TESTIMONY ON "INTEGRATIVE ONCOLOGY - CANCER CARE FOR THE NEW MILLENNIUM BY
RICHARD PAZDUR, M.D. DIRECTOR, DIVISION OF ONCOLOGY DRUG PRODUCTS
CENTER FOR DRUG EVALUATION AND RESEARCH
FOOD AND DRUG ADMINISTRATION
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Mr. Chairman, Members of the Committee,
I am Richard Pazdur, M.D., Director, Division of Oncology Drug Products (the
Division), Center for Drug Evaluation and Research (CDER), Food and Drug Administration
(FDA or the Agency). The Division’s mission is to ensure that new cancer drugs
are as safe and effective as possible and to facilitate access to promising
therapies for seriously ill and dying patients when no other treatment is available.
Prior to coming to FDA approximately nine months ago, I was associated with
the M.D. Anderson Cancer Center in Houston, Texas, for eleven years where I
was involved in patient care, cancer research, medical education, and administration.
Because of my prior experience with patient, academic, and scientific communities,
I am acutely aware of the impact FDA’s processes and decisions have on the public
we serve. Under the Federal Food, Drug, and Cosmetic (FD&C) Act and related
statutes, the Government has a vitally important role in helping to ensure that
the medical products upon which patients and their health care practitioners
rely are both safe and effective. These safeguards are particularly important
for our most vulnerable citizens, those who are seriously ill.
Having treated and worked with cancer patients and their families for the past
20 years, I have seen the face of desperation frequently. When the effective
treatment options have been exhausted, some cancer patients contact FDA asking
for help in getting access to an unapproved product that is being investigated.
We understand that cancer patients and their family members are often unfamiliar
with FDA’s legal and regulatory responsibilities, and often are unaware that
FDA cannot lawfully compel a company to supply an individual patient with an
investigational drug outside of clinical trials. To more thoughtfully work with
the concerns of cancer patients and their families, FDA hired staff in 1994
who are available to answer their questions and listen to their concerns. I
will describe the functions of this office in greater detail later in my testimony,
however, I want to emphasize that FDA staff spends time with these callers explaining,
to the extent that our confidentiality restrictions allow, how and why we make
I am pleased to share with you what our Agency is doing to accelerate the development
of new treatments for cancer, to provide access to unapproved treatments, and
to meet the needs of cancer patients and their families. First, however, I would
like to address the specific issues raised in your letter of invitation to FDA,
to the extent that information is available and public.
Mr. Chairman, you have requested that as part of our testimony, we discuss
clinical trials in complementary or alternative therapies for cancer that FDA
has under investigational new drug (IND) application status, information on
the types and numbers of calls the Agency receives regarding these therapies,
information we provide to the public about these treatments and about complementary
and alternative medicine (CAM), an explanation of the process that a family
goes through in being able to access a clinical trial for an alternative cancer
therapy and the reasoning why a less toxic, safer therapy cannot be tried prior
to a therapy that has known serious adverse events, and last but not least,
the role of freedom of choice in medicine.
I. CLINICAL TRIALS IN COMPLEMENTARY OR ALTERNATIVE MEDICINE
When it comes to clinical research, there are good studies, and then there
are the rest. FDA is interested in good studies and good data independent of
the type of therapy being tested. We do not categorize therapies but rather
seek good clinical data from whatever intervention is being tested. Our primary
obligations are those vested in us by Congress in the FD&C Act, namely to
help ensure that marketed medical products are properly labeled, safe, and effective,
and that the procedures in studies conducted on unapproved products are designed
to protect the vulnerable -- particularly patients with life-threatening diseases
and serious illnesses. To FDA, it does not matter whether the product or treatment
is labeled alternative or complementary, or mainstream or conventional. We are
indifferent as to the source and nature of any potential therapy as long as
consistent good manufacturing standards and good laboratory and clinical practice
Before gaining FDA marketing approval, new drugs, biologics, and medical devices
must be proven safe and effective by controlled clinical trials. Under the FD&C
Act, FDA must rely on evidence from adequate and well-controlled studies. The
persons who participate in those clinical trials need to be adequately protected
and fully informed of the risks and possible benefits of their participation.
