UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH
MEETING
MONDAY,
DECEMBER 15, 2003
The Advisory Committee met at 8:00 a.m. in the Grand Ballroom of the Gaithersburg Hilton, 620 Perry Parkway, Gaithersburg, Maryland, Dr. Lisa Guidice, Chair, presiding.
PRESENT:
LINDA C. GUIDICE, M.D., Ph.D. Chair
SUSAN A. CROCKETT, M.D. Member
PHILLIP DARNEY, M.D. Consultant (Voting)
NANCY W. DICKEY, M.D. Member
SCOTT S. EMERSON, M.D., Ph.D. Member
RALPH GREEN, M.D. Consultant (Voting)
MICHAEL F. GREENE, M.D. Consultant (Voting)
W. DAVID HAGER, M.D. Member
VIVIAN LEWIS, M.D. Member
LARRY LIPSHULTZ, M.D. Member
GEORGE A. MACONES, M.D., M.S.C.E. Member
JAMES L. MILLS, M.D., M.S. Discussant (Non-voting)
JOSEPH MULINARE, M.D., M.S.P.H. Discussant (Non-voting)
VALERIE MONTGOMERY RICE, M.D. Member
SONIA PATTEN, Ph.D. Consumer Representative (Voting)
JEANNE I. RADER, Ph.D. Discussant (Non-voting)
IRWIN ROSENBERG, M.D. Consultant (Voting)
BARRY SHANE, Ph.D. Consultant (Voting)
JOSEPH B. STANFORD, M.D., M.S.P.H. Member
TSUNENOBU TAMURA, M.D. Consultant (Voting)
JONATHAN A. TOBERT, M.D., Ph.D. Acting Industry Representative
MICHIEL C. VAN den HOF, M.D., via Guest Speaker
phone
KATHERINE WENSTROM, M.D. Consultant (Voting)
ELIZABETH YETLEY, Ph.D. Discussant (Non-voting)
JAYNE E. PETERSON, R.Ph., J.D. Acting Executive Secretary
SPONSOR REPRESENTATIVES AND CONSULTANTS:
ANDREW J. FRIEDMAN, M.D.
ANDREW M. KAUNITZ, M.D.
GODFREY P. OAKLEY, JR., M.D., MSPM
ANNA MARIA SIEGA-RIZ, Ph.D, R.D.
FDA/CDER REPRESENTATIVES:
DONNA GRIEBEL, M.D.
SCOTT MONROE, M.D.
DANIEL SHAMES, M.D.
LISA SOULE, M.D.
A-G-E-N-D-A
Call to Order and Opening Remarks and Introductions, Linda Guidice, M.D., Ph.D............................... 5
Conflict of Interest Statement, Jayne E. Peterson, R.Ph., J.D................................................... 8
Opening Remarks, Daniel Shames, M.D., Director, Division of Reproductive and Urologic Drug Products (DRUDP), FDA 11
Issue: The public health issues, including the safety and potential clinical benefit, associated with combining folic acid and an oral contraceptive into a single combination product.
FDA Presentations
Folate Nutrition and Metabolism and Influence on Neural Tube Defects (NTDs), Barry Shane, Ph.D................ 13
Folic Acid and Safety, Barry Shane, Ph.D......... 25
Folic Acid Fortification in the U.S., Planning, Implementation, and Monitoring, Elizabeth Yetley, Ph.D. 30
Assessing the Impact of Fortification on the Epidemiology of NTDs, Joe Mulinare, M.D.,
M.S.P.H.......................................... 40
Questions to Speakers............................ 48
Folic Acid Supplementation and Fortification in Nova Scotia, Michiel Van den Hof, M.D......................... 61
What is the Minimum Effective Dose of Folic Acid for Preventing NTDs?, James L. Mills, M.D., M.S...... 74
Questions to Speakers............................ 87
Break
Invited Sponsor Presentations (Johnson and Johnson, Pharmaceutical Research and Development, L.L.C.
Proposal Background and Overview, Andrew J. Friedman, M.D................................................. 100
Neural Tube Defects: Efficacy and Safety of Folic Acid, Godfrey P. Oakley, Jr., M.D., M.S.P.M........... 116
Need for Increased Folic Acid Intake Among Reproductive Age Women, Anna Maria Siega-Riz, Ph.D., R.D......... 134
Oral Contraceptive Use, Pregnancy Intendedness and Folic Acid Intake, Andrew M. Kaunitz. M.D.................. 144
Summary and Conclusion, Andrew J. Friedman, M.D. 150
Questions to Speakers........................... 152
Lunch
Open Public Hearing............................. 176
Presentation of Questions and Committee
Discussion...................................... 229
Break
Continuation of Committee Discussion............ 274
Adjourn
P-R-O-C-E-E-D-I-N-G-S
8:04 a.m.
DR. GUIDICE: Good morning. Would everyone take their seats, please. Good morning. I'm Linda Guidice and I would like to welcome everyone to the Advisory Committee for Reproductive Health Drugs. Today the issue will be the public health issues including safety and potential clinical benefits associated with combining folic acid with an oral contraceptive into a single combination product.
Before Jane Peterson reads the conflict of interest statement, I would like to go around the table and ask everyone to please introduce themselves and also their affiliation beginning on this end, please.
DR. TOBERT: I'm Jonathan Tobert. I'm the industry representative. I work for Merck.
DR. MULINARE: I'm Joe Mulinare from the Centers for Disease Control and Prevention.
DR. MILLS: I'm Jim Mills from the National Institute of
Child Health and Human Development, Department of Health and Human Services.
DR. PATTEN: I'm Sonia Patten. I'm the consumer representative on this
panel. I'm an anthropologist on faculty
at McAllistaire College in St. Paul, Minnesota.
DR. DARNEY: I'm Phillip Darney, Professor of Obstetrics,
Gynecology and Reproductive Sciences, University of California, San Francisco.
DR. GREEN: Ralph Green, Professor of Pathology and
Internal Medicine, University of California, Davis.
DR. CROCKETT: Hi.
I'm Susan Crockett. I'm a general
OB/GYN and I'm from Christus Santa Rosa Hospital in San Antonio, Texas.
DR. RICE: Valerie Montgomery Rice. I'm a Reproductive Endocrinologist and
Infertility Specialist from Meharry Medical College.
DR. WENSTROM: Katherine Wenstrom, Maternal-Fetal Medicine
and Reproductive Genetics from the University of Alabama.
DR. EMERSON: Scott Emerson from the Department of Biostatistics
at the University of Washington.
DR. SHANE: Barry Shane from the Department of
Nutritional Sciences and Toxicology, University of California, Berkeley.
DR. GUIDICE: I'm Linda Guidice. I'm a reproductive endocrinologist at
Stanford University.
DR. PETERSON: I'm Jayne Peterson. I'm the Acting Executive Secretary of the
Committee for today.
DR. GREENE: I'm Michael Greene. I'm a professor of Obstetric, Gynecology, and
Reproductive Biology at Harvard Medical School.
DR.
TAMURA: My name is Tamura from the
Department of Nutrition Sciences, University of Alabama at Birmingham.
DR. ROSENBERG: Irwin Rosenberg, Professor of Medicine and
Nutrition, Friedman School of Nutrition Science and Policy at Tuffs University.
DR. DICKEY: Nancy Dickey, Professor of Family and
Community Medicine, Texas A&M University.
DR. LEWIS: Vivian Lewis.
I'm Director of Reproductive Endocrinology at University of Rochester.
DR. LIPSHULTZ: I'm Larry Lipshultz,
Professor of Urology, Baylor College of Medicine in Houston.
DR. MACONES: George Macones, Maternal Fetal Medicine and
Epidemiology from the University of Pennsylvania.
DR. STANFORD: Joseph Stanford, Department of Family
Preventive Medicine at the University of Utah.
DR. YETLEY: Beth Yetley, Center for Food Safety and
Applied Nutrition at FDA.
DR. RADER: Jeanne Rader, Center for Food Safety and
Applied Nutrition, Food and Drug Administration.
DR. SOULE: Lisa Soule, Center for Drug Evaluation and
Research at the FDA.
DR. MONROE: Scott Monroe, Clinical Team Leader,
Reproductive Drugs, FDA.
DR. GRIEBEL: Donna Griebel, Deputy Director of
Reproductive Drugs, FDA.
DR. SHAMES: Dan Shames, Director of Reproductive
Neurologic Drugs, FDA.
DR. GUIDICE: Thank you very much. We also have someone who is one the
telephone, or will be on the telephone, and that is Dr. Michiel Van den Hof in
Nova Scotia.
DR. VAN den HOF: Dr. Van den Hof here. I can hear you.
DR. GUIDICE: Wonderful.
Welcome.
DR. VAN den HOF: Thank you.
DR. GUIDICE: I would like to introduce Jayne Peterson who
will read the conflict of interest statement.
DR. PETERSON: The following announcement addresses the
issue of conflict of interest with respect to this meeting and is made as part
of the record to preclude even the appearance of such at this meeting.
Based on the agenda it has been
determined that the topics of today's meeting are issues of broad
applicability. Unlike issues before a
committee in which a particular company's product is discussed, issues of
broader applicability involve many industrial sponsors and academic
institutions.
All committee participants have been
screened for their financial interest as they may apply to the general topic at
hand. To determine if any conflicts of
interest existed, the agency has reviewed the agenda and all relevant financial
interest reported by the meeting participants.
The Food and Drug Administration has
granted particular matter of general applicability matters waivers to those
participants who require a wavier under Title 18, United States Code Section
208. A copy of the waiver statement may
be obtained by submitting a written request to the agency's Freedom of
Information Office from 12A30 of the Parklawn Building.
Because general topics impact so many
entities, it is not prudent to recite all potential conflicts of interest as
they apply to each member, consultant, and guest speaker. FDA acknowledges that there may be potential
conflicts of interests but because of the general nature of the discussion
before the committee, these potential conflicts are mitigated.
With respect to FDA's invited industry
representative, we would like to disclose that Dr. Jonathan Tobert is
participating in this meeting as an acting industry representative acting on
behalf of regulated industry. Dr. Robert
is employed by Merck and Company.
In the event that the discussions
involve any other products or firms not already on the agenda for which FDA
participants have a financial interest, the participant's involvement and their
exclusion will be noted for the record.
With respect to all other
participants, we ask in the interest of fairness that they address any current
or previous financial involvement with any firm whose product they may wish to
comment upon. Thank you.
DR. GUIDICE: Thank you.
I would now like to ask Dr. Daniel Shames to give some opening remarks,
please.
DR. SHAMES: Thank you.
Good morning. Excuse my
voice. I have a bit of the local virus. I would like to welcome everyone on behalf of
the Division of Reproductive and Urologic Drug Products, today's meeting of the
Advisory Committee for Reproductive Health Drugs. I would also like to thank the speakers, Dr.
Guidice and our other advisors, for contributing their time and expertise.
The committee has been convened today
to discuss an important public health issue, the impact of increasing the
intake of folic acid by women of reproductive age on the incidence of neural
tube defects.
We will be asking you if the
fortification program that was put in place by the FDA Center for Food Safety
and Applied nutrition can be enhanced by targeting specific subpopulations of
women of reproductive age through supplementation of oral contraceptives with
folic acid. I want to convey to the
committee and other experts present today that we greatly value your opinions
and appreciate your advice.
On that note, I would like to report
that the division staff and myself are carefully reviewing your advice, the
transcript and other materials related to the Advisory Committee meeting that
we convened in the fall related to drugs for female infertility.
We will be developing a guidance
document on clinical evaluation of drugs for female infertility which we hope
we will publish -- will have a draft publication sometime in 2004. There will then be a public comment period
during which any interested party may communicate their comments to the
division.
In addition, we will be meeting within
a month with the sponsor whose NDA was the subject of the second day of the
fall meeting to discuss scientific and regulatory approaches for moving forward
with the drug product.
I will be here for the meetings today
and tomorrow and will be happy to talk personally with any of the Advisory
Committee members on issues specifically related to our last meeting or other
topics related to the division's mission.
Finally, I would like to briefly
describe today's agenda. We will hear
from speakers this morning invited by the FDA and by Johnson and Johnson who
will discuss the various aspects of folic supplementation. This afternoon the Advisory Committee will be
asked to answer questions regarding the need for additional interventions to
further increase folic acid intake in reproductive age women. Questions will also be posed about
potential safety concerns with folic acid supplementation, the identification
of specific populations that would benefit from additional supplementation, and
finally the suitability of oral contraceptives as a delivery vehicle for folic
acid supplementation.
We look forward to an interesting and
important discussion. Thank you.
DR. GUIDICE: Thank you, Dr. Shames. Sorry for mispronouncing your name. I'm highly sensitive to that myself.
I would now like to invite Dr. Barry
Shane to give his presentation on folate nutrition and metabolism and influence
on neural tube defects. Dr. Shane.
DR. SHANE: Is this working? Yes. I
was asked to give a general presentation on the roles of folate and how it's
handled in the body with particular regard to its role in NTD prevention. I'll talk primarily about that but would like
to point out that a very exciting area of folate research over the last few
years has been the realization that common polymorphisms in folate dependent
genes influence the risk of a number of diseases, not just NTDs but also cancer
and vascular disease.
The daily recommendations, or DRIs,
for folate in the future when we have enough information may be different for
various populations depending on their genetic profiles. By that I mean common polymorphisms, not
individual subsets of the population.
For most people this will be very
familiar. The bottom structure is a
reduced folate, polyglutamate form, which is the coenzyme form of the
vitamin. This is the form that functions
inside tissues and it is also the form that is retained by tissues.
The top structure is folic acid which
has a single glutamic acid on it and that is typical of a transport form of the
vitamin. Folic acid is not found in
nature. Folate is synthesized as a
reduced derivative but folic acid itself is handled like other folates. It is rapidly reduced and incorporated into
the folate pore.
Tissue folates are primarily
polyglutamates so most of the folates in the diet are these coenzyme forms of
polyglutamate derivatives and they are hydrolyzed in the gut to the
monoglutamate before they are absorbed into the body.
They are transported around the plasma
and transported into tissues by two transport systems. The most common one is the transmembrane one
but there is also a receptor-mediated system in some tissues such as the
placenta and the blood-brain barrier that is responsible for taking folates
into the tissue.
Once inside the tissue folate has to
be converted to a polyglutamate form to be retained. Cellular forms of folate that are
polyglutamates sometimes 500 fold higher than in the plasma because of this
polyglutamalation.
Incomplete conversion to polyglutamate
results in the release of the folate back into the circulation. When folate comes into the body or it goes
into the tissues, any that is not converted to folate will be released usually
by the liver. This is as a methylfolate
form so it's partial metabolism released as methylfolates into plasma. Circulating folate is normally primarily
methylfolate.
Tissue folates turn over quite slowly
and whole body folate turnover has been estimated at between 100 and 200 days
for half-life. This varies little bit
depending on the folate intake. But even
with high folate intakes the half-life has been estimated to be about 100 days
for overall body folate turnover.
When high levels of folates are given,
plasma levels increase and there doesn't seem to be a limit to the level of
folate one can achieve in plasma. But
tissue folates saturate quite quickly so it's quite difficult to drive up
tissue folate to very high levels.
This is not due to an inability to
transport the folate into the tissue.
It's a question of inability to convert enough of it to polyglutamate
forms to be retained so the folate will go into the tissue and it will come out
again as a mono- or diglutamate. Even if
one has 1,000 times the RDA one would not expect tissue folates to go up more
than about two or three fold. It's quite
a narrow range for most tissues.
The folate that goes into the body
when you have high levels of folate, you exceed the kidney threshold and so it
would be discreted as intake folate. The
folate and tissues that turn over the retain tissue is primarily turned over by
metabolism. It's irreversible cleavage
to other derivatives so that would not be reincorporated back into the body
core.
As I mentioned before, the half-life
of folates in the body, even with very high doses of folate, is still quite
long so if someone is on a high folate diet, they are likely to retain it for a
significant period of time.
This shows the RDAs. The RDA was set for folate a couple of years
ago and for the adult woman or man it's 400 micrograms a day. This is as food folate. This does not take into account any
requirement to prevent NTDs because by definition the RDA is supposed to meet
the requirements of 97.5 percent of healthy individuals and NTDs of way out in
the .1 percent at the top end of the scale for requirement possibly.
Now, because of this, the
recommendation was made that women capable of becoming pregnant should receive
an extra 400 micrograms of folic acid a day either as fortified food and/or
supplements. Because folic acid itself
is more bioavailable than folate in food, this would be equivalent to about 700
micrograms of extra food folates a day.
With the fortification of the American
food supply which was estimated initially to provide about 100 micrograms of
folic acid a day, in fact, the average intake appears to have gone up by about
200 micrograms a day which would be equivalent to about 200 micrograms a day
which would be equivalent to about 350 micrograms of food folate based on
bioavailability. Essentially what
fortification is done on average is supply people almost with a naughty extra
of food folate a day in terms of folate content.
So why do we need folate? Well, this shows the three major cytosolic
metabolic cycles that use folate. On the
bottom left is the thymidylate cycle. On
the bottom right is the purine cycle.
Folate provides one carbon for the
synthesis of thymidylate and purines, precursors that are required for DNA
synthesis and RNA synthesis. The reason
why megaloblastic anemia is the classical symptom of folate deficiency is due
to defective DNA synthesis in the erythropoietic cells.
The top cycle is methionine cycle
where at the very top is the methionine synthase enzyme which is one of two
B-12 enzymes that we have. If someone
get pernicious anemia and becomes severely B-12 deficient, that enzyme is
blocked and folate accumulate -- well, you can see the enzyme at the top is
blocked and folate get trapped as methylfolate.
The folate will be trapped as methylfolate here. Because
of that, there is no folate available for these other cycles so that's why if
you are B-12 deficient, you also display the same symptoms if you are folate
deficient. If you trap folate in this
cycle, it is no longer available for the other metabolic cycles.
I'm going to concentrate a little bit
on this cycle because this has received a lot of interest for various chronic
diseases where there is neural tube defects.
I'll be talking a little bit later about a common polymorphism in this
enzyme which produces methylfolate. That
is a risk factor for a number of diseases.
So this is the methionine cycle and
methionine itself is an essential amino acid.
We need it in the diet. But it's
a precursor for an activated form within adenosylmethionine which is the
predominate methylating agent in biology.
Adenosylmethionine will methylate a
large number of compounds. There has
been a lot of interest in the last few years in DNA methylation and
histomethylation which controls gene expression. Changes in methylation are very important
during development. They are responsible
for turning on and turning off a large number of genes including the
X-chromosome in women.
When adenosylmethionine donates its
methylgroup in the methylation reaction, one ends up with adenocele
homocysteine which is hydrolyzed homocysteine.
This can be exported into the plasma or it can be remethylated using
folate.
In the folate cycle, one common comes
from serine either directly here or by serine that is catabolized in the
mitochondria and that is another pathway which I won't go into but it's an
indirect pathway. One carbon form here
is reduced to methylfolate by an enzyme known as methyltetrahydrofolate
reductase. Then the methyl group is
transferred to homocysteine to regenerate methionine. The methyl group that is used in methylation
reaction is regenerated on the methionine or homocysteine backbone.
In NTDs there is an increased instance
or polymorphism, which I'll refer to later, in this particular enzyme. Also there's been reports that homocysteine
levels in the plasma of mothers of NTD babies is increased. So a lot of work has been going on on the
genetics of this pathway.
I'll briefly mention that is what
happens in most tissues. In the liver
there is additional pathways and homocysteine is converted to cysteine in the
transsulfuration pathway. There is also
a second enzyme which is folate-independent that can remethylate homocysteine
back to methionine. This enzyme is
present in human liver.
So
if you have a deficiency or some sort of genetic change in the pathways for synthesis
of methionine, homocysteine methylation, and adenosylmethionine synthesis, what
happens is the DNA is under methylated.
One ends up with elevated homocysteine and reduced methylation. This has been implicated to various degrees
of certainty or uncertainty in cancer risk, vascular disease risk, possibly the
demyelination of the curves in B-12 deficiency, and in NTD risk.
The thymidylate cycle if there is a
deficiency in folate or a change in the cycle, there is increased uracil
incorporation to DNA and this is implicated in cancer and anemia. Also there have been some studies showing or
suggesting that this pathway is defective in NTDs.
The relationship between folate and
NTDs, well, people in this room probably know better than me about whether it's
the No. 1 cause of birth defects in the U.S. but an interesting aspect of NTDs
is the neural tube closes in the fourth week of gestation post conception and
during this period the embryo is really dependent on the yoke sac for its
nutrition.
It's very clear that peri-conceptual
folate acid decreases the instance of NTDs and there have been a lot of studies
over the last few years on disrupting mouse genes that are involved in folate
metabolism. In a number of cases these
produce the NTD phenotype and in some cases is preventable by folate. Unfortunately, these genes do not seem to be
-- the defects in these genes do not seem to be the reason why humans get NTDs.
This will probably come up later this
morning but this is a study from Daly, the Irish group, and Jim Mills'
group. This shows the relationship of
early pregnancy maternal red cell folate to risk of NTDs. There is a very clear relationship between
lower red cell folate and increased risk for NTDs. I think Jim will probably discuss this later
but this sort of data has been used to estimate what sort of reduction one
might get in NTDs with various folate intakes.
So why does folate prevent NTDs? Well, the simplest answer is we really don't
know why folate has an effect on NTDs but it is very clear that the etiology of
NTDs is both environmental and genetic.
Of course, folate status being an important environmental aspect of it.
It's worth remembering not all NTDs
are going to be preventable by additional folate. In the last few years common polymorphisms in
various genes have been associated with NTD risk. I list two of them here, one in the MTHFR
enzyme I mentioned before involved in the methionine cycle. This is a common polymorphism and it's a case
risk for NTDs.
This is another enzyme involved in
folate metabolism. It actually uses one
carbon derived from mitochondria to incorporate into the cytosolic pore and
this has been identified as maternal risk for NTDs.
I have given a little bit of
information on polymorphism in the MTHFR enzyme. It's a C to T transition which changes amino
acid structure. In this country about
one-third of the allele is on the variant.
What we call the variant in this country and other countries is
sometimes the wild-type allele. Valine allele and the protein sequence of
this particular enzyme leads to an unstable protein if folate and riboflavin
levels are low. If someone has good
folate and riboflavin status, then there is no phenotype associated with this
polymorphism.
It's very interesting. There's a common polymorphism. In some cases over half the alleles in some
populations have this variant. The effects
of it are completely ameliorated by nutritional status. This is associated with elevated homocysteine
and decreased cancer risk so sometimes it's good having a variant.
In the case of NTDs the Irish group
have estimated that if your TT for this variant, it could explain about 15
percent of the population risk for NTDs so it doesn't explain all NTDs but it
could explain a significant portion of them.
As I mentioned before, elevated homocysteine is a risk factor for
vascular disease.
So as a nutritionalist we like this
sort of data because when we start thinking about RDAs, we start thinking here
is a classic RDI curve. At zero intake
100 percent of the population is at risk.
As you increase to 50 percent of the population at risk you have the EAR
for a nutrient and then at a high level you end up with an RDA for a nutrient
where 97.5 percent have enough.
It's possible that with some of these
common variants that the RDAs will be different for different subsets of the
population which I'm sure is something that is going to receive increased
attention in the future. Thank you.
DR. GUIDICE: Thank you, Dr. Shane.
It appears that Dr. Stover is snowed
in in Ithica so fortunately in our electronic age is slides have been passed
through the wires to Dr. Shane who will now present the next lecture on folic
acid and safety.
DR. SHANE: Don't ask me any questions. "I'm Patrick Stover from Cornell
University." The only reason why
I'm giving this is because he refers to me in the talk.
Basically there are no toxicities
associated with elevated folate intake.
I made a sort of glib comment a few years ago that essentially there
really is no data on safety. It's worth
remembering that when folic acid was first isolated, it was thought to be the
anti-pernicious anemia factor and it was used to treat people and it prevented
-- it was effective treatment, at least it had some response with pernicious
anemia patients in terms of anemia.
When B-12 was isolated a few years
later, it became clear that, in fact, these people were B-12 deficient, not
folate deficient. Since then you have
not been able to go into a drug store and get mega doses of folic acid and so
when I say there is essentially no data on safety, for some of the water
soluble vitamins we have only found out about toxicities.
Most of them are toxic but some of
them are toxic at high levels. We found
out about it by people who have taken ridiculously high doses of these
vitamins. There's no evidence that
folate is unsafe but there have been very few cases of people taking very large
doses.
We have gone through this. Patrick and I share slides. There have been three major concerns raised
about increased folate intake and they are listed here. The first and probably the most important is
masking vitamin B-12 deficiency.
Mask is not really a toxicity but it
has unintended adverse consequences if you mask B-12 deficiency. The reason why, as I said before, increase
folate will mask it is because the anemia of B-12 deficiency essentially is the
generation of a secondary folate deficiency.
There are many causes of B-12
deficiency. The classic one is pernicious
anemia which is due to autoimmune disease.
Many of the elderly have malabsorption problems for various reasons so
20 to 30 percent of the elderly may malabsorb B-12. Folic acid at intake is about 1 milligram a
day and has a good probability of masking B-12 deficiency in the sense that it
masks the symptoms of anemia.
The B-12 associated neurological
symptoms are not related to folate may be a methylation defect. It's really not known why the neurological
symptoms develop. There's no evidence
that folate itself will help in anyway or hinder the development of
neurological symptoms.
One of the concerns about
fortification or arguments about increased fortification was that the elderly
were potentially a group that could be adversely affected in terms of the B-12
status. Of course, targeting to a
younger population would reduce this concern significantly, although B-12
deficiency is not unheard of in the target population being considered
today. Maybe about 10 or 11 percent of
the cases of pernicious anemia or the early signs of pernicious anemia could be
attributed to the age group of reproductively active women.
A second concern that occasionally
comes up in the literature is impairment of zinc absorption by increased
folate. I'm not going to go through
these. I reviewed these a number of
years ago. I haven't followed the recent
literature but as far as I can recall, there was really nothing to it. There was no real evidence. Tamura worked on this and there was no real
evidence that increased folic intake would have any affect on the status.
There have been a number of reports
that increased folate may reduce the effectiveness of some drug therapies. These are therapies involving cancer
treatment or anticonvulsants. Again,
Tamura was involved in this. There's no
direct evidence that folate does negate these things. In fact, the evidence on anticonvulsants is
not very good that folate has an affect.
The antiepileptic drugs, I think, any pregnant woman would be under the
care of a physician if she was using antiepileptic drugs.
I think basically and, as I said, I'm
not an expert in this area, but in terms of the toxicity of folate itself,
there's really no evidence that folate is in anyway toxic. The only concern would be that it's really not
been tested because no one has really looked for toxicity of folate or had the
opportunity to serendipitiously observe the effect of a megadose over the last
50 years.
DR. GUIDICE: Does anyone have any questions for Dr. Shane
or Dr. Stover? Maybe it's too early in
the morning. Thank you very much.
I would like to invite now Dr.
Elizabeth Yetley to present on folic acid fortification in the United States,
planning, implementation, and monitoring.
DR. YETLEY: Thank you.
Let's see if I can figure out how to do this. Thank you very much. I am from the Center for Food Safety and
Applied Nutrition. I along with Dr.
Jeanne Rader, who is also on the panel, were the staff, I guess, that dealt
with the mandatory fortification of certain types of food with folic acid
several years ago.
This is a fairly rare event that we
would have a nationally planned, nationally mandated fortification
program. We've done it in a few cases
with nutrients such as iron, niacin, thiamine, and whatnot, but it has not been
commonly done. It is only done in
response to a documented public health need.
In this case, of course, the need to reduce the incidence of folic
responsive NTDs by increasing the folic intakes of women of childbearing age.
In order to do this, we do not have
legal authority to mandate fortification so what we do is work through our
labeling authorities and we mandate that those products that were labeled as
enriched, specified products labeled as enriched, must contain specified
amounts of folic acid.
We also allowed the continuation of
fortification of breakfast cereals because that had been done for many years,
as well as some of the meal replacements.
We did not because of DESHEA put any limits on dietary supplements.
The last line has an error. We finalized our regulations in January of
'96 and they became effective in January of '98 so there was a transition
period between 1996 and 1998 as manufacturers geared up to meet the new
requirements.
Just a brief overview of what our
characteristics of fortification program.
Once you mandate a particular nutrient to be fortified under specified
conditions, it becomes ubiquitous in the food supply. That ubiquitous is an advantage in reaching
the target population because you can increase their intakes without them
having to do anything. It's a passive
exposure on their part.
It
also has the disadvantage of reaching everyone who is not part of the target
population.
Ubiquitous also means that because we
eat about 20 to 25 different foods in a day, or at least different servings of
foods in a day, very small amounts, or relatively small amounts in a single
food when added to all of the other sources from other foods can add up fairly
rapidly.
Fortification is a lifetime exposure
so one needs to be cautious when you extrapolate from short-term studies in
terms of estimating effectiveness or safety.
It is cumulative which means that the exposure is not of short term.
Our dilemma in doing fortification, as
I've indicated, was that we had to make sure that the intakes were safe for all
consumers because all consumers are exposed.
While trying to improve to the extent possible the intakes of women of
childbearing age, and as has always happened with every fortification program
we've both ever done, we had considerable uncertainty surrounding every single
decision that we did. We never have the
luxury of a well-designed clinical trial to guide us in the process. We are always dealing with a considerable
degree of uncertainty.
Just as an example, this concept of
ubiquitous in the food supply, many, many foods will contain folic acid. If you had a bagel or a roll or a bun for
breakfast you got folic acid. If you had
orange juice you got folic acid. A
serving of orange juice will give you about 10 percent of the RDA.
I should not say McDonald's hamburger
but a generic fast food hamburger according to USDA composition files will
provide about 25 percent of the RDA for folic acid. It's in your pastas and casseroles which
contain pastas or rices. It's in the
breakfast bars and cereals. It's even in
the so-called fun foods, cookies and cakes.
It is ubiquitous. It is
everywhere. You cannot get away from it.
This just as an illustration of the
dilemma that we always have when we deal with a fortification program is that,
first of all -- let me explain this. The
vertical lines are the range of intakes of folate by the U.S. population. This was prefortification data. There's about a four-fold or five-fold
difference between what is called the low consumer which is the 10 percentile
intake of folate and the high consumer which was the 95th percentile of intake.
Our target population for increasing
folate intake at the time we did this fortification program was women of
childbearing age who had low intakes.
This is our target population. As
you can see there's nothing different about the target population than anyone
else. These are other age gender
groups. The conflicting demands that we
have to deal with is that as we increase the intake of our target group, it is
going to increase concurrently the intakes of everyone else and shift the
distribution of intakes for the entire population.
Just as a note of comment, and I don't
know quite what to do with this except to give you background, is that intake
distributions typically are very skewed and probably bimodal. This happens to be an old estimate of folate
intake immediate post-fortification. I
think the numbers are probably too low at this point in time.
The median intake for woman of
childbearing age is right here so while half of the women seem to be in a group
of women who have a normal distribution of intakes, half of the women have this
tail that can be a very extended tail.
The fortification intervention shifted
the entire curve so that one did achieve an increased intake in women at the
low end of this distribution, but the high end of this distribution tends to
move further than the low end just as background and FYI for you.
This is the reverse of a graph that
Barry Shane showed in terms of the nutrient function models that we use. This one happens to have optimum health at
the top, risk at the bottom. For a
nutrient, when your nutrient intake is less than optimum you have increasing
risk of adverse affects as your intakes go lower and lower. As a nutrient exceeds the optimum intake,
higher and higher intakes are associated with higher and higher risk of adverse
affects.
In this area between the optimal
requirement in terms of meeting your basic requirements versus adverse affects,
adding more nutrient within this range does not really give you added
benefit. Keeping that model in mind, one
can look at what we know about the relationship of folate intake to nutritional
status, particularly relative to the NTDs as well as to upper limits. Barry Shane, again, commented on this
briefly.
If you go to the Institute of
Medicine's report of several years ago in which they looked at -- they
established both an RDA and upper limit for folate. In essence, as Barry has indicated, 400
micrograms per day folate equivalents are enough to meet the folate status
needs of virtually all of the population.
Then for NTDs the IOM went on to say
that women should add 400 micrograms. In
other words, get to a total of 800 micrograms of folate a day in order to
reduce the risk of NTDs. However, the
report also notes that there is a paucity of dose response data. In
fact, there's just a little bit of dose response data from some observational
studies where the reliability of those intake estimates would be of some
question. There's a paucity of data. There's no dose response data between the 400
and 800. One of the significant
uncertainties we have is whether or not the actual requirement for the NTDs is
closer to 400 or closer to 800 or somewhere in the middle.
Also, as Barry Shane has noted, there
is significant uncertainty as to what the upper limit should be. Basically there was a virtual absence of data
for higher intakes so part of the uncertainty.
Okay.
Once we have done the fortification program we need to look at
monitoring afterwards, particularly because of the uncertainties. We need to do post-fortification monitoring
so that if we need to, we can make adjustments in the levels that we've added
to the food supply.
We have always assumed, and I'll give
you some data to support this, that using reports of consumers' intakes of
folate will underestimate probably very significantly the actual amounts that
they are actually consuming which means that using dietary data alone we will
underestimate effectiveness and we will underestimate potential for
safety. So FDA prefers to rely more in
the post-fortification marketing on biomarkers of folate status and on the
effectiveness as measured by changing incidence of NDTs.
Just
as a little bit greater explanation on our concerns about the reliability of
dietary intake data, since I think that this is one of the things that may be
considered by the panel, is that we know from a number of studies, particularly
intervention studies where they have actually looked at what people report they
intake and then they have other measures, clinical measures of what they have
actually consumed, that they significantly underestimate calorie intakes which
means that since calories carry nutrients they will underestimate the intakes
of other nutrients. This can be up to 30
to 40 percent depending on the situation.
We also know, and Jeanne Rader has
done a lot of work with this, that the old analytical methods that have been
used for food composition tables significantly under-reported the amount of
folate in foods. We also know that
because of FDA labeling rules manufacturers under-report the amount of folate
that are in their marketed foods.
At the same time when they are setting
RDAs -- when the IOM is setting RDAs, they will air on the side of making sure
that they protect everyone so prudence will have the RDA as high as possible so
it protects everyone. You have the RDA
that is going this way, you have the intakes with a bias that way, and the gap
between the two tends to be more alarming than is actually there.
This just illustrates our concern with
relying solely on dietary intake data.
This happens to be data from NHANES in which we were evaluating the
effectiveness of predicting iron status from dietary intake and from clinical
and biochemical measures. If you look at
dietary intake reports of women of childbearing age, 98 percent of the women
appear to have inadequate iron.
If you look at their clinical
biochemical indices, hemoglobin, serum ferritins, serum transferrin saturations
and whatnot, only about 4.5 percent actually had an impaired iron status. Once again, keep in mind that there is a
large disconnect between what you see with dietary intake and what you see with
clinical and biochemical measures.
This is not the slide I wanted so let
me give you a little bit of background on this slide and then I'll give you
some additional data that you can write down if you are interested. As I indicated, we like to use as much as
possible clinical biochemical measures of folate status. This happens to be data from Kaiser
Permanente in California in which they looked at the number of their patient
samples that were analyzed for folate that went above their high cutoff for normal
range and those that went below.
The time trend here is
interesting. This is the date at which
FDA published its regulation saying that we would require fortification of
folic acid. This is the date at which it
was fully effective so this is your transition period in which increasingly
more and more manufacturers started to add folate to food.
What you can see from this slide is
that they had an increasingly high number of their patient population with
serum folate levels that were above their upper cutoff. They have data for 1999 that goes even
higher.
What I intended to have on this slide
but did not have was data from the National Health and Nutrition Examination
Survey which is really a nationally representative population survey in the
U.S. that contains measures of nutrient status.
They do have measures before fortification of serum and red cell folate
and measures after.
If you compare pre- and
post-fortification data from that NHANES survey, if you look at serum the
median level went from 4.8 nanograms to 13 nanograms for women of childbearing
age. Did this affect women all across
the distribution? Yes. The 10th percentile folate for this survey
went from 2.3 to 6.4.
What about women with higher folate
status as determined by serum levels?
The 90th percentile serum folates went from 11.7 to 26.1 so a doubling
or a tripling of the serum folate levels.
If you look at the red cell levels, the median went from 159.9 to 263.6
nanograms per mL. The 10th percentile
consumer went from 92 to about 166. The
90th percentile went from 296 to 432.
You can see that the serum and red cell folate levels show a very
significant impact from the fortification program.
The bottom line in terms of food
fortification, the advantages are passive exposure. Consumers take in larger amounts without
having to take any extra -- make any changes on their part. The disadvantages, passive exposure. You can't get away from it. As I indicated, it's a balancing act between
safety and effectiveness.
In summary, these decisions are made
with a great deal of uncertainty in terms of effective intakes and safety but
they have made very significant impacts on folate status in terms of the U.S.
population. Thank you.
