Case Study: Tamoxifen A Drug’s Evolution From Fertility to Many Stages of Cancer Tamoxifen is:
• FDA approved as Nolvadex (brand name) • Currently most prescribed cancer drug in breast cancer • Used by millions in over 110 countries • SERM:(selective estrogen receptor modulators) exert estrogen agonist action in some
target tissues while acting as estrogen antagonists in others
How does Tamoxifen work?
Estrogen stimulates the growth of some tumors, primarily in the breast and female reproductive organs?(ER positive tumors). Tamoxifen is an oral synthetic hormone that binds to the estrogen receptor (ER) instead of estrogen and blocks the mechanism of growth for tumors that are stimulated by estrogen. It also maintains bone and lowers cholesterol. Side effects of Tamoxifen
Hot flashes, blood clots in the lung or major vein, strokes, and/or uterine cancer.
Tamoxifen is an agent that presents some unique characteristics and takes us through different development aspects
R It was developed for one use (fertility regulation), then proven effective for
R It started its effectiveness in metastatic breast cancer, moved to adjuvant
settings, and has now been tested and approved for breast cancer risk reduction in women who do not have breast cancer.
R It also introduced a new class of drugs - SERMs
Tamoxifen opened up the field of hormonal therapy. Newer “designer” SERMs become more effective with fewer side effects because of what was learned from Tamoxifen.
R Tamoxifen also ushered in targeted therapy
Scientists found it is effective only with ER+ (estrogen receptor positive) breast tumors. Patients are now routinely measured for ER status to learn which patients are more likely to respond to Tamoxifen therapy.
The following brief summary of the development of the drug Tamoxifen is presented to increase your understanding of the drug development process.
Tamoxifen: A Long History Basic Science and Preclinical Phase- Building on the Discoveries of the Past Principles and discoveries important before development of Tamoxifen
cancer were treated by having surgery to remove their ovaries (oophorectomy). The reason for response (1 in 3) was not discovered until 60 years later.
• In 1923 the first studies on what was later termed the “estrogen
• 1966, Dr. Elwood Jensen (U of Chicago) and Dr. Jack Gorski (U of IL) studied the theory of the presence of an estrogen receptor. Dr. Jensen later developed a test to determine the hormone receptor status of tumors so response to treatment could be more accurately measured.
Synthesis of the Drug
Several pharmaceutical companies were involved in the study of the
structure of antiestrogens in an effort to
Patenting the Compound During the
find a contraceptive. Dr. Dora Richardson at ICI Pharmaceuticals
synthesized triphenylethylenes and became the co-patent holder with Dr. Arthur Walpole on ICI 46,474 which later became Tamoxifen.
Dr. Arthur Walpole at ICI Pharmaceuticals (now Zeneca)
Tamoxifen First Studied
published results of antiestrogen compound ICI 46,474. First thought to be a “morning after” contraceptive, he felt it held promise for breast cancer. Ability to inhibit breast cancer cell growth
of tamoxifen to inhibit the growth of MCF- 7 ER positive breast cancer cells in culture
Lab findings about length of treatment Clinical Studies-Proving the drug works and is safe for humans First Clinical Studies in
tamoxifen) was marketed in Great Britain and
Britain………… Marketed in Great Britain
tamoxifen) was marketed in Great Britain and
as fertility drug…………. First Studied in
First evaluation of ICI 46,474 conducted at
Christie Hospital in England for the palliative
Cancer… Approved for
ICI received approval from the Committee on
the Safety of Medicines in the United Kingdom
for use of Nolvadex in the treatment of breast
UK…………… NCI Weighs
principle that ER negative patients would be
unlikely to respond to endocrine therapy.
Established the target for Tamoxifen therapy
Trials initiated Mid/late
Several trials of tamoxifen monotherapy were
as adjuvant to
initiated as an adjuvant to mastectomy (usually
mastectomy Studies of
Based on findings in the laboratory, clinical
studies add an arm to study longer than one
year tamoxifen in adjuvant clinical trials.
