Benefit of expedited regulatory approval for oncology drugs eliminated by slow reimbursement reviews and price negotiations
Nigel S B Rawson and David J Stewart
ABSTRACT
Summary: In an examination of 92 oncology drugs that received regulatory approval from Health Canada with a Notice of Compliance with conditions (NOC/c) since the policy was introduced in 1998 through to December 1, 2021, the authors concluded the “NOC/c policy has been successful in providing expedited access to promising therapies.” We investigated the time required by Canada’s Drug Agency (CDA) to complete reimbursement reviews and the pan-Canadian Pharmaceutical Alliance (pCPA) to perform price negotiations with manufacturers for 66 of the 92 drugs that were likely to have been eligible for review and negotiation. Twelve of the 66 drugs had no submission to CDA; potential reasons were identified for six. In the other 54 drugs, 37 (68.5%) had a positive CDA review and 17 (31.5%) a negative review. Only seven reviews (13.0%) took less than CDA’s claimed “typical timeline” of 180 days or less, while almost three-quarters were within its 270-day target. The pCPA’s targets of 40 business days (60 calendar days) for deciding whether to negotiate and 90 business days (130 calendar days) for completion of negotiations were achieved for only 37% of the recommendations and 41% of the negotiations. The resulting delays led to the time between NOC/c and final pCPA outcome being close to two years for over 50% of the drugs and almost three years for a quarter of them. This delay is compounded by government drug plans taking further lengthy time periods to decide whether to fund the drugs. The potential benefit to patient access of an expedited regulatory review resulting in an NOC/c is eliminated when unnecessarily extensive delays occur in reimbursement review and price negotiation processes established by government drug plans.
Authors credentials and affiliations:
- NSB Rawson PhD, CHPI affiliated scholar.
- DJ Stewart MD, Department of Medicine at the University of Ottawa and the Division of Medical Oncology at the Ottawa Hospital.
Disclosure: no conflicts declared.
Status: Peer reviewed.
Submitted: 09 AUG 2024 | Published: 20 AUG 2024
Citation: Nigel S B Rawson, David J Stewart (2024). Benefit of expedited regulatory approval for oncology drugs eliminated by slow reimbursement reviews and price negotiations. Canadian Health Policy, AUG 2024. https://doi.org/10.54194/KJRY1417 canadianhealthpolicy.com.
INTRODUCTION
Martin et al recently examined 92 oncology drugs that received regulatory approval from Health Canada by a Notice of Compliance with conditions (NOC/c) since the policy was introduced in 1998 through to December 1, 2021. The objective of the NOC/c policy is to provide patients with earlier access to promising new drugs for serious, life-threatening or severely debilitating conditions for which no therapy is presently marketed in Canada or a significant increase in efficacy or a significant decrease in risk is demonstrated relative to an existing drug marketed in Canada. Martin et al concluded that the “NOC/c policy has been successful in providing expedited access to promising therapies.” 1,2
The regulatory process is only the first step in getting drugs to Canadians. Reimbursement reviews performed by Canada’s Drug Agency (CDA) – formerly known as the Canadian Agency for Drugs and Technologies in Health – to provide recommendations for listing of drugs and price negotiations with drug developers carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) are completed after regulatory approval and take time, which can delay access to new medicines. The objective of this work is to investigate the time required by CDA reimbursement reviews and pCPA price negotiations for oncology drugs receiving an NOC/c.
