European Study: Many Oncology Drugs May Not Extend or Improve Life

Available US data show that only a small proportion of FDA-approved cancer treatments unequivocally benefit survival or quality of life (QOL). Now a European study published in BMJ finds that, at a minimum of 3.3 years after market entry, there was no conclusive evidence that many oncology drugs approved by the European Medicines Agency (EMA) between 2009 and 2013 either extended or improved life in most oncology indications, and although there were demonstrated survival gains over existing treatment options or placebo, they were often marginal. Study author Courtney Davis, PhD, and colleagues also note that most drugs entered the European market without evidence of benefit on survival or QOL.

The retrospective cohort study was based on publicly accessible regulatory and scientific reports on EMA cancer drug approvals from 2009 to 2013, a period during which 48 cancer drugs were approved for 68 indications. The study excluded pediatric indications and indications for the treatment of benign tumors. Supportive treatments and generic products were not considered. The study limited scoring on the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to drugs for solid tumors because the scale is not intended to be used to evaluate drugs that treat hematological malignancies.

Of the 68 indications studied, 12% were approved on the basis of a single-arm study. Thirty-three indications were first marketing authorizations and 35 were extensions. Overall, 72 clinical trials supported the approval of the 68 novel drug uses.

The authors found that only 26% of approved indications were supported by a pivotal study powered to evaluate overall survival (OS) as the primary outcome. None of the 10 conditionally authorized uses evaluated survival as the primary endpoint, and OS was evaluated as a primary study endpoint in only 31% of all drug indications that were granted regular marketing authorizations. Remaining drug indications were supported by trials evaluating a surrogate measure as the primary study outcome, and none of the pivotal trials assessed QOL as a primary endpoint.

The study found that at the time of marketing approval:

• 35% of indications were able to demonstrate a significant prolongation of survival
• The magnitude of the benefit in OS ranged from 1.0 to 5.8 months (median, 2.7 months)
• There was an improvement in QOL in 10% of indications
• Of 44 indications for which there was no evidence of a survival gain, in the subsequent postmarketing period, there was evidence for extension of life in 7% and reported benefit in QOL in 11% of indications

After a median of 5.4 years of follow-up (range, 3.3 to 8.1):

• Only 51% of the 68 approved cancer indications demonstrated a significant improvement in survival or QOL, while 49% remained uncertain
• Of 23 indications associated with a survival benefit that could be scored with the validated ESMO-MCBS tool, the benefit was considered clinically meaningful in less than half (48%) of indications

Although the goal of cancer treatment is to improve both the quantity and the quality of life, clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or surrogate measures of drug efficacy, the authors say. “These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival or [QOL] in all settings.” Recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low, the authors note, and it is concerning that many new, increasingly expensive cancer treatments, often promoted as breakthroughs, have marginal benefits that might not be clinically meaningful to patients.

“Most new oncology drugs authorized by the EMA from [2009 to 2013] came onto the market without clear evidence that they improved the quality or quantity of patients’ lives, and, when survival gains over available treatment alternatives were shown, they were not always clinically meaningful,” the authors conclude. Finally, they caution that little new information to guide patients or clinicians was generated in the post-marketing period studied—a situation with negative implications for both patients and public health.