Patients want to make informed choices about medical treatments, whether conventional
or alternative or complementary. This is possible only when there is adequate
data to provide the information upon which informed consent can be made.
CAM is a broad term referring to treatments that are either unapproved or not
widely accepted in this country. Treatments range from botanicals and animal
extracts to biofeedback to visualization techniques, chiropractic, homeopathy,
massage therapy, acupuncture, and prayer. As we have emphasized, FDA relies
on evidence, and is required to do so under the FD&C Act, from adequate
and well-controlled studies as its basis for approval, not on theories of healing,
animal studies or strongly held beliefs. Complementary and alternative treatments
are as readily studied in well-controlled trials as are conventional treatments
and some are being studied under National Institutes of Health (NIH) grants
and other funding sources. FDA is eager to see formal controlled studies of
CAM and has advised potential sponsors of such studies on study design and conduct.
Examples of products used in complementary and alternative medical practice
that are being or have been evaluated for the treatment of cancer either in
the United States (U.S.) or abroad, under an IND, include the following: Green
Tea extract(s) for cancer; Shark cartilage extract for advanced lung and other
cancers; ozone therapy for transfusion-related diseases; Antineoplastons for
cancer; Dietary Arginine Supplements for cancer; Vitamin D for cancer; and,
Zinc Supplementation in Head and Neck cancer patients.
In addition, we are developing a guidance on the study and development of botanical
products that facilitates their entry into clinical trials and will describe
how to develop appropriate specifications for these complex products.
FDA works with NIH’s National Center for CAM as well as the Division of Cancer
Treatment, Diagnosis, National Cancer Institute (NCI) in the pursuit of evaluating
unproven treatments for cancer. FDA is involved with these agencies in clarifying
existing regulations and policies and participating in ongoing meetings regarding
issues of mutual interest.
II. ACCESS TO A CLINICAL TRIAL FOR ANY CANCER THERAPY
The access process starts with a drug sponsor, a pharmaceutical company or
a research scientist at a university or at NIH, seeking to develop a new drug
it hopes will find a useful and/or profitable place in the market. Before clinical
testing begins, researchers analyze the drug’s main physical and chemical properties
in the laboratory and study its pharmacologic and toxic effects in laboratory
animals (pre-clinical studies). If the laboratory and animal study results show
promise, the sponsor can apply to FDA to begin testing in people.
Once FDA has reviewed the sponsor’s plan and allowed it to proceed, and a local
Institutional Review Board (IRB)(a panel of scientists and non-scientists that
oversees clinical research) approves the protocol for clinical trials, experienced
clinical investigators give the drug to a small number of cancer patients who
have no other available therapy. These Phase I studies assess the most common
acute adverse effects and examine the amount of drug that patients can take
safely without unacceptable side effects. Initial clinical studies also begin
to clarify what happens to a drug in the human body, how it is changed (metabolized),
how much of it (or a metabolite) gets into the blood and various organs, how
long it stays in the body, and how the body gets rid of the drug and its effects.
If Phase I studies do not reveal major problems, such as unacceptable toxicity,
the next step is to conduct a clinical study in which the drug is given to patients
who have medical conditions that may benefit from the drug; for potential cancer
drugs, often several different types of cancers are explored (Phase II studies).
Researchers then assess whether the drug has a favorable effect on the condition.
Testing experimental drugs in people inevitably presents ethical questions.
For example, is it ethical to give patients a placebo when effective treatment
is available? Not all authorities agree on the answer. The generally accepted
practice in the U.S., and one increasingly being adopted abroad, is that well
and fully informed patients can consent to take part in a controlled-randomized-blinded
clinical trial, even when effective therapy exists, as long as they are not
denied therapy that could alter survival or prevent irreversible injury. They
can voluntarily agree to accept temporary discomfort and other potential risks
in order to help evaluate a new treatment. In any trial in which a possible
effect on survival is being assessed, it is important to monitor results as
they emerge. That way, if a major effect is seen, positive or negative, the
trial can be stopped.