METHODS
CDA began its review process in 2005. In 2007, the review of oncology medicines was transferred to an interim process known as the Joint Oncology Drug Review (JODR). During this process, all drugs for cancer were submitted to Ontario’s Drug Benefit Program and reviewed by Ontario’s Committee to Evaluate Drugs and Cancer Care Ontario to provide listing recommendations. JODR evolved into the pan-Canadian Oncology Drug Review (pCODR), which began work in 2011. Information on reviews performed by JODR are unavailable. Consequently, this investigation was limited to oncology drugs that received an NOC/c after 2011 and, therefore, likely to have been reviewed by pCODR. The pCPA was established in 2010 and, therefore, most of the drugs were likely to have been eligible for a pCPA negotiation. For these drugs, reimbursement reviews and negotiations were identified from the websites of CDA and the pCPA. 3,4,5,6
RESULTS
Of the 92 oncology medicines with NOC/c regulatory approval, 66 (71.7%) were eligible for our analysis. Twelve drugs had an NOC/c approval after 2011, but no submission to CDA (TABLE 1). Two of these drugs had submissions to CDA withdrawn, leaving 10 for which no submission was identified. Of these 10, one had its NOC/c withdrawn, one was for an extension to the indication approved in an earlier NOC/c and may not have warranted a new CDA submission, one was withdrawn in the United States, and the other was a vaccine product unlikely to be reviewed by CDA. No alternative explanation for a lack of a CDA submission could be found for the other six drugs.
TABLE 1: 12 oncology drugs with NOC/c regulatory approval and no CDA submission.
| Brand name (generic name) | NOC/c date | Indication | |
| Arzerra (ofatumumab) | 09-03-2012 | Chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab | |
| Truseltiq (infigratinib) | 27-03-2015 | Metastatic cholangiocarcinoma | Drug withdrawn in USA |
| Ibrance (palbociclib) | 16-03-2016 | Metastatic HR+ HER2- breast cancer | Withdrawn from CDA |
| Tepadina (thiotepa) | 29-03-2017 | Central nervous system lymphoma | |
| Tecentriq (atezolizumab) | 12-04-2017 | Metastatic urothelial cancer | NOC/c withdrawn |
| Imfinzi (durvalumab) | 03-11-2017 | Metastatic urothelial carcinoma | |
| Keytruda (pembrolizumab) | 21-09-2018 | B-cell lymphoma | |
| Tecentriq (atezolizumab) | 21-09-2019 | Metastatic triple negative breast cancer | Withdrawn from CDA |
| Bavencio (avelumab) | 06-11-2019 | Metastatic Merkel cell carcinoma | Expansion of indication |
| Keytruda (pembrolizumab) | 14-12-2020 | Bladder cancer | |
| Verity-BCG (BCG strain Russian) | 24-12-2020 | Relapsing urothelial cell carcinoma | Submission to CDA unlikely |
| Opdivo (nivolumab) | 11-02-2021 | Colorectal cancer |
In the remaining 54 drugs, erdafitinib (Balversa) is currently under review by CDA and excluded from the analysis. In the other 53 drugs, brentuximab (Adcetris) had an NOC/c for two indications and submissions were made to CDA for each one; these were included separately so that our analysis comprised 54 reimbursement reviews (TABLE 2). Thirty-seven (62.7%) of the 54 CDA reviews were positive and 17 (28.8%) were negative. Summaries of the time taken by CDA to review submissions, the time taken by the pCPA to decide whether to negotiate and, where applicable, the time taken for negotiations are shown in TABLE 3. Only seven reviews (13.0%) took less than CDA’s claimed “typical timeline” of 180 days or less, but almost three-quarters were within its 270-day target. The pCPA’s targets of 40 business days (60 calendar days) for deciding whether to negotiate and 90 business days (130 calendar days) for completion of negotiations, which the pCPA aims to achieve 90% of the time, were accomplished for only 37% of the decisions about whether to negotiate and 41% of the negotiations. Re-submissions were made for six drugs – brigatinib (Alunbrig) for metastatic ALK+ non-small-cell lung cancer (NSCLC), ceritinib (Zykadia) for metastatic NSCLC, crizotinib (Xalkori) for ALK+ NSCLC, daratumumab (Darzalex) for multiple myeloma, larotrectinib (Vitrakvi) for NTRK solid tumours, and olaparib (Lynparza) for ovarian cancer – that initially received a negative CDA recommendation and not pursued for negotiation by the pCPA. The re-submissions resulted in positive recommendations and successfully completed negotiations. When these re-submissions were taken into account the median time between NOC/c and final pCPA outcome was 710 days (close to two years); a quarter took over 1074 days (almost three years). 7,8
TABLE 2: 54 oncology drugs with NOC/c regulatory approval and a CDA submission.