DR. GUIDICE: Thank you very much.
Our next speaker is Dr. Joe Mulinare
from the National Center on Birth Defects and Developmental Disabilities at the
CDC. He will speak on assessing the
impact of fortification on the epidemiology of neural tube defects.
DR. MULINARE: Good morning.
My name is Joe Mulinare. I'm a
pediatrician, medical epidemiologist.
I'm the Chief of the Prevention, Research, and Health Communications
Team at the National Center on Birth Defects and Development of Disabilities.
I've been asked to present an
assessment of the impact of fortification on the epidemiology of neural tube
defects this morning in the United States.
I'm pleased to be able to give you some very good news. The facts are that pregnancies and births
affected by spina bifida or anencephaly have declined significantly since
fortification started in 1998.
Hundreds of babies are being born who
are now healthy and not affected by the physical and emotional toll resulting
from these conditions which could have affected them and their families. As good as the news is, this decline is a
fraction of what we can accomplish.
Folic acid preventable pregnancies still occur and babies continue to be
born with these deadly outcomes.
In my presentation today I'll focus on
the following. First, I'll briefly
review some of the history and you'll see some slides that you have already
seen and you'll see some slides that you will be seeing.
Second, I'll review the ways to
achieve adequate folate levels. I'll
take Dr. Yetley's data and quickly put it into the computer and give you a
figure that reflects the data that she showed about NHANES before and after
fortification.
Third, I'll present data on the
changing prevalence of neural tube defect in the U.S. which is the ultimate
looking at how fortification and other attempts at increasing folic acid
consumption have shown the decline in NTDs.
Finally, I'll make some comments on
the options for continuing our efforts to eliminate folic acid preventable
NTDs.
Spina bifida and anencephaly are
severe central nervous system defects that result in serious disability and
death. About one in every thousand
pregnancies are affected with an NTD and we estimate that's about 4,000 NTD
affected pregnancies and about 3,000 affected births per year in the United
States. This was an estimate that we had
prior to fortification.
There is also actually about 300,000
to 400,000 NTDs that occur worldwide. If
you think about a possibility of preventing approximately 50 to 70
percent. That means that worldwide we
might be able to effectively prevent 150,000 to 200,000 NTDs every year.
This is some of the history. Some of you have seen this slide before. Basically these are the studies that were
done in the early '80s up until 1990 that were not randomized clinical trials
with the exception of one that was conducted in Wales in 1981. They essentially show the reduction in risk
from 40 percent to over 80 percent in decreased risk in having a baby with a
birth defect.
In 1991 with the landmark study done
in the UK by the MRC that demonstrated that folic acid alone could reduce the
risk of birth defects in women who had had a previously affected
pregnancy. The recommended dose of folic
acid that we used in the 1992 public health service recommendation actually
recommended 400 micrograms. With the
subsequent studies this dosage was confirmed in China in 1999.
This is the U.S. Public Health Service
Recommendation. Many of you heard of it
and know what the statements are but all women capable of becoming pregnant
should consume 400 micrograms of folic acid daily to reduce their risk of a
pregnancy affected by spina bifida or other neural tube defects.
Ways of achieving adequate folic acid
intake included improving the diet, taking a daily supplement containing folic
acid or consuming four to five foods. In
many ways, achieving an adequate intake through improving diet by increasing
the consumption of fruits and vegetables every day would be ideal.
It's apparent that this is difficult
and expensive for most women, especially when attempting to get folate intakes
up to 400 micrograms a day. The use of
dietary supplements is also a very reasonable approach because folic acid pills
are relatively inexpensive. I'll come
back to fortification in a moment.
Unfortunately, the education efforts
in health messages by a number of federal, state, and local groups over the
past 13 years have accomplished little to increase the use of supplements
containing folic acid.
Here are the Gallup polls conducted
through the March of Dimes. We have
observed an increasing proportion of women who have heard of folic acid. In fact, it's gone from about half to almost
three-quarters of the women in the United States that have heard about folic
acid.
Attempts to increase knowledge about
what folic acid does and when you should use it have not been too
successful. In fact, only about 13
percent of women know that folic acid can prevent a birth defect. Only about 7 percent know that it should be
taken prior to conception or before they attempt pregnancy.
The proportion of women who consume
folic acid supplements has changed little.
It's gone from about 28 percent to 32 percent over the last 10
years. Most disappointing is the fact
that there is very little, if any, evidence that there is an increasing trend
in use. Increases in blood folate levels
or decreases in NTD rates that we observed are very unlikely to have been
influenced by women's behavior in the use of folic acid containing supplements.
Fortification, however, of cereal
grain products, and increased amounts of folic acid in breakfast cereals, on
the other hand. appear to have had a considerable impact on delivering folic
acid to women of reproductive age.
The impact on blood folates in women
of reproductive age is clear from the NHANES data that Dr. Yetley just talked
about. Has you can see, before
fortification the serum folate levels before and after 13, a more than
three-fold increase in the levels and a similar substantial increase in red
blood cell folates from 160 to 260 nanograms per milliliter.
The ultimate measure of impact of
folic acid lies in the results that we have observed in the changing prevalence
of neural tube defects for the past three years. There are two birth defect surveillance
programs in the U.S. that have monitored and reported changes in the NTD
prevalence before and after fortification.
The first is from National birth
certificate data from the National Center for Health Statistics. As you can see, spina bifida and anencephaly
both have seen a reduction or decline in the prevalence of NTDs. About 23 percent for spina bifida and about
11 percent for anencephaly. These are
data taken before and after -- prevalences taken before and after fortification
for about a 19 percent overall decrease in NTDs.
The National Birth Defects Prevention
Network state surveillance data base also improves on the NCHS data by actually
including prenatally ascertained fetuses, fetal deaths, and some elective
terminations. The results here show a 33
percent decline in spina bifida and a 14 percent decline in anencephaly for
about a 25 to 27 percent decline overall.
These results demonstrate the folic
acid food fortification has helped to prevent the occurrence of spina bifida or
anencephaly in hundreds of babies.
Because mothers of these babies consumed additional folic acid in their
diet, their babies were born healthy without these birth defects and the
devastating physical and emotional stresses attached to these conditions will
not be experienced by these children, by their families, or in the community.
We estimate that there are about 4,000
NTD affected pregnancies before fortification.
Half are preventable.
Approximately 1,000 babies each year are born without NTDs since fortification. We have only partially attained our goal for
the complete elimination of folic acid preventable NTDs.
Think about it. Since January 2001 if we have helped to save
the lives of at least 3,000 babies, half of whom would have suffered with the
complications of spina bifida costing somewhere around $300,000 to $350,000 in
direct lifetime medical costs, our savings in health care costs would be about
$500 million. We should be proud of that
accomplishment.
We also have the opportunity to save
more babies from developing these devastating conditions so that they can live
healthier lives. Our objective should be
and is to do whatever is necessary to help all women of reproductive age to get
400 micrograms of folic acid each and every day.
In summary, we have seen blood folates
increase substantially since fortification began in 1998 and NTD prevalence has
decreased about 20 to 30 percent in the United States. Lower rates are consistent with the increase
in folic acid content in fortified foods.
There is little evidence available to demonstrate that dietary intake of
folate rich foods or reported use of vitamin supplements have increased
appreciably.
There still exist a need to prevent
the occurrence of an additional 1,000 NTD affected pregnancies, 1,000
additional babies who can be born healthy without the devastating affects
caused by these serious birth defects.
More options are needed to provide
additional folic acid to all reproductive age women at risk for having folic
acid preventable neural tube defect pregnancy.
An esteemed colleague wrote some time ago that, "The opportunities
to prevent birth defects are rare.
Opportunities to prevent birth defects
by an intervention as simple as taking folic acid are almost unheard of. Such an opportunity should not be
missed." We should be doing
whatever is necessary to safely increase the amounts of folic acid that women
of reproductive age need to prevent neural tube defects. Thank you.
DR. GUIDICE: Before going on to our next speaker, I would
like to invite any questions for our previous two speakers, Dr. Yetley and Dr.
Mulinare.
Dr. Rice.
DR. RICE: Have we seen any increase in any of the
vitamin B-12 deficiencies or any other potential complications while associated
-- we have seen this associated decline and increase in the fortification
process?
DR. SHANE: I really don't know but maybe Ralph would
have more information on that.
DR. GREEN: I think the answer to the question is that
there haven't been sufficient studies that have addressed the issue. Apart from the study that was published by
Jim Mills and, perhaps, Jim, you can comment on that.
After your comment, I would like to
have the opportunity to add something to that statement. Beyond Dr. Mills' study which examined
prevalency rates of vitamin B-12 deficiency among anemic patients which, I
believe, and, again, Jim, you should comment on this yourself, revealed no
change. I'm not aware of any other
studies. It has, of course, only been a
relatively brief time that folate fortification has been in use.
DR. GUIDICE: Dr. Mills, would you like to comment?
DR. MILLS: I don't make any great claims for this
study. What we did was to look at people
who were having B-12 determinations done at the laboratory in the Veteran's
Hospital in Washington, D.C. Our
hypothesis was that if there was a problem; that is, if they were masking, then
we would be seeing more people who had B-12 deficiency but did not have
anemia.
Essentially, as Ralph pointed out, the
proportion of people who are identified as B-12 deficient but were not anemic
has not changed since fortification occurred.
I want to be the first to point out the limitations.
This population has so much neurologic
disease that we were not able to determine who actually had neurological
disease at the time that they were studied.
That could be related to B-12 deficiency. What we can say is that we don't see more
people who have B-12 deficiency coming in without anemia but what we can say is
how that relates to the neurologic problems.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: Philip Darney, UCSF. Do I understand correctly that there are no
case reports of folate toxicity simply based on taking too much folate?
DR. SHANE: This is not my area but I'm not familiar with
any case reports of folate toxicity.
DR. GUIDICE: Dr. Green.
DR. GREEN: I would just like to add one comment to Dr.
Mills' comment about the limitations of his study and indicate that while I
think this is a very important type of study that needs to be conducted, in my
opinion a further limitation is that if you look at the overall prevalence
rates of anemia in a population such as that, you would not anticipate that a
large percentage of those anemias would be related to a B-12 problem but rather
to many other problems.
Consequently, the background noise, so
to speak, among a large group of patients who are anemic might obscure any
apparent change in the prevalence rates of low B-12 levels in an anemic
population.
DR. MILLS: May I clarify that? Our population was people with B-12
deficiency anemia. In other words, we
looked at all people who had B-12 determinations done. Then we just studied those who had B-12
deficiencies so we're not diluting out the effects by looking at iron
deficiency or folic deficiency or anything else.
DR. GUIDICE: Yes, Dr. Green.
DR. GREEN: I certainly don't wish to take too much time
of the panel. Perhaps it's my
misunderstanding of the design of the study but the anemia, if I'm not
mistaken, the group of patients with the anemia who were all comers regardless
of whether they were macrocytic or not.
DR. MILLS: We started out with all people who had a B-12
determination done in the laboratory.
From that group we identified the people who had low B-12s and that then
was the population that we looked at over time to see if from 1992 to 2000 the
proportion of people with B-12 deficiency who presented without anemia was the
same.
Incidentally, this is a population
that gets almost routine folate fortification if there is any suspicion that
they had alcohol problems or anything else that would put them at risk.
DR. GUIDICE: So, Dr. Rice, was your question answered?
DR. RICE: Yes.
DR. GUIDICE: Okay.
Before we go on, I just wanted to ask if anyone else had any additional
information with regard to any reports of toxicity in response to Dr. Darney's
question?
Yes, Tamura.
DR. TAMURA: I know only three things we should
consider. One is the one case report of
deep reaction to folic acid supplementation which was published in 1960, I
believe. There have not been any other
case report and we don't know exactly why it happened. That's No. 1.
No. 2 is in our department in 1970s IV
injection of folic acid was done and abnormal EEG, electroencephalogram, was
noticed and based on that data they suggested that it may be harmful to give
folic acid to people with epilepsy.
No. 3, this is very controversial but
in the 1960s and 1970s from British research groups published contradicting
data on the supplementation of folic acid may cause irritability or difficulty
falling asleep at night. One group said
yes and one group said no so I don't think there is clear cut side effect in
terms of that. In talking about the
possibility of the zinc absorption by folic, I think it's settled. I don't think that is an issue.
DR. GUIDICE: Thank you.
I would like to just remind the speakers around the table after you have
made your comments please turn your microphones off because it can interfere with
background noise.
Yes, Dr. Greene.
DR. GREENE: I do have one further comment. Not to belabor the point. Jim, I do apologize for extending this but I
first would like to say that the points that you raised about the study as
designed and I do this for clarification because, first of all, I want to state
that my prior statements did have an inaccuracy clearly since this is not
taking all comers with anemia.
However, I think that a substantive
point still is that if you take a population with low B-12, it's generally
acknowledged that with current assays there are serious limitations with
respect to specificity of such an assay for B-12 deficiency consequently. And this is an estimate and an estimate only.
Between 50 percent and perhaps
two-thirds of subjects who would have a serum B-12 level that is regarded in
the deficient range would not, per se, be vitamin B-12 deficient but rather
have a low level that is attributable to perhaps the entity known as food B-12
malabsorption prevalent among the elderly who have a chronic atrophic
gastritis. Whether this is clinically
significant or not remains to be determined.
Be that as it may, among that group
there would also be a substantial number of individuals among the elderly in
particular who would have anemia of other cause. And if the assumption is made that low B-12
level, low by virtue of being in the low range below the normal cutoff,
represented an anemia attributable to B-12 deficiency, I think that would
constitute a background noise.
So perhaps in my initial statement, in
fact, indeed in my initial statement there was a misrepresentation about the
background noise but I think that this one is still a substantive one.
DR. GUIDICE: Yes, Dr. Mills.
DR. MILLS: I think that's a good point that B-12
deficiency is not quite as simple as a number of other deficiencies in terms of
how one identifies it and the implications physiologically of having it. We were sensitive to this in terms of using
two different cutoffs for B-12 deficiency based on different B-12 levels and
also on wherever it was available looking at MMA as a confirmatory test. However, it is not a simple diagnosis and I
don't want anyone to think that it is.
DR. GUIDICE: Dr. Rosenberg.
DR. ROSENBERG: I think perhaps the limitation of the Mills
study for our purposes is not so much a question of whether the diagnosis of
B-12 deficiency or anemia. But I remind you
that the Institute of Medicine DRIs identified as a potential adverse effect of
too much folate above 1 milligram was not anemia. It was not the lack of diagnosis of anemia
but the fact that there might be progression of neurologic problems.
Obviously I think the information
which we would like to have with respect to the safety of fortification would
be -- is not available from any of the studies that I know of which would be a
change either in the prevalence or severity of neurologic problems in the
populations at risk.
DR. GUIDICE: Thank you for your comments.
Yes, Dr. Greene. The other Dr. Greene.
DR. GREENE: Dr. Mulinare, I have a question for you. Assessing the impact of folic acid
supplementation of the food supply on the incidence of neural tube defects is
complicated by a couple of things. One
is that the incidence of neural tube defects has been falling since 1960 which
was obviously well before we thought about folic acid. And also the incidence of prenatal
diagnosis and use of ultrasound has been increasing tending to diagnose these
things and frequently the diagnosed cases don't make it to birth certificates. The question I have is to what degree can we
be confident that the fall in neural tube defects that we've seen in recent
years is really due to the supplementation of food source with folic acid and
not manifestation of these other trends.
DR. MULINARE: I would like to say to the folks that are
running my program, please put up slide No. 32.
Then I can show you some of the data that we have that would help to answer
that question. Yes, the rates are --
NTDs have been decreasing since the 1960s and 1970s and a number of things have
happened over those years that are ecologically associated with that.
One reflects in 1973 putting folic
acid, 400 micrograms, or allowing folic acid 400 micrograms to be put into
multivitamins. Dr. Rosenberg could talk
about that because he was a member of those committees. In fact, he may have been the chair. I don't remember. That would have -- oh, it's not there. I'm sorry.
Don't hunt for it.
In the 1980s and in the early '90s we
appreciated the fact that prenatal diagnosis and the use of maternal alpha sera
protein would actually diagnose cases prenatally. Systems were put into place. First in a couple of states and then in eight
or nine states.
Some of those data I put up there
reflect the use of getting information from prenatally ascertained cases of
NTDs. You can see a leveling off of --
you can see a decrease in NTDs throughout the middle '80s and throughout the
'90s.
When you look at data that we've
gotten from prenatally ascertained cases, about anywhere from 25 to 50 percent
of NTDs may have been prenatally diagnosed.
We added those in to the declining rates. You could see that maybe from 1990 on the
rate was relatively stable, about .8 to one per 1,000.
That has gone on since the '90s. After fortification even when you include
information on prenatally ascertained cases, we have seen that 20 to 30 percent
drop. We can't say that's the whole
answer but we feel fairly confident that there is a contribution that has been
made.
DR. GUIDICE: Thank you.
Yes.
DR. RADER: May I go back a minute about the lack of
toxicity data -- I'm sorry, the toxicity data that you had asked about? When we were doing our development of the
documents that preceded the fortification proposal and then the final rule, we,
of course, went back and tried to dig out every bit of toxicity information
that we could find.
There is a surprising apparently lack
of that kind of data. As Dr. Tamura
mentioned, there is a few incidents of allergic reactions and some episodes
were under a clinical situation. Too
much folic was given and adverse things came about but usually there was an
underlying B-12 problem.
When you actually go back and look at
the possibility of overdosing during those years, the FDA did have a drug
regulation that regulated how much folic acid would be used in a clinical
setting and in the food supply in general.
Since folic acid was a food additive it couldn't be added willy nilly to
food so the chances of taking in high doses on your own initiative were very
low.
We tried to find old data for
breakfast cereals. Sometimes the cereals
would have neither folate or B-12.
Sometimes they would have both.
The levels vary all over the place so it was a very spotty
situation. You didn't have tablets and
bottles where you could take huge amounts during that time.
The apparent lack of toxicity was
probably as much due to the lack of being able to get it as a true lack of
toxicity. I think that is an important
point because it was different than some of the other B vitamins which were
much more freely available and much more freely added to foods before this
fortification.
DR. GUIDICE: Thank you.
Dr. Rice.
DR. RICE: This is bringing up something that Dr. Greene
sort of implied. Is there on the
reporting of NTDs because of our increase in prenatal diagnosis?
DR. GREENE: If you only ascertain them for birth
certificates, absolutely yes.
DR. RICE: To what extent do you think?
DR. MULINARE: The under-ascertainment from birth
certificates is about 40 to 50 percent.
You will not detect 50 percent of them and that is why we use in our
National Birth Defects Prevention Network programs that are actually looking
for prenatally ascertained cases.
Depending on the program it could be anywhere from 30 to 50 percent of
the NTDs that we are now finding that are related to fetal death or elective
termination or still births.
I might say I was asked to talk about
information from the United States but there are other places around the world
that have been doing some very interesting work including in Chile where there
is essentially not as much need for looking for prenatal ascertainment.
In a recently published study they
show that comparing pre-fortification and post-fortification data they actually
saw about a 30 percent reduction in the prevalence of NTDs. These are among women in Chile who don't
usually use multivitamins or take folic acid.
The rates of NTDs have been apparently very stable up until recently.
DR. GUIDICE: Thank you.
If there are no further questions, I think we can go on then. I hope Dr. Van den Hof is still on the phone. Are you there?
DR. VAN den HOF: Hello.
DR. GUIDICE: Yes. I
would like to introduce you. He is the
head of Maternal Fetal Medicine at Dalhousie University in Halifax, Nova Scotia
and will talk to us through the wires on folic acid supplementation and
fortification in Nova Scotia. Thank you.
Dr. Van den Hof.
DR. VAN den HOF: Yes.
Hello. I'm just waiting for my
first slide to come on. There is a
little bit of a delay. Here we go. There is about a 30 second delay so if there
is a mix-up in the slides, I won't know for about 30 seconds so just bear with
me.
Thank you very much for inviting me to
speak on our experience in folic acid.
This is Canadian experience. I'm
from Nova Scotia and if you don't know -- if you are not familiar with Canadian
geography, Nova Scotia is on the eastern seaboard close to Maine. We have a population of just over a million
people.
The next slide please. The history of folic acid has been reviewed
already but, to summarize it, there were numerous studies from 1976 to 1991
suggesting the benefit of folic acid supplementation. But it wasn't really until the 1991 MRC
vitamin study that someone has previously alluded to that finalized the benefit
of at least high dose folic acid supplementation to reduce open neural tube
defects in women with a prior history of this event.
Next slide, please. The following year Czeizel, et al. published
a study in the New England Journal of Medicine that confirmed the
benefit of supplementation to reduce open neural tube defects in low risk
women. There folic acid was given in a
multivitamin preparation. For both
studies folic acid was used prior to conception.
Next slide, please. Despite the good news associated with these
findings there was a considerable lag by at least Canadian health authorities
to increase public awareness about folic acid with eventual recommendations
coming from Health Canada, the Society of Obstetricians and Gynecologists of
Canada, and the Canadian Task Force on the Periodic Health Examination which is
a form we have to do these things. These
initiatives took place between 1991 and 1994.
Next slide, please. Public health officials during this time were
encouraged by the reduction in birth affected by open neural tube defects. This is a slide demonstrating the changes
that occurred during that time and alludes to a point that was raised by one of
the members earlier on.
Next slide. However, the reduction was due to an increase
in prenatal diagnosis and women undergoing pregnancy termination. This highlighted, for us, at least, the
importance of doing a very accurate population based study to define these
important outcomes.
As we can see in this slide, when we
took into account the increasing number of prenatal diagnostic cases with
pregnancy termination, the incidence have actually not changed at all.
Next slide. The problem, of course, was that despite the
known benefit of folic acid supplementation studies including our own audits
and our population, that the majority of women were actually not taking
preconception folic acid supplements despite the fact that this recommendation
was actually for all women capable of becoming pregnant.
Next slide, please. This eventually led to the folic acid
fortification in grain products and your date to have these products fortified
was January 1, 1998.
Next slide, please. In Canada fortification was actually mandated
to start no later than November 1, 1998 so about eight or nine months
later. It's interesting that the main
driving force for Canadian fortification was not the potential health benefit
but probably more related to the North America Free Trade Agreement and the
free movement of products across the border.
Next slide. The question we wanted to answer was whether
the recommendations for supplementation was effective. Then, more importantly was the relatively
small amount of fortification also effective.
Next slide, please. This is an important slide because in Nova
Scotia we have a very stable population.
As you know, in Canada we have a publicly funded health care system. In particular, for Nova Scotia there is a
reproductive care program for the province.
Part of their function is to maintain and run an extensive perinatal
database.
In Nova Scotia we encode information
on all births in the province with data being abstracted by trained registry
personnel. This includes a maternal
antenatal intrapartum and post-partum variables, as well as numerous neonatal
data. There are up to 1,200 variables
available for any case. Standardized
forms that are used throughout the province help us to get consistent
information and validation studies have shown the information to be reliable.
In addition, there is a provential
fetal anomaly data base which captures information on all antenatally diagnosed
anomalies including those that undergo pregnancy termination. All the pregnancy terminations for fetal anomalies
in our province occur in one tertiary care center.
By combining these two data bases we
can gather information on all births and birth defects that occur in this
province allowing us to do a true population-based study.
Next slide. Open neural tube defects are described in our
study, as alluded to before, as those involving spina bifida and anencephaly
and those including other, the rarer forms, including encephalocele.
Next slide, please. Based upon the timing of government and
institutional directives for folic acid supplementation, 1991 to 1994 were
considered by us to be presupplementation because it just wasn't being used and
there were not enough initiatives yet.
Really, by 1994 the initiatives had been completed so we considered 1994
to 1997 the years when supplementation initiatives had been maximized but
fortification had not yet begun.
Post-fortification was considered to
be the years following 1998 with the understanding that there probably was a
year of transition between 1997 and 1998.
In our publication the post-fortification was until 2002, the
publication that came out of the Canadian Medical Association Journal. Today I have also been able to include our
data until 2002 and, in fact, really right through to the end of June 2003 we
have data available.
Next slide. This is just again to acknowledge the debate
that has gone on about the risk of folic acid fortification with the potential
to delay diagnosis of vitamin B-12 deficiency, particularly in the elderly.
Next slide. This slide shows the lack of affect from
folic acid supplementation initiative in our province. There was essentially no change from 1991 to
1997 when supplementation initiatives were put in place.
Next slide. This slide shows graphically the same lack of
change in the incidence of open neural tube defects during those years. Although here I have shown, again, that birth
rate for open neural tube defects did drop as pregnancy terminations for
antenatally diagnosed cases increased.
Next slide. With fortification there was a dramatic drop
in the incidence of open neural tube defects in Nova Scotia from 2.58 per 1,000
births. We have a fairly high prevalence
of open neural tube defects between 1991 to 1997 to 1.17 cases per 1,000 births
from 1998 onward. The affect was seen
for both anencephaly and spina bifida and was highly significant both
clinically and statistically.
Next slide, please. This slides shows that the decline has been
maintained through 2002 and, again, emphasizes that the majority of affected
pregnancies are being antenatally diagnosed and that women in this circumstance
are often choosing pregnancy termination.
Next slide, please. Our calculations show that with the
introduction of fortification there was a 59 percent reduction in both
anencephaly and spina bifida with a 54 percent reduction in all open neural
tube defects. This is much higher and we
are obviously delighted than the reduction of 20 percent that had been
calculated through theoretical model.
Next slide, please. The question is can prevention be further
reduced. The study by Barry, et al.
involving provinces in China had suggested that in both high and low-risk
populations there was the potential to have reductions as low as .6 for 1,000
births. If this figure and this number
were correct, then there is the theoretical potential for another 40 percent
reduction in our population.
Next slide. Finally, this slide summarizes the affect of
folic acid fortification and supplementation in Nova Scotia between 1991 and
2002. No affect from supplementation
initiative but a fairly dramatic drop with fortification as a temporal
relationship. That affect was with
anencephaly and spina bifida but not necessarily for rarer forms of open neural
tube defects including anencephaly.
Thank you.
DR. GUIDICE: Thank you very much. Are there any questions for Dr. Van den
Hof?
Yes, Dr. Rosenberg.
DR. ROSENBERG: Dr. Van den Hof, I'm not sure if you can hear
me but maybe we can transmit this. Is
there any evidence from your interesting and promising study that there is an
increasing affect over time since 1998, or does it appear as though the affect
of fortification was achieved within the first year or two and now has
stabilized at a new level, or is there any reason to expect that over time
there will even be greater affect of the intervention?
DR. VAN den HOF: Well, our hope had been with the original
description of numbers up to 2,000 that, in fact, the 54 percent reduction was
perhaps minimal. But it seems that as we
analyze the data going in through 2,000 and even through to the first half of
2003 that, in fact, it appears to be stabilizing.
Of course, it's going to take a number
of years further because there are natural variations in incidence for neural
tube defects beyond the influence of folic acid that have to be taken into
account. It appears that the incidence
is stabilized as was originally described.
DR. GUIDICE: Dr. Macones.
DR. MACONES: Hi.
George Macones from Penn. Just a
quick question. It seems to me that
there are really two levels of recommendations for folic acid supplementation,
if you will. One is for women who have
had a prior affected child where we talk about the 4 milligrams, and then there
is obviously the goal of the fortification program which is more focused on
women who have not had a child with a neural tube defect in the past.
It seems to me that the data that you
present really aggregate both of those.
I was wondering if you could separate out the affect of the supplementation
which, again, I believe is focused more on women who have not had a child with
a neural tube defect in the past.
DR. VAN den HOF: Well, the vast majority of cases of open
neural tube defects, despite the high risk for recurrence, the vast majority of
cases for open neural tube defects continues to be in the low- risk population. That is the case for our population as well
even though our background risk for open neural tube defects had always been
higher than the world population.
I think the recommendations for
supplementation certainly within our population had been directed not -- had
been directed most strongly in the area of patients who had previously affected
pregnancies, but there was also a major public initiative for the low-risk
population because this is where the majority of open neural tube defects
occur. I don't think that is any
different really.
DR. GUIDICE: Okay.
There are two questions over here.
Dr. Emerson and then Dr. Wenstrom.
DR. EMERSON: I was sort of interested in your -- I think
this follows up on Dr. Macones' question.
Your data seems to show a much -- I'm extrapolating wildly here -- a
larger decrease for the live births rather than the terminated pregnancies. Is
there a tendency for the screening for neural tube defects that might lead to
the terminated pregnancies to be at a higher risk population and is that
perhaps evidence that what you're asking is that we're seeing a more dramatic
affect in just a subset of the population rather than in the entire population
which, I guess, goes with the idea of the genetic component and that there is
some neural tube defects that can't be addressed with folate supplementation,
and is there a lot of room for a lot more improvement?
DR. VAN den HOF: No.
Again, I think my own personal feeling is from our population the
majority of the affected pregnancies are not coming from patients who have had
previously affected pregnancies or babies.
The majority of our population are
still coming from patients who don't have a prior history, either personal
history or family history, and the patients who undergo pregnancy termination
aren't necessarily those who have had previously affected pregnancies either.
I think it does highlight the
importance, though, of antenatal screening and the importance of prenatal
diagnosis. The vast majority of
antenatally diagnosed neural tube defects, in fact, is through routine screening
at 18 to 20 weeks. A very small number
are further supplemented with the alpha fetal protein screening but that is
actually much less favorable way to screen.
DR. GUIDICE: And there was a second part of Dr. Emerson's
question and that was whether or not there was a --
DR. VAN den HOF: Sorry.
You'll have to repeat that.
DR. EMERSON: The question I had was how much more room do
you think there is for improvement?
DR. VAN den HOF: I think we probably have more room to
improve. I mean, I think one of the
questions that we had when we finished as we do our ongoing analysis for our
population is the fact that perhaps we are going to see a larger drop in risk
because we, in fact, had a higher background prevalence to start with.
The fact is that perhaps we may have
an ability to have a further reduction of theoretically as high as, I believe,
40 percent. Certainly my own personal
bias has been that, you know, I would like to see us try to increase the folic
acid exposure to our entire pregnant population so that I can maximize the
reduction and risk.
I think certainly for our population
there may be room for further reduction and I think that is the goal we should
go for.
DR. GUIDICE: Thank you.
Dr. Wenstrom.
DR. WENSTROM: You've seen both a greater reduction and
prevalence after fortification and before fortification you had a greater
prevalence of NTDs than we have here.
I'm wondering if that's because the MTHFR mutation is more prevalent in
your population. Do you know what that
is compared to its prevalence in the United States?
DR. VAN den HOF: Yes, we have studied that. That actually is probably the case. I'm certain there are areas within the U.S.
where there are probably areas of higher prevalence. Part of it probably relates to the ethnic
background for the population so that in Nova Scotia the population basically
comes from Wales and Scotland and Ireland, all the areas that are known to have
perhaps a slightly higher background risk for the gene mutations, and also over
the years have been known to have a high prevalence of neural tube defect. I think the observation is correct.
DR. GUIDICE: Thank you.
Thank you very much, Dr. Van den Hof.
DR. VAN den HOF: Thank you.
DR. GUIDICE: Our next speaker is Dr. James Mills and he is
the Chief of Pediatric Epidemiology at the Division of Epidemiology,
Statistics, and Prevention Research at NICHD at NIH. He will be speaking on what is the minimum
effective dose of folic acid for preventing neural tube defects.
DR. MILLS: Thank you.
As you can see, I was asked to talk about the minimum effective dose and
I would like to start out by acknowledging my college Dr. Caroline Signore who
is sitting by the door there who contributed a tremendous amount to this talk.
I will cover basically four
areas. One of the charms of going last
is you get to edit your talk as you go along because of all the things people
have already said. Given that, I'm going
to talk about why this is a difficult question to answer and what we can do to
estimate how much folic acid is needed to prevent neural tube defects. I'll talk about some of the actual experience
with fortification and then summarize.
First, why is it a difficult question
to answer? Well, it actually could be a
very easy question. That is, you could
simply take a very large group of women who are planning a pregnancy and give
them doses until you got down to a dose where they started to have a lot of
children with neural tube defect.
Of course, there is only one problem
with that approach and that is that it's highly unethical. I don't think anyone is ever going to do that
kind of study which leaves us with trying to answer the question in an indirect
way.
Now, we know something about effective
dose. We know from the clinical trials
that there are some doses which absolutely work. From the MRC trial 4 milligrams works. From the Hungarian trial 800 micrograms
works. The problem is I think most
people would agree that those are too high to use as a target dose for the
general population.
We then move to a slightly lower
quality level of evidence, case control studies. There are a number conducted in the United
States. Women were taking the standard
multivitamin which had 400 micrograms.
These all showed that 400 micrograms could effectively prevent neural
tube defects as well.
The
question I think is more are lower doses than 400 micrograms also going to be
effective.
Now, before we even try to address
that, I want to mention one other complication, and that is as Dr. Shane
discussed earlier, the MTHFR 677 T variant has a major affect on folic
metabolism. As you can see from our work
in Ireland, those people who have the wild-type CC will have on the average a
much higher red cell folate than people who have the homozygous mutant TT
type. This is just one other complication
we have to deal with.
Now, how can we estimate how much
folic acid is needed? Well, the first
attempt to do this was also mentioned by Dr. Shane and this was Dr. Leslie
Daly's work in Ireland where he used a cohort of 56,000 pregnant in Dublin who
were used then to do a nested case control study of neural tube defects.
The 84 women who produced children
with neural tube defects were compared with 266 normal control women to see how
their red cell folate levels compared.
Dr. Daly constructed a logistic regression equation to look at the
relationship between your level of red cell folate and your risk for having a
child with a neural tube defect.
You've already seen this graph which
essentially shows that your risk for having a child with a neural tube defect
decreases very dramatically as your red cell folate level increases going from
people who were essentially in the deficiency range of red cell folate with a
risk of 6.6 per thousand pregnancies of having neural tube defect offspring to
0.8 NTD pregnancies per thousand when your red cell folate is greater than 400.
Now, you notice in this slide there's
a little piece missing here. The problem
is that there were not sufficient data to look at the most interesting part of
the curve for our purposes and that is how much more decrease in neural tube
defect risk do you get as you increase red cell folate. One possibility is that the curve continues
down and that you can get a risk as low as 0.2 NTD pregnancies per thousand.
The other possibility is that this
levels off. We do know that the curve
has to flatten out at some point because there are things like trisomies and
other Mendelian defects which are simply not going to be folate preventable. Perhaps the optimal situation is .5 per
thousand. However, we do know for
certain from this analysis that 400 nanograms per mL, the red cell folate level
is highly protective against neural tube defects.
So how much folate acid then would a
woman need to be exposed to to raise the red cell folate to these levels that
would be protective? Well, this is a
study we did in Dublin at the Coombe Maternity Hospital with Dr. Sean Daly,
another Daly. This was a randomized
double-blind placebo-controlled trial with different doses of folic acid to see
how much it took to raise women's levels to what would be considered a
protective level. 121 women who worked
at the Coombe hospital received either a placebo, 100 micrograms, 200
micrograms, or 400 micrograms of folic acid a day.
One of the advantages to the study
design is that the women could come into the cafeteria, take the vitamin, sign
a sheet indicating that they had taken it.
For at least five days a week we had pretty good data on compliance.
Now, the results looking at red cell
folate showed, luckily for us, that if you took a placebo you didn't change
your red cell folate significantly. We
would have been a little nervous if that had shown a change. But then as you increased your dose of folic
acid, you had a significant increase in your median red cell folate, 100
micrograms producing an increase of 67 median, 200 micrograms per day an
increase of 130, and 400 micrograms per day an increase of 200. Again, highly statistically significant.
So we were able then to use these data
and plug those into the equation that the other Daly, Dr. Leslie Daly, had
calculated to drive an estimated change in neural tube defect risk. In other words, how much would this increase
in red cell folate drop your risk for having a child with a neural tube defect.
Once again, a placebo, of course, had
no affect but a 100 microgram dose per day reduced the risk for NTDs by
approximately 22 percent. 200 micrograms
reduced the risk by 41 percent and 400 by about 47 percent.
Now, one of the important points to
make here is this is a minimum estimate because, don't forget, this depended on
the women's compliance. Unlike the
fortification situation where you couldn't avoid getting folic acid if you
wanted to, these women had to take the pills.
Our estimate then would be that if you receive approximately 200
micrograms per day of folic acid, you would decrease your risk for having a
child with a neural tube defect by about 40 percent.
Now, another approach to this was
published by Dr. Nick Wald who reviewed all the literature on studies of folic
acid supplementation and reporting on serum folate levels. He essentially constructed a mathematical
model based on these trials to calculate a dose response relationship. This is essentially what Dr. Wald came up
with. It's interesting that the people
who were between age 20 and 35 had a smaller increase in serum folate for a
given dose of folic acid than the people who were age 40 to 65.