In some cases, a new treatment can be compared with established treatment,
as long as the effectiveness of the latter can readily be distinguished from
placebo and the study is large enough to detect any important difference. It
is also possible to evaluate new drugs in this situation in "add-on"
studies. In this kind of trial, all participants receive standard therapy approved
for treating the disease, but those in the treatment group also get the investigational
drug. The control group gets either no added treatment or placebo. Any difference
in results between the treatment and control groups can be attributed to the
We recommend that anyone interested in participating in a clinical trial discuss
the idea with his or her physician. Doctors are generally aware of investigational
drugs that might be of benefit to their patients and of clinical trials involving
these drugs. Detailed information can be obtained from a variety of sources,
including drug sponsors, FDA (if the information is public), and NIH. Clinical
trials are carried out at major medical research centers such as teaching hospitals,
at NIH, and even in doctors’ offices. Although they often involve hospitalized
patients, many clinical trials can be conducted on an outpatient basis, with
participants more or less going about their normal activities. The center or
institution where a study is to be carried out often runs newspaper ads recruiting
potential participants for clinical studies that tell readers where to call
or write for further information.
These and other aspects and implications of taking part in a clinical trial
must be fully explained in advance by the people conducting the trial, and patients
must agree to the conditions before they can participate. The hope of personally
benefiting from a new drug, or the desire to take part in research that might
one day benefit millions, is what makes people volunteer for clinical trials.
It should not prevent them, however, from finding out all they can about being
a part of the process.
III. Expanding Access to Investigational New Products
The ideal mechanism for a patient to receive a promising but unproven drug
is as a participant in a controlled clinical trial. Such trials provide appropriate
patient protections and potential benefits (for example, IRB review, informed
consent, free product or treatment, and FDA review of pre-clinical data and
the protocols for the clinical trials) and maximize the gathering of useful
information about the product, potentially benefiting the entire patient population.
It is not always possible, however, for all patients who might benefit from
the drug to enroll in controlled clinical trials.
In this situation, FDA believes that it is possible, and appropriate, to help
make certain promising, but not yet proven, products available to patients with
serious and life-threatening illnesses. This should be done in a way that does
not pose an unreasonable risk to the patient and does not prevent the collection
of the information needed to support the effectiveness and safety of the drug.
While the phrase "compassionate use" is commonly used to describe
some of the ways of making unapproved products available, there is no FDA regulation
or policy defining a "compassionate use." Compassion, however, should
be, and is, an element of all our activities. Section 402 of the Food and Drug
Modernization Act of 1997 (FDAMA) has codified certain FDA regulations and practices
regarding expanded patient access to experimental drugs and devices. FDAMA addresses
three expanded access procedures with respect to: 1) emergency situations; 2)
individual patient access to investigational products intended for serious diseases;
and 3) treatment IND applications and treatment investigational device exemptions
(IDE). The Agency continues to review current regulations and practices in light
There are a number of mechanisms FDA has used to provide access to promising
investigational therapies, including: treatment INDs; treatment protocols; single
patient INDs; emergency INDs; open label protocols; continued availability of
investigational devices; protocol or special exceptions; open label extensions;
parallel track; emergency use of unapproved medical devices; and treatment IDE.
In the drug development process, FDA’s primary point of contact is with the
sponsor of the product. At times, FDA communicates with a patient’s physician,
who is seeking permission to use an investigational therapy on an individual
patient, for example, when an individual patient is seeking access to an investigational
therapy for personal use, and who may or may not be eligible for enrollment
in a clinical trial.