| Brand name (generic name) | NOC/c date | Indication | CDA outcome | pCPA outcome |
| Atriance (nelarabine) | 22-09-2007 | T-cell acute lymphoblastic leukemia | RCC | Not pursued |
| Vectibix (panitumumab) | 03-04-2008 | Metastatic colorectal cancer | RCC | LOI |
| Xalkori (crizotinib) | 25-04-2012 | ALK+ non-small-cell lung cancer | DNR | LOI |
| Adcetris (brentuximab) | 01-02-2013 | Hodgkin’s lymphoma | RCC | LOI |
| Adcetris (brentuximab) | 01-02-2013 | Anaplastic large-cell lymphoma/mycosis fungoides | RCC | LOI |
| Istodax (romidepsin) | 16-10-2013 | Peripheral T-cell lymphoma | RCC | LOI |
| Blincyto (blinatumomab) | 07-03-2014 | Acute lymphoblastic leukemia | RCC | LOI |
| Bosulif (bosutinib) | 07-03-2014 | Chronic myeloid leukemia | RCC | LOI |
| Arzerra (ofatumumab) | 02-10-2014 | Chronic lymphocytic leukemia | DNR | Not pursued |
| Tafinlar (dabrafenib)/Mekinist (trametinib) | 06-03-2015 | Metastatic melanoma | RCC | LOI |
| Zydelig (idelalisib) | 27-03-2015 | Follicular lymphoma | DNR | Not pursued |
| Zykadia (ceritinib) | 27-03-2015 | Metastatic non-small-cell lung cancer | DNR | Not pursued |
| Iclusig (ponatinib) | 02-04-2015 | Chronic myeloid/acute lymphoblastic leukemias | RCC | LOI |
| Keytruda (pembrolizumab) | 19-05-2015 | Metastatic melanoma | RCC | LOI |
| Imbruvica (ibrutinib) | 28-07-2015 | Mantle cell lymphoma | RCC | LOI |
| Blincyto (blinatumomab) | 22-12-2015 | Min res dis pos B-cell prec acute lymphoblastic leukemia | RCC | LOI |
| Keytruda (pembrolizumab) | 15-04-2016 | Non-small-cell lung cancer | RCC | LOI |
| Lynparza (olaparib) | 29-04-2016 | Ovarian cancer | DNR | Not pursued |
| Darzalex (daratumumab) | 29-06-2016 | Multiple myeloma | DNR | Not pursued |
| Tagrisso (osimertinib) | 05-07-2016 | Non-small-cell lung cancer | RCC | LOI |
| Alecensaro (alectinib) | 29-09-2016 | Metastatic ALK+ non-small-cell lung cancer | RCC | LOI |
| Venclexta (venetoclax) | 30-09-2016 | Chronic lymphocytic leukemia | RCC | LOI |
| Opdivo (nivolumab) | 26-10-2016 | Metastatic melanoma | RCC | LOI |
| Blincyto (blinatumomab) | 28-04-2017 | Ph+ precursor acute lymphoblastic leukemia | RCC | LOI |
| Keytruda (pembrolizumab) | 08-09-2017 | Hodgkin’s lymphoma | RCC | LOI |
| Opdivo (nivolumab) | 10-11-2017 | Hodgkin’s lymphoma | RCC | LOI |
| Lartruvo (olaratumab) | 23-11-2017 | Advanced soft-tissue sarcoma | RCC | No agreement |
| Bavencio (avelumab) | 18-12-2017 | Metastatic Merkel cell carcinoma | RCC | LOI |
| Opdivo (nivolumab) | 23-03-2018 | Metastatic hepatocellular carcinoma | DNR | Not pursued |
| Imfinzi (durvalumab) | 04-05-2018 | Non-small-cell lung cancer | RCC | LOI |
| Lynparza (olaparib) | 04-05-2018 | Ovarian cancer | RCC | LOI |
