January 2013: Proposal for the inclusion of trastuzumab in WHO EML for treatment of HER2-Positive Breast Cancer

On 14 January 2013, Knowledge Ecology International (KEI), the University of California (San Francisco), Universities Allied for Essential Medicines (UAEM), Third World Network (TWN) and Young Professionals Chronic Disease Network: YP-CDN submitted a Proposal for the Inclusion of Trastuzumab in the WHO Model List of Essential Medicines for the Treatment of HER2-Positive Breast Cancer to WHO’s Expert Committee on the Selection and Use of Essential Medicines.

The Report of the Expert Committee, 2013 noted that:

The Expert Committee considered that the evidence showed that trastuzumab is an effective adjuvant treatment in early-stage breast cancer. The Committee agreed that trastuzumab meets the criteria for inclusion as an essential medicine in health systems that have the capacity for specialized diagnostic facilities and for delivering the other treatment modalities for the management of breast cancer. The Expert Committee considered that the cost–effectiveness is likely to be unfavourable and recommended that WHO should develop strategies to assist countries to determine how to manage purchasing decisions in relation to high-cost medicines in general, including those for cancer.

Given the need for the list of medicines in Section 8.2 of the EML to be reviewed, the Expert Committee decided that final specification of trastuzumab in the EML should be done by the Committee once the review is completed.

Section 8.2. Cytotoxic and adjuvant medicines: After considering the applications for the addition of imatinib and trastuzumab, the Expert Committee decided that an urgent review of this subsection was needed, using a process and structure Executive Summary similar to that used for the same section in the EMLc. This process would require identification in adults of the treatable tumours of public health relevance and identification of the medicines required to treat those tumours, within the context of a stepwise development of cancer care systems in the overall context of health system development. The Expert Committee considered the two applications in detail and noted the high quality of evidence showing relevant clinical benefits in support of both imatinib and trastuzumab but deferred the final specifications of the medicines and their inclusion until the review of the section of cytotoxics is completed.

In response to our petition on trastuzumab and other petitions on imatinib and trastuzumab, the WHO secretariat is preparing a framework to guide the 2015 Expert Committee in evaluating oncology and haematology drugs.

WHO’s proposed framework for oncology and haemotology for the EML in 2015 is a 3-step approach:

1. Analysis of available evidence-based treatment protocols for both oncology and haemotology. The most frequent adult oncology cancers are breast, lung, colo-rectal, gastric, prostate and renal cancers; for haematology the drugs that have demonstrated very large clinical benefits are imatinib (already evaluated n 2013) and leukemia and thalidomide for MM

2. Retrieve, present and discuss the estimated benefits and harms of each medicines [sic] most relevant outcomes

3. Categorization of each medicine for its estimated benefit and benefit/risk profile (using as guiding principle a threshold of clinical relevance above 3 months of progression free survival and overall survival) and classification of each drug as: already in EML, with large magnitude of benefit (and candidate for its inclusion), limited evidence of potentially relevant benefit and modest/marginal benefit.

The proposed EML framework would contain a disease approach which would include (breast cancer, colorectal cancer, lung cancer and prostate cancer) and a drug approach which would focus on drugs for hematology. The EML framework will currently only look at “adjuvant (early stage) and first line treatments (metastatic) in the first comprehensive review (using as a guiding principle a threshold of clinical relevance above 3 months of progression free survival and overall survival).”

The exception to this “first line treatment” rule would be for breast cancer where the WHO anticipates the need to consider pertuzumab and T-DM1 noting that they exceed the threshold of clinical relevance (6 months of progression free survival).

In November 2014, the WHO Department of Essential Medicines and Health Products (EMP) will convene an ad hoc working group of oncology experts to finalize a cancer review document. This document will be made public in December 2014 and will guide the Expert Committee in April 2015 in making informed decisions on already existing petitions on trastuzumab and imatinib and subsequent applications on anticancer products.