The commercial or other sponsor (e.g. NIH) of the investigational drug must
decide whether it is willing to make the product available for individual use
by the patient. Assuming it is, and such access cannot be provided through an
existing protocol, FDA may be asked to consider a physician-sponsored individual
patient IND. If the sponsor of the already ongoing study (the "owner"
of the drug or biologic) is not willing to make the product available, the single
patient study cannot proceed, even if the Agency has no objections to the treatment.
In considering such cases, the Agency is bound by strict rules of confidentiality
governing the types of information it can disclose to a physician about the
sponsor’s product and development data.
One may ask why FDA is involved in this process at all. That is, why should
not the physician and patient decide on the appropriateness of treatment. We
believe that the independent scientific consideration provided by the Agency
is critical and is an essential component of patient protection, when one is
considering drugs about which relatively little is often known. In the typical
single patient IND situation, especially those involving emergency IND requests,
the patient’s physician generally has only very limited information about the
investigational therapy being requested.
The Agency’s primary responsibility in deciding whether to allow a single patient
IND to proceed is to determine whether use of the therapy in the particular
patient involved would be reasonable or safe. In oncology, with respect to patients
for whom no curative treatments exist, our practice has been to permit almost
anything that is reasonably safe without regard to efficacy or potential efficacy.
There may be several INDs for the same product with each sponsor working confidentially
and in ignorance of what others are doing and of their results. FDA is often
the only party that has all of the information.
A. Can an unapproved therapy believed to be lesstoxic be tried prior
to a curative therapy that has known serious adverse events?
Indirectly harmful products are those that do not themselves cause injury,
but may lead people to delay or reject proven remedies, possibly worsening their
condition. For example, if cancer patients reject curative drug therapies in
favor of unproven therapies and the unproven therapies turn out not to work,
their disease may advance beyond the point where proven curative therapies can
There have been two well publicized cases where FDA refused to permit patients
to receive an unproven cancer therapy prior to receiving the standard of care
that was likely to cure the disease because, there was NO evidence
of clinical data to suggest a benefit from the investigational product requested.
More importantly, the standard of care for these two diseases was and is considered
"CURATIVE THERAPY," a rare opportunity in cancer treatment. Prior
to use of the curative therapy in these situations, death was the most certain
outcome for patients with these diseases. It is now highly likely that patients
can expect long term survival. In over 700 cases where curative treatments were
not available and patients requested use of this same unproven therapy, FDA
permitted such patients to go ahead with the treatment.
Researchers are constantly striving to improve on past accomplishments with
the goal of finding new and better treatments with minimum side effects. For
example, in childhood leukemia, progress was made in improving the cure rate
and decreasing the toxicity by substituting one drug at a time in multi-drug
combinations. Initial treatments for protecting or treating children with leukemia
in the brain were considered too toxic, but worth the risk due to the high cure
rate. With careful observation and no compromise in the cure rate, the toxic
therapies were replaced with less toxic therapies as newer drugs became available.
Now, the cure rate for some types of childhood leukemia are greater than 90
percent with excellent follow up and development.
As long as a curative treatment for a disease is available, FDA cannot permit
the use of an unproven product, and risk patients forgoing proven treatments
for that which is unknown.
B. The Office of Special Health Issues (OSHI).
FDA is mindful of the frustrations that patients with life-threatening illnesses
and their families experience when trying to obtain information about potentially
helpful therapies, especially when there is no standard therapy. In addition
to offices within FDA’s Center for Biologics Evaluation and Research (CBER)
and CDER that routinely provide assistance and information to consumers, the
Agency created OSHI to provide information and to work with cancer patients
and their advocates on cancer-related issues. Most activity in OSHI is on behalf
of patients with life threatening diseases, most often cancer and AIDS.
Usually, callers want information about treatments currently being researched.
For example, a kidney cancer patient called recently asking for access to an
unapproved biologic therapy. He was not eligible for the clinical trial and
asked if FDA could please get the drug for him or make the company give it to
him. After explaining that FDA cannot compel a company to supply a product,
an FDA staff member, trained to work with cancer patients, spent many hours
on the phone with this patient over the course of a week, explaining sources
of information regarding kidney cancer clinical trials and helping him to understand
options he might pursue in lieu of the trial he was not eligible to enter under
the company’s protocol.