Pilot study to determine
initiate a pilot study to determine whether
tolerance of 5
patients could tolerate five years of adjuvant
year treatment FDA Approval
FDA approves Nolvadex (NDA 17-970) for the
postmenopausal women in the United States
Before tamoxifen’s approval, no one wanted to study these kinds of agents. Once it was approved, it was difficult to move forward by testing better agents for a long time. Zeneca adopted a strategic approach by seeking FDA approval for new indications from trial results instead of accepting off-label use.
The chart below shows some of the additional applications for which Zeneca applied and which were granted for uses of Tamoxifen. These indications of the uses of the drug were granted through a process called a Supplemental New Drug Application. Each indication is a separate application and followed the drug approval process. If relevant data was available from past study phases that data could be used to support the supplemental NDA; if not, it was necessary to start studies with Phase I or II to gather the data needed to support the new use. Several Cooperative Groups participated in these studies: ECOG, SWOG and NSABP.
Post NDA approval activity—Supplemental NDAs
with chemotherapy in postmenopausal women with node-positive breast cancer Approved for adjuvant Tamoxifen alone in
postmenopausal women with node-positive breast cancer
Approved for advanced male breast cancer
approvals for Nolvadex:
prolonged overall survival of breast cancer patients Approved for reducing contralateral breast
incidence in women at high risk for breast
Approved for indication to reduce risk of
invasive breast cancer in women with DCIS, following breast surgery and
Testing does not start in the adjuvant setting. Why? Cancer drugs have side effects, so they are tested in a few people that show the biggest impact. Response in advanced cancer is easier to measure in early stage disease.
Many advocates took issue with the way Tamoxifen was being used for all women, even though results showed that only women with ER+ tumors benefited. They developed information directed toward women and doctors to minimize off-label use. Advocates played a major role in the wording used for “risk reduction” instead of “prevention” of breast cancer in 1998. Questions still remain: 1) Does Tamoxifen really prevent or just delay? 2) Is it worth the side effects to prevent a cancer that may not have occurred? 3) Does the way the Gail Model evaluate risk work for all populations (e.g. African Americans, others)? Many advocates took issue with the way Tamoxifen was being used for all women, even though results showed that only women with ER+ tumors benefited. They developed information directed toward women and doctors to minimize off-label use. Advocates played a major role in the wording used for “risk reduction” instead of “prevention” of breast cancer in 1998. Questions still remain: 1) does Tamoxifen really prevent or just delay? 2) Is it worth the side effects to prevent a cancer that may not have occurred? 3) Does the way the Gail Model evaluate risk work for all populations (e.g. African Americans, others)?
Because of the paradoxical lessons learned from tamoxifen as an antiestrogen could maintain bone density was subsequently used to justify the development of raloxifene as a SERM (selective estrogen-receptor modulator) for the prevention of osteoporosis. M Raloxifene approved
Results from Lilly’s Multiple Outcomes of Raloxifene Evaluations (MORE) study produced off-label prescriptions from many oncologists and non-oncologists. Even though Raloxifene shows promise to lower breast cancer, the study looked at osteoporosis. It did not include the statistical power to give a definitive answer for breast cancer. This kind of example can happen quite often.
Study compares Tamoxifen and Raloxifene Advocates are concerned about the design of this trial for many reasons. One of the main reasons is due to no placebo arm. Scientists counter that the first NSABP study had enough people to determine that Tamoxifen is better than placebo, although we regularly hear that you must do more than one trial to prove new study results.
Tamoxifen’s Next Step… Going Generic? The patent life of a drug is a consideration in the cost, production and testing time. After a patent expires, the compound is available for other companies to file Abbreviated New Drug Applications (ANDAs) that would allow the company to manufacture and sell tamoxifen as a generic drug.
Zeneca’s patent for Nolvadex (tamoxifen citrate) expires in 2002, FDA’s website shows four ANDAs (Abbreviated New Drug Applications) that have been filed by different companies to manufacture and sell tamoxifen citrate as a generic drug. Generics usually cost less for the patient.
Sound Good? Consider this:
R Tamoxifen was the only approved antiestrogen on the market in the United States
between 1978 and 1997. Other companies concentrated on traditional chemotherapies rather than endocrine until the success of Tamoxifen.
R The commitment to develop Tamoxifen while other companies pursued standard
approaches helped launch a new generations of drugs and therapies (e.g. anti-angiogenesis drugs). This kind of research is critical if we want to gain ground against cancer.