Now, there are some problems, I think,
with this study and one of them was that if you look at the predicted class of
folate levels from this study, they were far lower than what was actually seen
in the NHANES study that Dr. Yetley and some of the other speakers alluded to
where it was estimated that women were getting about 200 micrograms per day of
folic acid by food fortification.
The other, as you can see, the effects
were rather different, I would say probably inconsistent, by age. Why would this be? Well, first of all, the obvious differences
in these studies that Dr. Wald used also depended on compliance so that compared
to fortification you would probably see a lower increase in serum folate where
the women had to take the tablets than you would in a fortification situation.
But I think the more interesting issue
is that studies that Dr. Wald selected for the model probably had an
insufficient duration of exposure to reach a stable folate level. That is to say, if you don't wait long enough,
you don't see the maximum affect on serum folate.
This is shown on the slide which comes
from a report by Quinlivan and Gregory summarizing the literature on how long
it takes to reach a stable level. You'll
note that if you take a lower dose of folic acid per day, that's 200 micrograms
or less, it takes you about six weeks to get a stable blood level. If you take a higher dose, 400 or more, it
can take 12 to 14 weeks so that has to be taken into account.
Now, if you translate this into the
studies that were used in the Wald analysis, in the younger age group
interestingly only two of the six studies, or one third, were of adequate
duration to reach the stable folate level that you would need. In the older population half of the studies
were long enough to reach the stable level.
Over all fewer than half of the studies were of sufficient duration.
Now, that would explain the findings
here. That is to say, the lower response
of the younger age group could be because the studies didn't wait long enough
to see what the total affect of the folic acid would be. In summary, the
studies used in this model would lead to a systematic underestimation of the
affect of folic acid on serum folate.
Now, what do the current exposure
levels contribute to this? Well, this
has been discussed somewhat before so I'll show some summary slides. The FDA originally estimated that food
fortification would increase the women of childbearing ages exposure to folate
acid by about 100 micrograms per day.
A number of other people have used
clinical data and laboratory information to create their own estimate. These have shown, I would say, on the average
about a 200 microgram per day or greater estimated effect.
So how has fortification actually
affected levels? Since Dr. Shane was Dr.
Stover, I'll be Dr. Yetley for a minute.
This is the slide that you didn't have today which shows that in the
best study, which is women of childbearing age and a representative sample of
women, that the level was 4.8 before fortification. Fortification added an additional 8.2 to
serum folate levels for a total of 13. I
note that's 171 percent increase.
Just to amplify that a little, this
was the data from Kaiser Permanente which was essentially just specimens that
went to their laboratory and from Dr. Rosenberg's group from Framingham, all of
which showed a dramatic increase.
The same is true of red cell folate
levels and this, again, is a representative sample and shows a 65 percent
increase in red cell folate following fortification. These data, I think, are of relevance because
this is Canadian. Dr. Joel Ray in Canada
showed a very similar increase which suggest that their exposure seemed to be
somewhere to ours.
So to summarize this portion of the
talk, fortification probably increases folic acid exposure by 200 micrograms a
day or more in women of childbearing age and red cell folate levels by the best
measures through the HANES have shown that serum and red cell folate have
increased by 171 percent and 65 percent respectively. A very significant increase.
Now, how does this work in terms of
actual experience with fortification?
The gold standard is obviously how much would this additional 200
micrograms per day decrease neural tube defect rates because that's what it's
really all about. If this is decreasing
the rates to where we want, then that pretty much answers the question as to
what the minimum effective dose is.
Now, to amplify what was discussed a
little while ago by Dr. Green and others, one of the big problems that we face,
and this is from South Carolina data from Roger Stevenson, is that very few
neural tube defects first come to attention at delivery. If you notice, in their population 17
percent, which means that 83 percent were detected prenatally.
If you don't have a very good system
in effect and didn't have a very good system in effect prior to fortification,
you are going to miss a lot of these cases and you are going to get rates that
may not be quite accurate.
That's why I think that the last talk
was so important because in Nova Scotia they had all of these. They had the live births. They had the still births. They had the terminations. Nova Scotia is a very insular, in the
positive sense of the term, area so that it's possible to identify cases, not
to have people go to the next state or the next county or elsewhere for diagnosis
and to get a very good picture of the total experience.
As was also mentioned, their
fortification is very similar to the U.S., 150 versus 140 micrograms. As noted, their incidence fell by 54
percent. I would say this suggest that 200
micrograms, or somewhat more than that, is capable of decreasing the NTD risk
by over half so that the estimated effect in the Canadian population would be a
50 percent reduction given their current fortification levels. There are other data from Ontario to back up
the Nova Scotia experience.
I would also argue that if we had U.S.
data with comparably ascertained cases that we might very well see the same
thing. One of the problems that we have
in the U.S. is that we don't have the kind of system that enables us to do that
kind of thorough investigation.
So, in conclusion, it's difficult to
pinpoint the lowest effective dose of folic acid. However, our study from Ireland indicates 200
micrograms a day would prevent, or should prevent at least 40 percent of NTDs
in that population. Now we know that
actual experience in Canada indicates that 200 micrograms a day plus will
probably prevent 50 percent or more of neural tube defects.
Now, one of the key questions for this
group, I think, is that in the U.S. approximately 50 percent prevention may be
the maximum. However, it may be possible
that 70 percent are preventable. We
don't know if the current level of fortification would mean that we have maxed
out on our ability to prevent neural tube defects or if it would be possible to
prevent more.
To focus the conclusions on our
current discussion, given food fortification and supplement use in the U.S.,
many women are already at a level where they will not need fortified oral
contraceptives. For women who are using
supplements, fortified oral contraceptives might actually put them over the
Institute of Medicine's recommended limit.
However, for other women who do not
take supplements and who less fortified food, fortified oral contraceptives
could be very beneficial. Thank you.
DR. GUIDICE: Thank you, Dr. Mills.
Yes, Dr. Crockett.
DR. CROCKETT: Thank you, Dr. Mills. I have a couple questions for you. I want you to go back to the study that you
alluded to by Dr. Wald, the meta-analysis of the changes in the folate levels
in the age groups and supplementation.
You had showed a graph that showed that the age group of 20 to
35-year-olds had less of a change over time with supplementation than the older
age group. I was wondering how much of
that was due to their levels being higher to begin with compared to the older
age group.
DR. MILLS: I don't recall whether that's in Dr. Wald's
paper. That could be answered by going
back to the original studies that he included.
Does anyone know that?
DR. CROCKETT: Okay.
I think that is particularly fascinating since the topic of our
conversation is targeting that age group of 20 to 35 years.
The second question I had, and it may
seem kind of like an obvious thing but it doesn't seem obvious to me, is at the
very beginning of your talk you said that the higher doses, the 4 milligram or
the 800 microgram cases definitely work but they are too high. In light of the discussion that we've had
about the lack of toxicity of this drug to either the mother or the unborn
child, I was wondering how we determine that those doses are too high?
DR. MILLS: First of all, I don't think that lack of
evidence and toxicity is the same as evidence on lack of toxicity. That is the first issue there. The second is that in order to get the
general population of childbearing age women up to 800 micrograms a day, you
would have to put an enormous amount of folic acid into food because, as Dr.
Yetley pointed out, people eat varying amounts of fortified food.
It would require an enormous quantity
of folic acid and it would clearly put a number of people, a very large number
of people in the elderly age group above the Institute of Medicine's safe upper
limit so that you put a lot of people at risk for masking B-12 deficiency if
you were to do that.
DR. CROCKETT: Yes, but if we're talking about specifically
putting it in oral contraceptives which are not going to be affecting that
older population, how do we then apply the upper limit of the dosing to that
population?
DR. MILLS: That reduces the risk for masking B-12
deficiency substantially. As Dr. Shane
mentioned, about 10 percent of the people who have pernicious anemia are in the
age group of interest to us so it doesn't eliminate that risk. Then I guess you just have to decide if the
number of people in that risk group is sufficiently high that you would
hesitate to fortify oral contraceptives with that dose.
At some point, by the way, this might
be a good time to introduce this, I want to mention that there is an abstract
that was just recently published from the Society for Reproductive Medicine
reporting on use of methotrexate to terminate ectopic pregnancies
medically. They found that people with
higher blood folate levels were more likely to fail on the course of
methotrexate.
Although it's just an abstract and I
haven't seen the paper on it, it is something that we have to keep in the back
of our minds in terms of the potential problems that we could create by raising
folate exposure very high.
DR. GUIDICE: Yes, Dr. Wenstrom.
DR. WENSTROM: My question involves how alcohol affects how
much folate we absorb from fortification.
When I saw that -- when I read Nick Wald's study, it occurred to me that
maybe young people aren't seeing the effect because of alcohol use.
Other studies in which folic acid is
given to reduce the levels of homocysteine have shown that when you use alcohol
the resulting acid aldehyde breaks down folic acid in the gut and you absorb a
lot less. But I'm not aware of any
studies that have looked at that in terms of prevention of neural tube
defects. Do you have any data about
that?
DR. MILLS: I don't know of any published data whatsoever
on alcohol in relation to folic acid and neural tube defects. Does anyone else?
DR. SHANE: There is some data on alcohol affecting the
retention of folate in the body. I
believe kidney retention. I'm not aware
of any information that alcohol affects folate absorption per se.
DR. WENSTROM: Well, there is one big study looking at the
folate supplementation and the incidence of colon cancer, for example, that
show that folate was protective in people who did not use alcohol but it was
not protective if you used at least 15 grams of alcohol because that broke down
folate. Then
I have also seen it, as I said, in relation to homocysteine levels. I have always wondered if we should be
recommending more of supplementation for reproductive age women who use alcohol
but I haven't seen any data on it.
DR. SHANE: It's complicated because that's an
epidemiological study and it's interpreted by epidemiologists in terms of
mechanism. There is no direct evidence
that alcohol does any of these things.
Alcohol in those studies influenced some of the outcomes. For some of those epidemiological studies
looking at folate and vascular disease alcohol obviously has an affect on
that. There might have been some affect
of folate.
In terms of the colon cancer, it is
interesting that the MTHFR phenotype, the mutant allele, is protective. It is also protective at high folate, the
affect, so it's not a question of low folate where you would expect to see the
phenotypic effect.
There was some effect of alcohol in
that study but I think it's a stretch to interpret then when you are looking at
the effect of alcohol and looking at the folate on colon cancer incidence risk
to interpret the interaction between those two from the epidemiological
studies.
DR. GUIDICE: Dr. Rice and then Dr. Green.
DR. RICE: Nobody has really spoke about this but I have
a question on the Daly study. When you
all looked at -- when it was looked at the subgroup that had the maximum levels
of folate and RBC in the serum, what was the outcome of those infants? Have there been any fetal affects that we've
seen in patients who do have those higher levels in their serum or on the RBC
folate? That's my first part.
DR. MILLS: The Leslie Daly study looked at an NTD rates
as a function of red cell folate level.
They did not go back and look at the individual infants to see if the
ones who had NTDs despite the mother having a high red cell folate level were
in any way different from the ones whose mothers had low red cell folate.
DR. RICE: How about any other fetal effects? Has any studies looked at that? Nobody has really looked at that?
DR. MULINARE: With the community intervention trial it was
done with 400 micrograms of folic acid in China. They followed somewhere between 5,000 and
10,000 children of mothers who received 400 micrograms of folic acid. They have only looked at the early years and
haven't seen any differences in development between those children that were
exposed to folic acid in utero versus who were not.
DR. RICE: And then my second question, and maybe I
should know this back from medical school, but I'm assuming that folate gets
into the red blood cell by binding to some receptors, etc. Don't you end up saturating? Don't you get to a point where you can't
raise the level any higher?
DR. SHANE: Well, it gets in my transporter but it gets
in not as folic acid but as a reduced folate just like any other folate. A lot of folate binds hemoglobin so it sort
of sops up folate so you can get very high levels in the red cell because of
that.
It's difficult to saturate the red
cell with very many things. This is like
albumin and plasma. The hemoglobin in
the red cell tends to bind lots of different things.
DR. RICE: In some studies where they have given
patients injections, do you get to a point where you plateau out the serum
level? When you measure the serum level
don't you get to a point where it plateaus?
DR. SHANE: This has been done primarily in human studies
primarily in terms of using leucovorin as a rescue therapy or in cancer
treatment also to help FU treatment. A
lot of experimental models have been looked at.
It's very difficult to raise folate levels, say, in an experimental
tumor but the folate levels in plasma will go through the roof if you have high
levels of folate. There is almost no
limit to how high you can get plasma folate if you give very huge doses of
folate or any kind of folate to a person.
Red cell folates can go to very high
levels but as you saw in the studies here, they do not go up in these studies
of fortification to the same degree that plasma levels go up. I believe there is a theoretical limit to how
much folate can be stored in the red cell in tissues primarily. You can't get it up as high as the red cell.
The reason why red cell is a very
popular way of looking at folate status is from looking at the history of
folate status over a period of time.
That is why people tend to think red cell folate is more accurate if
someone is long-term status than measuring a single plasma level.
DR. RICE: Is the red cell also the most important in
determining toxicity if we would be able to determine that or has that been
determined based on serum?
DR. SHANE: I think it's dangerous looking for red cell
because you are looking at a cell that is in various states of dying however
long it's been there. In people with the
TT, the double modified allele of MTHFR, their folate distribution of red cell
is very different usually than in people with so-called normal. They have a different folate
distribution.
This does not seem to be that clear
cut that you have this difference in tissues but you do find in the red
cell. That may just reflect that
whatever enzymes are in the red cell during this period in circulation is gradually
dying and you are losing enzyme activities, cytosolic enzyme activities. I don't think the red cell is a particularly
good indicator of toxicity. Others may
have a specific example where they think it might be but I can't think of any.
DR. RICE: So you would use the serum level?
DR. SHANE: I would not use those as measures of
toxicity. I don't think a high level of
folate is an indication of toxicity. The
only concern I've really had about toxicity per se was that it's just never
been looked at. As I think Jim mentioned
before, people have not been exposed chronically to very high levels of folate
in the past. You would have to take
every pill in a bottle of vitamin pills to achieve megadoses of folate.
DR. GUIDICE: Thank you.
Dr. Green.
DR. GREEN: I have two comments. First of all, in relation to the question
that Dr. Crockett raised and was addressed by Dr. Mills with respect to the
at-risk population in terms of B-12 deficiency among women of reproductive age
and that is merely to point out in addition to that number which is in the
order of about 10 percent of all patients with pernicious anemia that there is a
distribution among those that is different according to ethnic group according
to several studies, most notably that of Carmel and Johnson who demonstrated
that the occurrence of pernicious anemia among the Hispanic population and the
Black population tends to affect older and, in particular, female patients.
Then just a brief addition to Dr.
Shane's comment. This is actually
contained in the information that was distributed as preparatory information
for this hearing with respect to the protective effect of the common MTHFR
polymorphism. It has been demonstrated not only for colon cancer but also
for acute lymphoblastic leukemia in children that the common TT homozygous
mutation or polymorphism confers some protective effect with respect to the
occurrence of acute lymphoblastic leukemia.
To my knowledge, there has been no demonstration similar to the one that
Dr. Shane referred to with respect to the protective effect of folate in those
individuals who are TT.
In other words -- no, I'm sorry. Let me change that and say the protective
effect of folate in those individuals who are CC who would appear otherwise to
be at increased risk.
In other words, to clarify this, as
long as the TT individuals have adequate folate nutrition since, as we heard
from Dr. Shane, their folate levels are generally lower, as long as they have
adequate folate, then they have the additional conferred protection against
colon cancer. I'm not aware of a similar
study with acute lymphoblastic leukemia.
DR. GUIDICE: Thank you.
Dr. Tobert.
DR. TOBERT: With regard to Dr. Shane's point about the
lack of clinical trial data with high doses of folate in the U.S. MRC trial, I
just want to make the committee aware there is an ongoing trial being conducted
in Oxford, the so-called SEARCH trial.
That trial is designed to test the homocysteine-lowering
hypothesis.
It started in 1998, 12,000 patients
being randomized to a two-by-two factorial, but the arm of interest here is to
two milligrams of folic acid but it's with one milligram of B-12. Still, it's 6,000 middle aged people who are
getting 2 milligrams of B-12. Those data
should be reported in 2005.
DR. GUIDICE: Thank you.
We have time just for a couple of comments. I think Dr. Rader had a question or a comment
but I think Dr. Shane has a direct response to the comment that was just made
so please go ahead.
DR. SHANE: I would just like to add that the VISP trial,
which was concluded which was on a more elderly population, stroke recurrence
rate. I'm not sure if it's published its
data but it will have data on 3,600 people, I believe, who have been exposed to
similar levels of folic acid. As far as
I'm aware, they have not found any toxicities associated with the administration
of folate.
DR. GUIDICE: Dr. Rader.
DR. RADER: I had a very short question for Dr.
Mills. I was interested in your comments
about the Wald paper. When you
recognized the inadequate length of duration of some of the studies, when you
took those out were you able to recalculate the data that was left that was
adequate to see if those two items were going to be possibly super imposable
or, at least, more parallel?
DR. MILLS: No, but I would be happy to have you do that
if you would be interested.
DR. RADER: I may take you up on that. Thank you.
DR. GUIDICE: Thank you.
I'd like to thank all of the speakers for the very informative talks
this morning. We'll take a 10 minute
break so that we can then hear from the sponsor. Thank you.
(Whereupon, at 10:25 a.m. off the record
until 10:37 a.m.)
DR. GUIDICE: Would everyone take their seats, please. We would like to go on with the rest of the
morning session. Please take your seats
so we can get started. Thank you.
I would like to also welcome one of
our committee members, Dr. David Hager.
Glad you could make it.
The rest of the morning session
focuses on invited sponsor presentations.
The first speaker will be Dr. Andrew Friedman who is director of Women's
Health Care Research at Ortho-McNeil. He
will present a proposal background and overview
Dr. Friedman.
DR. FRIEDMAN: Thank you, Dr. Guidice, members of the
panel. Good morning. On behalf of our organization, we are pleased
to have this opportunity to review our proposal for a combined oral
contraceptive folic acid product.
I just wanted to remind the committee
members that this is actually not a typical advisory committee meeting where
you may be asked to review NDA data to make decisions or recommendations about
whether to recommend approval of a drug or whether to remove the drug from the
marketplace. Rather, the purpose of this
meeting is to review a concept. In this
particular situation it's the concept of combining folic acid with an oral
contraceptive product.
At first blush this concept may appear
to be counter-intuitive. Why would
somebody want to combine something that prevents pregnancies with something
that prevents birth defect? Initially it
doesn't seem to make sense, but as you'll hear through our series of speakers
throughout the remainder of the morning.
This concept makes perfect sense.
Folic acid preventable neural tube
defects are still occurring in the United States. We've heard that from a variety of speakers
this morning. Such a combination product
would be able to prevent additional neural tube defects. We are not here to discuss the clinical
development plan which will be discussed with the FDA at a later date.
Now, such a combination product would
be used primarily by women who elect to use oral contraceptives as their method
of contraception and who are currently not taking multivitamins or folic acid
containing supplements. This would be
the primary target population.
Over the next hour to hour and a half
we'll be hearing information and data from a variety of speakers to support the
need for such a proposed product. I will
initially address with you our proposal background and overview.
After I speak you will hear from Dr.
Godfrey Oakley who is the former Director of the Division of Birth Defects and
Developmental Disabilities at the CDC and currently visiting professor in the
Department of Epidemiology at the Rollins School of Public Health, part of
Emory University.
I should add that Dr. Oakley is a
recently elected member of the Institute of Medicine. Dr. Oakley will be talking to you about the
efficacy and safety of folic acid for the prevention of neural tube defects.
Following Dr. Oakley's talk you'll
hear from Dr. Anna Maria Siega-Riz who is Associate Professor of Maternal and
Child Health and Nutrition at the School of Public Health at the University of
North Carolina in Chapel Hill. Dr.
Siega-Riz will talk to you about the need for increased folic acid intake among
reproductive age women.
Dr. Andrew Kaunitz will then address
the group. Dr. Kaunitz is Professor and
Assistant Chairman of the Department of Obstetrics and Gynecology at the
University of Florida Health Science Center and has worked on some of the ACOG
practice bulletins as they pertain to oral contraceptive use.
Dr.
Kaunitz will address the group on oral contraceptive use in the United States,
pregnancy intendedness and its relationship to folic acid intake.
I will return to the podium and
present a brief summary and some concluding remarks.
We've heard about neural tube defects
this morning. In the United States they
are the second most common group of serious birth defects, second to
cardiovascular birth defects. The neural
tube forms in the embryo between days 18 and 28 following fertilization. Failure of the neural tube to close will
result in a neural tube defect.
This slide shows two rather disturbing
pictures of the more common neural tube defects, spina bifida and
anencephaly. Spina bifida occurs when
the neural tube fails to close. The
lower portion of the neural tube fails to close.
The majority of these infants will
survive approximately 80 to 90 percent, but this is a life-altering congenital
anomaly often leading to lower body paralysis and sensory loss, loss of bowel
and bladder function, hydrocephalus which in turn may lead to multiple
operations and multiple hospitalizations.
There is immeasurable personal and family cost caused by children and
those around them who are affected by this disorder.
The average total lifetime cost for
medical care for this disorder has been estimated to exceed a half a million
dollars in many instances. In contrast
anencephaly results when the upper portion of the neural tube fails to fuse
and, in fact, the majority of the brain and brain substance fails to form.
In this instance the children -- this
is a uniformly fatal disease with fatality occurring either early in pregnancy
ending in miscarriage, later in pregnancy and in stillbirth, and in rare cases
where there is a live birth, there will be death shortly thereafter.
We've heard this morning from a number
of speakers how folic acid may actually prevent the vast majority of neural
tube defects. These are largely
preventable by adequate intake of folic acid if folic acid is started prior to
pregnancy. That's a very important point
in terms of when folic acid should be started.
We've heard estimates this morning
from a number of speakers that the approximate rate of neural tube defects in
the United States is about one in 1,000 or 10 in 10,000. There are estimates that may be higher or lower
than this but this is the generally accepted rate.
We've also heard from Dr. Mills and
you'll hear later from Dr. Oakley that through intervention trials we know it
is possible to decrease the rate of folic acid preventable neural tube defects
down to at least 6 per 10,000 and possibly lower than that. Again, maximum benefit is achieved when folic
acid is started prior to pregnancy.
This slide shows a time line of the
events of pregnancy, when it occurs, when it's diagnosed, when the neural tube
closes, and when a women is likely to see her health care professional for an
initial prenatal visit.
Here you can see that conception
occurs around the time of ovulation, about two weeks after a woman's last
menstrual period. Two weeks after that a
woman would have missed her first menses.
This would be the first time that pregnancy could possibly be diagnosed
but the neural tube development is already well underway already starting to
close shortly after that. In fact,
neural tube closure occurs by about day 28 to 30 after fertilization or some
six to six and a half weeks after a woman's last menstrual period.
Now, those of you in practice or who
have gone to obstetrician gynecologists or nurse midwives for care for
pregnancy realize that when you call to make an appointment to see your health
care professional the usual time one has to wait until seeing your professional
is about four weeks from the time of your phone call.
Even if the diagnosis is made right
when the period is missed, the usual time for a first prenatal visit at the
very earliest is about eight weeks or after the neural tube has closed.
This
is a problem because folic acid should be started before conception in order to
have maximum benefit in reducing neural tube defects.
Once a woman is pregnant she cannot
rely on her health care professional for timely counseling about the importance
of periconceptual folic acid. This women
would not receive a prescription for prenatal vitamins early enough to minimize
her risk of having a neural tube affected child.
Based on an extensive amount of
clinical trial data, some of which you've heard through speakers this morning,
some of which you will hear from Dr. Godfrey Oakley, the U.S. Public Health
Service developed a recommendation in 1992 that all women of reproductive age
consume 400 micrograms of folic acid daily.
The Institute of Medicine reaffirmed
this recommendation in 1998 when they suggested that all women of reproductive
age consume 400 micrograms of synthetic folic acid in addition to a diet rich
in natural folates. A number of medical
nursing and other professional organizations committed to maternal and child
health have embraced this recommendation.
Some of these organizations are shown here on this slide.
I would like to give a brief overview
of folate and folic acid. I cannot do it
to the expertise Dr. Shane but I will just give a broad overview to just tell
you some of the most pertinent facts and how these terms have been used
interchangeably, sometimes incorrectly so.
As you've heard, folic acid, or
folate, is a water soluble B vitamin that cannot be synthesized in humans so it
requires intake through the diet. It is
found in a variety of foods, some of which are shown up here, fruits, green
leafy vegetables, etc. Actually, the
darker the green color of the vegetables, the more folate is contained in those
vegetables.
As we've heard folic acid is a
synthetic form of folate and is more bioavailable. Almost two-fold more bioavailable than
natural folate found in foods. With
chronic use or ingestion folate can be stored in the body primarily in the
liver where about half of the store are kept and also in the red blood
cells. The red blood cells then are a
good proxy or marker for tissue stores of body folate. As we've heard, folate is required for a
variety of chemical reactions as a coenzyme.
Most notably DNA synthesis.
This
is a slide that you will see throughout the series of talks that you hear this
morning. What it depicts are the
interrelationships between folic acid intake, changes in blood levels of
folate, and decreases in neural tube defects.
Serum and red blood cell folate are
correlated after equilibrium is reached so after a few months of folate or
folate acid regular supplementation or use.
Throughout the talks that you hear this morning, references will be made
to both serum and red blood cell folate levels where data exist. Both levels are consistent and relevant
markers of folate status.
There are a number of ways that an
individual can obtain folate or folic acid through diet, supplement, or
prescription use and those are shown on this slide. One can obtain folic acid through a
prescription drug. Obstetrician,
gynecologist, family practitioners and nurses most commonly would do this with
prenatal vitamins which contain up to 1,000 micrograms of folic acid or one
milligram.
In addition, probably more in the
hematology world, pure folic acid can be prescribed and also in internal
medicine treating hyperhomocysteinemia pure folic acid can be prescribed again
at a dose of 1,000 micrograms per tablet.
Many of you also are familiar with
nonprescription ways to obtain folic acid such as vitamin supplements bought
over the counter at the pharmacy or health food store and many of these
preparations have between 400 and 800 micrograms of folic acid in them.
We've heard about fortification of
ready-to-eat cereals by Dr. Yetley and also about the grain fortification
program which was mandated by the FDA in January of 1998. These are additional ways that one can obtain
folic acid through the diet. Finally,
one can obtain folates through natural food sources such as the short list that
I showed previously.
So let's look at how successful some
of these ways have been to increase folic acid intake among reproductive aged
women. Regarding the intake of folic
acid through supplement use or prescription products, the March of Dimes has
conducted an annual survey since 1995 to determine folic acid awareness and
multivitamin use in reproductive age women.
We've seen some of this data earlier this morning.
These educational efforts are
tremendously important. It's important
to keep reinforcing the message that folic acid is important and how it's
important and to do this through public education awareness campaigns should be
continued.
Although the data showed this morning
was compelling in that awareness has increased, as was stated also earlier this
morning the use of folic acid containing vitamins and supplements has remained
relatively flat at about 30 percent of reproductive age women. So despite these aggressive campaigns, it is
unlikely that further efforts will dramatically increase the use of folic acid
supplements in the general population.
The reason for this is really quite clear. It is very hard to change behavior. Even
with education it is very hard to ask someone to do something new, something
different, something they are not already doing. Dr. Yetley actually raised this point when
she talked about the importance of the grain fortification program, that it's a
passive program. It increases folic acid
consumption without people having to do anything differently.
Speaking about the grain fortification
program, I think we've heard a large amount of data this morning. We'll hear some additional data later this
morning that this program has been very successful. We've heard data to suggest that the
estimated increase in the daily intake of folic acid has risen by about 200
micrograms per day and that this, in turn, has led to a decrease in neural tube
defects on the order of 23 percent.
We've heard other estimates of 19 percent, 20 to 30 percent. The bottom line, though, is that this program
has claimed some significant successes.
However, as Christine Lewis and others
from the FDA have stated in a relatively recent article, the estimate is that
the majority of reproductive age women still consume less than the U.S. Public
Health Service recommendation of 400 micrograms of folic acid daily. In fact, their estimate in this paper in 1999
post-fortification was that 68 to 87 percent of women still do not consume this
U.S. public health service recommendation.
In fact, the authors go on to conclude
that there is a need to explore ways to improve folate intake in targeted
subgroups. Specifically reproductive age
women while not putting other population groups at risk for excessive intake.
Two years after this article came out
authors from Tufts and the FDA concluded that no level of grain fortification
would ensure that all women of reproductive age would consume 400 micrograms of
folic acid through diet alone. This
conclusion underscores the need for additional vehicles, passive vehicles, to
deliver folic acid to reproductive age women who consume less than 400
micrograms daily.
Toward this end, we propose an oral
contraceptive folic acid product as one more way, one more vehicle to meet the
medical need as stated by Lewis and colleagues and supported by other authors
to target women of reproductive age who consume less than the U.S. public
health service recommended amount of 400 micrograms of folic acid daily.
There are many of these women out
there as we have discussed. These women
can be easily identified through a simple question about whether or not they
use supplements or multivitamins. Once
they are identified oral contraceptives are a logical vehicle to deliver folic
acid.
Oral contraceptives, as you will hear
from Dr. Kaunitz, are the most common method of reversible contraception in the
United States. Over 16 million women
currently use oral contraceptives so with such widespread use oral
contraceptives would be an appropriate vehicle to deliver folic acid and reach
a large number of women in the target population.
Such a product would be available by
prescription only so it would be highly regulated and controlled. Both the quality of the raw materials, the
folic acid as well as the sex steroids, as well as who gets the prescriptions. They would be under the care of a health care
professional and supervision.
This product would help in part to
fulfill an unmet medical need in reproductive age women and, as mentioned
earlier, would be targeted to those reproductive age women so it would not be
given to children or those above the age of 50.
These components, oral contraceptives
and folic acid, have been widely studied throughout the years and have
established efficacy and safety. Oral
contraceptives have been on the market for 43 years. Oral contraceptives are the most studied
medication in U.S. history. Their
efficacy is very well established and they have a good safety profile.
Folic acid, as we've heard from our
speakers this morning, reduces the risk of neural tube defects and there is
still the possibility that further neural tube defects could be eliminated or
reduced. It also has an excellent safety
profile as I will speak briefly to and Dr. Oakley will speak more extensively
about.
Folic acid as a prescription product
was first approved by the FDA in 1946.
It's been approved for 57 years as a drug at the 1 milligram dose. There are more than 1 billion person years of
use of doses that are at least 400 micrograms a day. This product has a wide therapeutic
index. We've heard about no known
toxicity this morning.
In fact, Goodman and Gilman, the
textbook used by medical students and physicians throughout the country, states
that oral folic acid usually is not toxic.
Even with doses as high as 15 milligrams a day there have been no
substantiated reported of side effects.
I should mention that in 1986 CFSAN,
the group from the FDA that regulates food and supplement use established a
registry for voluntary reporting of adverse events for vitamins and other
supplements. To date there is not a
single report of folic acid toxicity in this registry.
Now, although under-reporting may
explain in part some of this finding, under-reporting alone cannot explain zero
reports. In contrast, look at vitamin A
which has numerous reports of toxicity reported in this registry.
I would like to conclude with my last
two slides by just summing up why this makes sense. An oral contraceptive folic acid product
would ensure that the proposed population would have an intake of 400
micrograms of folic acid daily. This is
the amount recommended by the U.S. public health service. It
would not change any pill taking behavior.
This is one of the most compelling arguments that I can present to
you. It would provide increase in folic
acid to targeted women with low intakes through a passive means so it will
work.
Compliance is known to be better with
one pill rather than two so combining these products into a single tablet would
actually improve compliance and use and would have a further impact on reducing
the neural tube defect rate.
This would be a highly controlled and
regulated product. It would only be
dispensed by prescription only and under health care professional
supervision. We're talking about a dose
that is already present in supplements that can be bought over the counter
without supervision and without regulation.
Each component, as I've mentioned, has
good to excellent safety profile. The
risks, as we've discussed a little bit this morning and as we'll get into a
little bit more with Dr. Oakley's talk, associated with an incremental dose of
400 micrograms of folic acid are negligible, if any, in this proposed
population of reproductive age women.
So, in summary, oral contraceptives
are widely used by the target population and would be a convenient and
effective vehicle to co-administer folic acid.
It would provide the recommended 400 micrograms of folic acid on a daily
basis and would further compliment efforts by the U.S. public health service a
variety of professional and medical organizations to further reduce the
incidence of neural tube defects in our country.
Thank you for your attention and at
this time I would like to introduce Dr. Godfrey Oakley who will present the
efficacy and safety of folic acid for the prevention of neural tube
defects. Thank you.
DR. OAKLEY: Thank you.
I'm delighted to be here to talk about an opportunity to increase the
prevention of birth defects in our country.
As a way of a disclaimer, let me indicate that when I was the Director
of the Birth Defects Division at CDC, I was trying to figure out how could we
get more young women to consume folic acid.
The idea of putting folic acid in contraceptive pills came, led to
conversations with Dr. Michael Cafferson and Dr. Cafferson and I are the
co-inventors on the patent.
Now, let's get down to business. I would like to discuss and go briefly over
my comments today. I'm going to review
the efficacy. Folic acid has been shown
in randomized control trials to prevent spina bifida and anencephaly.
In contrast to many drug situations
there is enormous effectiveness data already out there. CDC conducted a community intervention trial
with 400 micrograms of folic acid that involved over 200,000 women before they
were pregnant and there were remarkable reductions in NTDs.
You heard about the grain
fortification program today that has exposed more than a billion people to
extra folic acid and what we've seen is a decrease in both Canada, the United
States and not shown earlier but in China and Chile reduction from this. We know effectiveness works.
Finally, I'll talk about safety. As Dr. Friedman said, this is a safe drug the
way this product is proposed, which would be to put it in another drug that is
used and supervised by a physician as another level of protection for women of
reproductive age.
Then for the part of the population
that is not women of reproductive age, by targeting sexually active women this
will give no more folic acid, not one single microgram of folic acid to anybody
50 or older or anybody that's a child.
I would like to share a data driven
dream. That is, we don't have Congenital
Rubella Syndrome in this country anymore and it is a remarkable achievement of
American pediatricians, American industry, American health care, parents,
everybody. We almost don't have any
cases now and they happen only when they are imported. We've had remarkable success.
I think we now have the data to allow
us to know that if we get enough folic acid into enough women, we can achieve
the total prevention of folic acid preventables, spina bifida. I am delighted to be here to try to help move
this along.
If I needed any encouragement, and
some of you know I don't need much encouragement on this topic, but if I needed
any encouragement on this topic, I visited the spina bifida association picnic,
the holiday picnic 10 days ago.
I had the opportunity to sit at my
table with a young couple who didn't know about folic acid before they got
pregnant and they had a four-month-old daughter with spina bifida. This young child had already had at the age
of four months five surgeries to have her shunts revised and had surgery
related to her club feet.
This is just a reminder that this is a
birth defect that can't be cured. It
must be prevented.
Dr. Friedman has shown you this slide
before. I'm going to be talking about
the relationship between the intake and the health outcome neural tube defects
at first.
Of course, Dr. Mulinare has shown you
a slightly updated version of this slide.
Since I stole my version from him about six months ago, it's not quite
as slick as his but you've seen this slide before and I'm going to mostly talk
about these two yellow bars and this yellow bar here.
This is an amazing slide. In my view this is a slide that is worthy of
generating of nobel prize for Professor Wald and his colleagues. The MRC just put out a press release after
looking at their funded studies for the last 70 years and they said in the
modern medical times this was one of the five most important studies that they
actually supported.
To get into this slide you had to be a
woman who previously had an infected child with anencephaly or spina bifida and
you had to be agreed to be randomized into a two-by-two design in which half of
the women either got 4,000 micrograms of folic acid or they didn't. Among the women who did not get 4,000
micrograms of folic acid, their rate of NTDs were 350 per 10,000 or, if you
like percentages better, 3.5 percent.
Among the women who got 4,000
micrograms of folic acid, there was a 75 percent reduction down to 1
percent. It's clear a powerful
protective effect demonstrated in a well done large randomized control
trial. It makes the point that not all
spina bifida and anencephaly are prevented by folic acid but an awful lot of it
is.
That data led the CDC two weeks after
the study was published to put out a guideline that was mentioned earlier that
all women who previously had an affected child when they were planning to get
pregnant should consume 4,000 micrograms of folic acid a day. There are women out there who on a regular
basis are taking 4,000 micrograms a day.
There is some exposure to that dose and it continues to be considered to
be a safe dose.
Then the second randomized control
trial came. This was roughly 2,500 women
who came to their doctor before they got pregnant and agreed to be randomized
into a group in which they either got Roche's at that time current prenatal
vitamin with 800 micrograms of folic acid or none.
As you can see here, the rates because
it's in the general population they are lower but among the women who did not
get the folic acid containing a multivitamin it was about 30 per 10,000. In this study there were no cases in the
treated arm. Both the MRC study and this
study were called off early by the data mining committee because they were both
so powerful protected studies.