Although we cannot disclose proprietary information about products under development,
we are able to talk with patients about any treatment that appears in public
access data bases, such as the NCI’s Physician Data Query database at cancertrials.nci.nih.gov
or through the NCI’s telephone service at 1-800-4-CANCER. This database contains
close to 1800 cancer trials; pharmaceutical company trials represent only 10
percent of that database. Additional information is available through the National
Library of Medicine’s clinicaltrials.gov website.
Section 113 of FDAMA requires drug companies to list trials of therapies for
serious or life-threatening diseases in a public access database once the trial
sponsor begins to investigate the effectiveness of that therapy. Our staff is
working actively with the National Library of Medicine and the pharmaceutical
industry to include more clinical trials into the clinicaltrials.gov
Our goals in serving patients with life-threatening diseases and their family
members are straightforward:
1) Promptness (returning patients’ and family members’ calls within
2) Accessibility (listening to the caller’s concerns and giving
him or her as much time as he or she needs);
3) Education (about the drug approval process and his or her options);
4) Assistance (providing additional information to the patient or
family member that may be helpful, e.g. other sources of information).
The nature of the calls vary greatly. Sometimes they are simple calls in search
of information on clinical trials. Often, the calls are more complex, such as
distraught patients or family members seeking access to a drug that has not
These calls, by their nature, are very difficult ones. OSHI has a trained staff
dedicated to providing as much assistance as possible to patients and family
members in extremely difficult situations. It is our responsibility to remain
reasonable and sympathetic, even in the face of the frustration and anger that
may be present. The staff explains the steps to follow in requesting access
to unapproved products. Patients and family members are encouraged to call back
as often as needed to get their questions answered or express their point of
view. OSHI receives approximately 1000 inquiries (phone and e-mail) from patients
and family members annually requesting access to unapproved products.
OSHI also works within the Agency to assist with patient and consumer requests
to become more involved with the drug approval process. There is a web page
that is updated regularly with information on AIDS and cancer issues. Specifically,
there is information on clinical trials, product approvals, meetings, and other
matters of interest to this constituency.
Also, we are discussing with sponsors ways to educate patients about the clinical
trial process. We know that recruitment of patients into cancer clinical trials
is often the rate-limiting factor in cancer drug development. Less than three
percent of adult cancer patients participate in clinical trials, in large part
because cancer patients do not know about clinical trials for which they may
be eligible, or fear being part of a study.
The Cancer Liaison Program within OSHI also serves as an access point for the
organized cancer patient advocacy community. Many cancer patient advocacy organizations,
in addition to providing valuable information to cancer patients, are focused
on monitoring the development of State and Federal policies governing a variety
of cancer issues, such as health insurance or research or, in the case of the
Agency, the drug development rules and regulations.
FDA’s Cancer Liaison staff actively participates in discussions of FDA policies
that affect the regulation and review of cancer therapies. Consequently, informing
the advocacy community about FDA policy matters and making certain that meetings
are convened between representatives of cancer patient advocacy organizations
and FDA specialists is one of our major responsibilities. We maintain
a 300-member mailing list that is used to notify the cancer community about
FDA advisory committee meetings, open public hearings or seminars on cancer
research or policy. As promptly as possible, we notify the cancer community
about FDA’s approval of a new cancer drug, biologic or device.
In furtherance of the Agency’s goal of educating cancer survivors and advocates
about FDA and the drug review and approval process, FDA’s Division of Oncology
Drug Products, in partnership with OSHI’s Cancer Liaison Program, designed a
pilot Visiting Oncology Patient Advocates Program.
Visiting advocates attend a one-week scientific seminar with FDA staff, followed
by two to four training sessions in the Division of Oncology Drug Products.