R Profits from the success of Nolvadex were reinvested to:
• Develop new drugs for breast and prostate cancer • Provide free Nolvadex and placebo for the NSABP prevention trial • Encourage new ideas and initiatives that would not have been considered 30 years
What happens to research development when a company doesn’t make money on their “cash cow” anymore? There is more to price controls and generic drug availability, and advocates need to learn about it with an open mind before making short-sighted statements. Case Study: Gleevec
From Killing Cancer Cells to Targeting What Makes Them
Gleevec was approved very quickly by the FDA because of special circumstances that are allowed for in the FDA approval process. Following is an overview of the special circumstances that factored into the rapid approval of Gleevec:
Accelerated approval is used for serious or life-threatening illnesses. Clinical trials show that the drug affects a surrogate endpoint that is likely to predict a real clinical benefit. Gleevec’s approval was based on three separate single-arm studies in about 1000 patients. These clinical trials were not designed to determine whether Gleevec improves survival. Commitments to perform several other studies were required for accelerated approval.
Gleevec: An Orphan Drug Too!
Orphan drug regulations apply to drugs for rare diseases. CML affects between 5,000 and 8,000 patients each year. Special considerations for orphan drugs means there are financial incentives for the company to develop it
Gleevec: What’s the Big Deal? The genetics revolution “took our level of understanding to a whole new level. Now we can develop treatments that correct or interfere with an abnormality. We couldn’t do that before.” Dr. Bill Gradishar, ASCO communications committee Chair; Oncologist, Northwestern University "It is important to recognize that today's approval is a culmination of years of work and years of investment, by many people in many different institutions, and even in different fields of medicine.” Health and Human Services Secretary Tommy G. Thompson “For the first time, cancer researchers now have the necessary tools to probe the molecular anatomy of tumor cells in search of cancer-causing proteins. Gleevec offers proof that molecular targeting works in treating cancer, provided that the target is correctly chosen. The challenge now is we’ve got to find these targets.” Richard Klausner, M.D., director of the National Cancer Institute Once more, it sounds like “the answer for which we’ve been waiting.” When questioned, scientists explain that we don’t know the ultimate outcome of this approach, but at least it looks like it may work in humans instead of just animal models. “Although the long term benefits of the drug are not yet known, early studies have shown that Gleevec will offer a significant improvement for many patients. However, further studies are needed to evaluate whether Gleevec provides an actual clinical benefit, such as improved survival, as well as to examine its effect when used in early stage disease.” FDA’s acting commissioner, Bernard A. Schwetz, D.V.M., Ph.D.
The approval process 30+ years ago was different than today’s. Today, there is much more pressure to approve drugs rapidly.
Comparision of Development of Tamoxifen and Gleevec Development Phase Tamoxifen Gleevec
and cytogenetic response rates. There were no controlled trials demonstrating a clinical benefit at time of approval.
blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
study comparing Gleevec (STI571) vs. Interferon (IFN) and Cytarabine (Ara-C) in newly diagnosed CML patients in chronic phase
Provide safety and efficacy update on current studies by July, 2001 A number of other requirements are specified in the approval letter.
The “Advocate Point”
The Advocate Handbook uses a special bullet to highlight ideas, issues, notes, and roles that are important to help you apply the information throughout the Cooperative Group system as a cancer patient advocate.
The “Info Bullet”
The Advocate Handbook also contains information bullets to offer additional insights on specific topics.
Pancreatitis is defined as inflammation of the pancreas and can be caused by a number of inciting factors. The pancreas is responsible for tasks such as glucose regulation and aids in the digestion of food. Accordingly, two separate parts are responsible for these functions: the endocrine portion, which produces insulin for glucose regulation and the exocrine portion, which produces enzymes for
infrequent by 24%. Mechanical and infection events werereported in the following frequencies: rare 41.5%, infrequent41.5%, common or very common 17%. Baclofen withdrawalevents were rare in 65%, infrequent in 27%, and common in 8%‘Intrathecal baclofen use in children with spasticity – a physi-of respondents’ experience. No difference in reported compli-cations was found on the basis of exp