Our petition for trastuzumab, currently marketed internationally under the brand name Herceptin, a product of Genentech/F. Hoffmann-La Roche Ltd., should be viewed in light of the fact that,

Currently, each year, at least 276,000 women worldwide are newly diagnosed with HER2-positive breast cancer (1.38 million * 20%) and in the year 2030, an estimated 540,000 women will be diagnosed with HER2-positive breast cancer (2.7 million * 20%). (Source: Proposal for the inclusion of trastuzumab in WHO EML for treatment of HER2-Positive Breast Cancer)

Our research on the price of trastuzumab showed that annual treatment costs (based on a patient using 150 milligrams per week) ranged from $23,000 in India and Pakistan, $45,710 in South Africa, more than $73,000 in Lebanon and $78,000 in Brazil.

In our petition, we underscored key parallels with between the Expert Committee’s review of our petition for an expensive cancer drug with the decision made by the special WHO expert committee in 2002 to place antiretrovirals on the WHO EML noting that “the addition of critical medicines to the WHO Essential Medicines List that appear unaffordable can, in reality, serve as a vital lever in expanding access to these medicines and in making them affordable. This would include but not be limited to actions by governments to overcome patent barriers — actions that were used to expand access to drugs for HIV/AIDS — and to measures that address the need for efficient regulatory pathways for approvals of less expensive biosimiliar/biogeneric products.”

Our analysis noted:

It is the view of the petitioners that it is possible to obtain trastuzumab at far lower prices than are currently available in any country. However, because trastuzumab is a monoclonal antibody, there are challenges to obtaining low priced versions. These challenges include the trade secrets associated with the manufacture of the drug, patents and test data protection, the difficult and in many countries undeveloped regulatory pathway for biosimilar products, and because of market entry barriers, the potential lack of competition among manufacturers supplying the drug.

WHO has several possible ways of dealing with the pricing issue. WHO could take the Roche prices as a state of nature and reject the application on the grounds that trastuzumab is not cost effective in a resource poor setting. Or, WHO could say that trastuzumab is medically important enough to be included in the list if the country can obtain the drug at an affordable price. WHO could also identify the measures that will be necessary to expand access to the drug at affordable prices, including the measures necessary to overcome intellectual property barriers, a biosimilar pathway for drug registration, including a WHO prequalification process for trastuzumab, and also the efficient procurement strategies that have proved to be useful in bringing down prices for HIV drugs.

In our summary, we stated:

Breast cancer is an urgent global health priority. In 2008, almost 1.4 million women were diagnosed with breast cancer according to Globocan; and nearly 500,000 of them died from the disease that year. In just two decades, the annual incidence is predicted to be as high as 2.7 million; the current prevalence is already above 5 million with much of the burden lying in developing countries experiencing an epidemiological transition. A United Nations High-Level Meeting on non-communicable disease prevention and control put the spotlight on non-communicable diseases (NCDs) as social and economic issues; with a crucial focus on cancer and newer strategies to enable access to essential medicines for cancers this decade. In that context, we lay our rationale for qualifying trastuzumab, a critical medicine for 20% of breast cancers that are HER2+, as an essential medicine for early stage breast cancer and metastatic cancers. There is clear benefit in disease-free and overall survival for women on trastuzumab. Here, we catalogue the most recent data on effectiveness from over 12,000 women studied and highlight the most recent safety and regulatory information. We note, as the special Expert Committee meeting in 2002 for HIV/AIDS noted, that the addition of critical medicines to the WHO Essential Medicines List that appear unaffordable can, in reality, serve as a vital lever in expanding access to these medicines and in making them affordable. This would include but not be limited to actions by governments to overcome patent barriers — actions that were used to expand access to drugs for HIV/AIDS — and to measures that address the need for efficient regulatory pathways for approvals of less expensive biosimiliar/biogeneric products. We further note the proliferation of chronic care centers in resource-poor settings that include testing, follow-up and provisions for chemotherapy, as well as innovations in treatment delivery that could support and enable the delivery of trastuzumab to patients worldwide.

The full petition is attached and can be found here: http://www.who.int/selection_medicines/committees/expert/19/applications/Trastuzumab2_8_2_A_Ad_Final.pdf

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