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[e-drug] Waxman letter to Bush re FDC double standards

E-DRUG: Waxman letter to Bush re FDC double standards
[Below an interesting, and well-documented (note references at the bottom!)
letter of Waxman to Bush about the technical document drafted for the
Botswana FDC meeting (starting today). Waxman  claims that the US sponsored
technical document is more stringent than FDA. Apparently Trizivir of GSK
got registered with less documentation than USA is now demanding from Indian
generic manufacturers. Waxman also notes that EMEA (European Drug Regulatory
Agency) has decided not to send delegates. Copied as fair use; WB]

March 26, 2004

The President
The White House
1600 Pennsylvania Avenue
Washington, DC 20500

Dear Mr. President:

Your Administration is circulating a proposal for consideration at an
upcoming international conference in Botswana that could impede access to
the low-cost drugs needed to save the lives of millions of people living
with HIV in developing countries. Adopting this proposal would be a tragic
mistake. Instead of erecting hurdles that could block or limit the use of
these life-saving therapies, the United States should be cooperating with
the World Health Organization and other nations to make the therapies
widely available as soon as possible.

In addition to affecting access to key medications, your Administration's
actions may be alienating essential U.S. allies. I have learned that the
leading drug regulatory authority in the European Union, the European
Agency for the Evaluation of Medicinal Products, is not sending any experts
to the Botswana conference, after having participated in the preliminary
conference in Cape Town, South Africa. It is difficult to imagine how
progress can be made without the participation of one of the leading drug
approval agencies in the world.

At issue are "fixed dose combination" drugs. These combination therapies
are promising medications that combine several essential treatments for
HIV/AIDS into one tablet and are considered the "first choice" for use when
available. Generic drug manufacturers operating in India offer these pills
at a fraction of the price of the individual brand-name drugs. The World
Health Organization has certified the quality of several of these products,
setting the stage for their use in the global campaign to treat three
million people by 2005.

Unfortunately, this promising development is being threatened by U.S.
actions. Monday, in Gaborone, Botswana, the United States is co-hosting a
meeting to discuss whether stringent safety and efficacy standards should
be applied to these low-cost combination therapies. On the agenda for
discussion in Botswana is a document circulated by the United States called
Scientific and Technical Principles for Fixed Dose Combination Drug
Products. The inflexible standards in the document could block the use of
well-supported and widely accepted generic combination therapies. In fact,
the proposed requirements are so unreasonable that they appear to exceed
the standards used by the U.S. Food and Drug Administration to approve
therapies for use in the United States.

I am not opposed to the establishment of reasonable safety and efficacy
standards for HIV combination therapies. Many observers believe that the
WHO already has such standards in place, and in other contexts, the United
States relies on WHO standards. If health experts conclude that some
revisions are necessary, however, there should be a concerted effort to
work within the WHO framework to revise its existing standards as quickly
as possible.

But I strongly oppose efforts to block the use of low-cost generic drugs
through the imposition of unnecessary and onerous drug approval standards.
It is no secret that U.S. pharmaceutical companies, which make brand-name
drugs, do not want funds to flow to generic drug companies in India. These
pharmaceutical companies are among your strongest political supporters,
having contributed over $40 million to your political party in the last
five years.[1] They should not be dictating policy on U.S. efforts to fight
HIV/AIDS in Africa and elsewhere.


In your 2003 State of the Union speech, you expressed your personal
commitment to funding low-cost therapies to counter the global scourge of
AIDS. You then proposed an ambitious agenda involving nearly $10 billion in
new U.S. funding to combat HIV in Africa.[2] As you said in the 2003 State
of the Union speech:

            Because the AIDS diagnosis is considered a death sentence, many
            do not seek treatment. Almost all who do are turned away. A
            doctor in rural South Africa describes his frustration. He
            says, "We have no medicines. Many hospitals tell people, you've
            got AIDS, we can't help you. Go home and die." In an age of
            miraculous medicines, no person should have to hear those

