M3 tamoxifen case study.pdf

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 Breast Cancer
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 length of
studies add an arm to study longer than one treatment
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 U.S………….
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 Other FDA
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
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.

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