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International Clinical Trials

Female Focus

Clinical trials are necessary to develop effective new cancer therapeutics and are essential to cancer care (1). According to Tufts Center for the Study of Drug Development, the estimated average industry cost per new prescription drug approval is about $2.6 billion and it can take over a decade to develop a new drug (2). This, combined with increasing societal pressures to more quickly develop safe and effective medications, makes drug development a challenging endeavour.

Despite these seemingly insurmountable hurdles, the FDA continues to approve new drugs at a record pace. Since 2005, the US Center for Drug Evaluation and Research at the FDA has averaged 25 new drug and biologic approvals per year, with an astounding 41 given the go-ahead in 2014 – the most since 1996, when 56 approvals were granted (3,4). For gynaecologic cancers, progress has been significantly slower, although 2014 was a banner year – marking the first time since 2006 that new agents were approved in the US for gynaecologic malignancies, and the first time in nearly 20 years that a new therapy was approved for use in women with ovarian cancer (5).

In the US, some 95,000 women are diagnosed with a gynaecologic malignancy each year. They now have more treatment options available to them and can expect to survive longer than ever before, but an estimated 28,000 women will ultimately die from their disease (6). Ovarian cancer is among the most lethal of the gynaecologic cancers, claiming more than 14,000 lives annually, while uterine cancer causes 8,500 deaths and cervical cancer 4,000 deaths per year.

Breakthrough Approvals

As noted, there has been an unfortunate lack of new drugs approved for gynaecologic cancers in the US. In contrast, the EMA passed two new agents for women with ovarian cancer – trabectedin in 2009 and bevacizumab in 2012. The FDA had not approved any new agents for ovarian cancer since June 2006, when gemcitabine was recommended for use in combination with carboplatin for women with advanced ovarian cancer who relapsed six months after completion of platinum-based therapy (5,7). Similarly, the last chemotherapeutic agent approved in the US for women with cervical cancer was also in 2006, when topotecan was passed for use in combination with cisplatin in women with advanced, persistent or recurrent disease (8).

The drug development industry witnessed a major reversal of this trend in 2014 with the approval of the poly (adenosine diphosphate ribose) polymerase inhibitor, olaparib (3,9), for use in BRCA-mutated advanced ovarian cancer, and bevacizumab for use in women with both advanced ovarian cancer and advanced cervical cancer (10).

While these new drug approvals are a testament to the cooperation of partners in pharma and academia – and, most importantly, women with gynaecologic cancer – one must contemplate what challenges to rapid drug approval continue to persist and how the industry can capitalise on the current progress and momentum.

Trial Design

A well-designed cancer trial is the foundation of all oncologic drug approvals and answers specific questions about a specific patient population in a scientifically rigorous manner. The study must be ethical, interesting and clinically relevant to the disease under consideration (11). In Phase 3 ovarian cancer trials, the most relevant question to ask is if the experimental regimen provides a therapeutic benefit as compared to the current best-known treatment.

Overall survival (OS) remains the gold standard for demonstrating clinical benefit and represents the time from randomisation to death. This endpoint is unambiguous and not open to interpretation. Other endpoints – including progression-free survival, time to progression, response rate, time to tumour growth and patient-reported outcome measures – have also been used to demonstrate clinical benefit (5,12).

Endpoint Debate

There has been considerable debate regarding the most appropriate endpoint for ovarian cancer trials. In The Society of Gynecologic Oncology's (SGO's) recently published guidance for clinical trial design in ovarian cancer, OS was noted to be “an imprecise and impractical endpoint due to a long initial post-progression survival, frequent active treatment including crossover treatment, and considerable length and cost needed to demonstrate OS” (13). As a result, many have advocated the use of these other endpoints as surrogate markers for OS in ovarian cancer trials.

It is interesting to note that these surrogate markers had been used for drug approvals prior to 2014. Despite the use of surrogate endpoints in the FDA’s recent approvals of olaparib and bevacizumab, it remains unclear which of these endpoints is the best for ovarian cancer trials. Consultation with the FDA prior to initiation of the trial is necessary to confirm that the proposed endpoint properly assesses the efficacy of the experimental agent so any potential bias is minimised (12).

Enrolment Barriers

Once the study endpoints have been defined and protocols finalised, what steps are necessary to accrue patients into these clinical trials so the experimental question can be answered? It has been reported that in the US, only 2-4% of adult cancer patients participate in National Cancer Institute sponsored clinical trials (14). The reasons for such poor enrolment on cancer trials is complex. For women with gynaecologic malignancies, low enrolment has been blamed on a relatively low incidence of disease, when compared to other solid tumours and overly strict inclusion criteria (14).

