that the data pertaining to viral marker rates
among applicant donors are not meaningful in terms of assessing
the safety of plasma for further manufacturing. Despite this strong-
ly held belief, ABRA has begun a data collection effort to respond
to requests for applicant donor data. The applicant donor data that
have been collected to date are incomplete. Inclusion of these data
in the GAO report would have been misleading.

ABRA provided GAO with the data needed to perform its anal-
ysis. These included prevalence rates for all donors, incidence rates
on qualified donors and residual risk rates on qualified donors. In-
clusion of the California Department of Health Services data in the
GAO report was unfortunate, particularly in light of significant
limitations of the data_set and the lack of data verification ac-
knowledged by GAO. The ABRA-supplied data represented the
most comprehensive, complete and accurate data set available for
the industry.

What the ABRA data show is that source plasma is extremely
safe. For the HIV virus the probability that an undetected but po-
tentially infectious window period donation may enter a manufac-
turing pool is 1.47 per million donations. All HIV window period
donations are known. All HIV window period donations from
known seroconverting donors are interdicted under the inventory
hold standard. The 1.47 per million probability represents the re-
mote likelihood that a nonreturning qualified donor’s last donation
may be in the window period despite the fact that it does not test
positive using current testing technologies.

The data for HCV and HBV are also profound. With the promise
of PCR testing within reach, the probability of a potentially infec-
tious window period donation entering a manufacturing pool for
HCV will fall from approximately 36 per million donations to only
3.32 per million donations. Like HCV, with PCR in place, 100 per-
cent of all the HCV window period donations from known
seroconverting donors would be removed under the inventory hold.
For hepatitis B, currently 91 percent of all window period dona-
tions are removed under the inventory hold.

As the GAO report points out, these source plasma data are com-

ble to those reported from the American Red Cross. The only
Fiscrey ancies between the two data sets exist for hepatitis B, and
the GAO report notes this is partially due to the transient detect-
ability of hepatitis B virus and the fact that source plasma donors
donate more frequently than do whole blood donors.

The comparability of these two segments of the industry is not
news. The comparability of source plasma and whole bl indus-
tries was demonstrated as early as 1985 in an article published in


130

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114

Chairman Shays, Representative Towns, and Members of the House Human Resources
Subcommittee, I am Brian McDonough, Chief Operating Officer and Responsible Head of the
American Red Cross Blood Services. Thank you for this opportunity to respond to the report by
the General Accounting Office (GAO) on the safety of plasma derivatives.

As the Subcommittee is aware, the principal role of American Red Cross Blood Services is that
of the nation’s largest supplier of transfusable blood components, serving more than 3,000
hospitals across the country. The American Red Cross collects almost 6 million units of whole
blood through the generous donations of 4.5 million volunteer donors annually. The Red Cross
is both a provider of transfusable blood components and plasma derivatives. Consistent with the
needs of transfusion medicine, units of whole blood are separated into specific components
following donation -- red blood cells, platelets and plasma. Due to the relatively limited need for
plasma for transfusion, most of the plasma recovered from whole blood donations is fractionated
into various plasma derivatives.

Red Cross plasma derivatives account for 15 to 20 percent of the nation’s supply. Unlike the
commercial providers of plasma derivatives, the Red Cross does not fractionate its own plasma
products, We contract with Baxter Healthcare's Hyland Division and the Swiss Red Cross to
‘manufacture antihemophilic factor, intravenous immune globulin (IGIV) and albumin products
under the FDA licenses of those companies. Approximately 80 percent of the plasma Red Cross
recovers from six million volunteer donations of whole blood is fractionated by Baxter.

The American Red Cross is a distributor of plasma derivatives fractionated under the FDA
licenses of other companies. As such, while not directly responsible to the FDA for the
compliance of these firms, we must exercise due diligence to ensure that products distributed
under our label are manufactured in compliance with FDA regulations. We have worked with
Baxter and the Swiss Red Cross to assist them in their compliance efforts, and continue to
monitor and evaluate corrective actions undertaken by both fractionators. Further, the American
Red Cross is responsible for maintaining its own Good Manufacturing Practices (GMPs) during,
the processing of blood donations, from the time of collection through distribution.

GAO Report on Plasma Derivative Safety

We were pleased to work the GAO staff on this study, and commend them for their diligence in
assuring that the study accurately compared differing data sets presented by Red Cross and the
American Blood Resources Association (ABRA). We believe that the GAO estimates pertaining
to volunteer blood donors are generally accurate. Susan Stramer, Ph.D., Director of the Red
Cross National Confirmatory Testing Laboratory and Roger Dodd, Ph.D., Director of the
Transmissible Diseases Department of the Red Cross Holland Laboratory, worked closely with
the GAO staff. As you know, the American Red Cross Jerome Holland Laboratory, located in
Rockville, Maryland, is the world’s premier blood research facility. Drs. Stramer and Dodd
provided data to the GAO and discussed the various issues involved in identifying and
quantifying the viral marker rates among first time and repeat volunteer blood donors.


