by ecancer reporter Clare Sansom

There has been controversy and debate over the process of approving drugs for clinical use, and the criteria used to determine which experimental drugs should be licensed, ever since this process was first introduced.

The debate has been particularly heated where recent drugs for cancer are concerned, as these are expensive treatments that often confer quite limited benefit in devastating diseases. The recent debate over the FDA’s decision not to grant full approval for the monoclonal antibody bevacizumab (Avastin™) in metastatic breast cancer (MBC) has highlighted these issues.

This has now been discussed at length in two commentaries published in the same issue of the Journal of Clinical Oncology, with the authors drawing conclusions that can be applied more generally to the approval process for novel anti-cancer drugs.

The FDA’s decision to refuse full approval for bevacizumab came three years after it had granted a provisional “accelerated approval” to the same drug. Full approval is only granted once the agency has been convinced through randomised, controlled clinical trials that the drug offers “an acceptable balance of benefit and harm”.

Much of the controversy discussed in these papers arises from the end points used in these clinical studies. The duration of overall survival (OS) has historically been taken as the standard end point for clinical trials used in evidence for drug approvals, but this is not always practicable, particularly where survival can be long.  

In the first commentary, Gary Lyman of Duke University, Durham, North Carolina, USA and his colleagues described the trials used in the evaluation of bevacizumab.

The main trial that provided evidence for the drug’s original accelerated approval was the open label Eastern Cooperative Oncology Group trial E2100, which showed a significant benefit from the use of bevacizumab with paclitaxel in the first-line treatment of metastatic breast cancer. However, this trial was not designed to provide evidence for full approval, and limitations in its design, including lack of a placebo control, lack of information on mild and moderate adverse effects, and missing data made it unsuitable for this use.

The data used in the application for full approval included additional data from E2100 and data from two further randomised controlled trials: AVADO, which compared bevacizumab to docetaxel, and RIBBON-1, which compared several widely-used standard chemotherapy regimens with and without the addition of bevacizumab.

Both trials reported significant if modest increases in progression free survival (PFS) in the arms including bevacizumab, but no significant increases in overall survival.  There were also more and more serious adverse events in arms containing bevacizumab, and the FDA concluded that there was not enough evidence of the drug’s benefit to grant full approval.

Lyman and his colleagues highlighted the controversy ignited by this data over the relative value of OS and PFS as end points for clinical trials used as evidence for drug approvals. Many oncologists have highlighted the fact that survival after progression is affected by second- and subsequent line treatments, and that this dilutes the observable evidence from OS of the effectiveness of the study drug.

The commentary authors suggested that it should be possible to use surrogate end points such as PFS and quality of life in evaluating the evidence required for drug approvals, and that a debate on how these can best be used to determine whether a drug confers “meaningful clinical benefit” is overdue.

The second commentary, by Javier Cortés of Vall d’Hebron University Hospital, Barcelona, Spain and his colleagues, continued the discussion of PFS as an alternative endpoint in clinical trials of drugs for cancer, citing the increases in PFS observed in all three clinical trials used in the evaluation of bevacizumab [2]. Cortés and his co-authors described a meta-analysis of the three trials which confirmed an increase in PFS but not in OS.

However, they claimed, meta-analyses should not be used to draw conclusions from criteria that were not the primary end points of the trials concerned; all these trials had used PFS as the primary end point. In this case, the overall survival of the enrolled patients would be determined by the further treatments they received, and there was no evidence to suggest that these did not differ between arms.

There are other examples of drugs where a benefit recognized by clinicians has not been reflected in reported OS results from clinical trials, including aromatase inhibitors for hormone receptor positive breast cancer. Many oncologists have similarly cited anecdotal evidence of clinical benefit with bevacizumab in MBC in expressing disappointment with the FDA’s recent decision.

The conclusion from both commentaries was that focusing only on overall survival in evaluating drugs for advanced cancer is likely to lead to more refusals of licenses for potentially useful treatments. Progression free survival and quality of life measures will have value as alternative end points, provided that the trial designs have sufficient statistical rigour.

References

[1] Lyman, G.H., Burstein, H.J., Buzdar, A.U., D'Agostino, R. and Ellis, P.A. (2012). Making Genuine Progress Against Metastatic Breast Cancer. J. Clin. Oncol., published ahead of print 27 August 2012.

[2] Cortés J., Calvo, E., González-Martín, A., Dawood, S., Llombart-Cussac, A., De Mattos-Arruda, L., Gómez, P., Silva, O., Perez, E.A., Rugo, H.S., Lluch, A. and Hortobagyi, G.N. (2012). Progress Against Solid Tumors in Danger: The Metastatic Breast Cancer Example. J Clin Oncol., published ahead of print 27 August 2012.