            AIDS can be prevented. Anti-retroviral drugs can extend life
            for many years. And the cost of those drugs has dropped from
            $12,000 a year to under $300 a year - which places a tremendous
            possibility within our grasp. Ladies and gentlemen, seldom has
            history offered a greater opportunity to do so much for so

To make the available funding go as far as possible, the cost of the drugs
purchased with U.S. funds needs to be as low as possible. Today, the
lowest-cost and most promising drugs are generic combination therapies,
which are now available at a price as low as $140 per patient per year.[4]
These are widely considered the "first choice" for treatment when

Since your State of the Union speech, however, the Administration has
shifted away from supporting the purchase of generic combination therapies
with U.S. funds. Instead, the United States is now circulating a proposal
for drug approval standards that calls into question the existing WHO
certification process and would appear to make it difficult, if not
impossible, for the international community to purchase low-cost generic
combination therapies. This new proposal will be the subject of an
international conference being held from March 29 to March 30 in Gaborone,

The Current WHO Approval Process

The international standard for the safety, effectiveness, and quality of
HIV drugs is set today by WHO. International donors, including the
U.S.-funded Global Fund to Fight AIDS, Tuberculosis, and Malaria, rely upon
WHO's expert reports and evaluations to determine which drugs to purchase.
Because of the preeminent role of WHO in international health, many
observers have assumed that drugs meeting WHO standards would be eligible
for purchase using U.S. funds for HIV in Africa. Indeed, in other settings,
the United States has relied on WHO assessment and review for purchases
with U.S. funds.

There are two key elements of the WHO approach to HIV medications: expert
recommendations and quality review.
In 2003, WHO convened an expert panel to make recommendations about
appropriate therapy for HIV in resource-limited countries. The panel, led
by Dr. Scott Hammer of Columbia University, included 15 recognized experts
in HIV treatment throughout the world. In October 2003, more than 200
institutional and organizational partners reviewed the draft document,
which was then made available for public comment before final publication
in December 2003.[6] These recommendations represent the best practices for
HIV treatment in the developing world. Among the highlighted treatments are
regimens combining three drugs that are available for simple administration
in the form of single pill combinations.[7]

Complementing the WHO's recommendations for therapy is the organization's
pre-qualification process for pharmaceuticals. This process certifies the
quality of drugs for purchase by U.N. agencies.

Based on a standard procedure developed by WHO's Expert Committee on
Specifications on Pharmaceutical Preparations, the pre-qualification
process is rigorous. Manufacturers must provide data on the active
ingredients, product formula, manufacturing method, stability, and
bioequivalence. A team of WHO experts, including staff of drug regulatory
authorities from developed and developing nations, must assure that the
products meet scientific specifications. Inspectors must certify that the
manufacturing sites adhere to international standards.

There is wide international support for the WHO approach. U.N. agencies,
the World Bank, and such nongovernmental organizations as Doctors Without
Borders all have used WHO-certified and recommended drugs. National
regulatory agencies also factor in the recommendations and certifications
of WHO in deciding what drugs may be used in their countries.

Indeed, WHO-certified drugs have been purchased and used by U.S. agencies
for years in combating diseases in developing countries. For example, the
U.S. Agency for International Development has set standards for procurement
of non-FDA-approved drugs. In these standards, grant applicants are advised
to find "information to attest to safety, efficacy, and quality" by asking:

Is the drug recognized as being safe and efficacious and recommended for
the proposed application by recognized experts in the field, for example,
CDC or WHO? . . . Is the drug product on the WHO essential drugs list for
the proposed indication?[8]

U.S. funds also purchase oral polio vaccine through the United Nations
Children's Fund (UNICEF).[9] This vaccine is no longer available from an
FDA-licensed manufacturer. Instead, UNICEF relies upon a WHO
prequalification system for vaccines that is similar to its process for
drugs.[10] Similarly, the Global Fund to Fight AIDS, Tuberculosis and
Malaria, which receives U.S. funds, has agreed that grantees can purchase
WHO-certified drugs.[11]

There are several HIV combination therapies that have been pre-qualified
under this WHO review process. These therapies include Triomune and
Triviro, generic medications manuctured in India that combine in a single
pill the recommended regimen of stavudine, lamivudine, and nevaripine.