116

viruses—those viruses that incorporate the fatty coats of cells in their structure, such as HIV and
HCV—and do not work as well on non-enveloped viruses such as hepatitis A virus (HAV) and
Parvovirus. (HAV and Parvovirus are substantially reduced by partitioning during the
fractionation process.) One method of pathogen inactivation being developed involves the use of
iodine to inactivate viruses and bacteria in plasma products. In this method, iodine is chemically
linked to resin called Sephadex®; the resulting product is used in a filtration system in which the
plasma product is passed through two tubes, one containing iodine-Sephadex® and the second
Sephadex® alone. Pathogenic organisms are inactivated by the iodine bound to the Sephadex®
in the first tube, and excess iodine is trapped in the Sephadex in the second tube, resulting in a
product that contains no active pathogens and no iodine. So far, the use of the iodine/
Sephadex® virus inactivation procedure has focused on IGIV. Holland Laboratory scientists are
now investigating the use of iodine/ Sephadex® in the purification of other plasma products.

Cellular Blood Products
Holland Laboratory researchers are also researching the inactivation of viruses in cellular blood
products, such as Red Blood Cells (RBCs). Virus inactivation procedures like iodine/Sephadex®
are only applicable to noncellular blood products, such as plasma. Current efforts underway at
Holland Laboratory to inactivate viruses in cellular products are focused on the use of a
light-activated dye, dimethyl methylene blue, called 491. A light-activated molecule 491 binds
to the nucleic acids of viruses, and when activated by light, causes the viral nucleic acids to
break, thereby destroying the infectivity of the virus. This type of system is feasible for use in
RBC products because RBCs contain no nucleic acids of their own and therefore cannot be
damaged by 491 action. The results of the preliminary studies using 491 showed that the product
successfully inactivated viruses in RBCs without damaging quality of the cells after storage.

491 can also inactivate white cells present in RBCs because, unlike red cells, white cells do
contain their own DNA. White cells, or leukocytes, are associated with some adverse transfusion
reactions and filtration to remove leukocytes from RBCs is recommended in some instances.

Surveillance for Emerging Infectious Diseases

ARCNET
The American Red Cross research and surveillance program, known as ARCNET, is a
cooperative program between the Holland Laboratory and researchers in Red Cross Blood
Services Regions throughout the country to monitor the epidemiology of transfusion-transmitted
diseases. ARCNET investigators work with our current and deferred volunteer blood donors, to
gather information critical to disease surveillance. Through an Internet-based communications
system, ARCNET allows speedy exchange of the latest scientific information about existing and
emerging infectious diseases. ARCNET maintains a central repository for epidemiologic data,
used to support research studies undertaken at the Holland Laboratory and at a number of Blood
Services Regions. In addition, Red Cross is studying the possible impact of Chagas’ disease and
a number of tick-borne infections on the safety of the blood supply.


Statement of Rep. Christopher Shays
September 9, 1998,
Page 2

Third, the success of those industry initiatives to inactivate or remove viral agents
depends heavily on consistent compliance with strict regulatory standards governing
‘manufacturing practices and procedures. In view of recent FDA inspections citing numerous
violations of good manufacturing practices (GMPs) at plasma fractionation facilites, this GAO
finding compels us to ask: What is being done to minimize the risks to blood product safety, and
blood product supply. posed by widespread failure to comply with good manufacturing
practices?

In May, we heard testimony that compliance-related production shortfalls, along with
surging demand, have created chronic, critical shortages of immune globulins, the plasma-
derived antibodies needed by some to fight disease. Both the FDA and the plasma industry
described ambitious plans to strengthen regulatory policy and company compliance without
‘compromising blood product safety or supply. Today we look to both for word of progress, not
more plans, toward full regulatory compliance and timely production of needed plasma-derived
products

(Our three year investigation of blood safety issues has included seven prior hearings, and
full Committee adoption of specific findings and recommendations to protect the safest blood
supply in the world from emerging infectious agents. Our goal, shared by patients, regulators
and the blood products industry. isa vigilant, comprehensive. science-based system of
safeguards that yields necessary medicines while avoiding the need to make false, potentially
deadly, trade-offs between product safety and adequate supply.

‘Toward that goal, we asked the GAO, the FDA, and representatives of blood banks, the
plasma industry and plasma patients to help us address the risks of paid versus volunteer donors
and the importance of GMP compliance in minimizing those risks.

‘We welcome their testimony.


93

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 11

Finally, before I turn the microphone over to my colleague Dr. Waytes, you
should also be aware that we don't view the QPP, the current voluntary
standards, or any of the industry's programs as stagnant. This siide is simply
list of a number of initiatives we currently have in various stages of discussion
and implementation.

‘They are development of basic and train the trainers level workshops for plasma
center personnel on QA and cGMP issues; further improvements to the QPP
standards related to NDDR, viral marker rates, donor screening, and cGMP and
A criteria; expanding patient and regulatory liaisons and communication; and
development of a plasma center location guideline.