Those two studies and some of the case
control evidence that Dr. Mills and others talked about led the Public Health
Service, the CDC, the NIH, and the Food and Drug Administration they issued on
September 11, 1992, the MMWR report that recommended that all women get 400
micrograms of folic acid a day. You've seen this before so maybe I'll save
a little time and move to the third study.
This is the effectiveness study.
We move from efficacy which has been demonstrated to show that we have
effectiveness. These are data from the
large China study where there were over 200,000 women in two parts of the
country.
In the northern part of the country
the rate of NTDs is very high, one half of 1 percent of all babies have either
anencephaly or spina bifida and infant mortality, as it were, of five just from
those two birth defects when these babies die.
The other part of the study was done in the southern part of China where
the rates are about like what they are here, about one per 1,000 or 10 per
10,000.
One motivation for doing this study is
that although the public health service made policy that all women should get
400 micrograms of folic acid, there wasn't a single study in which women had
actually gotten only 400 micrograms of folic acid. One randomized control trial had folic acid
at 10 times that dose and the other randomized control trial had not only 800
micrograms but it also had multivitamins with it.
Then all the case control studies, the
observational studies were mostly of women consuming a multivitamin. Of course, in this country a multivitamin has
400 micrograms of folic acid but it also had extra vitamins.
This study was done in part to look at
would just 400 micrograms of folic acid a day have the protected effect that we
sort of deduced that it would and there is extreme good news here. As you can see from the northern parts where
the rates were high the women who were highly compliant, their rates dropped
from 50 to 7 per 10,000, more than an 85 percent reduction.
In the south where the rates were
lower they dropped from 10 to 6 per thousand among the highly compliant. So here we have efficacy data --
effectiveness data that is highly supportive of the notion that folic acid
prevents birth defects.
We've had a lot of discussion on what
has happened with fortification this morning.
I think I won't say much other than to note that I don't think has come
through quite as clear in all the presentations this morning but for many years
cereal companies have been able to voluntarily add vitamins to their
products. Totals had 400 micrograms of
folic acid since the middle '70s.
But what is tough to break out from
the blood data post-fortification is the changes that other cereal companies
have made in their products. To make a
long story short, there used to be five products that had 400 micrograms of
folic acid per serving and now there is some place between 50 and 100 so
increased consumption occurred passively by people not changing their brands
but just by their brands having more folic acid in them.
Having said all of that, there seems
to be a pretty good agreement by most people that the current consumption is
about 200 micrograms. Think about that
as a statistician for just a minute. If
the median is getting 200, that means 50 percent are getting less than
200. I mean, there are clearly women --
most of the women still are not getting the 200 micrograms to say nothing of
the 400 micrograms that is still the public health service recommendation.
Now, you've seen these data from Dr.
Mulinare. This is the prefortification
level. This is the transitional
time. This is the after fortification
among the nine birth defect surveillance programs that try to do a good job of
counting the prenatally diagnosed and terminated pregnancies.
These are data from the birth
certificate studies so the rates are a bit lower but I think they respond to
one of Dr. Rosenberg's questions in the sense that these are the years when
fortification happened and since fortification it seems to be a plateau. It looks like it actually did happen. We got it over 18 months to 36 months and
then we haven't seen further decreases in NTDs.
Now, we had a whole talk by telephone
on the Nova Scotia data and I was glad to hear more details on that. I only have one slide but I think it's a very
important study because it was an island, very intensive look for all cases of
NTDs. Of course, before fortification
roughly 26 per 10,000 and after fortification roughly 12 per 10,000. I, like the former speaker, think that is too
high.
If we've demonstrated in China that we
can get down to six, and I agree with Dr. Mills that maybe the number might be
five and we really don't know whether it's five or one or seven or what it is,
but I believe we can do better and certainly in Canada this is a nice
observation that more folic acid would further reduce the incidence of these
birth defects.
These are data from Quebec which also
has a very good prenatal diagnosis follow-up system in place so they can add
not only the children with NTDs at birth but those that were prenatally
diagnosed and terminated. This study is
about 10 times as big as the study from Nova Scotia just because there are more
people in Quebec than there are in Nova Scotia.
As you can see, essentially the same
data. The rates before around two. The rates after like shortly over one. Of course, it happens and then it kind of
plateaus. It looks like we're not going
to get anymore benefits from fortification.
Now, let me talk about the other
part. I think we've demonstrated that
with the health outcome of NTDs, there's no question that folic acid is
effective and efficacious. Now, we also
propose and other have proposed that by seeing that relationship between plasma
folate or serum folate you can predict the reduction in NTDs.
These data were shown to you by Dr.
Mills in a slightly different format.
They were shown in a curvolinear because they had linear
coordinates. Dr. Wald graphed these same
50,000 -- the data from the 50,000 pregnancies in Dublin and he used a log-log
scale.
The reason for using that log-log
scale is that the slope of this line is such that if you double the plasma or
red cell levels, you are approximately half the NTD rate. I'll say it again. If you double the blood cell, the plasma or
serum folate or double the red cell folate, you are approximately half the NTD
rate.
You can see that that occurs all
across the rather common levels of plasma or folate in Dublin. This is primarily a nonsupplementing
population and a population before -- not fortification and they didn't take
supplements.
As Dr. Mills pointed out, we really
don't know what the shape of this curve is out past 10 nanograms per mL. Or if you multiplied that by 2.224 in the
other units. So we don't know what it is
out here. Maybe we'll find out one day
but we can't do a randomized controlled trial to figure out what that is
because that would be unethical.
Now, a question that we will be asking
the committee is what is the evidence that there would be residual effect after
you stop taking an OC with folic acid in it.
Everybody seems to understand if you are taking it and you got pregnant
while you were on it, you would be protected.
You would be as good as other women taking 400 micrograms.
These are data from some dutch women
of reproductive age 70 percent of whom were taking OCs. At baseline they have
five nanograms per mL folate levels and they took 500 micrograms of folic acid
a day. In such four weeks -- just four
weeks they had a level that was more than twice what it was at baseline. Even in the first cycle it would be good news
and protection.
Eight weeks after stopping they still
have a plasma level that is roughly twice what it was at baseline so even eight
weeks after these women on the average would have about 50 percent fewer babies
with NTDs than they would have had if they had never taken this product.
These data are from studies in men and
a few women after having a heart attack.
I don't show them to you to be representative of young women but I do
show them to you because these are data that are currently available that show
baseline levels of 6.8. These men and
women were feed 400 micrograms for three months so it's a three-month
study. Then they were taken off for
three months and measured again.
Even after three months off here the
dose was 400 micrograms, there is roughly a 50 percent increase suggesting that
these women, if these were women who had been on a contraceptive pill, would
have a 25 percent lower risk of having a child with an NTD if, in fact, they
had been taking such a product like this before they got pregnant.
Now, I want to talk about the safety
for a bit. Folic acid has an excellent
safety profile. Hard to dream of a drug
with a more safe profile. It's been
available by prescription in the 1 milligram levels for 57 years. It is currently recommended to women who
previously had an affected child to take 4,000 micrograms a day when planning a
pregnancy.
I agree with Dr. Shane there is no
data to suggest that this drug is toxic in anyway. A study that I almost mentioned in answer to
someone's question is that there is a study in Boston at the time of birth in
which women -- it was a nutritional study, a history study, in which they
looked at blood folates on the fetal side and blood folates on the mother's
side and they looked at it across large differences in intake from no extra
folic acid to 6,000 micrograms a day.
There was a three-fold concentration
on the fetus' side for serum across that whole level. This is set up for babies to get enough
folate. Babies need folate because they
need to make cells and you can't make cells without DNA and you can't make DNA
without folic acid so this is set up that way.
With red cells it did just as Dr.
Shane suggested. It plateaued and I
forgot exactly where it plateaued but at some level above a milligram a day it
began to plateau in this group of women.
So, we have that data but we also have
the data from the randomized control trials which is the usual data committees
look at. And we have the randomized
control trial in England, the MRC study and the Hungarian study and, again, no
suggestion of adverse effects from the consumption of 4,000 micrograms or 800
micrograms.
Of course, the large Chinese study,
200,000 women who took 400 micrograms for around a year there were no
indication of any adverse effects. Of
course, these children are being followed up by the CDC in order to make sure
and to be able to tell if there might be some unexpected effect but so far
nothing has been reported.
Now, let's talk about this tolerable
upper limit a bit. It is true that the
food and nutrition board while making policy for something that would be to the
whole population, not a health care provider, set a tolerable upper intake
level. They set it as 1,000 micrograms
of synthetic folic acid for people who would not be under a physician's
supervision.
I think it's important, as Dr.
Rosenberg talked about, the data that were used. The data essentially for this, as they said,
limited evidence that excessive folate may precipitate or exacerbate neuropathy
in vitamin B-12 deficient individuals. Most of the data came from studies, three
cohorts in the late 40s and early 50s in which people were diagnosed with
pernicious anemia who were being adequately treated with liver extract and they
were deliberately taken off of an effective therapy and given large doses of
folic acid because they felt at that time maybe folic acid would prevent
this. The doses ranged from 5,000
micrograms a day to 50,000 micrograms a day.
Never any discussion about toxicity
from that level of exposure. Of course,
if you take someone off an effective therapy and you treat them with a drug
that is not the effective therapy and it's a serious disease like pernicious
anemia, they are going to get sick again.
It turns out 25 percent of these
people didn't get sick again. Probably
had folate deficiency or something. A
third of them got sick again with their neuropathy but no anemia. A fourth got both and another fourth got the
other. These are the data that lead to
the hypothesis that there might be a masking issue.
The point of this is this is a very
cautious level. No one should have the
idea that consuming 1,010 micrograms of folic acid is going to make anybody
sick. That is not the point of this
recommendation. I have been in circles
where I thought that was misunderstood so I just wanted to make sure that
people understood what the quality of the data was.
Then there was the -- and the lowest
dose of this observed was at 5,000 micrograms that took a five-fold protective
effect so that is where this upper intake level comes from of 1,000 micrograms
of folic acid.
And the office report from the IOM put
this statement in their document.
"In general the prevalence of vitamin B-12 deficiency in females in
the childbearing age is very low and the consumption of supplemental folate at
or above the upper limit in this group is unlikely to produce adverse
effects." This is said for women
who are not seeing a doctor to get more folic acid. These are women who get folic acid from just
having fortified products.
So let me summarize. The efficacy of folic acid in lowering the
risk and preventing neural tube defects has been adequately demonstrated in
well done randomized controlled trials.
We know it is highly effective from studies done in communities and the
evaluation of fortification programs in the United States, Canada, and in
Chile.
One point that I didn't make in my
talk and in the summary that I would like to respond to, and that is when we
try to figure out what is the least effective dose. For me the question is what is the lease
effective dose that will prevent almost all of the birth defects.
It is not the least effectiveness dose
at which you might get five percent or 20 percent or 40 percent. It is the least effective dose. What is the lowest dose that we could get
all. I agree with Jim we don't know
exactly what that is but the default position for the IOM and for CDC and the
FDA still is 400 micrograms.
On the safety issue, it is a safe drug
made even safer in this situation because women are going to get this extra
folic acid under a health care provider's supervision. It's made safer for older people and children
because no older person or no child will get any folic acid from this product.
Vitamin B-12 deficiency in
reproductive age women is unusual and, as I said just in the previous slide,
even the Institute of Medicine thought that it was very unlikely that women
would have any adverse effects from going over a thousand micrograms of folic
acid a day.
Then the final bullet is wouldn't it just
be wonderful to prevent more kids from having folic acid preventable birth
defects and that's what we can do by having this product available to health
care providers and their patients. Thank
you.
I got wound up just a little bit and I
forgot to introduce the next speaker.
The next speaker is Dr. Anna Maria Siega-Riz who is a Professor of
Nutrition at the University of North Carolina, Chapel Hill.
DR. SIEGA-RIZ: It's a pleasure to be here today. It's actually just a pleasure to be able to
stand up. For some reason this doesn't
seem to be going as we would like. Can
we get my next slide, please? Maybe this
will be a stretch break and people can move around a little bit. That might get you awake. Here we go.
This is my slide. There we
go. Perfect.
So I'm going to be talking to you
today about folate status among women of reproductive age. I'm a nutritional epidemiologist by training
and I actually focus on the perinatal period.
There's three points to be made with
my talk today. Basically ones that you
have heard in slightly different versions from our previous speaker but
basically that we can obtain folic acid through diet or multivitamins. Second, that the fortification program has
really not benefitted everyone equally. There are still many individuals that
do not consume the public health service recommendation of 400 micrograms on a
daily basis. And the fact that we can
actually identify women with low folic acid intake by using some simple
questions.
I believe it's important to keep in
mind these relationships shown in this slide and the previous two speakers have
also alluded to. I'll be talking about
each one separately.
So when we are looking at the
relationship between the dose of folic acid and red blood cell or serum folate
levels, we have this nice study done by Wald and colleagues that actually
provided individuals with varying levels of folic acid for three months and
then measured serum folate levels.
As you can see from this slide, there
is actually a very nice incremental increase in median serum folate levels with
increasing dose of folic acid. And as
has previously been shown, with 500 micrograms of folic acid given imperfectly
every other day -- I think Dr. Oakley just presented the results given on a
daily basis -- but even having people who are not very compliant taken every
other day, you still see after four weeks of treatment a doubling in the serum
folate levels. And after discontinuation
for eight weeks, the levels are still elevated almost double above what the
baseline levels were.
Now focusing on the relationship
between folic acid intake and NTDs directly without having to go through
increases in red blood cell or serum folate.
There was a nice study done by Moore and colleagues that was just
published in the epidemiology journal that actually showed the relationship
between total folate, folate intake from both diet and supplements and actually
adjusted for bioavailability and the risk of NTDs. As you can see in this slide, it actually depicts
a very nice decreased relationship with increasing dietary folate intake.
In fact, for those women who took
greater than 1,200 dietary folate equivalents compared to the women in the
lowest group, this was associated with a 77 percent reduction in the risk of
NTDs.
I know you guys have seen this slide
but you are going to see it a couple more times during my talk. I just think it's phenomenal that we can
actually show this very nice relationship between red cell folate and the
prevalence of NTDs. It has been pointed
out several times that we really don't know how much further this decreased
risk can go if we move red blood cell folate out further.
Well, how do we know where we are as
far as in the United States? In order to
monitor both dietary intakes and folate status in the United States, we need to
accomplish that with data from nationally represented surveys. We are lucky enough to actually have two such
data sets, the NHANES data set and the continuing survey food intake for
individuals.
The NHANES is very strong in the fact
that it collects not only dietary intake information, but also upon medical
examination they collect blood so that we can actually look at both red blood
cell and serum folate levels. The
continuing survey of food intake for individuals which was last done prior to
fortification in '94 and '96 collected very good dietary data and social
demographic information.
I bring this up because these data
sets have actually been used to model the effect of what fortification would
have done to dietary intakes among women of reproductive age.
This was a nice study done by
Christine Lewis published in the American Journal of Clinical Nutrition
that actually used data from prior to fortification, the NHANES 1988 to '94
data sets, and the CSFI '94 to '96. They
used the food consumption patterns in those two surveys and then took the food
composition tables that were associated with those surveys and estimated the
amount of folic acid that would have been contributed to the diet due to
fortification. They didn't reanalyze
foods. They just estimated the effect.
Then they looked at based on those
food consumption patterns what would the percentage of individuals who actually
would meet the public health service recommendation just based on dietary
intakes alone. What you can see is that
for 11 to 19-year-olds only 13 to 21 percent of women would be meeting the
public health service recommendation through fortified foods. In fact, 27 to 32 percent of 20 to
49-year-old women would actually be meeting the recommendation.
This correctly led the authors to
conclude, as you heard before by Dr. Friedman, that post-fortification 68 to 87
percent of reproductive age women would not be consuming the public health
service recommendation of 400 micrograms per day.
Therefore, they concluded that we
needed to explore other ways to provide folate intake to a targeted subgroup of
women such that it would also not affect younger individuals and older
individuals. This kind of a conclusion
is really the impetus for this kind of product that is being proposed today.
Well, where are we in terms -- I think
you saw this slide. Dr. Yetley actually
provided the results and then either Dr. Mills or Mulinare, I can't remember
right now, actually had the graph. This
actually shows it a little bit more in depth.
Where we have the levels of red blood cell folate, because that's really
what we're interested in, prior to fortification in green and then orange after
fortification.
Here is the mean. You can actually see that, in fact, we have
increased it substantially. At the 10th
percentile, the 50th percentile, and the 90th percentile you can see, in fact,
that the whole distribution has shifted to the right so we have increased blood
levels.
But the other thing I want to point
out is that the median 50 percent of women are at 264. The 10th percentile is at 166. I want you to keep that in mind as I show you
this next slide with I know you are nauseated over, but I think it's important
to realize that the median where 50 percent of women are at, it's still
associated with the risk of about 25 NTDs per 10,000 line births. Then, in fact, if you go to where the 10th
percentile is, that's going to be associated with about 40 NTDs per 10,000 live
births.
If you remember, the 90th percentile
was at 423. It has been alluded that if
you are at that level of about 400 nanograms per milliliter, we don't want to
call it the optimal range, but it is a good range because, in fact, at that
range NTDs are only at about .8 per 10,000 live births. In fact, our goal is actually to move women
down this line to actually prevent more NTDs.
So how can we actually identify low
consumers? Well, based on previous
research there have been several methodologies that have been used to identify
who are low consumers. These have been
questions related to supplement use and they can be questions related to
supplement use and they can be questions related to use in the last two days,
the last week, or the last 30 days. It
has been used by both CDC and NHANES. Or
even consumption of cereal in the past 24 hours, that has been used by NHANES
and CSFI.
Whether you ask these questions in any
one of these formats, you can actually identify women with lower levels of
serum and red blood cell folate if, in fact, they are a nonconsumer, a
nonconsumer supplement, or a nonconsumer cereal. Let me show you some of that data.
This is a very nice study done, the
Georgia Family Planning Study that was funded by CDC at Emory. In fact, in a group of women attending these
family planning clinics, they actually looked at those women who took
supplements right here versus those women who did not take supplements and
measured their serum. And you can see
the fact that there is a statistically significant difference. There is a four nanogram milliliter
difference between the two and this was regardless of cereal intake.
We can actually duplicate this study
using the NHANES data which is what I've done here. In fact, using the NHANES question of,
"Did you take a supplement in the last 30 days," we can distinguish
women so that, in fact, women who actually reported taking a supplement in the
last 30 days had a red blood cell folate of 325 versus those who didn't at 251. You can even see the difference in the
median.
Now, this 75 nanograms per milliliter
difference if you go back to the wall of data is actually you can estimate that
there would be a 27 percent reduction in the risk of NTDs if you could get the
women who were unsupplemented to the supplemented level.
So I think it's interesting to note
that based on the scientific evidence to date that despite numerous educational
efforts in this country both by physicians and the March of Dimes, there is
still only 30 percent of women who are taking a supplement or who are reporting
taking a supplement on a regular basis because, in fact, we know that is
probably even less so if we really measured compliance.
Even after fortification and the
studies that have come out estimating the number of women who would meet
recommendations, just this past year the ACOG, the American College of
Obstetrics and Gynecology, has actually concluded that folic acid intake from
dietary sources alone are insufficient to meet the recommendation.
And I think it's interesting to note
that in that Georgia Family Planning study that I just reported to you that
there were 17 percent of women who reported using the supplement. There were 42 percent of women who were using
oral contraceptives so, in fact, if you could supplement or fortify oral
contraceptives with folic acid, you actually would be moving this 17 percent to
42 percent of the population who would be meeting the public health service
recommendation.
So, in summary, I think we can say
that not all women of reproductive age have benefitted equally from
fortification because their maternal red blood cell folate values aren't all up
to where we want them to be.
With the simple question about the use
of multivitamins with folic acid, subpopulations with lower folate values can
be identified and an oral conceptive folic acid product would actually help
many reproductive age women to meet the public health service
recommendation.
I think it's important to understand
that this is a very targeted product.
This product is being targeted to sexually active women so, therefore,
we can make a difference.
Now I would like to actually introduce
to you our next speaker, Dr. Andrew Kaunitz, who will be talking about oral
contraceptive use and pregnancy intendedness and folic acid intake.
DR. KAUNITZ: Thanks for giving me the opportunity to speak
this morning. My name is Andrew
Kaunitz. After completing an OB/GYN
residency in Chicago years back, I spent two years in Atlanta as an EIS officer
in the Division of Reproductive Health at CDC.
Since then I've been with the University of Florida where my
responsibilities include patient care, teaching, and research. This morning I'll be discussing oral
contraceptive use, pregnancy intendedness, and folic acid intake.
I would like to start with an overview
of my brief presentation. I'll be
pointing out that oral contraceptives represent the most common choice of
reversible birth control used by U.S. women.
Because oral contraceptives are rapidly reversible, many women conceive
soon after stopping oral contraceptives.
We recognize that in consistent highly
motivated users the pill, oral contraceptives, represent a very effective form
of birth control. In typical use,
however, the overall annual failure rate appears to be in the ballpark of eight
per 100 OC users annually. We also
recognize that some groups of oral contraceptive users experience substantially
higher failure rates.
I'll present data from Oregon that
indicate that pregnancy intendedness strongly predicts folic acid intake at the
time of conception and I'll go on to conclude that an oral contraceptive
combined with folic acid would represent a sensible approach to reducing the
risk of neural tube defects in offspring of some of our reproductive age
patients.
Looking at national survey data which
examines contraceptive use by U.S. women, we recognize that overall somewhat
over 16 million women are currently using oral contraceptives in this country
making the pill far and away the most prevalent reversible method of birth
control used by U.S. women. We are
talking about large numbers here.
We also recognize that ovulation
returns rapidly after women stop the pill.
The survey data tells us that about 11 percent of OC users will discontinue
the pill in any given year which would represent about 1.8 million women
stopping the pill annually.
About a third of these, or about
600,000, stop birth control pills specifically to conceive and because, again,
fertility does return rapidly after women stop the pill, we can anticipate that
the conception rate within three months of stopping the pill would approximate
50 percent.
The majority of women who stopped the
pill or, for that matter, stopped any method of birth control for the purpose of
conceiving, failed to notify their clinicians promptly. What that represents is a lost opportunity in
terms of preconception counseling.
We recognize that when used
consistently in highly motivated consistent daily tablet takers, oral
contraceptives represent a very effective method of birth control indeed. Package labeling currently for oral contraceptives
suggest a 0.1 percent annual failure rate.
This means that among 100 women taking
the pill for a year, we can anticipate fewer than one pregnancy or
contraceptive failures in that group of 100 women taking OCs for a year. The high efficacy, however, of birth control
pills is limited to those patients who are consistent daily pill takers day in
and day out.
In contrast, we see a very different
picture with typical use of the pill. In
a perfect world all oral contraceptive users would be perfect users of the pill
and would never miss a pill and would take every pill properly. However, oral contraceptive users, as with
all patients, are human and as with any chronic medication imperfect use is
common.
National Survey of Family Growth data,
which forms the basis for class labeling for oral contraceptives, suggest that
overall typical users experience about a five percent failure rate. More recent analysis of National Survey of
Family Growth Data, in fact, would suggest about an 8 percent overall failure
rate.
When subgroups of women are analyzed
in the National Survey of Family Growth, for instance, teenagers of low-income
background failure rates as high as 30 percent or more are observed.
We recognize, of course, that the
discrepancies between the very low failure rates with perfect use, on the one
hand, and much higher failure rates with typical use, on the other hand, relate
to consistent versus inconsistent or incorrect use of oral contraceptives. Such incorrect or inconsistent use of the
pill has been estimated to account for as many as one million pregnancies in
U.S. women annually.
I would like to now focus on the
concept of pregnancy intendedness.
Overall we recognize that about half of the pregnancies we take care of
in U.S. women represent unintended pregnancies, but for purposes of this
presentation, the concept of intendedness is important when we look at
pregnancies because of the strong association between pregnancy intendedness
and periconceptual intake of folic acid supplementation.
The study I've located in the
literature that has best identified this association comes to us from
Oregon. In the next three bar graphs I
will be presenting data from this Oregon data base.
Overall these investigators who
surveyed post-partum women, women who had recently delivered in the state of
Oregon noted that based on the reports of these recently delivered women, among
women with intended pregnancies about 50 percent -- almost 50 percent reported
taking folic acid supplements at the time of conception. In contrast, about 15 percent, far fewer
women who had unintended pregnancies, reported taking folic acid at the time of
conception. Looking at subgroup analysis, when the Oregon investigators
divided their analysis by age, notice that the same association held whether
older women or teenage women were analyzed.
But when the focus was on teenage women with unintended pregnancy, note
that only 6 percent -- that's correct, only 6 percent of teenage women in
Oregon with unintended pregnancies reported taking folic acid supplementation
at the time of conception, the time when it's needed.
We can do better. The other subgroup analysis I'll present
relates to income. Once again, this
predictive association between pregnancy intendedness and folic acid
supplementation at the time of conception held whether higher or lower income
women were examined. The Oregon
investigators noted that in low-income women with unintended pregnancies only
11 percent reported taking folic acid supplements at the time of
conception. Again, we can do better.
To summarize, a large number of U.S.
pregnancies, as well as deliveries, are associated with recent or current use
of the pill. Many reproductive age women
including those using oral contraceptives under consume folic acid
supplementation. Those least likely to
consume adequate folic acid at the time of conception include those not
intending pregnancy. This group
obviously includes, as I pointed out, a large number of oral contraceptive
users.
For these reasons, adding 400
micrograms of folic acid to an OC formulation would provide the recommended
amount of folic acid to at-risk, as Dr. Siega-Riz pointed out, sexually active
women, the group of women we want to target, for more folic acid intake at the
time of conception. This would reduce
neural tube defects in women currently or recently using oral contraceptives.
Thanks very much and at this time I
would like to ask Dr. Friedman back to the podium for summary and conclusion of
our presentation.
DR. FRIEDMAN: Thank you, Dr. Kaunitz.
In closing, I have two slides which
will summarize a lot of what you've heard today from our speakers and also
includes points made by previous speakers this morning.
You've heard from a number of speakers
this morning that neural tube defects are common, serious congenital anomalies
that are largely preventable with adequate folic acid intake. You've also heard especially from Dr.
Siega-Riz that a large number of reproductive age women do not consume the
amount of folic acid recommended by the U.S. Public Health Service.
You've heard from Dr. Oakley, Dr.
Shane, and others that folic acid is highly safe. It has a wide therapeutic index. Dr. Siega-Riz has underscored that although
grain fortification has resulted in higher median folate intake, higher blood
levels, and a reduction in neural tube defects, that many women, especially
those at the lower end of the folic acid consumption curve, still do not
consume the recommended amount of folic acid daily.
Dr. Kaunitz has discussed oral
contraceptives, that they are the most commonly used form of reversible
contraception and are a highly effective form of contraception. They are rapidly reversible. So using oral contraceptives as a potential
vehicle to deliver more folic acid to more reproductive age women would
potentially reach a large number of these women.
Oral contraceptives has a good safety
profile. However, many women will
conceive while taking OCs largely due to incorrect and inconsistent use, and
many will conceive shortly after discontinuing oral contraceptives as fecundity
is normal at that time.
Women who do not intend to conceive
are less likely to use folic acid supplements and Dr. Kaunitz has discussed
this in the Oregon PRAMS study. This
makes unintenders and, as we said before, all women taking oral contraceptives
do not intend to conceive so these women are particularly vulnerable to not
having adequate intake of folic acid on a daily basis. The proposed population for such a product
can be easily identified. It is those
women who do not take supplements or multivitamins.
To summarize, combining oral
contraceptives with folic acid would provide the U.S. Public Health Service
recommended amount of folic acid to many reproductive age women would reduce
the number of neural tube defects in this country with negligible, if any,
incremental safety concerns.
On behalf of the sponsor and our
consultants, I would like to thank you for your attention and I would turn this
over to the Chair, Dr. Guidice.
DR. GUIDICE: Thank you, Dr. Friedman. I would now like to open this next session to
questions from the committee starting with Dr. Darney and then Dr. Rosenberg.
DR. DARNEY: Thank you.
Phillip Darney, University of California, San Francisco. Any member of the -- any of the presenters
could answer this question. It seems to
me that what we need is a calculated risk benefit ratio and we're not quite
clear about the risk but we are clear about the benefits.
We could begin that with an estimate
of a number of women needed to treat to prevent a case of NTD. I wonder if that's been done. I think it is possible to estimate that number
needed to treat. If there are 16 million
users of birth control pills in the United States, how many do you estimate
would use this particular pill? Do I
understand correctly that there would be just one kind of pill that contained
folic acid? If the number needed to
treat is very large, then having only -- you might not reach very many people.
DR. FRIEDMAN: We've presented in a briefing packet a model
that shows assumptions based on the raw data and some of the serum data from
the Georgia Family Planning Clinic study to give some broad sense of
potentially how many people this could reach.
The FDA, in fact, did a calculation when they were considering grain
fortification and estimated that they may protect against 116 neural -- prevent
116 neural tube defects on an annual basis and its assumptions can be
challenged, but the point being that a large number of women use oral
contraceptives. It's impossible to predict the penetration of such a product
in the marketplace, but we do know that there are a large number of women who
do not consume the U.S. Public Health Service recommendation. Although no specific number can be predicted
with absolute certainty that such a product would have an impact in reducing
some neural tube defects with negligible incremental risk.
Dr. Cafferson, would you like to
respond as well?
DR. CAFFERSON: Phil, if I understand part of your question
related to the notion that the options would be so narrowed by this proposal
that the numbers of women who could advantage themselves from this would be
severely limited.
I think it's safe to say -- well, No.
1, the purpose of our getting together today is to consider the concept alone
but I think it is entirely safe to say that if the concept seemed to be a
reasonable and acceptable one, we would want to make this as widely available
as possible.
Our products, for example, cover about
between our estrogens, progestins, the dosages would cover about 80 percent
thereabouts -- I would have to get you the exact numbers -- of the type oral
contraceptives used in the U.S. right now.
The intent would not be to funnel into one particular option but, again,
this portion of the discussion is premature.
However, I'm optimistic
so we'll see. Did that get at your
questions? By the way, on the numbers
needed to treat we have not done those calculations because we have been basing
this on the general concept of OC users.
DR. DARNEY: My point -- question was directed at the fact
that you could do such a calculation but there are so many birth control pills
available, 20 or 25, that this particular group of pills might not reach many
of the 16 million pill users. It might
not reach enough of them to make much impact on the condition.
DR. FRIEDMAN: I mean, there's no way one can predict with
certainty. Historically the products
from our company has had a fairly broad penetration. A lot of people would have the potential
option of using this product. It could
prevent some neural tube defects. That,
I think, is unquestionable. How many is
open to debate but wouldn't just preventing some be enough with no incremental
risk without having a precise number?
DR. DARNEY: Are you asking me the question. Yes, it would be but I am saying you could
prevent more if it were more universally available.
DR. FRIEDMAN: We would hope that would be the case.
DR. GUIDICE: I think the goal of our committee is the
concept and I'm not aware that this would necessarily preclude or be limited
only to this particular birth control pill.
Perhaps other companies that serve the 16 million users may also then
opt to add this unless there is something in the whole process that I'm not
understanding through the FDA. Would
this not be an option for other companies as well?
DR. GRIEBEL: We've been sidebarring on that and we're not
sure of the implications of the patent that was mentioned earlier we have on
this so, from a regulatory standpoint, we don't know the answer to that.
DR. GUIDICE: Thank you.
Dr. Rosenberg and then Dr. Stanford.
DR. ROSENBERG: In exploring with you the concept, I would
appreciate some clarification on the issue of whether the concept here is that
the target group for this proposed prescribed drug that has a combination of oral
contraceptives and folate would be those people that were identified as having
low -- likely to have low folate intakes, or is the concept that all people
that would be getting oral contraceptives would be prescribed the combination? That's one question.
And the other question is, and perhaps
Dr. Kaunitz or somebody can help me with this.
The concept of putting together folic acid with oral contraceptive would
also imply that combination would be sensible at a metabolic level. I've heard very little here about a lot of
the older work that indicated that there was an interaction between estrogens
and folic acid metabolism.
I know that there's been much less of
that since the dose of oral contraceptives have decreased over the past few
decades but what is the current understanding of the nature of the interaction
between estrogen and folic acid with respect to the metabolism of one or the
bioavailable of one in relation to the other?
DR. FRIEDMAN: Okay.
I'd like to answer those questions.
In answer to the first question, the proposed population would be those
women who elect to use oral contraceptive as their method of contraception and
who do not take vitamins or supplements containing 400 micrograms of folic
acid. It would be up to the individual
prescriber to decide if additional women could benefit and those decisions
would be made on a case-by-case basis.
In response to your second question, I
would like to give a brief response and then ask Dr. Lynn Bailey from the
University of Florida to add any comments that she may have. Early studies looking at the potential interaction
of oral contraceptives and folate suggested that oral contraceptives, and these
were the old formulations as you mentioned with extremely high doses, may lead
to lower serum folate levels. I can
think of two papers by Shojania in 1969 and 1972 that made this
suggestion.
However, more recent case controlled
studies containing 70 women and 48 adolescents that were published in the last
three to four years suggest no such interaction with current low-dose
formulations. I would like Dr. Lynn
Bailey to add any other comments she may have.
DR. BAILEY: I think the best data to address is Dr.
Rosenberg's data from the HANES survey in which the folate status of oral
contraceptive users versus nonusers was compared and there was no
difference. This was in women in terms
of their calorically adjusted intakes.
There was no difference in folate status and oral contraceptive users
and nonusers.
DR. GUIDICE: Are there any other comments on the
metabolism or excretion or the interactions?
Dr. Crockett has a comment
specifically to that.
DR. CROCKETT: I guess in follow-up to your question, I
would like to know specifically about if you have tested the
pharmacoavailability of combining the oral contraceptive with the folate in a
combined pill taken at the same time?
The secondary question to that, why
are you considering putting them in a single pill instead of putting it in the
placebo pills like we do with the iron?
Would that maybe be a different concept to explore where you would
higher doses in for just that week and not have to worry about bioavailability
problems?
DR. FRIEDMAN: The question about doing pharmacokenetic or
pharmacobioavailability studies was raised.
The point really of today's meeting was to discuss the concept, not the
clinical development plan but clearly such a bioavailability study would be a
very reasonable thing to consider.
Following today's meeting and pending the outcome of today's meeting we
would meet with the FDA at a later date to discuss the appropriate clinical
plan.
Your question about whether it would
make sense to consider putting folic acid in the last seven days of a 28-day
pill pack, the so-called inactive pills or non-steroid containing pills was
also raised. We feel it would be more
advantageous to women to have 28 out of 28 days of folic acid exposure to
maximize their benefit and to make sure that they receive 400 micrograms of
folic acid on a daily basis.
DR. GUIDICE: Dr. Stanford and then Dr. Tobert and then Dr.
Emerson.
DR. STANFORD: I'd just like to point out a couple of
implications from the FDA's model on page 39, the briefing book, as I
understood it at least. They did a model
base assuming that the 400 micrograms of folate would be added to the oral
contraceptives of all 16 million users in the United States. They are modeling about 107 NTDs to prevent
it of which 24 would be prevented among women who were also taking a
multivitamin.
That seems to me just to be a little
bit -- I want to be clear about that. We
are talking about is it being targeted at those who are already taking a
multivitamin or not and this model includes apparently 24 being prevented among
those already taking a multivitamin.
The other implication of the model of
the 107 prevented, you can just do a quick back-of-the-envelope
calculation. If there are 16 million --
a little over 16 million users, that's about 160,000 number needed to treat per
case prevented.
But that would be presumably identical
for women taking folic acid supplements, or at least additional folic acid
supplements in the case of the 24 prevented that were already taking
supplements. In other words, the number
needed to treat would presumably be the same for just taking in additional
folic acid or combining it into the pill.
DR. GUIDICE: Thank you.
That's actually in the sponsor's book on page 39.
Dr. Tobert.
DR. TOBERT: Yes.
This question is for Dr. Friedman or Dr. Oakley. It concerns the choice of the dose of 400
micrograms a day. My question is really
is that enough to optimize the reduction in NTDs? In the first place, if a woman gets pregnant
while she's taking the oral contraceptive, then she was missing a good number
of tablets usually so she wouldn't be getting 400 micrograms a day.
In the second place, I understand that
body pools of folate are large but not every woman is going to conceive within
three months after stopping the oral contraceptive.
If she conceives six months later,
would there be any advantage to a higher dose of folic acid? In other words, I think this is an
imaginative idea, creative idea but I'm wondering if it's optimized and perhaps
the dose of folic acid should be higher.
DR. FRIEDMAN: I'm going to ask Dr. Oakley to respond to that
question.