The Proposed New Standards

Recently, senior Administration officials have questioned the adequacy of
the WHO review process. In testimony earlier this month before the
International Relations subcommittee of the Appropriations Committee of the
House of Representatives, Global AIDS Coordinator Randall Tobias stated:

            You and I know that a process has developed in this country,
            where if you or I take a prescription to the local pharmacy and
            get it filled and it's filled with a generic drug, then we know
            that what we take home is going to be the exact, precise
            duplicate of the drug that was originally developed by a
            research-based pharmaceutical company and that the FDA, through
            its process, will have insured that the dosage, the safety, the
            effectiveness, the strength, the active ingredients, the purity
            and so on and so on, are exactly identically the same.

            When people describe generic AIDS drugs, they're talking about
            something very different. They're talking about drugs that are
            being made by somebody, some place in the world, that may well
            comply with all of these standards. They may well be perfectly
            safe and perfectly effective and totally consistent. And then
            again, they may not be.

            The problem is, there is no process, no principles, no
            standards in place today, from a regulatory point of view, to
            make that assurance.[12]

Ambassador Tobias's statement ignored the extensive WHO system of expert
review and prequalification, which constitutes a process, includes
principles, and sets standards. Nonetheless, the allegation that there is
no oversight of generic HIV drugs has driven U.S. policy. At Monday's
conference in Gaborone, Botswana, the United States will lead discussion on
a document called Scientific and Technical Principles for Fixed Dose
Combination Drug Products.[13] Approximately two weeks from now, this
document is to be finalized.

The new standards proposed in this document appear likely to block the use
of the low-cost generic drugs that are currently pre-qualified by WHO. In
fact, the proposed requirements are so unreasonable that they appear in
some circumstances to exceed those of the U.S. Food and Drug
Administration. In some instances, they may even require studies that would
be unethical to conduct.

The problems with the document appear principally in the proposed
requirements for those HIV combination therapies that fall into two
categories referred to as Scenario 2 and Scenario 3.

Scenario 2 includes those fixed-dose medications that are composed of drugs
whose combination use is well established, at the exact same dose that they
are used in clinical practice. This scenario appears to encompass the HIV
combination therapies that are most promising today. For example, it would
appear to apply to Triomune and Triviro, two generic HIV therapies have
already been reviewed and prequalified by WHO. Each of these two drugs
combine three drugs (stavudine, lamivudine, and nevaripine) in a dosing
regimen that has been well established as safe and effective. There is
tremendous interest in using these combination therapies in developing
nations on convenience and cost grounds. In fact, Triomune and Triviro are
already being used successfully in several countries.[14]

Under the new standards being circulated by the Administration, however, it
appears questionable that Triomune and Triviro would be approvable. The
document proposes to require for each drug covered by Scenario 2 "a
justification supported by data or literature . . . to support the
advantage of the combination over monotherapy with each of the individual
entities." In other words, the manufacturers of these drugs would have to
produce studies comparing and demonstrating an advantage of the combination
against stavudine, lamivudine, and nevaripine individually. This is an
unnecessarily onerous standard.