‘Quality Plasma Program
1007 krprovererts

+ Aopen Done Sanders
+ Ve rar te Sed



38

donors. Donor screening criteria identify behavior that
correlates with higher risk for disease and higher risk of
contaminated blood. For example, FDA has recommended that
prisoners not be used as donors because it has been found that a
high percentage of all prisoners are drug users. Thus, although
in the past blood and plasma were allowed to be colleted in
prisons, that is no longer the case. It is difficult, however,
to identify and isolate other large segments of society that may
be high risk, thus selection must be done on an individual donor

basis.

Iv. PLASMA POOLS

In order to manufacture sufficient quantities of plasma
derivatives, most manufacturing facilities are designed to work
on a large production scale, using large plasma pools. These
plasma pools are derived by combining units from thousands of
individual donations. The number of units combined into a common

mixture for processing is known as "pool size."

A major recent advance in assuring safety of plasma derivatives
is gene amplification based testing by polymerase chain reaction,
or PCR. After individual units are collected and the marker
positive units eliminated, the plasma industry now combines
several hundred units into mini-pools for further testing by

newer methods that are not yet feasible to use on individual

14


158

Alpha One Foundation

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Caldovaia Pace Medical Center
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AS OF SEPTEMBER 9TM, 1998.

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125

With not nearly enough plasma products available for the dependent users we offer

the following recommendations:

Industry needs to identify and prioritize customers with essential medical needs,
for whom these products are life sustaining, (previously untreated patients
(PUPS) with bleeding disorders, immunocompromised hemophiliacs, primary
immunodeficient, and Alphas currently on product).

© Industry and government need to work cooperatively with hospital pharmacies
and buying coalitions to encourage rationing protocols.

. Industry and goverment need to work with medical societies to promote
responsible usage of products during shortages.

© Homecare pharmacies, wholesalers, and specialty distributors should report on
product distribution and purchasing should be restricted so that they are not
able to amass a surphus.

© Industry and govemment should support safety net programs established by
consumer organizations which use small portions of the available supply, but
allow access to physicians treating large numbers of patients.

Industry should accelerate its compliance performance and take responsibility to
fulfill its commitment to consumers for whom their products are life sustaining.

¢ The FDA should coordinate GMP activities and communicate within the
agency new programs or protocol that could affect supply.

© We are also concemed that regulators and the industry need to change their
collective dynamic from adversarial to cooperative. Increased communication
and cooperation is essential, including technical assistance from the regulators.

© In the case of Alpha One augmentation therapy there is not, and will not be an
adequate supply of product until another manufacturer introduces an additional
product to the market place. We therefore recommend an allocation system
that prioritizes patients currently on product and guarantees delivery of product
to these patients regardless of the healthcare delivery system they choose.

© The above recommendations must be met or we will have to reconsider export
policy. If we are not able to meet US demands under the guidance of
conscientious product use, American consumers of plasma derivatives are going
to ask for export controls. In the case of recombinant AHF products we feel it
is unacceptable to export over 50% of the market supply.


100

IPPIA Voluntary Initiatives Presenation Reference No. 007842
Page 18

collected for each of the three viral markers, The data collected over the first six
months, will be analyzed statistically, so that a meaningful maximum cut-off level
can be established. Each donor center will be required to maintain a viral marker
rate below this limit as part of its QPP certification. Facilities exceeding the limit
will be identified for corrective action or exclusion from the program. This
standard will be implemented in January 1998.

HBsAg 0.008%
anti-HIV 0.0019%
ant-HCV 0.012%

In order to obtain an estimate of the expected viral marker reactive rates to be
obtained in the above plan, ABRA has undertaken a viral marker data collection
effort conceming confirmed positive rates of units from Qualified Donors at
Participating centers.

Retrospective data was collected prior to July of this year from varying time
periods ranging from 6 weeks to 6 months from all industry laboratories. This
data represents a total of 3.175 milion donations collected from nearly all
industry plasma centers, and is shown as follows:

ABRA Confirmed Viral Markers from Qualified Donors

HBsAg 0.005%
anti-HIV 0.0019%


41

toward this goal even for products that never have been
documented as transmitting viral agents. Most plasma derivatives
already are processed specifically to inactivate or remove many
viruses. There are highly effective mechanisms for removing or
inactivating lipid enveloped viruses such as HIV, HBV, and HCV.
The technology to inactivate heat stable, non-lipid enveloped
viruses, such as the Hepatitis A virus, or agents such as CJD
while preserving the functions of plasma proteins, however,

currently is not available.

While all the above safety measures enhance the reduction of
risk, without adequate viral inactivation, the other safety
measures will not provide the measure of assurance that is
necessary for public safety. The application of GMP to this
process is particularly important. If viral inactivation and
removal processes are not carried out in accordance with GMP
standards, the companies will not be able to provide the

necessary level of assurance that the finished product is safe.

VI. EMERGING INFECTIONS PLAN

The greatest threat to the blood supply is posed by unknown or
emerging agents that may not be inactivated or removed during
processing. Realizing that there constantly will be emerging
infectious agents which pose threats to the safety of the blood

supply, FDA is committed to developing a strategy for each

a7