Participants receive one-on-one orientation from FDA scientists and attend
division drug review meetings. At the completion of the program, each visiting
advocate will write a "reaction paper" about the program, and will,
we hope, through speeches, workshops and articles, educate their cancer constituency
about the experience.
IV. REINVENTING THE REGULATION OF CANCER DRUGS AND FDAMA
For the past four years the Agency has been working under the "Reinventing
the Regulation of Cancer Drugs," initiative, which included: 1) Expediting
approval of cancer therapies; 2) Encouraging new uses of marketed products in
cancer treatment; 3) Expanding access to investigational cancer therapies that
have been approved in other countries; and 4) Including cancer patients on our
Oncologic Drug Advisory Committee that reviews cancer therapies.
In addition, FDAMA codified many of FDA’s initiatives and existing programs
intended to expedite drug development and expand access to unapproved therapies.
FDAMA also created powerful new incentives for the development of treatments
- Expediting development, review, and approval of new products.
FDA has implemented mechanisms designed to increase access to new drugs, biologics,
and medical devices by expediting their development, review and approval. All
of these programs have been instrumental in shortening the time to marketing
approval for cancer drugs and biologics. FDA programs include:
- Expedited development under Title 21, Code of Federal Regulations
(CFR) Part 312, Subpart E expedites the development, evaluation, and marketing
of new therapies intended to treat persons with life-threatening and severely
debilitating illnesses. Since the effective date of the Subpart E regulations,
there have been 48 new drug applications (NDA) approved that had been identified
for expedited drug development under Subpart E while in the IND stage. Of
these NDAs, nine were for cancer, and 39 were for indications other than cancer,
including several for conditions that occur in patients with cancer.
- Priority Review to speed the review of NDAs, biologics license applications
(BLAs), and effectiveness supplements that could have important therapeutic
impacts. A priority designation is intended to direct overall attention and
resources to the evaluation of applications for products that have the potential
for providing significant therapeutic advances. FDA’s goal is to review a
priority NDA within six months rather than the standard review time of ten
months. Since 1996, five biologics and 31 drugs (20 NDAs and 11 supplements)
for cancer therapies have received priority review and approval.
- Fast Track section 112 of FDAMA, amends the FD&C Act to consolidate
the various provisions intended to facilitate the investigational development
and approval of drugs and biologics that provide significant advances in the
treatment of serious diseases. This codified FDA’s accelerated approval regulations,
21 CFR Part 314, Subpart H and 21 CFR Part 601, Subpart E, unified provisions
for consideration of serious and life-threatening diseases, established the
provision for "rolling" review of marketing applications and thus
consolidated FDA’s approach to expedited drug development and approval. To
provide clear information to industry regarding participation in the fast
track process, we issued a guidance document on this provision in September
It is important to note that FDAMA did not alter FDA’s effectiveness standard,
except by giving explicit authority to the Agency to rely on a single, adequate
and well-controlled study with confirmatory evidence, in particular cases, as
support for approval. Even for drugs intended for serious and fatal illnesses,
there must be substantial evidence that the drug will have the effect it purports
to have. The law recognizes, however, that the magnitude of the effect that
needs to be demonstrated might vary depending on the urgency and clinical need.
It therefore permits FDA to approve drugs for serious or life-threatening illness
that provide meaningful benefit compared to existing treatments where there
is a demonstrated effect on a surrogate endpoint that is reasonably likely to
predict a real clinical benefit but where a real clinical benefit has not yet
been clearly shown. A surrogate endpoint is a laboratory effect or other clinical
measurement that does not itself directly measure clinical benefit but is thought
to predict clinical benefit. The effect on clinical benefit is then ascertained
in postmarketing clinical trials (Phase IV studies).
FDA’s goal is to improve significantly patient access to promising cancer treatments
without compromising patient safety or the requirement that drugs be proven
safe and effective before they are sold. Importantly, FDA regulations emphasize
safeguards for the protection of human subjects, including the requirement for
informed consent, IRB review, conduct and review of animal studies prior to
human testing, IND safety reports and updates, and adverse drug reaction reports.
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