In fact, this standard appears to exceed FDA requirements for approval for
sale in the United States. In 2000, FDA approved a brand-name combination
therapy, GlaxoSmithKline's Trizivir (containing the drugs zidovudine,
lamivudine, and abacavir), on the basis of bioequivalence data. Contrary to
the new international standards being circulated by the United States,
there were no clinical trials of the combination against the individual
components. Trizivir's labeling refers to one adult and one pediatric study
comparing the combination to zidovudine and lamivudine together;[15] it
mentions no studies comparing the combination to each of the individual
drugs as monotherapy. Even if the combination of zidovudine and lamivudine
were considered "monotherapy," there were no studies comparing the triple
combination with abacavir alone.[16]

In some situations, where monotherapy is not the recognized treatment for a
life-threatening disease, a comparative trial would be unethical. This
would most certainly be the case if a study were required today to
establish that Triomune and Triviro were superior to each of their
individual components.[17]

Scenario 3 groups together two dissimilar situations: (1) a single pill
combination composed of components that have not been shown to be safe and
effective in combination and (2) a single pill combination composed of a
proven combination, where only the dosing regimen has been altered.
Standards under Scenario 3 also appear to be unreasonable and to exceed FDA
requirements for some products that would fall in this category.

The proposed document would require clinical trials against established
treatments to show which one is better. A clinical trial to establish the
noninferiority of a combination therapy with a change in dosing regimen
compared to the standard combination would, in most cases, be prohibitively
large and expensive, effectively eliminating this type of drug. I recognize
that in many cases, such drugs should not be marketed without new clinical
data data. However, for some drugs with a minimal change in dosing regimen,
such a study could exceed FDA requirements.[18]

In addition, where the drug combines for the first time two drugs that have
dissimilar but well-established indications, FDA does not necessarily
require a clinical study comparing the combination with monotherapy. In
such cases, the advantage may be presumed based on existing information
about the effectiveness of each component for its indication.[19]

Implementation of the Proposed Standards

Monday's meeting in Botswana will not cover the question of who might
implement a new set of approval standards for combination therapies. This
question, however, is also critical to assessing whether the U.S. effort to
assure the safety and effectiveness of these drugs will become an
unnecessary drag on their timely purchase and distribution.

Establishing a parallel process to WHO to approve drugs for international
purchase would make little sense. Such a process could set up conflicting
international standards, confusing countries and donors. It could also open
the door to political interference, especially if implementation were left
with an organization or agency that could be swayed by manufacturers or
others with a commercial interest in the outcome.

If global health experts believe additional standards for HIV drugs are
necessary, these standards should be quickly built into the existing WHO
process. Such a step will accomplish the goal of assuring the quality of
drugs without creating duplicate bureaucracies and unnecessary delay.


Adopting the proposed standards being circulated by the United States could
have major adverse consequences.  It is obviously critical to be confident
that all drugs for HIV are safe and effective.  This goal, however, does
not require the imposition of inflexible standards that may block access to
essential, life-saving therapies.

To fight the scourge of AIDS on the continent of Africa, a global effort is
required. Donors from around the world, including the United States, must
commit significant resources as quickly as possible. International
expertise in drug review must be brought together to allow for efficient
approval and quality manufacturing of essential therapies. Working
together, the nations of the world can literally save millions of lives by

Your approach, however, appears to be dividing the key allies the United
States needs. For example, I have just learned that the leading drug
approval agency in the European Union, the European Agency for the
Evaluation of Medicinal Products is not sending any of its experts to the
Botswana conference, after having participated in the preliminary
conference in Cape Town, South Africa.

I urge you to cooperate and lead in this global effort. The United States
should not break off from the rest of the world, disparage its standards
for drug approval, and then squander precious funds on unnecessarily
expensive therapies.


                                                /s Henry A. Waxman

                                                            Henry A. Waxman

                                                Ranking Minority Member

[1] Center for Responsive Politics, Pharmaceuticals/Health Products:
Long-Term Contribution Trends (online at

[2]White House, Fact Sheet: The President's Emergency Plan for AIDS Relief
(Jan. 29, 2003) (online at

[3]President George W. Bush, State of the Union Address (Jan. 28, 2003)
(online at http://www.whitehouse.gov/news/releases/2003/01/20030128-19.html

[4]South Africa Gears up for AIDS Fight, New York Times (Nov. 21, 2003).