DR. OAKLEY: As Dr. Yetley said in her slide, there is
always uncertainties in making policy decisions and so here is another place
where there clearly is some uncertainty.
Most of the data that is available is at least 400 micrograms of folic
acid and that was what the public health service did in '92. Of course, the Institute of Medicine Group in
'98 reaffirmed that number. The China
study shows us it makes a lot of difference in NTD rates.
I have a bias, maybe like yours, that
maybe even more than that might be good but I think we don't have the evidence
for that other than the fact that we don't know where that curve from Dublin
actually plateaued because there are no data to tell us where it plateaus. One day hopefully we'll know that but we
don't know that yet.
I do think that you raise another
issue, and we didn't show slides on this, but if you look at people who take
400 micrograms, 600 micrograms, 800 micrograms, or a milligram for three months
and then stop, at three months after being off the residual level is higher for
those -- these were men mostly who were post-heart attacked. Theirs were high if they took a milligram so
you certainly raise an important issue.
Oh, there it is. This is just the slide. Fantastic.
So you can see what I just said is true.
It's on this slide. Basically if
you have a higher dose your residual levels are going to be higher. Thank you very much.
I read another paper that I think is
very interesting of someone trying to guess what is the optimal dose for
homocysteine. I think a group of people
from Holland. Or, at least, I just
read. I think it's just been published. I think there was some discussion on that end
point as to whether it should be 400 or 800 and it's some place still in that
range.
I think they suggested that maybe 400
might be enough on the homocysteine side.
But, of course, the fetus which has much more rapidly dividing cells
than an adult does is likely to need even more folic acid than an adult.
DR. TOBERT: Actually, to that last point, if I may, I
mentioned the SEARCH trial earlier. The
investigator of that trial decided they require 2 milligrams of folic acid as
well as 1 milligram of B-12 which also reduces homocysteine a bit to get the
maximum effect on homocysteine.
DR. OAKLEY Just a comment on that. I think that people doing studies want to
make certain that if it's a negative study it isn't negative because the dose
wasn't big enough. I don't think that
I've ever heard that out of Nick Wald's mouth but, in fact, you've heard it out
of Nick Wald's mouth that there was a very small study from Wales that used
4,000 micrograms which was before Nick designed the study. When Nick knew that and then just wanted to make
sure that was enough.
Clearly 4,000 is probably enough and I
would agree with you that some place in the 400 to 800 range. Jim probably thinks it's a bit less and the
bottom line is if we had all the data we needed, we could make the decision and
know exactly what we don't know and we may never know.
DR. GUIDICE: Thank you.
Dr. Emerson.
DR. EMERSON: I just wanted to clarify on your slide 14 you
showed a diagram of the causal pathways that seem to imply that you thought
there was maybe a pathway that led from intake to decreased NTDs that wasn't
reflected in the serum levels. Is that
right?
DR. FRIEDMAN: If we could have slide 14 up. You might consider this a design flaw. We debated this extensively and you happened
to pick it up. Basically, no, we are not
suggesting an alternate pathway. Rather,
what this was meant to show is that there are data to suggest that this
relationship holds.
And there are data that basically
bypass measuring biomarkers for folate and show that increased intake leads to
decreased NTDs. It is not suggesting an
alternative mechanism. Rather, the path
of the data. Thank you for bringing that
up.
DR. GUIDICE: Dr. Montgomery Rice and then Dr. Green.
DR. RICE: This is to Dr. Kaunitz. In the Rosenberg study what percentage of
those patients were taking OCPs as a method of their contraception within three
months of conceiving? Or contraceptive
pills within three months.
DR. KAUNITZ: The question for Dr. Rice is in the Oregon
data of the recent moms surveyed what was their contraceptive use pattern at
the time they conceived. To my
knowledge, Dr. Rice, the investigators did not report that in their article.
DR. RICE: So they reported unintended pregnancy but
didn't ask the people if they were using anything?
DR. KAUNITZ: It was in a pediatrics journal.
DR. RICE: So they assumed that they weren't?
DR. KAUNITZ: They may have the data but to my recollection
-- we can look here. We have the article
here and I'll take a look and make sure I'm not wrong because I may be. In reading the article I don't recall any
presentation about contractive use at the time of conception. I'll look right now.
DR. RICE: So all of them were unintended then probably
if they weren't using anything.
DR. KAUNITZ: What they did focus on was intendedness of
the pregnancy at the time of conception.
DR. RICE: Okay.
DR. OAKLEY: So then they asked questions about the
intendedness rather than asking about methods of contraception?
DR. KAUNITZ: I don't believe they reported contraceptive
use by this cohort of women but I need to look again to make sure I'm not
missing that.
DR. GUIDICE: Thank you.
We have time for two quick questions before we break for lunch. Dr. Green and Dr. Stanford.
DR. STANFORD: My comment is just to her question. There are different ways of measuring
intendedness. The PRAMS way of measuring
intendedness is to say, "Did you have your pregnancy sooner than you
wanted, about the right time, or later?"
It doesn't say anything about, "Were you using birth
control?" It just asks about timing
and that's how they measure intendedness in PRAMS and that's what those data
are based on is PRAMS.
DR. RICE: What is PRAMS?
DR. STANFORD: Pregnancy Risk Assessment and Monitoring
System. It's a CDC based system for
monitoring pregnancies in a number of states.
DR. GUIDICE: Thank you.
Dr. Green.
DR. GREEN: Dr. Guidice, thank you. This may not be short, I have to say, but
I'll try to be as brief as I can. It
does somewhat address an issue that we haven't yet addressed. It returns to the question of safety.
First, let me reiterate, I think, what
Dr. Mills said which I think summarizes very nicely the reason why I raise this
point, I believe, and to perhaps paraphrase him he said that lack of evidence
of toxicity does not equate with evidence of a lack of toxicity.
The reason for my comments
specifically are that much of what we have seen and, indeed, I do agree with
that, address the issue of toxicity with respect to large doses. That's very apparent from some of the data
that Dr. Oakley showed.
And also just for purposes of
clarification, and I think that Dr. Rosenberg will bear me out, in relation to
the Institute of Medicine's study in which the question of upper limits and
safety issues were addressed, the important consideration and the reason for
the caution that was expressed in that report stem not so much from the studies
that Dr. Oakley referred to in that high dose range of 5,000 micrograms and up,
and there were several of those, but rather -- and it was an argious search
through the literature -- rather single case reports that appeared in the
literature with respect to dosages of folate below 1,000 micrograms and, in
fact, in some cases even below. If my
memory serves me correctly, we were able to identify six such individuals.
Now, that in and of itself doesn't
really prove anything one way or another.
We've heard, I think, compelling evidence to say that in the target
group this imaginative approach, and I agree that it is as somebody said
previously, to increase folate intake in women of reproductive age represents a
relatively small risk in terms of the masking of the untoward effects with
respect to pernicious anemia.
But there is another issue that is
gaining a lot of attention and what I refer to here is the whole field of
epigenetics largely based on some animal work but also now being supplemented
from some human work.
There is evidence that comes forward,
and I'll address briefly the animal work, fully acknowledging that mice are not
humans but, nonetheless, the observations that have been carried out on a
particular strain of mouse, the agouti mouse, which has transposable elements
in the upstream region of this particular agouti gene very nicely and
excitingly show the effect of epigenetics specifically from the point of view
that supplementation with methyl groups, and it's known that methyl groups play
a key role in the control of certain genes in the upstream promoter
region.
There are islands that are rich in
what are called CpG islands, lots of cytosines that control the regulation of
those genes. The administration of large
doses of a combination of folic acid as well as, I believe, choline and
methionine, altered not in the maternal dams themselves but in their offspring
the expression of this gene to the extent that there were changes which some, I
think, might conclude were beneficial.
Specifically, that those offspring instead of being light colored yellow
mice were dark colored mice.
Also, that the obesity that occurs in
the light colored variety was counteracted so that the offspring were less
obese so there would apparently be if you take that into the human context a
beneficial effect. Indeed, some of the
effects have increased. Methyl groups
might be beneficial but equally so there may be some that we don't know about
at this stage that could be deleterious.
This has been raised and largely is a theoretical question in the
literature.
I'll read just one line, if I may,
from the conclusion or summary of a paper that appeared in Molecular and
Cell Biology by an author by the name of Waterland who says, and based on
the experiments that I described, and that supplement I see that was given to
the agouti animals was folic acid B-12, choline, and betaine.
The conclusion is these findings
suggest that dietary supplementation long presumed to be purely beneficial may
have unintended deleterious influences on the establishment of epigenetic gene
regulation in humans. This is purely
theoretical and purely speculative.
I raise it only because I think that
in essence there are a lot of unknowns in this field and there is no literature
to cite other than the literature that I have mentioned that comes from
animals. There are suggestions that
there may be epigenetic factors at work in other diseases.
I'm not talking here about folates and
methylation but epigenetics in general.
The best example would be disorders where there are differences in
parental imprinting in, for example, the Prader-Willi Syndrome and related
disorders. I'm sure many of the group
here are aware of those.
With those remarks not in any way
wishing to suggest that we have concrete evidence, it is merely to emphasize
that the evidence that we have is based on large doses and toxicity questions. We do not have any evidence at this stage in
terms of long-term for the obvious reason that changes -- global changes in
folate nutrition in this country have been of relatively recent duration. Thank you.
DR. GUIDICE: Thank you.
DR. FRIEDMAN: If I may, I would like to ask Dr. Steven
Zeisel, Professor and Chair of the Department of Nutrition at the University of
North Carolina, to just respond to some of the comments made.
DR. ZEISEL: Dr. Green's point is that there may be
unanticipated effects of folic acid administration. It is true that methylation of promoter sites
in genes can regulate that gene expression.
It's a very important part of developmental biology.
The agouti study is in an animal
model, mice. I look at another methyl
donor, choline, and it's very clear that pregnant mice if given a choice choose
a higher methyl diet than they are offered by normal animal lab chow and so it
may very well be that the agouti study is describing the effects of restricting
mice artificially to a diet that they wouldn't have selected as a pregnant
animal that is low in methyl groups and that optimal may be the higher amount.
I think, though, to put everything in
perspective, you have to think about that we are asking the woman to take 400
micrograms of folic acid as a public health recommendation. Whether she takes the folic acid from a
vitamin pill or from cereal or from a birth control pill that contains it
doesn't change her relative risk. By
making this option available to women, we are only trying to help a public
health recommendation be met and not introducing a really new risk to the
woman.
DR. GUIDICE: Thank you.
I have a question along those lines.
Is there any evidence of any increased imprinting disorders over the
period of time in which folic acid has been supplemented such as -- I mean,
Prader-Willi is very rare.
Bechwith-Wiedermann is extremely rare.
I'm wondering if there are any data on that.
DR. GREEN: To the best of my knowledge there are no data
that are available. I raise this, as I
say, only as a theoretical consideration and that increased levels of folate
as, I think, Professor Zeisel has indicated, could have beneficial as well as
potentially deleterious effects. I
certainly agree with his statement that doesn't know more than to recommend or
to create an option whereby the recommended level would be attained by a
fraction of the population.
DR. GUIDICE:Dr. Mills and then Dr.
Wenstrom.
DR. MILLS: There is a potential confounding issue here
and that is that there is a distinct possibility that some assisted
reproductive technologies are increasing the rates of bechwith-Wiedermann and
Prader-Willi and Angelman Syndrome.
I mention that in part to underscore
the problem that we have that if there is any complication of a high exposure
to folic acid, it's unlikely we are going to be able to detect it because
everybody is exposed. It's difficult to
do the usual strategy of investigation which is to compare and expose to an
unexposed group.
DR. GUIDICE: Thank you.
Dr. Wenstrom for the final comment.
DR. WENSTROM: I was just going to mention that there is a
group in Baltimore that has been keeping track of the number of
Bechwith-Wiedermann Syndrome children born as a result of assisted reproductive
technologies and in that small series -- well, I mean, it's a large series when
you consider how rare that is -- they found no difference in reported folic
acid use between mothers who did or did not give birth to the baby with
Bechwith-Wiedermann which suggest that something relative to ART itself and not
necessarily diet.
DR. GUIDICE: Yes, and also the procedure that's been
implicated as more ICSI as opposed to just general in vitro fertilization. Almost across the board all women who go to
ART programs get folic acid supplementation as part of their regimen.
Thank you. So we will now reconvene at 1:15 for the open
public hearing. The committee has a
reserved section of the restaurant here in the hotel called the Tarragon Room
for lunch. Thank you.
(Whereupon, at 12:31 p.m. off the
record for lunch to reconvene at 1:15 p.m.)
A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
1:21
p.m.
DR. GUIDICE: Please take your seats, everyone. Before we begin the afternoon session, I am
told I need to read a particular statement for general meeting matter, and that
is that both the FDA and the public believe in a transparent process for
information gathering and decision making.
To ensure such transparency at the open public hearing session of the
advisory committee meeting, FDA believes that it is important to understand the
context of an individual's presentation.
For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement to advise the committee of any
financial relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting.
For example, the financial information
may include a company's or a group's payment of your travel, lodging, or other
expenses in connection with your attention at this meeting. Likewise, FDA encourages you at the beginning
of your statement to advise the committee if you do not have any such financial
relationships. If you choose not to
address this issue of financial relationships at the beginning of your
statement, however, it will not preclude you from speaking.
I would like to call the first
speaker, Eileen Carlson and then followed by Douglas Sorocco from the Spina
Bifida Association of America, Spina Bifida Foundation.
MS. CARLSON: Good afternoon, everyone. My name is Eileen Carlson. I'm from Washington, D.C. and my brother and
my son both have spina bifida, the nation's most common permanently disabling
birth defect which affects approximately 70,000 Americans.
As you all know, recent studies have
shown that if all women of childbearing age were to consume 400 micrograms of
folic acid daily prior to becoming pregnant and throughout the first trimester
of pregnancy, the incidence of spina bifida could be reduced by up to 75
percent.
Former CDC and Prevention Director
Jeff Koplan has stated that the agency's folic acid prevention campaign has
reduced neural tube defect births by 20 percent. While progress has been made in convincing
women of the importance of consuming folic acid supplements and maintaining
diets rich in folic acid, each year approximately 4,000 pregnancies still are
affected by spina bifida.
Clearly gains must be made in
educating health professionals and women of childbearing age of the importance
of consuming folic acid prior to becoming pregnant. Our nation must consider and implement new
and creative ways to facilitate women's consumption of adequate amounts of
folic acid to reduce the risk for spina bifida pregnancies.
So as you consider the public health
benefits of allowing oral contraceptives with folic acid augmentation to be
sold, I would like you to consider the challenges of life for individuals and
families affected by spina bifida. This
is my story.
In 1967, my brother Danny was born
with spina bifida, myelomeningocele, and hydrocephalus. Although Houston, Texas had major medical
facilities, our obstetrician had my father transport his newborn son to the
children's hospital in our family station wagon. But we were lucky; if Danny had been born a
hundred miles away, he probably would not have survived.
Today he lives by himself in an
apartment and is in reasonably good health.,
He has endured scores of surgeries throughout his life -- he claims the
number is 36 -- and has never been able to walk. Like many adults with a severe disability,
particularly those who must rely on a wheelchair, Danny has encountered many
serious obstacles -- sometimes insurmountable -- in his efforts in finding meaningful
employment, making friends, developing romantic relationships, and become an
active participant in his community.
When my husband and I began to think
about starting a family, I spoke with my OB/GYN who said that I was not at an
increased risk of having a child with spina bifida. He was wrong.
Just for your information, he is now a professor at a very prominent
medical school.
I, however, had read the recent
research showing that folic acid can prevent many occurrences of neural tube
defects. When I learned that I was
pregnant, I took prenatal vitamins which included folic acid. But three months into my pregnancy we learned
that our baby had spina bifida because during a high level sonogram his head
showed the typical "lemon sign" and a lesion was visible on his
spine.
Had I been taking birth control pills
with folic acid prior to my pregnancy, the level of folic acid in my system
could very well have made a difference in my son developing spina bifida. Naturally, when we learned about his spina
bifida we were devastated.
We made plans to deliver Sean by
C-section to avoid any further damage to his lesion at a medical center with a
NICU. I began eating like crazy to
fatten up our baby up in case he was premature.
When I began having premature contractions, I was put on bed rest. However, our son, Sean, was born full term at
37 weeks weighing 7 pounds, 9 1/2 ounces, and very healthy in spite of his
disabilities.
He spent ten days in the NICU and
special care nursery, and his healthy cries sparked the comment, "Who's
the kid with the lungs?" He had two
surgeries before he came home to close the lesion on his back and to place a
V-P shunt in his brain for hydrocephalus.
The hospital bill came to more than $100,000.
The first few years of Sean's life
were a constant parade of doctor visits, diagnostic exams, physical therapy,
and four more surgeries. These years
were naturally a real challenge to our emotions, our family stability, as well
as our finances. In spite of Sean's
physical problems, we made special efforts to expose him to the world around
him and provide opportunities for social interaction and play. We were aware of the risk of learning
disabilities in children with spina bifida, which my brother suffers from, and
some of which were recently shown to be due to a lack of experience and social
interaction in the early formative years.
We also decided not to try to have any more children on our own because
of the risk that they, too, might have spina bifida.
Today I'm happy to say that Sean is
doing very well. He's 6 1/2, has leg
braces and walks with a walker. He has
even walked a half a mile and up three flights of steps but he still needs a
wheelchair for long distances. He is
bright, happy, very social and at this point he's mainstream in a regular first
grade classroom in a D.C. public school.
So far he is on target academically.
He has many friends.
One of the biggest challenges in his
life is incontinence which most people with spina bifida must struggle with in
varying degrees all their lives. He
wears diapers and has to be changed a couple of times a day at school. Our public school does not have -- most D.C.
public schools do not have elevators so we are going to have to be looking for
a different school for him sometime soon.
We know that Sean is likely to need
more surgeries in the future to repair a clogged or broken shunt or tethered
spinal cord, straighten out twisted bones or a twisted spine, enlarge his
bladder, or relive pressure from abnormal fluid in his spinal cord also known as
cerentomyelele.
However, we consider ourselves truly
fortunate. We have good health insurance
that pays for most of our medical bills including a $5,000 wheelchair, $7,000
leg braces. We are blessed with very
abundant medical facilities in this area including three excellent spina bifida
clinics.
In the realm of experience with spina
bifida, Sean is truly one of the lucky ones.
I am actively involved with the local chapter of the Spina Bifida
Association and I've seen firsthand the challenges and burdens that many other
families must face.
Twelve-year-old Mark has never walked,
is developmentally delayed, gets his nourishment from a feeding tube, and has
been hospitalized repeatedly for life-threatening bowel obstructions.
Fifteen-year-old Holly, who walks with
only a small leg brace, was doing great but was recently hospitalized for
tethered cord surgery, faces bladder enlargement surgery as well, and possible
lyposuction for her lypomyelomeningocele.
Cameron was born doing great but
suffered from tethered cord and his physical abilities have been severely
impaired. He had to go through, I think,
four surgeries by the time he was six months old.
Some of our kids and adults must
breathe with a respirator and some suffer from severe scoliosis that twists
their bodies like pretzels. As one mom
has said, having a child with spina bifida or suffering from spina bifida is
like going through a minefield. You
never know when something is going to come up and, boom, there's another major
medical problem or another surgery.
These medical and physical challenges
can damage families, break up marriages, and cause serious financial
burdens. Some estimates suggest that the
lifetime cost of a person with spina bifida is $1 million.
I hope that my experience has given
you a snapshot of what it is like to face the challenges of spina bifida. We love our son just as he is and he is truly
perfect in our eyes. But at the same time,
we would do just about anything to take away his spina bifida.
One of our greatest frustrations is
the lack of public knowledge about spina bifida and about how to reduce the
risk of a spina bifida pregnancy, even among health care professionals which is
truly shocking, especially in this country.
But the greater tragedy is that some babies are being born with spina
bifida because their mothers were not aware that simply taking folic prior to
pregnancy could have prevented this birth defect.
I believe that including folic acid in
oral contraceptives is an important step both for preventing the occurrence of
spina bifida and for helping inform the public at large, OB/GYNs, women of
childbearing age, and others in the public health community. How many seriously crippling birth defects
are 75 percent preventable with the simple step of taking a vitamin?
I am very grateful for this
opportunity to testify for this effort and I wholeheartedly urge your support
and thank you for your consideration of my views.
DR. GUIDICE: Thank you.
Douglas Sorocco. Please limit your comments to no more than
five minutes. That's for all
speakers. Thank you.
MR. SOROCCO: Good afternoon and thank you for allowing me
to share my story with you today. My
name is Doug Sorocco and my wife Kristen and I live in Oklahoma City. I am also an individual living with spina
bifida. I'm a former board member of the
Spina Bifida Association of America and founder of the Youth & Adult
Alliance.
The Youth and Adult Alliance is the
subcommittee of the SBA Board that reaches out to young adults and adults with
spina bifida. I appreciate this
opportunity to speak with you today as you consider the public health benefits
of allowing oral contraceptives with folic acid augmentation to be sold. To that end, I would appreciate your
consideration of the challenges of life for individuals such as myself who live
with spina bifida.
From a very early age my parents
stressed upon me the fact that because of the spina bifida I would need to be
able to earn my living using my mind.
Professionally, I'm a partner in the intellectual property law firm of
Junlap, Codding & Rogers and I specialize in biotechnology and life
sciences. Notwithstanding this fact,
however, neither myself nor my firm have any financial impact by these
proceedings.
I was born in between two generations:
people born with spina bifida prior to the widespread use of shunts and those
born thereafter. Those of the prior
generation and I only survived because we did not need shunts. After the introduction of the shunt, however,
a huge "bubble" generation has come about. This bubble generation has survived even in
face of the fact that they are more medically involved than most of us who
didn't survive prior to this period.
This bubble generation is decreasing
in number, however, as the knowledge and importance of folic acid consumption
is having a significant impact on decreasing the number of pregnancies affected
by spina bifida.
My entrance into the world was also
very abrupt. I am my parents' first
child and they had no prior knowledge of my having spina bifida prior to being
born. The lesion into which my spinal
cord had grown wasn't even diagnosed or fixed until I was almost two years
old. Today this lesion would be repaired
within hours of birth.
As far as my parents were concerned,
however, I was fixed after my back surgery (a notion that was not dispelled by
my neural surgeon) and, therefore, did not have to be treated any different or
have any special accommodations made.
My parents had the same expectations
and hopes for me that they would have for any child. Unfortunately, the terribly complex medical
issues encountered by my so-called "bubble generation" required that
my parents' attitudes and the way that they treated me and their attitude or
philosophy must be changed or modified somewhat in application to this new
generation.
The success I achieved should not have
really happened. Although my parents'
ignorance or lack of knowledge was not significantly detrimental and may, in
fact, been helpful is not a model that should be advocated or adopted. Everything I have accomplished and will
accomplish is because of my parents and the way they raised me to be
self-sufficient, independent, and fearless, traits that most parents of
children with spina bifida try to instill in their children.
With respect to this more medically
involved generation, however, these traits must be supplemented with proper,
aggressive, and proactive medical intervention.
In this manner, both the independence and health of the individual can
be maintained. I must admit, however,
that the fearlessness or willfulness, as my mother would call it, is not a
trait she would necessarily call a success.
Although I'm not perfect and I have a
lot of things that I want and hope to accomplish in my life, all the success
that I have had, once again, is due to my parents and the unconditional support
and love of my wife.
There is a third factor that cannot be
dismissed -- I'm lucky. I'm extremely
lucky. I am lucky that my lesion was not
complete. Some nerves did remain intact
and I can walk. I am lucky that I did
not have hydrocephalus or require a shunt.
Finally, I'm lucky that the misleading and inaccurate medical advice my
parents received concerning my spina bifida was not fundamentally detrimental
to my health and development.
Unfortunately, in many areas of the
U.S. misleading, inaccurate, and inadequate advice that does negatively impact
individuals with spina bifida currently is being given. False or inaccurate information, as Eileen mentioned,
is leading to the decline in the health of individuals with spina bifida and in
many cases premature and certainly preventable death. Many women do not know of the fact that
consumption of a simple B vitamin is capable of decreasing the incidence of
spina bifida up to 75 percent.
Notwithstanding the "parade of
horribles" that I and Eileen and other individuals with spina bifida can
list, I am extremely fortunate in comparison to others with spina bifida. When I first became involved with the Spina
Bifida Association of America, I was overly eager and naive. I published my work phone number in the
national newsletter and invited individuals with spina bifida to contact me. The number of calls completely overwhelmed
by office staff. I received call after
call from adults who had nowhere to turn.
These adults could not obtain appropriate medical care. They could not participate or be involved in
social activities.
Finally, these individuals with spina
bifida were being foreclosed completely from being able to fully participate in
their communities. While each one of us
acknowledges that spina bifida has in many ways shaped our character and made
us stronger individuals, we would gladly forfeit these "benefits" in
lieu of a life without limitations.
Although I have, once again, been
extremely fortunate in my life, ignorance can no longer be the accepted
standard of care. While I certainly
believe that parents, family, loved ones, and medical providers are the primary
determinants in an individual with spina bifida's life and success, the
government does have a role to play.
The complexities of this birth defect
necessitate coordinated, robust, and fully integrated and funded programs to
promote the lives and health of all those affected with spina bifida and, most
importantly, the prevention measures such as ensuring that all women of
childbearing age know that they should consume adequate levels of folic acid
prior to becoming pregnant.
Spina bifida is a complex,
infuriating, and to our families and friends, an oftentimes frustrating
problem. Folic acid, while not a
cure-all, is the best hope for preventing the further occurrence of spina
bifida and decreasing the emotional, physical, and certainly the financial
impact that spina bifida has on our families and ourselves.
While the Centers for Disease Control
and Prevention has reported progress in convincing women of the importance of
consuming folic acid supplements and maintaining diets rich in folate, each
year approximately 4,000 pregnancies still are affected by spina bifida. Clearly our nation must do more to educate
health professionals and women of childbearing age of the importance of
consuming folic acid prior to becoming pregnant.
As part of such an effort, I believe
that we must now undertake new and creative initiatives to facilitate women's
consumption of adequate amounts of folic acid to reduce their risk for spina
bifida pregnancies. The fortification of
breads and grains is one step in the right direction and another would be
including folic acid in oral contraceptives.
I am very grateful for this
opportunity to testify on this behalf.
Thank you.
DR. GUIDICE: Thank you very much.
The next speaker comes from the
Reproductive Health Technologies Project (RHTP) and is Ms. Kirsten Moore.
MS. MOORE: Good afternoon. Thank you for this opportunity. I am the President of the Reproductive Health
Technologies Project, a nonprofit advocacy organization based here in
Washington, D.C. Our organization does
not receive any funding from any pharmaceutical company.
Our mission is to advance the ability
of every women to achieve full reproductive freedom with access to the safest,
most effective, appropriate, affordable, and accessible technologies for
ensuring her health and controlling her fertility.
For over a decade we have worked to
expand women's access to safe and effective contraceptive technologies and we
strongly support the development of this particular product, a combined oral
contraceptive/folic acid product.
In the interest of time, our statement
is available and will be included in the docket. I'll skip through the many reasons why. You've heard them from the presentations this
morning. I would just like to put before
you some of the specific considerations we would like to raise with this
committee.
Although the number of birth defects
prevented by a combined folic acid oral contraceptive product may be relatively
small, the public health benefits of this product outweigh the risks. Extensive clinical data supports the safety
and efficacy of both folic acid as a means to reduce neural tube defects among
newborns and oral contraceptives to prevent pregnancy. Therefore, any clinical research programs
should focus on questions relevant to a combination product.
A combined product provides an
important bridge between contraception and pregnancy, a transition that is
fluid for many women. For example, more
than 16 million women in the U.S. currently use some form of oral contraception. Of those, approximately 6 percent stop OC use
within 12 months to become pregnant.
Furthermore, although the majority of
women taking oral contraception do not currently intend to conceive, neither
human nature or technology is perfect and there are more than 1 million
unintended pregnancies each year among contraceptive users, more than half of
which are carried to term.
No. 4, a combined product has the
potential to increase adherence for oral contraceptives and intake rates for
folic acid. For example, the currently
"inactive" pills in the monthly oral contraceptive cycle will contain
folic acid in the new product, thereby giving women a reason to continue taking
oral contraceptive pills throughout their entire cycle. Similarly, because so many women use daily oral
contraceptive pills, their intake of folic acid will increase overall.
Fifth.
Finally, a combined oral contraceptive/folic acid product holds
significant potential for women in low resource settings where serum folate
levels are often low and resources and access is limited.
Although not a part of the FDA's
mandate, when we asked the company about the availability of this product for
such populations, they advised us of their intent to pursue such options and
have had preliminary discussions with U.S. Agency for International
Development. We certainly hope similar
efforts would be made here in the U.S.
Assuming that an oral
contraceptive/folic acid product continues to maintain the functions of each
original compound, we believe a combined product has the potential to improve
the overall health of women and their newborns and support its development. Thank
you for your consideration of these views.
DR. GUIDICE: Thank you.
The next speaker is Dr. John Grossman.
MR. GROSSMAN: Good afternoon. I want to thank the FDA, Dr. Guidice and her
panel for allowing me to participate in this important process that will serve
the interest of women and their families.
My name is John Grossman. I am Professor of Obstetrics and Gynecology,
Microbiology and Tropical Medicine, Prevention and Community Health, and Health
Services Management and Leadership at the George Washington University. I'm also Executive Vice President of the
Society Gynecologic Investigation.
For the record, my comments do not
reflect the positions of either of these organizations. I am here today to speak to the panel sharing
my own perspectives. These are based on
nearly three decades of clinical practice, most of which has been in the
service of women with significantly complicated pregnancies and my professional
service as an educator and policy maker in prevention of community health.
I'm addressing the panel today because
I believe that this proposal has great potential to benefit many women. I have no financial relationship with the
sponsor, nor with their competitors, and I have no financial interest in this
product whatsoever.
The association between folic acid
deficiency and neural tube defects is well-established. Policy statements and campaigns to increase
the percentage of women of childbearing age who consumed the recommended daily
allowance of folic acid by credible and prestigious entities such as the March
of Dimes, CDC, Institute of Medicine, NIH, American Academy of Pediatrics,
ACOG, as well as many other agencies speak to the importance of this public
health measure.
In 1992 the USPHS recommended
fortification of the U.S. food supply with folic acid. The FDA's subsequent action in 1996 to
initially permit and subsequently require addition of folic acid to specific
flour, breads, and other grains was an important first step in reducing the
incidence of neural tube defects in the United States. Several sources of epidemiologic evidence
suggest that this action has reduced the incidence by 20 to 30 percent.
Unfortunately, this approach falls
short of reducing the burden of disease by the additional 30 to 50 percent that
might be achieved through optimal folic acid supplementation overall. More importantly, the North Carolina Birth
Defects Monitoring Program and other agencies have clearly identified a
subpopulation of minority and undereducated women of childbearing age who are
at high risk for folic acid deficiency and subsequent pregnancies complicated
by neural tube defects.
For a variety of reasons, many of
these women are unlikely to benefit from any of our current approaches
including nutritional fortification, use of vitamin supplementation, or early
diagnosis of pregnancy and initiation of care.
Although no child should develop a
preventable malformation, this vulnerable population of women are economically
least well-prepared to deal with such misfortune. I believe that the sponsors have demonstrated
that folic acid supplementation of birth control pills is safe and effective
for its intended use and that it has potential to benefit not only this group
of women and their families but many others as well.
The families of the 2,500 babies born
in the United States each year with neural closure defects each incur
additional lifetime costs of at least $500,000.
Reducing the burden of disease by the full 50 percent estimated to be
achievable by folic acid supplementation would prevent more than $600 million
the additional new health costs per year, to say nothing of the pain and
suffering that could be avoided.
I urge the panel to recommend approval
of this concept because it would be an important next step in that
direction. Folic acid supplementation of
birth control pills represents a safe and effective approach to reducing the
prevalence of folic acid deficiency in women of childbearing age by utilizing
the established scientific advances of both medicine and public health for the
benefit of all women and their families.
Thank you for your attention.
DR. GUIDICE: Thank you.
The next is a representative from the
National Association of Nurse Practitioners in Women's Health. The speaker is Susan Wysocki.
MS. WYSOCKI: Hello and good afternoon. My name is Susan Wysocki and I'm the Women's
Health Nurse Practitioner as well as the President and CEO of the Nurse
Practitioners in Women's Health which is located in Washington, D.C. Neither myself nor my organization had any
financial incentive for speaking at this hearing.
What our incentive is is the fact that
NPWH founded in 1980 to assure the provision of quality health care to women of
all ages by nurse practitioners. As
nurse practitioners we place a very strong emphasis on health promotion and
disease prevention. This emphasis on
prevention includes preventing problems during pregnancy and problems to the
developing fetus.
You've already heard about neural tube
defects and the role of folic acid but I would like you to focus on one very
important aspect of this. That is that
folic acid and its ability to prevent these defects has a very small window,
seven weeks of pregnancy. That is often
the challenge to us as nurse practitioners.
We emphasis planned pregnancy
including the intake of folic acid prior to conception and throughout those
first weeks of pregnancy. However, our
abilities to reach every woman and to impact her decision really are very
imperfect. We appreciate the fact that
efforts have been made to get folic acid in other passive ways to women to
decrease the rate of neural tube defects but we haven't achieved everything
that is possible.
Oral contraceptives, as you know, are
the most popular reversible method of contraception in the United States. Highly effective in preventing pregnancy but
you just heard not perfect. In fact,
approximately 1 million unplanned pregnancies occur in OC users and in the
United States.
In particular, because these women are
using oral contraceptives and not planning to become pregnant, then they aren't
and may not be using folic acid. They
are not motivated to do so. In addition,
many of these women have a delay in pregnancy and they miss that seven-week
window to seek the advice of a health care professional early on in that
pregnancy.
Providing that public health service
recommended 300 microgram daily use of folic acid via passive method as in oral
contraceptives would be guaranteed to provide 400 micrograms daily to women
without changing prescription writing or pill taking behaviors.
Chronic use of combination OC folic
acid product would increase body folate stores and could prevent these defects
in unplanned pregnancies and even pregnancies that are planned shortly after
discontinuing oral contraceptives.
In summary, we strongly support this
concept. This product would increase
folic acid consumption in low-intake women and would make another major step in
the health of women and the health of pregnant women in the United States. Thank you very much.
DR. GUIDICE: Thank you.
The next speaker is Felicia Stewart
who represents the Association of Reproductive Health Professionals.
DR. STEWART: Members of the Committee, we appreciate very
much the opportunity to appear before you today. My name is Felicia Stewart and I'm the Chair
of the Board of Directors of the Association of Reproductive Health
Professionals which is an international organization of 12,000 health
professionals who are researchers, clinicians, and educators in the field of
reproductive health and family planning.
I also service as an Adjunct Professor
of Obstetrics, Gynecology and Reproductive Sciences at the University of
California, San Francisco, and am the Co-Director of the Center for
Reproductive Health Research and Policy there.
On behalf of the ARHP I am very happy
to provide these comments and they do represent the opinion of the organization
with regard to combining folic acid supplements with oral contraceptives.
Like many of the speakers before, I
have included in our testimony, and it is available to you in written form,
many points that have been made several times but our overview points, and I
would just like to comment on the points that we haven't already heard about.
ARHP supports the expansion of
contraceptive options to meet the diverse needs of U.S. women. We feel that a product that contains folic
acid has the potential to help prevent serious birth defects among children born
to women whose intake is lacking in this vitamin.
Certainly it is hard to overstate the
importance of this kind of prevention effort in view of both the financial and,
most importantly, the personal and human costs involved in this particular
condition.
Because neural tube defects develop
early in pregnancy, it is very common, as Ms. Wysocki just pointed out, for
women not to be aware of the pregnancy at all during the time interval in which
supplementation would be essential.
Although many women do begin taking
supplements in advance, many women do not and the most recent data this year
from the CDC PRAMS Review indicating that only about 30 percent of women are
taking an appropriate level of folic acid supplementation and that less than
half of all women take any kind of a multivitamin during the months before
pregnancy is of concern to us.
Certainly fertility rapidly returns
when women who have been using oral contraceptives stop. Often their pregnancy can be initiate before
they would have any idea that this had occurred.
Despite the fact that oral
contraceptives are effective, we do have a very significant number of women who
discontinue them for various reasons and become pregnant, have an unintended
pregnancy, or become pregnant while they are taking the method but not able to
use it correctly and consistently in a way that provides the effectiveness that
we would otherwise hope oral contraceptives would provide.
So an oral contraceptive supplemented
with folic acid is a convenient and effective possibility that may well provide
to be of significant benefit to women in reducing this risk.
There is another very important
potential benefit that none of the speakers have mentioned that I think
deserves to be underscored and that is that the fact that a provider is
explaining to the woman what this pill is and what the folic acid is for and
what the whole concept is about means that providers will be reminded and
prompted to address the issue of planning for pregnancy and making sure that
women have a chance to understand the precautions that are important in
ensuring optimal pregnancy outcomes.