To further investigate the reasons why accruing patients for gynaecologic trials is such a challenge, research retrospectively examined all patients treated at a single institution over a period of three years. It found that about 72% of women who were eligible for a clinical trial declined participation (15). The most common reason cited was a perception of harm by taking part. In addition to patient misperceptions, the research noted that there was a significant amount of physician bias on who should and should not be offered a trial; 20% of eligible patients were not offered participation in a study, despite satisfying the inclusion and exclusion criteria. Reasons cited for this included patients who were deemed poor candidates due to co-morbid conditions, and patients who were anticipated to be non-compliant.

Tackling Misconceptions

Correcting both patient and investigator misconceptions will take the combined efforts of all research professionals. For patients, this should occur at the start of the informed consent process. While they are the subjects of experimental treatments, there is the potential for benefit and they have protection under the law.

There is also a need to change the perception that only people with no other options need to enrol in clinical research. It should be made clear that any patient’s participation is voluntary and they can withdraw from the study at any time. For investigators, it is important to resist the temptation to 'cherry pick' patients for trials, instead presenting the opportunity to all who satisfy the study requirements (15).

Designing and executing clinical trials in women with gynaecologic cancer is a complex process. To be successful, the trial must carefully consider the endpoints that will allow it to be designed in a way that demonstrates safety and efficacy of the study drug, while providing meaningful clinical benefit. In addition, it must address the concerns of women with gynaecologic malignancies about participating in an experimental treatment. Adherence to these principles may improve the design of clinical trials, facilitate patient accrual, help to speed new drugs to the market and, ultimately, improve the outcomes for these women.

References
1. Hirsch BR, Califf RM and Cheng SK, Characteristics of oncology clinical trials, JAMA Intern Med 173: pp972-978, 2013
2. Tufts Center for the Study of Drug Development. Visit: http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study
3. Novel New Drugs 2014 Summary. Visit: www.fda.gov/downloads/drugs/developmentapprovalprocess/druginnovation/ucm43029
4. Weschler J, FDA updates policies to continue gains in new drug approvals, Applied Clinical Trials 24: p8, 2015
5. Herzog TJ, Armstrong DM and Brady MF, Ovarian cancer clinical trials endpoints: Society of Gynecologic Oncology white paper, Gynecol Oncol 132: pp8-17, 2014
6. Foundation for Women’s Cancer Fact Sheet. Visit: www.foundationforwomenscancer.org/wp-content/uploads/facts-about-gynecologiccancers.pdf
7. Gemzar package insert. Visit: http://pi.lilly.com/us/gemzar.pdf
8. FDA approves Avastin to treat patients with aggressive and late stage cervical cancer, FDA news release. Visit: www.fda.gov/newsevents/newsroom/pressannouncements/ucm410121.htm
9. Olaparib package insert. Visit: www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf
10. Bevacizumab package insert. Visit: www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf
11. Cummings SR, Browner WS and Hulley SB, Concerning the research question in designing clinical research (3rd edition), Lippincott, Williams & Wilkins, 2007
12. Padzur R, Endpoints for assessing drug activity in clinical trials, The Oncologist 13 (supp 2): pp19-21, 2008
13. Herzog TJ, Alvarez RD and Secord A, SGO guidance document for clinical trial designs in ovarian cancer, Gynecol Oncol 135: pp3-7, 2014
14. Kuroki L, Stuckey A and Hirway P, Addressing clinical trials: Can the multidisciplinary tumor board improve participation? A study for an academic women’s cancer program, Gynecol Oncol 116: pp295-300, 2009
15. Manders DB, Paulsen A and Richardson DL, Factors associated with clinical trial screening failures in gynecologic oncology, Gynecol Oncol 133: pp75-76, 2014

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Jason D Hurt, MD, is Medical Director – Oncology at Medpace. Specialising in oncology trials, he has led the development of agents specific to gynaecologic cancers and breast cancer, and established relationships with key opinion leaders in women’s cancers. His research interests include pharmacogenomics and the use of biologic therapies in gynaecologic cancer. He completed his residency at Texas Tech University and was a gynaecologic-oncology fellow at The Ohio State University before joining the faculty at the University of Pittsburgh Medical Center-Magee Women’s Hospital.
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