[5]World Health Organization, Fixed Dose Combinations for AIDS,
Tuberculosis, and Malaria (Dec. 16-18, 2003)(online at:

[6]World Health Organization, Scaling up Antiretroviral Therapy in
Resource-Limited Settings: Treatment Guidelines for a Public Health
Approach, 2003 Revision (Dec. 2003) (online at

[7]Id., at 15-16.

[8]U.S. Agency for International Development, Requesting USAID Approval to
Procure HIV Test Kits and Other HIV/AIDS-Related Pharmaceutical Products:
Guidance and Sources of Information (Jan. 2002).

[9]Centers for Disease Control and Prevention, Global Immunization Division
(2004) (online at http://www.cdc.gov/nip/webutil/about/divisions/gid.htm)
(The United States "[p]rovides polio vaccine, through UNICEF, for National
Immunization Days and mop-up campaigns to eradicate polio").

[10]World Health Organization, Procedure for Assessing the Acceptability,
in Principle, of Vaccines for Purchase by United Nations Agencies (2002).

[11]The Global Fund to Fight AIDS, Tuberculosis, and Malaria, Report of the
Third Board Meeting (Oct. 10-11, 2002) (online at
http://www.theglobalfund.org/en/files/boardmeeting4/ gf%20b4%2002%20

[12]Global AIDS Coordinator Randall Tobias, Testimony before the House
Appropriations Committee, Foreign Operations Subcommittee, FDCH Political
Transcripts (Mar. 18, 2004) (emphasis added).

[13]Conference on Fixed-Dose Combination (FDC) Drug Products, Scientific
and Technical Principles for Fixed Dose Combination Drug Products, Draft
(Mar. 9, 2004) (online at http://www.globalhealth.gov/fdc.shtml).

[14]Medecins Sans Frontihres, Factsheet, Two Pills a Day Saving Lives:
Fixed-Dose Combinations of Anti-Retroviral Drugs (Feb. 2004) (online at

[15] According to Trizivir's label, pediatric patients had a "limited
response" to the addition of abacavir.

[16]GlaxoSmithKline, Trizivir: Prescribing Information (2002) (online at
http://us.gsk.com/products/assets/us_trizivir.pdf). In general, FDA's
clinical research requirements are more flexible than those proposed in the
document, permitting the agency to accept less evidence of safety and
effectiveness in the case of serious and life-threatening diseases where
there is no satisfactory alternative therapy. See 21 CFR 312, Subpart E and
21 CFR 314, Subpart H. The proposed standards do not acknowledge the need
to weigh risks and benefits in light of the severity of the disease and the
lack of satisfactory alternatives.

[17]U.S. Department of Health and Human Services, Guidelines for the Use of
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 23 (Mar.
23, 2004).

[18]If a change in dosing regimen increases the frequency of dosing, FDA
may, depending on pharmacokinetic and pharmacodynamic (PK/PD)
relationships, sometimes consider bioequivalence data a sufficient basis
for approval. Even if the change decreases frequency of dosing, FDA
sometimes approves such changes without clinical data, depending on PK/PD
relationships. For example, sustained release versions of immediate release
drugs, like Wellbutrin SR, can sometimes be approved without clinical
trials. See also FDA, Guidance for Industry: Providing Clinical Evidence of
Effectiveness for Human Drug and Biological Products, 7 (May 1998).
Immediate release drugs can, in the right circumstances, also be approved
for less frequent dosing regimens than were used in the clinical trials,
e.g., propranolol was approved for twice daily use on the basis of a trial
showing that propranolol was safe and effective when used 3 times a day,
together with PK/PD data. See also, FDA, Guidance for Industry: Providing
Clinical Evidence of Effectiveness for Human Drug and Biological Products,
8 (May 1998).

[19] For example, the FDA recently approved Caduet, which combined
amlodipine and atorvastatin in a single pill for the first time. According
to the drug's label, the agency did not rely on any clinical studies, other
than bioequivalence studies, comparing the combination to its constituents.

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