I would be hopeful, frankly, that this
may, in fact, turn out to be a very important benefit in terms of reducing the
number of women who begin pregnancy smoking or begin pregnancy not realizing
the importance of alcohol consumption or use of medications or drugs that may
be toxic or illegal drugs.
By addressing this issue of dealing
with pregnancy as something that you plan for and really try to make sure
you're in your healthiest best shape is something that we'll be reminded to do
just by the fact that we're giving women a new product that contains a concrete
example of a good first step in accomplishing that task.
For these reasons, ARHP respectfully
recommends that the FDA allow further progress in the development of this oral
contraceptive containing folic acid because we believe that such a product
could be an important benefit for women in the United States and
internationally. We thank you very much
for the opportunity to make these comments.
DR. GUIDICE: Thank you.
The next speaker is Melinda Ray from
the Association of Women's Health, Obstetric and Neonatal Nurses.
MS. REID RAVIN: I'm not Melinda Ray. I'm Claudia Reid Ravin and I am speaking in
her stead today. I am a certified
nurse-midwife currently working for the Association of Women's Health,
Obstetric, and Neonatal Nurses, or AWHONN.
Thanks for the opportunity to be here.
I am speaking as a representative of
AWHONN's 22,000 health care professionals.
AWHONN members are registered nurses, nurse practitioners, certified
nurse midwives, and clinical nurse specialists who work in hospitals,
physicians offices, universities, and community clinics across North America as
well as in the armed forces around the world.
AWHONN receives financial support for
educational programming from Johnson & Johnson. However, neither the association nor myself
have a financial incentives for support of this proposed product.
You've heard the benefits and I won't
repeat them here. AWHONN supports
policies that incur to women of childbearing age to consume 400 micrograms of
synthetic folic acid every day. We also
maintain that nurses have the responsibility to inform their patients of the
benefits of folic acid consumption during routine visits.
As primary care providers, nurses play
a significant role in promoting primary prevention health behaviors. Nurses, therefore, have a responsibility to
provide counseling on a host of health issues including contraceptive choices
as well as prevention of birth defects.
Women generally are low consumers of
folic acid with only 30 percent of all women consuming a vitamin supplement with
folic acid. Women who are not
considering pregnancy are believed to be even less likely to consume folic acid
on a regular basis because their focus is on preventing pregnancy rather than
birth defects.
Each year over 70 million American
women use oral contraceptives in an effort to prevent pregnancy. However, roughly 1 million women a year
become pregnant while taking birth control pills and half of these unintended
pregnancies go to term. As a result, it
is vitally important that the folic acid message be conveyed to women not
thinking about getting pregnant.
While women may recognize the need to
take folic acid, actually changing behavior by purchasing foods which in folic
acid and/or adding it to one's daily pill taking routine is another issue. A 2002 March of Dimes survey indicated that
while contemplators of pregnancy are more likely to take multivitamins with
folic acid, 25 percent who take a multivitamin forget to take it every
day. This behavior is not unusual. Research into medication taking habits
indicates that as many as 20 percent of patients have difficulty using their
medications consistently.
It is our opinion that the inclusion
of an oral contraceptive that includes folic acid would help health care
providers communicate a strong public health message that preconceptual folic
acid is important.
In addition, providers can be assured
that women of childbearing age taking this product are receiving the
recommended daily allowances of folic acid.
The addition of 400 micrograms of folic acid supplement to an oral
contraceptive provides the health care provider with a unique counseling
opportunity.
We know that health care providers
should screen women of childbearing age for folic acid consumption in an effort
to promote taking a daily multivitamin and to prevent neural tube defects. We also know that 53 percent of women not
taking a daily multi-vitamin indicated that they would likely do so if their
health provider simply encouraged them.
The potential availability of a combined
oral contraceptive gives providers an additional option and prescriptive choice
that can be a flag to have a discussion with a patient who may be either
unaware of the benefits of folic acid or not see themselves as needing folic
acid because they are not yet contemplating pregnancy.
Since the science indicates that
preconception consumption of folic acid is critical for the prevention of birth
defects, and statistically 50 percent of pregnancies in the United States are
unplanned, we assert that the woman who does not wish to become pregnant may be
at the greatest risk of being a low consumer of folic acid.
The desire of the women to prevent
pregnancy through the use of oral contraceptives should be seen as an ideal
opportunity for counseling on the benefits of folic acid consumption. Thank you.
DR. GUIDICE: Thank you.
The next is a representative for
Healthy Mothers, Healthy Babies National Council on Folic Acid. The contact person is Donna Gentry.
MS. BOLES: Good afternoon. My name is Anita Boles, and I'm the Executive
Director of the National Healthy Mothers, Healthy Babies Coalition. In my role as the current chair of the
National Council on Folic Acid, I am pleased to give brief comments before this
committee on the concept of an oral contraceptive that includes a folic acid
supplement.
The National Council on Folic Acid
would like to thank the committee for the opportunity to discuss this important
issue. The council is a partnership of
over 80 organizations whose mission is to improve the health by promoting the
benefits and consumption of folic acid.
Let me also say here that the council has no financial incentive for
speaking at this hearing.
As we are all aware here, folic acid,
a widely available B-vitamin, is critical for proper cell division and
growth. It is especially important
during the early weeks of pregnancy when the embryonic neural tube, which later
becomes the brain and central nervous system, is forming and closing.
We know that defects in the closure of
the neural tube result in the development of a group of birth defects commonly
referred to as neural tube defects. We
also know that the consumption of 400 micrograms of folic acid taken prior to
conception and early in gestation can prevent as many as 70 percent of neural
tube defects.
In the late 1990s the National Council
on Folic Acid began an educational campaign targeting two separate audiences,
the pregnancy contemplator and the non-contemplator. The contemplator, of course, are women who are
thinking about or planning a pregnancy; while non-contemplators are women who
are not currently thinking about having a baby.
In spite of our diligent educational
efforts, and the efforts of many, many groups across the country, as you just
heard through the AWHONN testimony, a 2002 March of Dimes survey indicated that
only 30 percent of women of childbearing age, that's 18 to 45, take a vitamin
supplement with folic acid every day and 25 percent of those who take a
multivitamin forget to take it every day.
This data suggest that women generally
remain low consumers of folic acid even while contemplating pregnancy. Following that logic, the NCFA members assert
that the non-contemplators of pregnancy are at an increased risk of low folic
acid consumption. We assert that the
addition of a folic acid supplement to an oral contraception routine for the
non-contemplator makes sense for two reasons.
First, by putting folic acid in oral
contraceptives, we can ensure that women who are actively trying to prevent pregnancy
can radically reduce the risk of an NTD-affected pregnancy should a
contraceptive failure occur.
Each year, as we are all aware, over
17 million American women utilize oral contraceptives in an effort to prevent
pregnancy. And despite the pill's high
rate of efficacy, roughly 1 million women a year become pregnant while taking
birth control pills. Half of these
unintended pregnancies go to term.
Supplementation of a birth control pill with folic acid will provide
these non-contemplators with the recommended protection level of 400 micrograms
of folic acid a day and provide some piece of mind to women and their families
in the event of an unplanned pregnancy.
Second, the supplementation of folic
acid in an oral contraceptive makes sense because folic acid is one of the few
water soluble vitamins that is retained in the liver and red blood cells for a
period of up to three months. While more
research is needed, early studies suggest that the folic acid that remains in
the system may afford some level of protection in the prevention of an
NTD-affected pregnancy. Many women
choose to take oral contraceptives because of the ease in converting back to a
fertile state.
When a women decides to stop taking
oral contraceptives, health care providers, of course, have the responsibility
to counsel women about folic acid supplementation. However, women who may not have seen a health
care provider or who have become pregnant within the first month of ceasing the
pill consumption, maybe even before they begin taking their folic acid
regularly.
The potential for an added three
months protection for the new contemplator of pregnancy may have a tremendous
impact on the prevention of neural tube defects. This is why the National Council on Folic
Acid respectfully recommends to this committee to allow the development of an
oral contraceptive that includes 400 micrograms of folic acid. We believe that such a product can help in
the fight to reduce the incidence of birth defects in this country. Again,
on behalf of the National Council on Folic Acid, thank you for the opportunity
to provide these comments in support of the concept of an oral contraceptive
that includes a folic acid supplement.
Thank you.
DR. GUIDICE: Thank you.
Our next speaker is Ms. Sonya
Oppenheimer.
DR. OPPENHEIMER: My name is -- excuse me. I don't have much of a voice but I came
anyway. My name is Sonya Oppenheimer. I'm a developmental pediatrician, Professor
of Pediatrics, and Director of the Division of Developmental Disabilities of
Cincinnati Children's Medical Center in Cincinnati, Ohio.
Most important, I've been the Director
of the Spina Bifida program at the hospital since 1970, a long time. This program serves all children and adults
with spina bifida that are born in our tri-state region. In addition, more recently, we've been
providing prenatal counseling.
I'm appearing at this hearing because
I have a strong personal commitment to continue to support all efforts to
prevent this significant birth defect. I
have no financial relationship with any company or group that might be impacted
by this meeting.
In the early '70s, and it's
interesting listening to everybody because I've been around for a while, the
young president of the Spina Bifida Association, which was newly formed at that
time, and a man who was also the father of a young child with spina bifida, and
I attended a CDC-sponsored conference at the urging of Dr. Oakley to discuss
the possibility of adding folic acid to bread in an effort to decrease the incidence
of the birth defect.
At that time the conversation was much
different than what I'm hearing today.
It was, "This is nonsense.
What are you doing? There's no
proof." On and on and on. We enthusiastically supported an aggressive
research program to prove the effect of folic acid. There, however, at that time were obviously
still questions if folic acid was the only answer so supplementation of food
was abruptly dropped.
During the past 20 years, as you've
been hearing, research appears to have confirmed the effectiveness of folic
acid in decreasing the incidence of spina bifida. This currently brings us to the
recommendation to supplement folate in birth control pills.
Ohio's Bureau for Children with
Medical Handicaps has a state committee which is rather unique. In this committee, which is rather unique,
and in this committee there are representatives from the six clinics in Ohio
that serve children and adults who have spina bifida. this allows us to track the number of infants
born in Ohio.
All the clinics over the past few
years have seen a drop in the number of children born with spina bifida. But, unfortunately, we do not have the
numbers of pregnancies that have been terminated and that is a number we should
not forget because it's a lost number and those people who elect to terminate
the pregnancies suffer a great deal when they have made such a decision.
Prior to 1999 in our clinic we average
about 20 to 25 newborns a year. In 2003
we've had 11 new babies born and I have direct knowledge of at least two
pregnancy terminations. Of interest,
three of these new babies that were born do come from -- the parents come from
a lower socioeconomic status and are having tremendous troubles in trying to
help their child keep the appointments understand what's happening. And a couple of them, indeed, are considering
abandoning those children.
We've routinely asked about folic acid
use and the usage, as we've heard, is very variable. I'm not going to repeat numbers that we've
been talking about but when folic acid supplementation was first entertained in
the '90s everybody said, "Hey, Sonny, great. You won't have a job anymore. You are going to be out of business because
there won't be any other babies born."
Unfortunately, that's not what's
happening and we keep seeing all of the problems that are occurring including
not even mentioning the problems that the adults who we also serve are having
as they have gone into adulthood. I hope
you strongly consider the proposal to add folic acid to oral
contraceptives. Thank you.
DR. GUIDICE: Thank you.
The next is a representative from
Planned Parenthood Federation of America.
The contact person is Vanessa Collins.
MS. COLLINS: Good afternoon to all and thank you so much
for giving me the opportunity to speak today.
My name is Vanessa Collins. I'm Vice President for Medical Affairs for
Planned Parenthood Federation of America.
I have no personal financial relationship with the sponsor. Planned Parenthood affiliates do, indeed,
purchase oral contraceptive products from the sponsor.
We have 124 affiliates across this
nation that operate over 850 health care clinic sites. Planned Parenthood Federation of America
enthusiastically supports folic acid supplementation of oral contraceptives.
The addition of folic acid to oral
contraceptives is an important public health measure that allows women to
postpone pregnancy while simultaneously preparing for future healthy
pregnancies. Such supplementation is the
true embodiment of the meaning of family planning.
That
is, deciding whether and when to have children and ensuring an environment in
which every child is wanted, loved, planned for, nurtured, and provided for.
As you've heard, the incidence of
neural tube defects could be reduced by 50 to 70 percent if folic acid
supplementation precedes pregnancy and is continued at least seven weeks
through gestation. Dietary folic acid
fortification has resulted in approximately 20 to 30 percent decline in neural
tube defects which means an additional 20 to 50 percent decline is possible.
The public health impact of adding
folic acid to oral contraceptives goes way beyond reductions in neural tube
defects. The very act of adding folic
acid to oral contraceptive pills enables an important dialogue opportunity
between the clinician and the woman as alluded to by Felicia Stewart earlier.
Both the clinician and the woman have
the opportunity to move beyond the issue of the moment; that is, pregnancy
prevention, and begin a dialogue about preventive measures that should be
employed in the present to prepare for the healthiest possible future
pregnancy.
It allows for a teaching moment when a
clinician can give anticipatory guidance about the importance of vitamin intake
during the time period when pregnancy is contemplated, suspected, or diagnosed
with the first prenatal visit has not yet occurred. For neural tube defects preventable through
folic acid intake, this information is critical.
Adding folic acid to oral
contraceptives is personal, societal, and the medical recognition that most
women using reversible contraception plan to become pregnant in the
future. Adding folic acid to oral
contraceptives also acknowledges that when unintended pregnancy does occur
whether from method or use failure, the best possible situation for the woman
and for the ongoing pregnancy is a situation where she is at least physically
prepared to nurture an ongoing pregnancy.
These concepts are important to all
women intending future childbearing and are especially important to the women
who has delayed childbearing in order to more fully participate in civil and
professional endeavors in addition to fulfilling her role as a mother.
In this increasing technological
society many women find it necessary to delay childbearing in order to complete
educational and skill attainment required to reach their professional
aspirations. Fecundity drops with
age. For this reason, when the women who
has delayed pregnancy decides to conceive, it is imperative that she attempt
and achieve conception in the best possible physical condition.
Folic acid supplementation will assist
in achievement of this goal. Adding
folic acid to oral contraceptives is a public health measure similar to adding
fluoride to the drinking water. The
difference is that adding folic acid to oral contraceptives can be successfully
targeted only to the intended beneficiaries.
That is, women of childbearing age.
This measure will positively benefit
millions of women and millions of pregnancies over the course of time. It is estimated that eight out of 10 women
take oral contraceptives at some point in time in their reproductive
lives. Many of these women have been on
more than one oral contraceptive formulation.
Many of these women will benefit from the addition of folic acid to an
oral contraceptive formulation because there is pretty high probability that
woman may be exposed to that formulation at some point in time in her life.
In any given year 60 million of 70.1
million women of reproductive age are taking oral contraceptives. We do not know precisely how many of these
women have low folic acid intake. We do
know low folic acid intake tends to occur more frequently among women of low
socioeconomic status, the very women who in general is at risk for
environmentally induced poor pregnancy outcomes.
While folic acid supplementation will
only have an effect on the incidence of neural tube defects, the potential for
dialogue because of the addition of folic acid to oral contraceptives opens the
door to discuss other measures that will likely improve pregnancy
outcomes. As mentioned before, the
issues around early prenatal care, preconception weight loss, smoking
cessation, nutrition, etc.
While a product containing folic acid
will be most beneficial to those women with low folic acid intake, the beauty
of this concept is that women with adequate folic acid intake will not be
harmed. The primary concern of excess
folic acid intake is that of masking vitamin B-12 anemia. This is an issue for the elderly and is not
an issue for healthy reproductive age women taking oral contraceptives.
Four hundred micrograms is the
proposed daily dose for oral contraceptives.
Four hundred micrograms a day is the recommended amount of folic acid by
the institute of medicine and the United States Public Health Services.
This dose is less than 10 percent of
the 5,000 microgram dose a day that may temporarily correct anemia due to
vitamin B-12 deficiency. The bottom line
is that there is very, very little downside to the addition of 400 micrograms
of folic acid to oral contraceptives and the potential benefit of
supplementation of oral contraceptives with folic acid is substantial for
women, their pregnancies, their families, and society. Thank you.
DR. GUIDICE: Thank you.
I'd now like to call, please, Mr.
Douglas Rose.
MR. ROSE: Thank you.
It's a pleasure to be here. My
name is Douglas Rose. I'm President of
Irwin R. Rose and Company in Indianapolis, Indiana. We are a commercial real estate firm
specializing in apartments and multifamily housing across five states. I'm here on behalf of my wife and
family. I'm here as a parent of a child
who was born with birth defects. Our
youngest, Emily, age 4, was born with achondroplasia which has nothing to do
with the subject matter you are contemplating here.
While medical science knows a great
deal now about achondroplasia, for example, the gene has been identified where
a genetic insult occurs. The location on the gene, etc., has been identified. The prevention science is a long way from
reality. Fortunately, that's not the
case with folic acid preventable birth defects.
By the way, let me state if it wasn't
implied, I have no financial interest in anything being discussed here and I'm
here at my own expense on my own time.
I'm here to urge the FDA to approve the marketing of this drug/drug
combination as quickly as possible for, at a minimum, the benefit of the
hundreds of thousands of women. I've
heard the figure here this afternoon a million women each year become pregnant
while taking oral contraceptives or those women who become pregnant having
stopped taking oral contraceptives.
Approval of this drug/drug
combination, these two drugs which are already approved drugs, will, I believe,
have a dramatic impact on women's public health in the United States. Some of the facts are not in dispute. Not nearly enough of the eligible population
of women of reproductive age are receiving the recommended daily dose of B
vitamin folic acid. That's a shame. It's tragic.
It's tragic that today in Indiana and across America babies continue to
be born with this most devastating birth defect. When we learn about these issues and begin
reading about these issues, it's difficult to describe to you how shocked and
angry we were when we discovered that many of these cases could have been
prevented by simply introducing B vitamin folic acid. It's shocking. What you have before you today is a wonderful
opportunity to advance women's public health, advance the health of
babies. Every baby deserves to be born
free of birth defects with an opportunity to live a full life.
Every family with a child without
birth defects is a child helped. I know
a little bit about the challenges the families face. I liken birth defects to acts of terrorism. I know that may sound odd but terrorism is
indiscriminate. It's devastating. It crosses socioeconomic lines. It has lifelong impacts.
It impacts not only the baby who is
born with the birth defect but the child's siblings, parents, extended
family. There are no words sufficient
that I know of that can adequately describe what a family deals with when they
bring home a child born with birth defects.
I really appreciate this
opportunity. If I appear to be nervous,
that's because I am. Standing in front
of all of you leading experts is quite overwhelming to me. I felt this was important enough to come here
and speak my mind for just a few minutes.
When our daughter was born, we were
determined -- she will have many opportunities and a full and complete
life. Yes, with difficulties that will
lie ahead -- we were determined to make a difference.
Each of you now have an opportunity to
make a difference for hundreds, perhaps thousands of women and their families
and their healthy babies. You each
should be very proud of this opportunity that you have. So many families will be grateful. I'm grateful to you for this opportunity and
wish you all a happy holidays. Thank
you.
DR. GUIDICE: Thank you.
The next is an organization, American
College of Nurse-Midwives, and the speaker is Deanne Williams.
MS. WILLIAMS: Good afternoon. I am Deanne Williams. I'm a nurse mid-wife and I'm Executive
Director for the American College of Nurse-Midwives. Even though I've spent quite a bit of time
preparing for and getting here and waiting for my opportunity to speak, you'll
be glad to know that I don't have anything to say that you haven't already
heard and I'm not going to take your time.
If I were sitting there, I would be getting a little cranky right now.
I will summarize one summary statement
that you've heard from the nurse-midwives, you've heard from the nurse
practitioners, you've heard from the obstetrician gynogologists, you've heard
from the clinics that are providing these services that this is an important
decision that will have a significant impact and I urge you to move speedily to
approving this request. Thank you.
DR. GUIDICE: Thank you.
Now our last speaker is Dr. Richard
Falk who represents the American Society for Reproductive Medicine.
DR. FALK: I think I should represent the Washington
Redskins being last. I should say I have
no financial incumberances which will affect my testimony.
My name is Richard Falk. I'm a gynecologist and reproductive
endrocronologist. As Linda said, I
represent the American Society for Reproductive Medicine. The society is a multi-disciplinary
organization of approximately 9,000 members representing every state, the
District of Columbia, and more than 100 foreign countries.
The mission of this society is the
advancement of art, science, and practice of reproductive medicine central to
which is the health of women and their children. It's difficult to be entertaining and
informative at this juncture after following so many erudite speakers but, as
we all know, hearing the lyrics again and again tend to make us remember the
song so I'll read our brief statement.
The full statement is outside.
It is well accepted that consumption
of folic acid supplements during early pregnancy reduces the incidence of
neural tube defects by 50 to 70 percent.
The U.S. Public Health Service now recommends that all women capable of
becoming pregnant supplement their diet rich in natural folates with 400
micrograms of synthetic folate acid.
The oral contraceptive pills are a
widely utilized method of contraception.
In the year 2000 12.9 million married and sexually active unmarried
North American women used this medication.
Despite its proven efficacy there are approximately 1 million unplanned
pregnancies in OCP usage annually.
Approximately half of these
pregnancies result in a live birth.
Because these are unanticipated pregnancies, it is likely that most of
the women have not supplemented their diets with folic acid. In addition, oral contraceptive usage is
associated with decreased intentional absorption of folates and some studies
have shown diminished plasma folate levels as well.
Combining the recommended 400
micrograms supplementation of folic acid with an oral contraceptive would
increase the body stores of folate and would be expected to result in a
decrease in neural tube defects in children born of unplanned pregnancies.
The ASRM, therefore, enthusiastically
supports the development and distribution of a combined OCP folate
preparation. Thank you.
DR. GUIDICE: Thank you.
I would like to thank all of the individuals for sharing their
experiences and their comments and also the organizations for their comments.
There were several other individuals
and organizations who may be sitting in the audience and have expressed a
desire to speak additionally and their filing of this information actually
occurred after the deadline so we will be unable to accommodate them at this
time but we would like to thank you for being here.
In addition, we had some letters, one
of which came from the March of Dimes and the other from Dr. Vladimir Varlileky
from the University of Alabama in support of this concept.
As charged to the committee, one of
our charges in addition to the discussion is to provide advice to the FDA with
regard to particular issues for the issue at hand. There is a list of five questions and I would
like to now open the floor for the committee to discuss these five questions.
The first question is -- I would like
to reassure the committee also that there will be time for discussion about
these questions as we go forward and perhaps other issues that may come up as
well.
The first question is, "Are
further increases in folic acid intake beyond what is available from fortified
cereals likely to result in public health advances in preventing further neural
tube defects?"
Is there any discussion on this by any
of the committee members drawing from what you have read in your packets and
also from the presentations today?
Dr. Darney and then Dr. Montgomery
Rice.
DR. DARNEY: Phillip Darney. I assume this increase means if more women
were taking folic acid rather than a change in the mean serum concentration of
the population. That's an increase in
prevalence, right, rather than an increase in dose?
DR. GUIDICE: I think that is an excellent question to ask
our representatives from the FDA for clarification, please.
DR. GRIEBEL: I think what we're asking is does it -- that
first part of the phrase is in addition to the food fortification, would
additional supplementation which would be further increases in folic acid
intake. Basically we're referring to the
concept that we are discussing today.
DR. GUIDICE: Is that clear? Dr. Rice.
DR. RICE: I assume that you also mean what will be able
to be required in the diet plus if a person was taking supplement. So are you saying beyond that if they were
taking the supplement as prescribed, oral contraceptive plus folic acid, they
wouldn't be taking anything else additionally other than what's in the diet.
My question was to Dr. Yetley, I
believe, the people who spoke earlier.
When you look at the 25 foods that you say people commonly take in their
diet that have supplement, if you look at an average diet, what is the maximum
amount in general of a reproductive age woman actually gets in that
consumption?
If you look at the variety of foods
that a person typically gets in a day, is that that 200 number that we're
talking about that people are getting?
What is that amount? You know
what I'm saying? If I eat some cereal or
drink some milk and then I have a salad and some chicken for lunch, if I eat
those type of things, what am I typically going to get in a day?
DR. YETLEY: Well, obviously there's a wide range of
intakes. I think the other point is that
we don't have a good accurate estimator.
I mean, we can make estimates but they are probably significantly under
reported.
I clearly is feasible for a woman and
not without a lot of stretching to achieve a good diet plus additional
fortification folate from the diet, particularly if she eats breakfast cereals
or other foods that are highly fortified.
It is certainly feasible and not a huge stretch of the imagination to
get there.
I think what you have is probably a
lot of women who may or may not have good diets but are not in addition taking
either a supplement or a breakfast cereal which I think, at least at the
current time, the recommendation is. I
don't know whether that answers your question or not but if you make an
estimate of could they get a good diet eating fruits and vegetables, dairy,
whatever, following dietary guidelines of the U.S. Government, yes.
DR. RICE: So they can't get that 400. We know that they don't based on when you
look at the NHANES data, etc. When you
look at the typical -- when you do those surveys, you know that they are not
actually getting it.
DR. YETLEY: Let me just make a comment. There was a lot of emphasis this morning on
the Lewis, et. al, paper and I am a co-author of that paper so I wanted to put
some cautions in interpreting that paper.
That paper was done before fortification had been implemented. We didn't know at that time what the
marketplace would do and the marketplace responded much more significantly and
to a much larger degree than we estimated in that paper.
We also did not have good analytical
data on the folate content of foods. Now
that we have better data we know that we underestimated on that. For a number of reasons, that's a very
significant underestimation and, therefore, underestimation of actual intake
and overestimation of how many women don't meet the dietary pattern.
My guess is I would rely more on the
serum data because I think that tells you how many women aren't from whatever
sources actually getting sufficient folate.
I would recommend you look at the serum and red cell data rather than
the dietary data which is very fraught with error and probably
underestimations.
DR. RICE: Okay.
Thank you.
DR. GUIDICE: Is there any further discussion with regard
to this particular question?
Dr. Lipshultz, Dr. Dickey, and Dr.
Rosenberg.
DR. LIPSHULTZ: This is just kind of a point of
information. That is, we're being asked
to comment on likely to result in advances and I'm just trying in my own mind
to quantitate these advances in terms of the 16 million women.
I did not understand the response from
the representative from Johnson & Johnson as to whether or not this
combination will be available for all companies or is this specifically for a
Johnson & Johnson product and, if so, how many of the 16 million women will
be able to profit from this combination?
DR. GUIDICE: Someone from the sponsor like to
respond? Dr. Friedman.
DR. FRIEDMAN: The question was about how many of the 16
million women who currently use oral contraceptives could potentially benefit
and about potential available of such a product to other makers of oral
contraceptive products?
DR. LIPSHULTZ: The question is is this restrictive in the
ability to combine these two, or is this going to be just globally available to
all manufacturers?
DR. FRIEDMAN: Well, currently we are here today to really
discuss the concept to see if the concept itself makes sense to this
committee. We feel it does and have
presented arguments to that effect.
With regard to issues of other
companies, it's a little premature now to speculate on their interests in such
a product. Johnson & Johnson has
always been open to discussion of co-licensing or co-marketing products with
other companies and would remain so but at this point in time, it is, I think,
very premature to speculate on how that could play out over time.
DR. LIPSHULTZ: I mean, I think you could give me just idea
as to the marketplace in terms of oral contraceptives and Johnson &
Johnson. Are we talking about 50 of
women use Johnson & Johnson oral contraceptives? 80 percent, 40 percent? I mean, if you could just generally give me
an idea. I mean, I'm sure you have these
numbers available.
DR. FRIEDMAN: Dr. Cafferson will address your question.
DR. CAFFERSON: The answer is no, I don't have numbers
available for a perspective product but when we're talking about -- you'll tell
me if I'm addressing your question appropriately. Given the current usage patterns for
estrogens and progestins, the type estrogens, the type progestins, the type
regimens for those products that would be available to any company, in this case
ours, for development with folic acid, it would exceed, I believe, probably 85
percent of current usage of pills.
So I think that may get at what you
are after. If we look at norethindrone
products, if we look at levanorgestrol products, if we look at ethanol
estradiol, etc., if we take it in the broadest sense of what this could mean,
it could be very, very broad coverage.
However, as Dr. Friedman mentioned, we are really here focusing on the
concept itself. I understand, Dr.
Lipshultz, you are after the broader what might the public health consequences
be.
DR. LIPSHULTZ: The reason I'm doing that is because the
numbers that we hear today are based on 16 million women taking pills. Now, is that a realistic number based on the
combination? Will 16 million women be
able to get this combination?
DR. CAFFERSON: As far as being able to get this combination,
certainly they would be able to get any combination and would be prescribed
appropriate combinations, but I think part of that question -- another response
to that question is to remember that we are currently, and have been for years,
the dominant suppliers of oral contraceptives in the public sector as
well. The availability of these pills,
we believe, would be broad.
DR. GUIDICE: I think one of the issues -- I'll get to you
in just one second -- I think what Dr. Lipshultz is getting at, and may be in
the minds of others around the table as well, is whether the 85 percent of 16
million, and clearly there would be -- well, there would likely be other
individuals who would benefit from this besides the 16 million women who are
currently taking OCPs, but does Johnson & Johnson make 85 percent of those
pills? I think that's the question that
is being asked.
DR. CAFFERSON: The answer is --
DR. GUIDICE: Or components of them.
DR. CAFFERSON: Yeah.
The answer is no. We have about
40 percent of the market now I'm referring to.
However, zero of that 40 percent contains folic acid. The question, as I understood it, was what
could the availability be versus what the availability may be versus what
restrictions on that availability might be so there are two different questions
but you have both answers.
DR. GUIDICE: Thank you.
Dr. Emerson.
DR. EMERSON: Just to follow up on that. I mean, I think what we are really being asked
to talk about here is the public health impact of making this decision that
there is no product at hand or there is no issue.
Even if there were a product at hand,
if the person walked in here talking about doing this that currently had a .01
percent of the market share, there's this issue of is this is a good product, a
good idea of putting it in there, they are looking at the possibility of
marketing such a product and hopefully capturing more of it.
I think that's what we have to address
more than truly the Johnson & Johnson question specifically is the idea of
whether there would be a public health benefit.
The question at hand here is just starting out is there room for
improvement in folate intake or is everybody already taking everything they are
going to take.
DR. GUIDICE: Dr. Rosenberg, did you have a comment you
wanted to make?
Yes, Dr. Mills and then Dr. Hager.
DR. MILLS: I'd like to address that question in terms of
particularly what Dr. Rice was asking earlier following Dr. Yetley's
comments. I think there are two ways to
attack this. One is to look at the
reduction in neural tube defects that we have currently experienced. A number of the speakers this afternoon
talked about a 20 to 30 percent reduction.
I think it's very important to note that is based on incomplete data and
that is probably not an accurate reflection of the current achievements. The better the data the greater the
reduction. If you look at the Canadian
studies they are in the range of 50 percent.
I think the real question is can we do better than 50 percent. That is, is there another 20 percent of
neural defects that are fully preventable and there may be but I don't know for
sure that there are.
The second way to address that
question is to look, as Dr. Yetley suggested, at the blood levels. If you look at a red cell folate level saying
that 400 is target, and I admit this is just based on reasonable evidence, not
great evidence, then there's still a number of people who are not meeting that
goal, so that using the red cell folate as your standard there are a number of
people who could benefit from additional folic acid. I would just suggest those as ways of
approaching the question.
DR. GUIDICE: Thank you.
Dr. Hager.
DR.
HAGER: I would just indicate that I do
think that this is a broader topic than just the concept. Not a single one of the public speakers said
an oral contraceptive with folic acid supplementation. They all said oral contraceptives with folic
acid supplementation. Although we are
discussing a concept, I believe it is important to the function of the
committee that we indicate that, in my opinion, that we see this as a concept
that needs to be applied like we would herd immunity.
This is for the best public health
impact. We're talking about if folic
acid is beneficial, and certainly there is some evidence that indicates that
folic acid can decrease the risk of neural tube defects, then we need to be
sure that concept is conveyed to benefit all women who would be exposed to the
use of oral contraceptives rather than just limiting it to one product.
Regarding the public health effects,
we don't truly know the number needed to treat to reduce further that risk of
neural tube defects. We need information
on that. We don't know the effectiveness
after 90 days or so as far as binding and the amount that is still left in
plasma levels.
We don't know about women who
discontinue so we need some further follow-up.
I would say that I think the public health implications based on what we
have heard are that folic acid certainly can benefit. I would hate to see us limited to a single
product.
DR. GUIDICE: Thank you.
Dr. Dickey, you had a comment?
DR. DICKEY: Well, again, I think if we answer the
question that has been posed to us, it really doesn't have anything to do with
what our sponsors talked about. The
question is simply are further increases in folic acid intake likely to result
in improved public health outcome.
It's not that it's not available. Technically you could get it through diet,
you could get it through multi-vitamins, but it's clear as you read through the
material, to me, that we have a substantive portion of the population at risk
that is not taking advantage of diet, vitamin supplements, or other
mechanisms.
The answer to this question -- quite
aside from this specific concept, the answer to the question about folic acid
intake is yes, our society could benefit from further mechanisms to make folic
acid available.
DR. GUIDICE: Thank you.
Dr. Tamura.
DR. TAMURA: Let's assume that we are going to say yes to
this first question. Then I would like
to know considering that the national decline in the rate of NTDs already
happening before we knew that folic acid was indeed effective to prevent NTD,
and also this mandate by FDA that so-called enriched cereal and grain products
should be fortified with folic acid started in 1998 so further decline in NTD
prevalence.
Now, my question is if we answer yes
today, how we are going to monitor that our answer would be correct or
not? That's what I would like to know.
DR. GUIDICE: And I'm wondering who might provide us some
insight into that either on the committee or from the FDA.
DR. RICE: Again, we are not -- we're talking about a
concept today. I am assuming that
regardless of what our vote is for this, that there are going to be lots of
additional or some additional studies that are going to answer a lot of the
questions related to safety, toxicity, dosage, etc. I think those questions will then be part of
what the FDA will do when they assist with the development of studies that will
hopefully begin to develop this product.
I am assuming that we are only here to
talk about the concept and address those issues and then that nothing is going
to come to market for a while because there's got to be some phase -- maybe
some phase 1 but definitely some phase 2 trials, some other trials that look at
what the appropriate dose is and what are the safety issues associated with it,
what are the pharmacokinetics that are associated with combining them. I think those issues will be answered with
the properly designed studies. I
definitely would like to know if I'm wrong in making that assumption.
DR. SHAMES: No, you are correct. There are -- we need to address the concepts
here. There are lots of details that we
are not talking about that really we can't talk about here. They are regulatory issues and legal issues
that we haven't even totally addressed ourselves.
We have constructed these questions in
such a way that at least we can know if we should even move forward on this
concept so that's really what we're talking about.
DR. GRIEBEL: But I would like to add that if there are
important issues that you think that we need to know more about such as
specific safety information that you would need to know before you felt
comfortable with this, we would like to hear what those are and people's ideas
on how to get those answered.
DR. GUIDICE: Dr. Tolbert.
DR. TOBERT: I would like to comment on an issue from a
few minutes ago. There seemed to be an
implication that Johnson & Johnson, who I presume have intellectual
property in this area, should put it into the public domain because this is an
important public health advance. It is
an important public health advance and I hope it's very widely available but
lots of other products of pharmaceutical companies are as well. I mean, there would be no pharmaceutical
industry if the pharmaceutical industry did that. I presume what will happen is Johnson &
Johnson will market oral contraceptives containing folic acid. That may give them an advantage over their
competitors. Doctors may write
prescriptions preferentially for those products but that's how the system
works. These products will be available
to anybody who cares to take them and any doctor who cares to write the
prescription for them.
DR. GUIDICE: Thank you.
Dr. Rosenberg.
DR. ROSENBERG: In exploring the concept, I think it's
already been mentioned that we really should be talking about folic acid intake
beyond what is currently contributing to folic acid nutrition in the diet, not
just fortified cereals. That point has
already been made. It's important to
reflect on whether we are trying to increase folic acid nutrition or trying to
increase simply the intake of crystalline folic acid. They are not exactly the same and I think
that does deserve a little further clarification.
To add to that, I would say does the
concept include the idea that for public health reasons we really want the
woman who conceives to be in the best possible health, the best possible
nutritional status for her own health and for the health of the fetus and,
therefore, is it unreasonable to think that this concept should allow consideration
of more than folic acid being added to a drug which is used
preconceptionally.
It's true that there's this powerful
relationship in the research between folic acid intake periconceptually and
prevention of neural tube defects, but is part of the concept here is an
opportunity to deliver improved nutrition to women in a way that would have an
impact on their periconceptual or preconceptual nutrition status. This is a leading edge example. Is that part of the concept in the view of
the FDA?
DR. SHAMES: I just think that we first have to get past
this one supplement that has a clear benefit and if we haven't solved that here
with the committee on a scientific level, then we have to go and try to see if we
can address it on a regulatory level. If
that all works out, then we can talk about other things. I think we need to get over this first.
DR. ROSENBERG: But it is a concept that we're talking about
here.
DR. SHAMES: Well, I would like to hear what you have to
say about this particular concept first, I think.
DR. GUIDICE: I hope these are comments that are relevant
to the concept at hand.
DR. CROCKETT: I would like to make a motion that we end
discussion on Question No. 1 and move to a vote, please.
DR. GUIDICE: Okay.
A motion has been put forward that we end discussion on Question No. 1
and put it to a vote. It's been seconded
and this committee doesn't usually have motions and approvals, etc. However, I think we have heard the entire
range of issues. I think we are probably
in a very good position right now to take a vote unless there is someone who
has a burning issue.
Is this a burning issue, Dr. Green?
DR. GREEN: I'll let you judge that. It's an issue that concerns a point that was
brought up, and a very relevant one, by Dr. Mills in this discussion that
speaks to, I think, Question No. 1, and I don't think we'll be able to come
back to it, which is are further increases in folic acid likely to result in
public health advances.
Certainly I would agree with the
overall notion that 400 micrograms figure on red cell folate would be a good
yardstick to do that. What I have not
heard, and please forgive me if there is information that was presented that
addresses this issue, is whether the value, 400 or any other level, when you
look at the distribution curve for red cell folate in the population at large
and the effects of increased folate intake, the effect that would have on the
shift of that distribution curve would affect the fraction of the population
that might be at greatest risk. Specifically, from what we've heard,
those where we are addressing an issue of gene nutrient interaction. Particularly the TT homozygotes. Is there any information? I mean, one would predict given that this is
a common polymorphism that the distribution of red cell folate is going to be
trimodal within that population.
This may not be apparent from looking
at a distribution curve but my question is if you look at the left-hand side of
that curve buried within that group surely must be the TT group. The question is does 400 micrograms of red
cell folate, is that attainable for that group?
DR. GUIDICE: Dr. Mills, since you were commented upon --
DR. MILLS: Since I got tagged.
DR. GUIDICE: Right.
DR. MILLS: There are some data. Unfortunately, I can't give you chapter and
verse but there's a paper by Ann Malloy looking at the Irish cohort that showed
how the TT allele relates to folate levels and whether that can essentially
explain the folic acid effect. Or,
actually to be more specific, what proportion it can explain and there's a
great deal that is independent of the TT if that helps to answer the question.
DR. GUIDICE: Thank you.
Many of the comments that had been made around the table including this
one and also the issue of potentially other supplements or, at least,
conceptually added to oral contraceptives can certainly be, I hope, included in
our recommendations to you beyond these six questions for subsequent evaluation
and consideration by the agency.
I would like to move forward and
restate Question No. 1 and then I will go around the room and pick on
people. That is, to ask directly for the
voting members for their yes or no answers.
The question is, "Are further increases in folic acid intake beyond
what's available from fortified cereals likely to result in public health
advances in preventing further neural tube defects."
For each question we'll start on
different sides of the room so people don't feel particularly picked upon but
at this time I would like to begin with Dr. Hager, please.
DR. HAGER: Yes.
DR. GUIDICE: Dr. Patten.
DR. PATTEN: Yes.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: Yes.
DR. GUIDICE: Dr. Green.
DR. GREEN: Yes.
DR. GUIDICE: Dr. Crockett.
DR. CROCKETT: Yes.
DR. GUIDICE: Dr. Rice.
DR. RICE: Yes.
DR. GUIDICE: Dr. Wenstrom.
DR. WENSTROM: Yes.
DR. GUIDICE: Dr. Emerson.
DR. EMERSON: Yes.
DR. GUIDICE: Dr. Shane.
DR. SHANE: Yes.
DR. GUIDICE: Myself, yes.
Dr. Greene.
DR. GREENE: Yes.
DR. GUIDICE: Dr. Tamura.
DR. TAMURA: Yes.
DR. GUIDICE: Dr. Rosenberg.
DR. ROSENBERG: Yes.
DR. GUIDICE: Dr. Dickey.
DR. DICKEY: Yes.
DR. GUIDICE: Dr. Lewis.
DR. LEWIS: Yes.
DR. GUIDICE: Dr. Lipshultz.
DR. LIPSHULTZ: Yes.
DR. GUIDICE: Dr. Macones.
DR. MACONES: Yes.
DR. GUIDICE: Dr. Stanford.
DR. STANFORD: Yes.
DR. GUIDICE: For the record, that was a unanimous round of
yeses. Thank you all.
The second question is, "Can we
define a subpopulation among women of reproductive age that needs additional
folic acid?" We have heard through
several different talks today about some subpopulations including women of
lower income. I'm just wondering if
there is any discussion about this. Also
including, I guess, for genetic polymorphisms.
Dr. Rice.
DR. RICE: Linda, we haven't spoken about diabetics or
epileptics. I know they have more neural
tube defects. With people taking
antiepileptic medications does the folate supplementation been shown to reduce
neural tube defects in that population of patients? I know there's some work by Abereese and some
models that show that it did and I'm just wondering. Dr. Greene is shaking his head no so he's
going to share it with us.
DR. GREENE: To the best of my knowledge, there is not yet
any data suggesting that folic acid supplementation is efficacious in reducing
the incidence of neural tube defects amongst women with diabetes melitis. I don't know that that's been studied in
women with epilepsy.
DR. WENSTROM: It has been studied and it works if you're
taking one of the drugs that acts as a folic acid antagonist like
carpomesopine. Valporate has a very high
risk of neural tube defects but it works by a different mechanism. I believe it affects the homeobox gene. But the folic acid antagonist would respond
to folic acid supplementation.
DR. GUIDICE: Yes, Dr. Crockett.
DR. CROCKETT: I think our speakers this morning did a
really nice job of presenting several different options about identifying
subpopulations that needed folic acid supplementation. I think some of those suggestions that they
had or that they used in the studies were either testing directly the serum RBC
levels of the folic acid or identifying by questionnaire those patients at
higher risk for neural tube defects, or those not adequately taking dietary
supplements or adequate dietary intake to achieve the recommendations. I would say that the answer to No. 2 is yes
and suggest that we use those markers to explore how we would further define
that subset.
DR. GUIDICE: Dr. Wenstrom and then Dr. Hager.
DR. WENSTROM: I would like to ask why we would need to do
that. Thinking back to, for example,
giving pregnant women multivitamins. If
you are eating a balanced diet, you really don't need them, although there is a
small proportion of pregnant women that would benefit.
Instead of trying to figure out who
those women are, we just suggest that they all take multivitamins. Since folic acid has such low risk and is so
inexpensive, do we need to identify a subpopulation? I mean, wouldn't that make it more expensive
and to what end?
DR. GUIDICE: Dr. Greene.
DR. GREENE: In studies done of women who were counseled
about the importance of folic acid and about which foods were rich in folic
acid, this was at least in the days prior to supplementation of flour, it was
demonstrated that there was not a significant improvement or, at least, not to
the levels recommended for folic acid intake merely by dietary counseling, that
women didn't really achieve adequate levels of folate intake until they took a
dietary supplement.
Now, I don't know -- I haven't seen
data about that done since fortification food supply but clearly before the
food supply was fortified, just merely counseling women didn't get the job done.
DR. WENSTROM: Can I clarify what I meant? That's not what I meant. I meant if we're talking about putting folic
acid into birth control pills, I would say is there any down side to just
offering that to all women? Why do we
have to pick out women that would particularly benefit since it's low risk and
inexpensive?
DR. GUIDICE: Dr. Mills, Dr. Dickey, and then Dr. Lewis.
DR. MILLS: I think the concern is that people, at least
the people in the Institute of Medicine report thought that 1,000 micrograms
was the upper limit that we wanted people to be getting per day. Just doing a little fast math, if someone is
already taking a vitamin tablet, that's 400.
If they are eating total for breakfast, apparently the average serving
that a woman actually takes is about 600 micrograms per day.
Then you've got the fortified foods so
I don't think I would want that woman being told to take an oral contraceptive
that contains folic acid. That would be
my rationale for trying to separate out the women who are having a low intake
of folic acid as compared to those who may be having a high intake.
DR. GUIDICE: I skipped over Dr. Hager so before Dr.
Dickey.
DR. HAGER: Well, I would agree with that. I think we do want to include as many people
as possible as we have all said but we do need to be careful about those who
are already supplementing or you have adequate dietary supplementation as well
as exogenous supplementation as you were saying. I think what this question points out to me,
and we have heard today, the need for improved educational methods. Apparently
the methods that we have used and we have failed as physicians for which I
apologize to adequately emphasize this to our patients in obstetrics but we
need to come up with some new ways to not only enhance supplementation but to
educate women about their need to take supplements and to improve their diet.
DR. GUIDICE: Dr. Dickey.
DR. DICKEY: Unless I don't recall accurately, the 1,000
is a somewhat arbitrary number. The IOM
has said it. They have attempted to say
to avoid things like masking pernicious anemia but, in fact, again from a
safety perspective, particularly in the reproductive age group for women there
is little data I recall seeing suggesting that you would be harming somebody if
you got them above 1,000.
I think in terms of question 2, yes,
there are some subpopulations we've heard today. They tend to be young women. They tend to be people with unintended
pregnancies. Therefore, perhaps, not
motivated to supplement. Certainly low
income. Some data we might have to
extrapolate but if you look at both Canada and the China study, maybe those
people who live in the north where there is less easy access to some of the
high folic acid foods.
But I think it comes back down to what
Dr. Wenstrom has said. It's cheap, it's
very safe, and so even though you can identify populations, I'm not sure what
you gain by identifying populations within the subgroup of women of
reproductive age.
DR. GUIDICE: Dr. Lewis and then Dr. Emerson.
DR. LEWIS: I would almost turn the question around. It's not that it's a subpopulation that needs
additional folate but a subpopulation that might be harmed by additional folate. The questions that -- not the questions but
the criteria that were posed this morning, as you said, Dr. Crockett, they are
adequate, you know, dietary supplementation and so on. I
mean, that identifies the people who probably already have adequate folic acid
and offering them a birth control pill that contains folate probably is not so
beneficial. Also from the study this
morning some 50 percent of intended pregnancies were not women who conceived
some 50 percent of intended pregnancies were not taking folic acid supplementation. There is a huge area of the population that
needs education about the importance of folate supplementation.
DR. GUIDICE: Dr. Emerson.
DR. EMERSON: Well, I guess my question was do we have to
define needs or can we go on the definition based on the recommendation that
women of childbearing age should be taking 400 micrograms supplementation in
which case identifying the subpopulation is easy. It's the women who aren't.
DR. GUIDICE: Yes, you have a comment?
DR. SHANE: It's not quite true because the women who are
not taking the pill are supposed to be getting half of that from fortified
food. Food is fortified specifically for
this problem, the NTD problem, although it's had other advantages possibly in
reducing homocysteine.
The idea of food fortification was to
reduce the instance of NTDs. Taking the
pill on top of the fortification is actually giving more than the
recommendation, although it probably would not be a problem to do that.
DR. GUIDICE: Dr. Wenstrom.
DR. WENSTROM: But I still believe Nick Wald's paper. In his analysis he predicted that at this
level of fortification the incidence of neural tube defects would drop by 20
percent and that's what we've seen which, to me, suggest that the fortification
isn't optimal. Adding extra folic acid
on top of that would be expected to decrease the incidence further.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: I agree with Dr. Wenstrom. It seems to me that all the data we've seen
identifies the group as needing the supplementation as those who would be more
likely to take birth control pills. I
think a bigger problem is that the very ones who are likely to need it most are
the ones who are least likely to take birth control pills but it can only help.
DR. GUIDICE: Yes, Dr. Patten.
DR. PATTEN: Yes.
I'm not a clinician and I need some information from a clinician. Is serum folate a routinely conducted part of
blood work and, if not, is it prohibitively expensive to conduct?
DR. ROSENBERG: The answer is no and no.
DR. GUIDICE: Dr. Hager.
DR. HAGER: Just one other things about identifying a
subpopulation. If we identify and label
a subpopulation, it may have the adverse effect of saying to those individuals
not in that population, "You don't need as much folic acid."
My concern is, and I think I'm hearing,
that we want all women to understand they need folic acid. Now, is there a maximum dose above 1,000,
above 2,000? I don't think that's real
clear but we don't want to convey to a population or subpopulation of women
that, "You don't need supplementation, in my opinion."
DR. GUIDICE: So the issue, I guess, before the committee
is how we advise the FDA whether we answer the question or whether we change
the question and reflect what I think I'm hearing around the table, although
I'm not sure there's a completely unanimous agreement on this.
The issue is that there is variable
usage, both usage of cereals and other foods, and it appears that the
supplementation efforts have not gotten women of reproductive age up to the
amount of folic acid to maximize reducing neural tube defects down to whatever
that unknown percentage is or unknown incidence is.
What I'm hearing is that it's better
to supplement everyone with the additional benefits, as we heard from several
of the individuals during the open public hearing, that there will be
discussion about health and taking care of one's self in either planning a
pregnancy or during the first trimester and during the whole pregnancy. So there are added benefits to this entire
approach which really go beyond the whole issue of just adding folic acid to
birth control pills.
So it seems that there is an
opportunity to supplement via a mechanism of supplementing folic acid to birth
control pills that will target a certain population, i.e., women who are taking
birth control pills, some of whom are not taking enough folic acid and some of
whom are probably maybe even more than they need, but that the safety margin is
quite significant and so why does it matter?
Why do we need to identify anyone?
As you mentioned, part of routine prenatal care and the routine blood
draw is not to draw a serum folate level.
I will ask the committee whether they
would like to actually answer two questions.
One is, is there a need to identify subpopulations and then, secondly,
can we identify subpopulations?
Dr. Mills and then Dr. Macones.
DR. MILLS: I actually see this as a very simple clinical
management issue. I think that when the
woman walks into the clinicians office. The
question is, "Are you taking a supplement containing 400 micrograms of
folic acid?" If the answer is yes,
you say, "Good," and you do not give them the oral contraceptive with
folic acid.
If the answer is no, you say,
"You should take an oral contraceptive with folic acid." I think that is going to avoid the potential
problem of over exposure to folic acid because, as Dr. Shane pointed out, the
average women is getting 200 micrograms of folic acid right now through food
fortification. If she's taking a
supplement, she's getting 600 micrograms of folic acid.
There's nobody that I know of who
thinks that taking more than 600 micrograms of folic acid is going to
substantially increase a protective effect.
We're talking more about whether 400 micrograms is sufficient. I don't see any benefit to giving someone who
is already taking a 400 microgram supplement additional folic acid.
I do think there could be a risk. I also don't see it as a difficult problem to
determine who should get it and who shouldn't because the woman who isn't
taking a supplement is a likely candidate in terms of needing it. The woman who is already taking a supplement
doesn't need it.
DR. GUIDICE: Thank you.
Mr. Macones.
DR. MACONES: Yes.
Related to that I guess why we're having this debate about whether or
not we should be giving this folic acid supplement and birth control pills to
all patients is because we don't know, at least I didn't see data about how
sensitive and specific asking that exact question is.
If you ask a woman if she's taking a
folic acid supplement, how often will she not have an appropriate red cell
folate level? To me without knowing the
sensitivity and specificity of asking questions like that or asking about
someone's diet, I don't think we could really adequately answer that first
question.
That, to me, would seem to be a very
important study to do, to actually assess whether or not asking simple
questions like that accurately predict what someone's red cell folate level
is. If they do, then we can end this
debate. If we detect 100 percent of the
patients, we can ask simple questions and just, again, give this supplemented
birth control pill to those people.
On the other hand, if it's not very
sensitive, if we only detect 80 percent given the very low risk, we might just
consider giving it to everyone as Dr. Wenstrom pointed out.
DR. GUIDICE: Dr. Greene and then Dr. Montgomery Rice.
DR. GREENE: In part the answer to this question is
getting into the next question which is the issue of potential toxicity. I would like to just make two points. One is, with respect to what you were saying,
Jim, what are you worried about if the woman is eating her Total and taking her
multivitamin and also, by the way, taking a birth control pill that has 400
micrograms? Obviously that gets to the
next question.
The other thing I think that we need
to consider as a practical matter is that the more complicated you make
medicine, the less likely it is to get done right. I think that we have to anticipate the
probability that if oral contraception -- if supplementation with oral
contraceptive pills with folic acid catches fire, as it were, and seems like a
good idea, it's unlikely that pharmacists all over the country are now going to
start stocking the 20 or 25 different brands of birth control pills with and
without folic acid in them.
I think we have to anticipate the
possibility or probability that if this seems like a good idea, it's probably
going to happen with most of, if not all, oral contraceptives and pharmacists
are not going to double their shelf space to carry those with and without a
folic acid with all of the other combinations of steroids that are available
and dosage regimens that are available, sequential, etc. I think we have to anticipate that looking a
little bit down the road.
DR. GUIDICE: Dr. Rice.
DR. RICE: Dr. Mills said something that was sort of, in
my opinion, contradictory to all these other presentations that show that one
slide over and over again which is that the plasma folate level and NDT risk,
that as that concentration went up, that we did see a decrease in neural tube
defects so there may be some potential in taking more than 600 micrograms. If
I remember, the Wald paper talked about if you took 1 milligram versus 5
milligrams, that the incidence of neural tube defect did continue to
decrease. This concern that 400 is
enough, I mean, that's somewhere down in our question, but I don't understand
what you were saying about the 600 micrograms and nobody would agree that at
600 micrograms there is any more protective effect because that's not what the
literature is saying unless I'm interpreting it incorrectly.
DR. GUIDICE: Dr. Mills.
DR. MILLS: There are a number of case control studies
that showed a major reduction in neural tube defects in women who were taking
400 micrograms of folic acid a day, so that's the first point.
The second point is that we don't know
exactly how many micrograms of folic acid it takes to raise your red cell
folate to 400. I would suggest that if
you take it religiously, in other words, if you don't skip three or four times
a week, that you probably will raise your red cell folate to over 400
micrograms with -- sorry, over 400 with 400 micrograms per day.
And the Walk study, which actually is
the Leslie Daly study, doesn't go all the way out. In other words, there's a point where there
weren't enough exposures to now what the effect is so it's not clear, as we
were discussing this morning, whether increasing the amount of folic acid that
you take in is actually going to continue to decrease the rate of neural tube
defects.
I want to state again that there are
two kinds of studies. It's a shame we
didn't actually have someone who talked about all of the studies reducing
neural tube defects with food fortification because there are U.S. studies
which show a drop from around 19 to say 30 percent and those studies were
incomplete.
They didn't have available to them
data on all the pregnancies. They didn't
have data on all the terminations. There
are Canadian studies which show a drop to 50 percent with almost the identical
fortification level. Those studies did
have all the prenatal terminations, still births, and all the other
outcomes.
So the point that I want to make is
that with an exposure of approximately 200 micrograms per day in fortified
food, the good studies show a 50 percent reduction so I don't think that the
data suggest that you need 600 micrograms per day, particularly since we are
already getting that 200 in food whether women are taking supplements or not.
DR. GUIDICE: Dr. Wenstrom and then Dr. Dickey.
DR. WENSTROM: Some people would say a reduction -- you said
you could get a 50 percent reduction. I
guess that is in reference to the Nova Scotia trial. But there are other studies that suggest we
could reduce it even further but we're talking about two different things. I think we started off talking about safety
and then started talking about efficacy.
The MRC trial used 4 milligrams a day
and none of those women had problems as a result. If someone is taking 200 in their diet and
then takes a 400 milligram supplement and then also gets it in birth control. That is still less than the 4 milligrams
those women took without any adverse effects.
I think the upper limits beyond which you would see some toxicity are
probably very high.
In terms of efficacy, that 4 milligram
trial reduced the recurrence risk by more than a 50 percent reduction. It was a 78 percent reduction. You could argue that an increased dose could
have further benefit without increased risk.
DR. GUIDICE: Dr. Dickey, you had a question?
DR. DICKEY: A question for Dr. Mills, I think, because I
think I'm saying the same thing Dr. Wenstrom is saying. It's not an issue of whether the current data
mostly points at 400 micrograms. The
question is is there data that suggest that there is a substantial safety issue
if patients -- if people who are taking folic acid find themselves at a 1,000,
1,200, or up to 4 milligrams.
DR. GUIDICE: Just a quick reply and then Dr. Emerson
because we are sort of blending questions here.
DR. MILLS: The Institute of Medicine recommended a
thousand micrograms of folic acid as the upper limit so that their data
suggested that there was a problem. Ten
percent of pernicious anemia occurs in this age group so there is definitely a
vulnerable population for that. That's
basically as much as can be said about that.
There are also questions now about
whether you start to block the effects of methotrexate when people get high
folate levels. That is the very early
stage of investigation so that we don't know that.
We could ask the FDA experts over here
what people would be getting if they started taking an oral contraceptive with
folic acid on top of a multivitamin and fortified cereal. I think you're going well over 1,000
micrograms a day and I just don't think it would be safe given that I don't see
any additional benefit in that population.
DR. GUIDICE: Dr. Emerson.
DR. EMERSON: My comment is just one about being careful
with the percent reductions. It's not
absolutely clear to me that our target should be a certain percent reduction. It's not absolutely clear to me that our
target shouldn't be reducing the level to 6 per 10,000 which some slide or
another was putting forward this idea.
Canada had a higher rate of neural
tube defects. It's easier to have a big
percentage decrease when you have a bigger rate to start out with, particularly
if what you are attacking is perhaps an environmental cause rather than some
genetic cause.
So, you know, going to Canada versus
the United States and we have the one study in China that showed big
differences between the northern part and the southern part. This is what makes it difficult. We don't have the data to say whether we
really can reduce it that much more but there is certainly some suggestion that
it can be reduced more.
And then the safety question that
comes up is going with that 1,000 milligram dose and saying how hard and fast
that is. We do have roughly 900 subjects
that got the 4 milligrams per day. We've
got roughly 3,700 in Hungry that got 800 micrograms per day which is a fairly
sizable safety population.
DR. GUIDICE: So we have Question No. 2, or Question 2-A, I
guess, and that is -- I would like to impose on Dr. Wenstrom to pose a question
to the committee about whether or not there needs to be a subpopulation
defined.
DR. WENSTROM: You'd like me to reword Question 2?
DR. GUIDICE: No.
Actually, I would like for you to reword your comment about the lack of
necessity for Question No. 2.
DR. WENSTROM: Considering the large safety margin of
supplemental folic acid is it necessary to identify a subpopulation who would
be the only people to get additional folic acid.
DR. GUIDICE: Okay.
For this I would like to call again upon members. Since you have answered one question so you
know who you are now. Just go around the
table starting on this side with Dr. Stanford.
DR. STANFORD: I would say that -- I mean, we don't
absolutely know for sure but if we're talking about women of reproductive age,
we're talking about 400 micrograms and not higher levels. I would say the reasonable answer is we
probably don't need to subidentify.
DR. MACONES: No.
DR. GUIDICE: To identify a subpopulation.
DR. LIPSHULTZ: No.
DR. LEWIS: No.
DR. DICKEY: No.
DR. ROSENBERG: I think we do need to identify
subpopulations. I think the rationale
for this is that there are populations whose protective effects are not being
achieved.
I think that we, therefore -- and I
think unless you totally reject the safety issue and accept the idea that there
are no safety issues and that there's a very wide safety margin and, in a
sense, therefore, reject the position of the Institute of Medicine, I think
there is a need for defining subpopulations and I think they can be defined.
DR. TAMURA: No.
DR. GREENE: I would answer the question that, yes, we can
identify a subpopulation that needs additional folic acid. I would also argue that they are the ones who
are least likely to be aided by this proposal.
DR. GUIDICE: The question at hand is, "Is it
necessary..." It's not the question
written down. This is 2-A. "Is it necessary to identify the
subpopulation in reproductive aged women?"
DR.
GREENE: No.
DR. GUIDICE: I vote no.
DR. SHANE: I think we should and I think the exclusion
should be people who are taking vitamin pills really. It's a very simple population to identify.
DR. EMERSON: I'll go with that same variance, that there
is not a need to identify a population that can take the supplementation but
once they have already taken the supplementation, they don't need to do it twice.
DR. WENSTROM: But we're talking about the same thing,
right? Whether they get the supplement
in the form of a pill or whether they get the supplement in --
DR. EMERSON: That's what I mean.
DR. WENSTROM: So you're not defining a subpopulation that
should only be taking a supplement, right?
You're just saying if they are already taking a supplement they
shouldn't take another one.
DR. EMERSON: That's correct.
DR. WENSTROM: So really you're voting no then if they are
not identifying the subpopulation.
DR. EMERSON: I'm not identifying the subpopulation to get
supplementation except if you were to say we've already got some people out
there who are getting it.
DR. WENSTROM: Okay.
I say no also.
DR. RICE: No.
DR. CROCKETT: No.
DR.
GREEN: I say yes for the reasons that
were given by Dr. Shane. I would also
point out that there's no -- we have no indication as to the duration for which
anyone taking an oral contraceptive with folate in it would be taking such a
supplement.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: Yes, we can identify a subpopulation.
DR. GUIDICE: We're asking is it necessary to identify a
subpopulation. I guess it has been --
DR. DARNEY: No.
DR. GUIDICE: Okay.
DR. PATTEN: Yes, I think you do need to define a
subpopulation. It would be those women
who are not taking multivitamins with the 400 milligrams. I think it will not be so easy to identify
those women, however.
I think the simple question is,
"Are you taking a multivitamin?"
I think a more difficult question, unless all multivits have 400
micrograms of folic acid, is to ask a woman, "Are you taking a
multivitamin with 400 micrograms of folic acid?" I think many women could not answer
that. Tell them to bring their bottle of
vitamins along to the clinic visit.
DR. GUIDICE: Just to clarify, the supplementation includes
women who are on the multivitamins or women who would need oral contraceptives
with folic acid. I don't want to change
your vote but just to inform you that for that interpretation the answer would
be no.
DR. PATTEN: I'm saying you do need to identify women who
are not taking multivitamins with 400 micrograms of folic acid. That's what my yes means.
DR. GUIDICE: Okay.
Thank you.
Next, Dr. Hager.
DR. HAGER: No.
DR. GUIDICE: Okay.
Thank you.
Yes, Dr. Stanford.
DR. STANFORD: I'd just like to second Dr. Macones'
suggestion that there really need to be some studies about what is the
sensitivity and specificity of the question, "Are you taking
multivitamins" for a gold standard of red cell folate levels. I think that would be a very valuable background
piece. That's just something for the
FDA.
DR. GUIDICE: Thank you.
Now to answer Question 2-B. The
result of that was 14, no and 4 yes. And
Question 2-B then is directly written here.
"Can we define a subpopulation among women of reproductive age that
needs additional folic acid." This
is women beyond those who are --
DR. LIPSHULTZ: I'm sorry.
Didn't you negate this second part by changing the first part?
DR. GUIDICE: I think that we have. I just want to be sure that the FDA has enough
information from us. You don't need us
to do the second part? Okay. Then Question 2 has been answered.
We could have a break at this point
and come back in 10 minutes or complete No. 3 but I think this may spur quite a
bit of discussion so let's take a 10-minute break.
(Whereupon, at 3:36 p.m. off the
record until 3:47 p.m.)
DR. GUIDICE: Would everyone take their seats, please, so
we can continue. The third question is,
"Are there any safety issues associated with folic acid supplementation targeted
at reproductive aged women? If so, what
are they and would these safety issues not be a concern below a certain level
of supplementation and, if so, what is that level." I don't see a question about above a
certain level but perhaps we can entertain that as well.
Dr. Crockett.
DR. CROCKETT: I'll start this one. I have a couple questions about this. It struck me as we were going through this
discussion about safety and toxicity, which I realize are not the same
thing. Folic acid is already approved
with a category A labeling which means that there have been studies showing its
safety in the first trimester of pregnancy.
As we discussed the safety issues
concerned with folic acid supplementation in this target population, I think
it's important for us to keep in mind that we do have the second patient to
keep in mind, the fetus. As we were
going through our talks this morning I kept hearing there's not enough data on
the higher end of the safety spectrum.
There's not enough data. We don't have studies. We don't have this. I'm wondering, and I'm going to pose this to
the FDA or whoever can answer it, where did the studies come from that gave it
a category A pregnancy rating and where were they this morning because I think
that would be helpful.
DR. GUIDICE: That's a very good point. Could someone from the FDA enlighten us in
that regard?
DR. GRIEBEL: We don't know the answer to that. We don't know the exact studies that were
done.
DR. GUIDICE: Okay.
Does anyone around the table know?
DR. ROSENBERG: No, I don't have the answer to that but I
would just elaborate further on the question.
We have from the Institute of Medicine, I think, a number that has to do
with safety or upper level with respect to pregnancy. I don't remember what that number was, nor do
I believe how that was derived.
Was that derived on the basis of
specific data or was that -- my guess is it was just an extrapolation from the
adult data. But it does raise the
question of whether there is information that indicates the safety range for
the fetus with various doses of folate.
We obviously have the experiment of the 4,000 micrograms which were an
effort to prevent recurrent neural tube defects but I'm not aware of how much
work we have about the range of folate doses and the effects on early fetal
development.
DR. GUIDICE: Dr. Wenstrom and then Dr. Darney.
DR. WENSTROM: Even if our FDA representatives can't tell us
the data, if folic acid has already been approved, unless we have reason to
suspect that it behaves differently when it's combined with an oral
contraceptive, why do we need to answer this question again? By its very approval hasn't that question
already been answered?
DR. MONROE: Well, our questions are all sort of
interrelated and related to if you felt that adding additional folic acid would
be meritorious. We wanted to know if you
have some concerns about what level would you then be concerned about
toxicity. You've had some general
discussions about that and that was the purpose of that question.
So what you're sort of implying is
there's no upper bound. Well, we don't
have any such data that would say that so we wanted to know from the committee
up to what level would they not have any concerns were you to feel that
additional supplementation would be of benefit.
DR. GUIDICE: Dr. Rice.
DR. RICE: I guess we would side with you all. You all have already approved 1 milligram
doses, correct? I mean, if you get 200
from the diet and then let's say I take another 400 with the supplement and
then, oops, I end up taking a birth control pill with another 400, I'm just at
my 1 milligram.
I mean, if you already have it
approved for safety at 1 milligram, what's the question? I mean, are you asking would we be concerned
if we wanted to have 4 milligrams? Maybe
we would but we would expect that before that what happened there would be some
safety studies done before that level would be approved.
DR. GUIDICE: Yes.
DR. ZEISEL: It might help if you consider that every
obstetrician in this room is prescribing vitamins for pregnant women that
contain folic acid and contain 800 of folic acid, or a milligram depending on
the preparation. If you're worried about
fetal health, think about that you all for years have been prescribing 800 or a
milligram of folic acid to every woman who has a baby -- is going to have a
baby with you.
DR. MONROE: I would just like to say that is not exactly
analogous because there you are talking about just for the duration of a
pregnancy, If you are going to add this
to a supplement that a woman might be taking for four or five years, the level
which might not be a problem for eight months might not be equally safe over a
course of four or five years. I'm not
sure if they are identical questions.
DR. GUIDICE: Dr. Rader and then Dr. Shane.
DR. RADER: I think there's a little confusion and it's
probably because our drug regulation for folic acid goes back to the '70s. It's not approved for pregnancy. I think that's a misnomer. It's approved to treat the megaloblastic
anemia that may come up but it's a megaloblastic anemia treatment.
On the labeling according to our old
regulation of a product of 1 milligram that would be given in that dose, it has
to bear the label that doses above about .1 to .25 milligrams of folate may
mask the anemia vitamin B-12 deficiency.
There's a labeling stipulation on that old drug regulation. I know it's old and hasn't been updated but
it's not "approved for pregnancy."
It's approved to treat megaloblastic
anemia so this is a whole different matter just so you're not taking up
something that is a blanket assumption.
It isn't approved for pregnancy.
It's approved to treat a disease.
DR. CROCKETT: I understand that. I guess I didn't phrase that correctly. You're absolutely right. It's indicated for the megaloblastic anemia
but it's got a pregnancy category safety rating of A and almost nothing we use
has A.
DR. RADER: Well, we know that the regulation goes back
at least to '75 and before so whether there were a lot of good studies done or
whether those studies would pass mustard now is an open question. It's a very, very old regulation that wasn't
updated at a time when -- it was just like left there like a grandfathered in
thing. The nature of the studies done
I'm not certain we could even find that now from that many years ago.
DR. CROCKETT: In that case, I would like to make a
suggestion to the FDA that in the process of following this up that those
studies get pulled up and looked at.
DR. GUIDICE: Dr. Shane.
DR. SHANE: I was going to mention that probably most
people are aware that before folic acid was isolated it was described as the
Wills Factor which facts there was missing in megaloblastic anemia pregnancy. Where we often think about megaloblastic
anemia with B-12 deficiency and worry about the age if given too much folic
acid, in pregnancy if someone is megaloblastic they think folate deficiency,
not B-12 deficiency.
Having said that, when we discuss
folic acid it's not always clear to me that people understand that we're
talking about very large doses of folate being supplied to people compared to
what they used to get in the diet. it's
not a trivial small extra amount of folate.
As I mentioned, the 200 micrograms of
folic acid that is really supplied with fortification, although it doesn't meet
the 400 micrograms suggested by IOM and others is equivalent to an RDA
essentially of food folate. Most people
before were not receiving the RDA for food folate. RDA is enough for 97.5 percent so it's pretty
much a dabling of the folate intake of the population just for the 200.
The concern about folate toxicity,
it's really not toxic. It's not a
traditional safety issue. It's a masking
issue. The folate itself isn't
toxic. Having the targeted population in
this case reduces some of the concerns about that kind of safety, but it's not
illuminated entirely because 10 percent of the people who develop megaloblastic
anemia are in this age group. There's
less of a concern than if the whole population was getting this amount of
folate but there is still a concern that remains which should be thought about.
DR. GUIDICE: Yes, Dr. Wenstrom.
DR. WENSTROM: Can you give that a number for me? I mean, if 10 percent of megaloblastic anemia
patients are reproductive age, how many pregnancies per year -- there are 4
million pregnancies a year. How many
would include a mother with pernicious anemia?
DR. SHANE: Ralph would probably know that better than
me.
DR. GREEN: Actually, I had this question earlier over
lunch from someone. I have to say as a
disclaimer it's only an estimate. My
estimate came from data on the overall prevalence of pernicious anemia in the
population which conservatively ranges around 1 to 3 percent so let's take a
figure of 2 percent.
If you take that, generally speaking
if you apply that figure to the elderly population who are, as we've heard,
considered to be at greatest risk, in the U.S. population currently we're
talking about 35 million people in that age category and 2 percent of that
population is around 600,000 so getting on at maximum to about a million. Now, that's the elderly population.
If we extrapolate from that and say
that 10 percent overall of pernicious anemia might occur in the age group of
women who are of childbearing age, then it would be 10 percent of that figure
at maximum. So 10 percent of 600,000
would be 60,000 potentially but, again, there are a lot of assumptions
there. There are a lot of estimates
there and I'm sure there are people here who could find fault with that
reasoning.
DR. GUIDICE: Dr. Wenstrom.
DR. WENSTROM: It's just hard to believe because I've never
seen a case in a pregnant woman. Has
anybody?
DR. HAGER: I've never.
DR. ROSENBERG: B-12 anemia?
DR. WENSTROM: Pernicious anemia.
DR. GRIEBEL: Can I just --
DR. WENSTROM: My concern is masking pernicious anemia.
DR. GRIEBEL: I'm sorry.
Can I just clarify that I'm not talking about during pregnancy? Again, I think the important point that was
made on the other side of the table from the FDA is we're talking about a
possibly five to 10-year duration of taking this amount of folic acid. I agree it's excessively rare. I have seen cases. It's excessively rare during pregnancy but
we're dealing here with increased folate intake over a period that could extend
over several years.
DR. GUIDICE: Dr. Montgomery Rice.
DR. RICE: I need some of the nutritionists to help me
with this. Tell me if I took a milligram
a day tablet, if you can, what level am I going to have in my serum and when
are you going to become concerned about it for a safety reason? Then explain to me this cumulative effect,
this theoretical cumulative effect that we are kind of alluding to because this
is a water soluble vitamin. Help me with
this from a pathophysiological point of view.
DR. SHANE: Well, I don't subscribe to the cumulative
effect. I think what happens is you
build your stores up t a certain level of intake. It's not really stores. It's just that it happens to be in
tissue. There's no store waiting to be
used for anything. Above a certain level
you get rid of it essentially.
DR. RICE: Right.
So you max out in your tissue.
You have a saturation level.
DR. SHANE: You max out so it's not going to be -- there
are really probably no harmful effect per se for having the maximum level, you
probably don't need the maximum level but there have probably been no harmful
effects per se.
Pernicious anemia is a condition that
develops over many years and you're talking about a population -- a large
population a small percentage of which may be developing pernicious
anemia. They are losing their ability to
absorb B-12 and you reach a point where your stores disappear and you don't
display the anemia. That's really the
safety concern.
DR. RICE: But they are developing the pernicious anemia
but they are not developing it because of a cumulative effect. They are developing it because they are
taking a dose that got them to that point --
DR. SHANE: No, no.
There's some discussion about whether high folate will exacerbate the
symptoms of B-12 deficiency but I don't think there is any real evidence that's
the case. A concern is the masking. If you have very high folate stores, it can
prevent the symptoms of your B-12 deficiency because the anemia is due to an
induced folate deficiency. Do you
understand? So if you don't get the
anemia, then you may develop a neurology which is much more difficult.
DR. RICE: Okay.
And then the 1 milligram. If I'm
taking that 1 milligram dose, what is my serum level going to be?
DR. SHANE: The serum level is going to be probably twice
as high as if you were taking the 400 micrograms.
DR. RICE: Okay.
DR. GUIDICE: Dr. Wenstrom.
DR. WENSTROM: It isn't in this book but I read an editorial
by Dr. Wald saying that if you don't identify pernicious anemia until you've
had neurologic symptoms. That doesn't mean
that they are permanent and they are usually entirely reversed with
therapy. His argument was that even if
folate masks the symptoms of pernicious anemia, once you recognize it it's
entirely treatable. Do you think that's
true?
DR. GREEN: I think our knowledge on that is if there has
been B-12 deficiency resulting in neurologic damage of greater than six months
duration, then there is pretty good evidence that a considerable proportion of the
neurologic damage is irreversible so it's really a question of how severe and
for how long. Any unrecognized B-12
deficient myloneuropathy that goes six months or longer is at risk of being
irreversible.
DR. GUIDICE: So it sounds like we have identified a
population where there are not so much safety issues but masking issues and,
therefore, safety issues. Is this
correct? Does the group agree upon this?
DR. RICE: But we're already doing that in
practice. A large percent of our
patients take a supplement of multivitamins which may have 400 micrograms every
day and they eat their fortified cereal, etc., etc.
They are already getting some dose that
may be getting up to some upper limits.
Since we fortified foods and since we now have the dosages in
multivitamins, etc., are we seeing an increase in the incidence of pernicious
anemia being masked by excessive amounts of folate?
DR. GUIDICE: Anyone?
Yes. You have a comment?
DR. OAKLEY: Godfrey Oakley again. I just wanted to make clear of what I heard
as confusion and that is it should be clear that folic acid doesn't cause
pernicious anemia. I mean, you lose
intrinsic factor. That's how you get
pernicious anemia.
If you lose intrinsic factor and
you've got anemia or you get neuropathy, then you can go see a doctor. You can have a B-12 level and so on. The concern here would be would someone not
show up because they had been on enough folic acid to keep the anemia from
coming up.
What is toxic about that is not
getting B-12. It's not about getting --
it's not because you are getting folic acid.
Of course, if a clinician has a suspicion, then he or she could order a
B-12. I think Dr. Mills' paper sort of
speaks to this a little bit. I think
it's the only data out there post-fortification.
As I understand it, they essentially
didn't find any evidence in the elderly who were at risk for having a problem
from the current fortification that has gone on. Now, you could do a different study and so on
but the current evidence doesn't suggest that there's a problem.
DR.
GUIDICE: Dr. Crockett, Dr. Shane, and
then Dr. Darney.
DR. CROCKETT: I have a real problem trying to answer No.
3. I think we have identified one very
important factor but the most disturbing thing to me is that we are being asked
to have a discussion about safety issues when there is no good study for us to
refer to.
It kind of makes our discussion a moot
point. What I would like to suggest is
that the FDA as they develop a clinical trial plan with the company, that they
recommend that there be toxicity testing and safety testing. This is a question that is going to come back
to the FDA or a similar committee at a future time once it's tested and
done. I think there is a tendency because folic
acid is a nutrient or a nutrition supplement and to not look at it as a
bioactive drug. I think that is a
mistake. I think that it should be
looked at as any other drug with appropriate phase 1, 2, 3 trial testing and
develop it.
DR. GUIDICE: Thank you.
I lost my roster of people. I
think Dr. Darney was in the queue and Dr. Mills next.
DR. DARNEY: I wanted to pursue Dr. Montgomery Rice's
issue and ask whether or not a relatively high dose, overdose beyond the
minimum daily requirement of folate, is more effective in masking or it doesn't
matter how much you take, it's masked even at a low dose of supplementation.
DR. SHANE: You need large doses to mask
effectively. As I mentioned this
morning, before people realized there was such a thing as B-12 and they thought
folate was the factor missing in pernicious anemia patients, large doses of
folate were given and did treat the hematological symptoms.
I think it was five or 10 milligrams,
wasn't it, Ralph? Five to 50 milligrams,
so that's why you don't get five to 50 milligram folate pills now at your local
drug store.
DR. DARNEY: So wouldn't that 400 we're talking about be
trivial in relation to 50?
DR. SHANE: No. I
thought the question here would be there is a 1 milligram limit out there from
the IOM report. Is there a reason why
that should be changed for this particular population? Of course, when one sets these upper limits,
they are supposed to be set for safety considerations. Not that 1.1 is bad for you and 1 is okay but
1 should be fine and maybe 5 would be fine but you don't know so you set it at
1 to be on the safe side.
People may think for this particular
group where pernicious anemia is less likely to be a problem than in the
overall population that includes the elderly where maybe a high level might be
okay. Without going into all the details
about why a particular upper limit is set, it's difficult to just give a
number.
DR. GUIDICE: Dr. Mills and then Dr. Rosenberg and then Dr.
Lipshultz.
DR. MILLS: As Barry has suggested, all of the data we
have on masking was due to therapeutic errors so it's never been studied
systematically. The lowest dose of folic
acid that has been associated with masking is 400 micrograms.
The IOM and other groups have picked
1,000 micrograms as the safe upper limit, in part because they thought that was
the dose where it looked from very incomplete data as if masking became a real
serious problem. That is a guess based
on limited data but there was a reason for saying 1,000 micrograms was the
limit.
The other point I want to bring up is
that this isn't the only issue. If you
gave people larger and larger doses of folic acid, eventually you would reach a
point where drugs that work by antagonizing folate would be compromised and
methotrexate is a good example of that.
It essentially just works by blocking the folate enzyme.
That's why the abstract I mentioned
this morning suggesting that women you have the highest blood folate levels
were the least likely to respond to a therapeutic dose of methotrexate for
ectopic pregnancy because that may be the first sign I know of in the
literature that people are starting to reach the levels of folate where you are
blocking those effects.
There are a number of reasons why that
would be a very serious problem because, as you all know, methotrexate has a
great number of clinical applications including as a chemotherapeutic agent and
it could be very tricky to identify that kind of a complication in the sense
that you would simply see more people dying of cancer who were getting a
recurrence of cancer, but it would be awfully hard to pin down that it was
because methotrexate was being compromised by a very high folate level.
DR. GUIDICE: Thank you.
Dr. Rosenberg.
DR. ROSENBERG: With respect to masking, meaning that vitamin
B-12 deficiency anemia, megaloblastic anemia, responds to folate and,
therefore, its diagnosis is delayed or masked, there is data, as Jim Mills
indicated, that indicated that one can see that kind of hematologic response in
doses as low as 400 micrograms, even though a lot of the earlier work was done
with larger doses when it was thought that these large doses of folic acid
might be the appropriate treatment for pernicious anemia even before B-12 was
discovered as the actual cause.
I remind you that there is also this
literature which shows that not only do some of these doses of folic acid,
which may in the early days have been ranging from 2 up to 5 or 6
milligrams. Not only were they able to
change the hematologic picture but while these people were being erroneously
treated with folic acid, many underwent significant worsening of their
neurologic problem and leaving open the question of whether that was simply a
delay in the treatment with B-12 or a result of the interaction of folate and
B-12 which we know occurs in certain metabolic cycles. I
think to use the word masking as the description of the toxicity risk here is
okay as long as we understand the complexity of what we're talking about. I do agree with the challenge to the FDA, or
whomever, that this is an area that is still not well defined and we are
dealing with safety concerns without much data upon which to base our
judgement.
DR. GUIDICE: Dr. Lipshultz, Dr. Friedman, Dr. Darney.
DR. LIPSHULTZ: I think this discussion is going on
long. Perhaps longer than necessary
because we are trying to make a round peg fit into a square hole. I mean, it's called a supplement but clearly
this has gone beyond a supplement and we are now back to trying to discuss
safety on a drug that has never been studied rigorously the way a
pharmaceutical needs to be studied.
I think if this is going to be
packaged with a pharmaceutical, it needs to be studied like a pharmaceutical
and has to be moved out of the realm of an additive or a supplement. I think really to answer this question is
very premature because it's never been studied the way it should have been studied
had it come to market as a pharmaceutical drug.
DR. GUIDICE: Thank you.
Dr. Friedman.
DR. FRIEDMAN: There are just a few points I would like to
make. One is just to remind everyone on
the committee that the Institute of Medicine recommendation of an upper limit of
1,000 is for people who are not under the care or the supervision of a
physician. This would be a prescription
product. That's No. 1.
No. 2, if you think of how people
could get to 1,000, we've talked about examples of people taking their
multivitamins, eating their Total. Those
things have B-12 in them so many of these people will be getting B-12 as
well. I think that's important to
realize.
The third thing is we're not talking
about giving a whopping dose. We are
talking about an incremental dose for a woman every day of 400 micrograms so I
would ask the question what is the likelihood that an incremental dose of 400
micrograms could cause safety concerns?
If we remember the figure that 30
percent of reproductive aged women are currently taking a multivitamin every
day and 16 million women are taking birth control pills every day and they've
done so chronically, there is a lot of clinical data out there, basically
in-field data that attest to the safety of this combination.
DR. GUIDICE: Dr. Darney and then Dr. Green.
DR. DARNEY: I wanted to disagree with two of my
colleagues. We're talking, as Dr.
Friedman said, about supplemental dose, not a therapeutic dose. I don't see that -- I don't understand why it
would require a complete re-review and classification as a medicine.
In regard to the methotrexate issue,
all patients who receive methotrexate are under a physician's care and we
always ask them before we treat GTD or ectopic pregnancy, "Are you taking
vitamins and don't eat your spinach?" so that we don't have that effect
occur.
DR. GUIDICE: Dr. Green.
DR. GREEN: Just a very brief comment about one thing
that I think is very important to point out to the entire panel here with
respect to the comments made by Dr. Friedman.
That was the comment about the protective effect of vitamin B-12 in any
of the multi-vitamin supplements or the breakfast cereals which contain vitamin
B-12.
That is to point out that the disease
that we're concerned about here, malabsorption of vitamin B-12 caused by
pernicious anemia, will not respond -- will not respond to the amount of
vitamin B-12 present in these multivitamin preparations or breakfast cereals. Generally 5 micrograms, nowhere near enough
because they are malabsorbing so they would absorb at best a fraction of a
microgram.
DR. GUIDICE: Thank you.
Dr. Lewis.
DR. LEWIS: I would sort of propose that we reword this
question, "Are there any safety issues within the realm of the limits set
by the Institute of Medicine,"
because we are wandering all over the map here from talking about 5
milligrams down to 400 micrograms associated with folic acid supplementation
and, if so, what are they.
Then we've heard illusions to cases of
vitamin B-12 deficiency being masked by as little as 400 micrograms of folic
acid which is clearly an important observation.
If these are in the realm of case reports, I think we have to think of
that differently than if it's a specific incidence among people who are
receiving that much medication.
I assume the Institute of Medicine
researched this fairly intensively before coming up with that limit. I think we are well within that limit with
what we're talking about.
DR. GUIDICE: Well, it seems that we're at a point where we
perhaps can look at question No. 3, perhaps with the modification of the
IOM. I think the major point of this
question is to identify women who would be at risk in terms of folate
supplementation.
One of the issues -- one of the groups
that we seemed to have identified, since we've spent a lot of time discussing,
is women with pernicious anemia or who will develop pernicious anemia. There was also a mention of women yet to
undergo methotrexate therapy. We haven't
really discussed some other groups, women who are on anti-epileptic drugs. There are several groups that are in a
special category with regard to folate supplementation.
One would expect that if physicians
are prescribing oral contraceptives with this supplement, that this would be
part of the counseling and interaction or health care provider. I would assume that something would be done
certainly in the labeling of the combined product.
I would like to ask the committee -- I
think we've had enough discussion. We
have two other questions after this. We
haven't really touched upon one of them but if we could go around the room now
and take a vote on are there any safety issues associated with folic acid
supplementation targeted at reproductive aged women.
And if someone wants to add the 1,000
milligram maximum. I don't know if there
is a consensus on this -- I'm sorry, microgram -- maximum on this. Is there a consensus in the committee about
adding that with the IOM recommendation of 1,000 micrograms?
Dr. Hager.
DR. HAGER: Would it not be possible to pose the question
as you are regarding safety issues that the safety issue that we're all talking
about is basically dosage. The answer is
that we don't have enough information. I
don't think gestational trophoblastic disease is an issue.
PA may be in a very small group of
patients but it seems to me that the safety issue that we're all hinting about
is dosage and we don't have enough information.
It certainly seems as though there's not a major problem with current
doses of the supplement of 400 micrograms.
DR. GUIDICE: Dr. Wenstrom.
DR. WENSTROM: I think the major safety issue is taking it
without being prescribed by a doctor. In
fact, it sounds like taking it as part of a birth control method would be safer
because you would be under a doctor's care and you would be evaluated for all
these possible risks.
I think the safety issues are for
those women that goes to Sam's Club, buy a quart of folic acid and take it
unsupervised. Really I think the safety
issue is taking it without being supervised by a physician. You don't even have to mention the dose. I guess what I'm saying is if you're being
seen by a clinician at regular intervals, most of the concerns we have would be
identified by that physician, right?
DR. ROSENBERG: I don't know how serious we want to be about
the specificity of the question. Is this
question now about are there safety issues about folic acid supplementation in
reproductive age women? It doesn't say
if delivered with a oral contraceptive.
I'm not sure what the intention of the question is.
DR. RICE: Maybe the FDA can help us with what they
really want us to answer. I thought they
wanted us to answer that if there was a product that was available or
contraceptive pills and it had 400 micrograms of folic acid in there, would
that be a safety concern based on the amount that women are getting in their
fortified and maybe the amount they would get in a multivitamin. Would that be a safety issue? Is that what the question is?
DR. GRIEBEL: Yes.
DR. RICE: Okay.
Can we answer that question since they said yes?
DR. GUIDICE: Now we can have a simple yes or no vote. Let's start then with Dr. Hager.
DR. HAGER: No.
DR. GUIDICE: Dr. Patten.
DR. PATTEN: Yes.
And this is my reason for saying yes.
I am told that those cases of masking that have occurred and then
identified have occurred at cases where there were 1,000 micrograms or more of
folic acid being administered. My safety
issue is the woman who is getting the supplemented contraceptive, getting 200
micrograms in her diet, and taking a multivit.
We've been told that there are
approximately 600,000 people in reproductive age who conceivably have
pernicious anemia assuming that half of those are women. Not right?
60,000. Sorry. Assume half of them women. Here is the thing I'm thinking of. We're trying to prevent perhaps 1,000 neural
tube defects using this approach. Are we
putting at risk a thousand or more women who may have pernicious anemia
masked? That would be my question. That's why I say yes. There's a safety issue.
DR. GUIDICE: Okay.
Thank you.
Dr. Darney.
DR. DARNEY: Well, I want to retort by saying no because
we were just told that if you ate a Big Mac and drank a quart of orange juice,
you could mask your pernicious anemia.
Yet, we're talking about people who will be under the care of a doctor
who will say, "If you take these birth control pills with folate, you
really don't need to take a supplement."
DR. GUIDICE: Or eat a Big Mac.
Dr. Green.
DR. GREEN: I say yes.
I do want to point out that I don't think that there's any way that one
can set up an equivalency between risk to potential infants of neural tube
defects and women who may have megaloblastic anemia masked so it's not that
issue at all. It's merely that 1,000
micrograms is the dose recommended by IOM as the upper limit for safety and, as
such, the answer to the specific question, "Are there safety issues?"
is affirmative. I vote yes.
DR. GUIDICE: Thank you.
Dr. Crockett.
DR. CROCKETT: If we're specifically talking about the 400
microgram level, which I believe you included in the question, my answer is
no. However, I'm not convinced that the
company has identified the optimum dosing and there may be safety issues at
higher doses that are not known yet.
DR. GUIDICE: Thank you.
DR. RICE: No.
DR. WENSTROM: No.
DR. EMERSON: No.
DR. SHANE: No at 400 provided they are not taking
supplements as well. Last time my yes
was converted to a no.
DR. GUIDICE: I say no with some of the above caveats.
DR. GREENE: No, I'm not worried.
DR. TAMURA: Yes, I am worried but even why is that I
don't know where the person who is going to be prescribed folic acid containing
oral contraceptives have enough time to ask questions to physicians. The reason why I'm saying is when my wife was
pregnant she had slightly above normal range of hematocrit and the nurse
practitioner came in and said, "Your wife needs iron." I said, "Why?" She couldn't answer and we didn't give iron to
my wife. That's what's happening so yes.
DR. GUIDICE: Thank you.
Dr. Rosenberg.
DR. ROSENBERG: Well, are there safety issues? I would have to say yes. If the predominant vote of the previous
question was don't define the population, and we're talking about everyone,
then clearly we are going to have considerable numbers of people who are
getting more than a milligram a day of crystalline folic acid from a
combination of their oral contraceptive and other supplements and the 200 or
300 crystalline folic acid that they are also getting from other sources. If we don't define a subpopulation, then I
think we have safety issues.
DR. GUIDICE: Thank you.
Dr. Dickey.
DR. DICKEY: I think I have to agree yes. I don't think we have the data to answer the
question to be perfectly honest with you.
I don't want us to lose track as most of our conversation has been about
the masking of pernicious anemia if there remain some other safety issues that
need to be addressed such as people taking medications that may have some
antifolate inhibitors there or activity there.
At 400 micrograms probably not with the data we've heard today but I
have to say the data has been anything but clear.
DR. GUIDICE: Dr. Lewis.
DR. LEWIS: No.
DR. LIPSHULTZ: Yes.
DR. MACONES: No.
DR. STANFORD: I'm going to go with Dr. Dickey. It's unknown with the current data.
DR. GUIDICE: Thank you.
We've already answered -- we've had quite a long discussion on this and
since we have half an hour to answer the last two questions, I think we have
probably given the agency enough information for 3-A and 3-B as well so I would
like to go on to No. 5.
PARTICIPANT: What was the result?
DR. GUIDICE: The result?
What is the total? Dr. Crockett,
what was your vote? Was it a yes or a no?
DR. CROCKETT: No.
DR. GUIDICE: Okay.
So the result of the vote was 11 no and 7 yes.
Question No. 5, "Is an oral
contraceptive pill a reasonable delivery vehicle if additional folic acid
supplementation is likely to provide public health advances in preventing
further neural tube defects?" Then
A, "If so, would 400 micrograms be a reasonable dose. If 400 micrograms is not appropriate, what dose
of folic acid should be provided?"
Please note that we are asked to vote
on the question and Section A. I think
we have actually had the discussion in B but if there is additional discussion
needed, we can certainly devote some time to that. Is there any discussion about the overall
question, No. 5?
DR. ROSENBERG: Did we skip 4?
DR. GUIDICE: Yes, we did.
The reason for that is that we have already had so much discussion. In fact, it was almost included -- it was included
in the last question as an implicit assumption of 400 micrograms so I thought
we would go straight to the next 400 microgram question.
Does the committee need to discuss
whether or not -- essentially this is really the concept of the entire meeting
whether this is a reasonable vehicle in which to supplement or provide
additional folic acid supplementation to women of reproductive age.
Dr. Dickey.
DR. DICKEY: I think that it is a reasonable vehicle but
it is not a vehicle without its own problems.
For example, for the unintended pregnancy that occurs for a woman who is
currently taking contraceptives, it should obviously address the problem.
There's reasonable data that says up
to three months out you maintain a fair amount of increase in your folic acid
but there wasn't a lot of data about what happens at 4, 5, 6, etc. There was some implication that the education
that goes along with using a supplemented oral contraceptive might, in fact,
motivate a few people. I think it is a
reasonable delivery vehicle but it's certainly not a panacea for the problem.
DR. GUIDICE: And the issue of continuation or persistence
of folic acid X number of months out we still have yet to address in question
No. 4.
Dr. Greene.
DR. GREENE: I would like to ask the representatives or
the sponsor to polish up their crystal ball for us and tell us the degree to
which the promotion of other steroid contraceptives that are not administered
orally may undermine the potential public health benefit of oral
contraceptives. In other words, as more
women choose hormonal contraceptives delivered not orally, how is that going to
affect this as a public health intervention.
DR. GUIDICE: Please identify yourself.
DR. CAFFERSON: My name is Michael Cafferson. The question comes in a few parts for
me. No. 1, since this is a concept and
no products exist, and we're talking about orals today, one of the questions
that comes up is would other delivery systems (A) be amenable and, if they were
amenable, be of interest for development.
The answer is I'm not certain of the first part but we would certainly
look at that. Would we be interested if
they were amenable to what I hope will be found to be a reasonable
concept? We would certainly probably be
visiting with you again to talk about that possibility.
To be more specific in answering your
question, if we take as the premise other delivery systems do not now and won't
have this option, I would say that my assumption is, No. 1, virtually all
contraception and family planning decisions would be predicated on what woman
or a couple and a health care provider determine will be the most appropriate
method of contraception.
Secondarily, if a product were
selected such as an oral contraceptive, then that subsequent discussion if we
presume the subpopulation, those women not taking other supplements, then that
discussion would happen.
It's hard for me to predict exactly
what penetrants other than oral deliveries would have. There have been waxing and waning successes
with different entrants. Implants would
be one extreme. The still on the rise
patch another. And there are obviously
many other potential delivery systems.
As has been said a number of times,
none of us view this as the one and only way to reduce NTDs. It's one more contribution so would other
delivery systems reduce some of that potential population? Sure, but that's why this is only one of what
I hope will be many more approaches to get to that magical all NTDs that are
preventable by folic acid being prevented.
DR. GUIDICE: Thank you.
I'm just wondering if we need an awful lot of discussion about Question
No. 5 or if we should go directly to a vote.
Let's go straight to a vote then.
Dr. Stanford, starting on your side
this time. This is, again, for proof of
concept here.
DR. STANFORD: So all three questions or -- I'm sorry. I'm a little unclear.
DR. GUIDICE: Just the first part.
DR. STANFORD: Okay.
I think it is reasonable.
DR. MACONES: Yes.
DR. LIPSHULTZ: Yes.
DR. LEWIS: Yes.
DR. DICKEY: Yes.
DR. ROSENBERG: Yes, but I must return to the idea that it is
yes particularly because of the possibilities of dealing with subpopulations.
DR. GUIDICE: Yes, if we are living in an ideal world.
DR. GREENE: Yes.
DR. GUIDICE: Yes.
DR. SHANE: Yes.
DR. EMERSON: Yes.
DR. WENSTROM: Yes.
DR. RICE: Yes.
DR. CROCKETT: Yes.
DR. GREEN: Yes.
DR. DARNEY: Yes.
DR. PATTEN: Yes.
DR. HAGER: Yes.
DR. GUIDICE: Thank you.
I think that was unanimous also.
Now for 5-A, "Would 400
micrograms be a reasonable dose?"
Dr. Crockett.
DR. CROCKETT: You know, I wanted to expound a little bit on
the reasonable delivery thing. I want to
compliment the drug company. I think
it's brilliant this idea of delivery in this manner. I think they should be lauded for taking this
active part in public health in trying to prevent birth defects in unborn
children even before they are conceived.
That's something rare. I preceded
my comment because I'm not happy about how they have done their selection of
their dosing.
I believe that they have picked a
relatively safe dose but I'm not sure that it's the most efficacious dose and I
would definitely like to see some more dose testing and see if we can further
reduce the incidence of neural tube defects and further impact the public
health problem with increasing doses.
DR. GUIDICE: Thank you.
I guess the real question is do we have enough data to recommend that
400 micrograms would be a reasonable dose.
Yes, Dr. Lewis.
DR. LEWIS: Well, in some way it would be nice to see
another -- it would nice to see a dosing study given the current fortification
policies and different dietary intake that people have in the United States. It would be nice to see a dose finding study.
DR. GUIDICE: Dr. Rice and then --
DR. RICE: And I still am remembering in the back of my
mind that there's some studies that really have talked about the absorption of
folic acid in different dosages of oral contraceptive pills. I mean, I think it is important that we have
more information.
I think 400 micrograms is a reasonable
place to start but I do think you've got to do some dose studies to know that
you are getting the optimum. Then I
still think there's some relevance to the fact of those other studies that show
that as you increase the dose, you do see a decrease in neural tube
defect. I
know about the folic levels. I got that
part but I still think there is some relevance.
I think we need to be -- if we're going to do this, we might as well
make sure that we're given the best dose to get the maximum benefit.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: By dose finding we don't mean looking at the
ultimate outcome. Do we mean looking at
what would be administered and looking at serum ferritin or red blood cell concentrations? Is that what we mean by dose finding?
DR. LEWIS: Folate, not ferritin but, yeah. That's what I meant.
DR. GUIDICE: And that type of thing I think probably would
be addressed in any subsequent discussions between the sponsor and the agency
in terms of setting up a clinical trial if one is needed.
So does the committee feel comfortable
moving forward on voting on 4-A because we have been asked to vote on that,
although not on 4-B because we've had the discussion.
Yes.
DR. HAGER: I would just like to ask if we could -- I
know we've done a lot of dividing but is 400 micrograms a reasonable dose? I would say yes, it is, but is it an ideal
dose, I would say no. I don't know. I would kind of like to vote that way if I
could.
DR. GUIDICE: Yes, Dr. Tamura.
DR. TAMURA: Recently I reviewed four papers where
investigators evaluated how much plasma folate declines over a period of three
to eight weeks. This is a very extreme
case, worst scenario. Based on 160
micrograms of folate per day it came out fairly consistent data which range
from 3.5 to 4.2 nanomols per liter per week.
Which means 1.5 nanograms per mL.
Looking at the study
published in Journal of Nutrition in October indicating that folate intake from
bread where fortification is mandated, 12 women had less than 200 micrograms a
day of intake. Also three percent of
women, they studied about 600 women, less than 100 micrograms a day.
If you give 400 micrograms with oral
contraceptives for, let's say, a year or so and then stop, then average waiting
period for them to get pregnant would be about three months. I don't know what the initial value is but
let's say it's going to be 50 nanomols per liter which is about 22 nanograms
per mL because they are taking fairly large doses of folic acid, within eight
weeks it will reduce to 22. Within 12
weeks it goes down to 4 nanograms per mL.
I'm not saying that the decline in
plasma folate completely parallels to the decline in tissue folate but if we
target the initial folate value or initial tissue stores as high as possible by
these oral contraceptives, we will be safer to say that will be effective even
after three months of discontinuation of oral contraceptive.
We are targeting low socioeconomic
population. That's what everybody seems
to agree. They may have much lower
folate intake than the general population.
Therefore, I am a bit hesitant to say 400 micrograms would be
ideal. I think we need to have very
careful assessment here how much we should give together with oral contraceptives. I'm talking about worst scenario, worst case
scenario but we should consider that. I
recommend to do some studies.
DR. GUIDICE: I think you are in agreement then with Dr.
Hager who said that the 400 micrograms sound reasonable but we really don't
know.
I would like to begin the vote,
please, with Dr. Hager.
DR. HAGER: Reasonable, yes; ideal, no.
DR. GUIDICE: Dr. Patten.
DR. PATTEN: I will agree reasonable but I would never
support using that level without definitive research being done.
DR. GUIDICE: Dr. Darney.
DR. DARNEY: Yes.
DR. CROCKETT: What Dr. Hager said.
DR. GUIDICE: And Dr. Green.
DR. GREEN: Reasonable, yes. On the second part, I would really like to
say absent any information I would prefer to -- and also given the earlier
discussions about safety issues abstain from the vote on Part B but Part A,
yes.
DR. CROCKETT: Sorry, Dr. Green. I would say reasonable, yes; ideal, no.
DR. RICE: I would say reasonable, yes; ideal, no. But I also want us to remember that if you
have that long period of time three to six months that a women is trying to get
pregnant and hasn't, remember she's probably going to have some recommendation
to be on a supplement. Sorry, I
shouldn't have added that to my vote.
DR. GUIDICE: We've not exactly been a yes or no only kind
of vote today.
DR. WENSTROM: Yes, reasonable.
DR. GUIDICE: And ideal?
DR. WENSTROM: We can't answer that. Probably not.
DR. EMERSON: So reasonable, yes and who knows on ideal.
DR. SHANE: Yes and maybe.
DR. GUIDICE: Yes and I don't know.
DR. GREENE: Yes, I think it's reasonable and I'm sure
that the sponsor would do dose range finding studies as part of the
application.
DR. TAMURA: For (a) I would say reasonable but, like I
said, study is needed.
DR. ROSENBERG: Three hundred years into the Age of Reason
we're gathered here on a quantitative question and voting on what is
reasonable. But having made that
observation, yes, I think 400 is reasonable for a simple reason and that is
that I can tag it not to what feels reasonable but that there is at least a
recommendation out there which is 400 micrograms of crystalline folate and this
would deliver that. In that sense it's
reasonable but I would reiterate the need for some further study about what
would be the most useful dose.
DR. DICKEY: Reasonable yes. Further study is needed before we know ideal.
DR. LEWIS: Ditto.
DR. LIPSHULTZ: Yes, same answer.
DR. MACONES: Yes.
DR. STANFORD: Yes.
DR. GUIDICE: Thank you.
That leaves us the tally.
Eighteen yes on the reasonable. I
think we've had quite a bit of discussion on ideal subsequent.
Now the final question, and we have
touched upon this. It's a little bit
difficult to answer the question and to vote on it without much information but
the question is, "Would the benefit of prior folic acid use persist if
conception occurs after discontinuation of folic acid?" Again, it's not stated how long after
discontinuation. We've heard some data. There were some that was presented.
DR. DICKEY: I was going to say I think we've seen data
presented that eight to 12 weeks there is some, though not at the same level
obviously. It a decremental persistence
so I think the answer has to be sure, it persist. We don't know how long and those questions
need to be asked and answered so that you can appropriately counsel patients,
prescribe, etc.
DR. GUIDICE: Dr. Greene.
DR. GREENE: Yes, but I would point out that what's been
demonstrated is that folate levels in red cells persist but it hasn't been
proven that protection against neural tube defects also persist for weeks after
stopping the medication. The studies of
red cell folate as relates to risk of neural tube defects have been all over
the lot over the years.
DR. WENSTROM: I don't think we can answer this question
without answering question 5 because, as Dr. Tamura said, it's dose
related. The higher dose you're on, the
longer it's going to take to wash out.
DR. GUIDICE: Dr. Green.
DR. GREEN: I would just like to point out that red cell
folate does appear to be, for reasons that Dr. Shane gave earlier, the best
indicator of continuing folate status.
But it is historical in terms of what is in the red cells is what got
there when that cohort of red cells overall was formed. Consequently,
we have no information to know what the target cell would be with respect to,
say, neural tube defects, presumably the developing blastocyst and, at that
stage, red cell folate on average represents the legacy of an average of three
months of folate studies.
DR. GUIDICE: I think also when you think of a population
that is on oral contraceptives, say, with the supplementation, if there is an
accidental pregnancy, then they would go off the OCP and then they would go on
a multivitamin with folic acid so it's unlikely that there would be a huge amount
of time.
Secondly, the taking of the -- for
those individuals who are planning a pregnancy stop their birth control pills
and then decide, "Well, I'll wait a month or so," usually those
women, if they are under the care of a physician or a health provider --
another health provider, would have some counseling with regard to
supplementation with folic acid.
One of the populations that is
probably the most at risk are women who decide to stop the pill for whatever
reason. Maybe not planning a pregnancy
or even planning a pregnancy but don't go to anybody to talk about it and
that's the population that is probably at the highest risk.
I think we do need some additional
information. We've heard about the
half-life of the red cell folate stores or the whole body stores which seem to
be very long but I'm not sure that we've really heard enough information about
the protective period when there's a washout of the folic acid being taken.
DR. SHANE: That's because no one knows. Even if you know how fast body stores go
down, you don't know what level is optimum to prevent NTDs. It's not likely to be found out by one of
these dosing studies that was suggested.
That's just going to tell you how much is in plasma but there's no way
to relate that as far as I know if you go back to one of Jim Mills' studies to
relate that to NTD risk for actual NTDs.
It's like everything. It clearly will persist for a while and the
level will get lower but it seems as if you have to go to a physician to get
the prescription to get the pills with the vitamins in, then maybe that should
be part of the requirement that physicians say that if you go off this to
become pregnant, you should take vitamin pills instead of the mixture. Then they don't have to go back to the doctor
to get the drugs.
DR. GUIDICE: And it may be also that with more and more
discussion the entire population will have its consciousness raised about the
importance of folic acid supplementation.
Dr. Emerson.
DR. EMERSON: I guess I was just being naive but I was
always assuming that it was the plasma level that would have any effect on the
fetus development so that's what we would really want to be seeing for the
long-term thing and we don't have that.
DR. SHANE: I can assure you that if you do a dosing
study, the more you give the higher the plasma level up to infinity
essentially.
DR. EMERSON: But those stores that we have after you stop
taking the folate, it starts coming out of those stores or whatever and
maintains the plasma level at some value but we don't have that date. Right?
DR. SHANE: Part of it will come out of tissues. Most folate actually turns over by cleavage
so most of the stuff that goes into a tissue and gets retained in the tissue
doesn't come out again as an active form of folate.
DR. OAKLEY: The fetus has to have the plasma.
DR. SHANE: Well, the fetus clearly has to have the
plasma just like any other tissue. As
far as I know, it's not really clear whether the folate has to go in very early
in gestation or it keeps supplying the fetus during the first four weeks.
DR. EMERSON: So that would argue that without knowing how
the plasma behaves we know absolutely nothing about whether there would be a
continued affect.
DR. SHANE: You know how plasma behaves. It will go up and up.
DR. EMERSON: No, no, this is after you've stopped.
DR. SHANE: After you've stopped.
DR. EMERSON: The question is after you've stopped
receiving folate what is the persistence of that effect and we only have it on
the red cells. We don't have it on
plasma.
DR. GUIDICE: Thank you.
So we have now -- I guess we need to do our formal vote on Question No.
4 and please give a simple yes or no. If
you have a major caveat and it's ditto, you can say ditto around the table.
Dr. Stanford, this is your opportunity
to massage the question somewhat.
Dr. Emerson has a comment.
DR. EMERSON: Just because I did want to look up what the
thing was on the plasma since I was saying we didn't have that but I do stand
corrected that we do have it. For eight
weeks post-discontinuation where baseline was at 5 and then four weeks of
treatment it was 11.9 and then at eight weeks after discontinuation it was
still at 9. I don't have a sample size
on that.
DR. OAKLEY: About 200 young Dutch women.
DR. GUIDICE: Thank you.
DR. STANFORD: Yes.
DR. MACONES: Yes.
DR. GUIDICE: The question is, "Would the benefit of
prior folic acid use persist if conception occurs after discontinuation of
folic acid?" We're not voting on a
dose because we don't know or for how long.
DR. LIPSHULTZ: Okay.
So yes.
DR. LEWIS: Yes, and we don't know.
DR. ROSENBERG: Yes, even if conception doesn't occur.
DR. GREENE: No. I
know of no data that suggest that neural tube defects are prevented after discontinuation
of folate.
DR. GUIDICE: I'm just re-reading the question. I would say that I would have to
abstain. I don't really know the answer
to this.
DR. SHANE: Yes, for a limited period.
DR. EMERSON: I'll go with yes.
DR. RICE: Even though Dr. Greene is technically right,
I'm going to still say yes.
DR. CROCKETT: Me too.
DR. GREEN: I say yes on available evidence.
DR. DARNEY: Yes.
DR. PATTEN: Yes.
DR. HAGER: No.
DR. GUIDICE: Can we have a tally on this, please? Twelve yeses, two nos, one abstention, and
two of our members had to go catch airplanes.
Before we leave, I just want to ask
the agency if there are any other questions that you would want us to be
thinking about or answering for you. If
not, thank you. I would like to thank
all the members of the committee and all the participants in the open public
session and also members of the sponsor.
I hope we have given you the information that you need.
Tomorrow's meeting occurs in this room
and begins at 8:00. Please come before
then. Thank you.
(Whereupon, at 5:00 p.m. the meeting
was adjourned.)