| Alunbrig (brigatinib) | 26-07-2018 | Metastatic ALK+ non-small-cell lung cancer | DNR | Not pursued |
| Folotyn (pralatrexate) | 26-10-2018 | Peripheral T-cell lymphoma | RCC | LOI |
| Opdivo (nivolumab) | 15-11-2018 | Melanoma | RCC | LOI |
| Idhifa (enasidenib) | 06-02-2019 | Acute myeloid leukemia | DNR | Not pursued |
| Lorbrena (lorlatinib) | 22-02-2019 | Metastatic ALK+ non-small-cell lung cancer | RCC | No agreement |
| Libtayo (cemiplimab) | 10-04-2019 | Cutaneous squamous cell carcinoma | RCC | LOI |
| Keytruda (pembrolizumab) | 11-04-2019 | Metastatic urothelial carcinoma | DNR | Not pursued |
| Vitrakvi (larotrectinib) | 10-07-2019 | NTRK solid tumours | DNR | Not pursued |
| Keytruda (pembrolizumab)/ Lenvima (lenvatinib) | 20-09-2019 | Advanced endometrial cancer | RCC | LOI |
| Rozlytrek (entrectinib) | 10-02-2020 | NTRK extracranial solid tumours | RCC | LOI |
| Polivy (polatuzumab) | 09-07-2020 | Large B-cell lymphoma | RCC | LOI |
| Bavencio (avelumab) | 10-12-2020 | Urothelial carcinoma | RCC | LOI |
| Keytruda (pembrolizumab) | 05-02-2021 | Hodgkin’s lymphoma | RCC | LOI |
| Keytruda (pembrolizumab) | 03-03-2021 | Colorectal cancer | RCC | LOI |
| Abecma (idecabtagene vicleucel) | 26-05-2021 | Multiple myeloma | DNR | Not pursued |
| Tepmetko (tepotinib) | 27-05-2021 | Metastatic non-small-cell lung cancer | DNR | LOI |
| Retevmo (selpercatinib) | 15-06-2021 | RET+ non-small-cell lung cancer | RCC | LOI |
| Gavreto (pralsetinib) | 30-06-2021 | RET+ non-small-cell lung cancer | RCC | No agreement |
| Minjuvi (tafasitamab) | 19-08-2021 | Large B-cell lymphoma | DNR | LOI |
| Lumakras (sotorasib) | 10-09-2021 | KRAS non-small-cell lung cancer | DNR | UC |
| Pemazyre (pemigatinib) | 17-09-2021 | Metastatic cholangiocarcinoma | DNR | Not pursued |
| Zepzelca (lurbinectedin) | 29-09-2021 | Metastatic small-cell lung cancer | DNR | Not pursued |
| Enhertu (trastuzumab deruxtecan) | 15-06-2022 | Metastatic HER2-low breast cancer | RCC | LOI |
DNR: Do not reimburse; LOI: Letter of intent; RCC: Reimburse with criteria and/or conditions; UC: Under consideration
TABLE 3: Time taken for CDA reviews, pCPA negotiation decisions and negotiations, and time between NOC/c and pCPA outcome.
| CDA reimbursement reviews | pCPA negotiation decisions | pCPA negotiations | Time between NOC/c and pCPA outcome | ||
| Initial assessments | With resubmissions | ||||
| No. | 54 | 54 | 39 | 54 | 54 |
| Median | 220 days | 86 days | 149 days | 633 days | 710 days |
| Interquartile range | 192 – 263 days | 45 – 133 days | 81 – 252 days | 332 – 894 days | 438 – 1074 days |
| % of reviews within 180 days | 13.0% | ||||
| % of reviews within 270 days | 74.1% | ||||
| % of decisions within 60 days | 37.0% | ||||
| % of negotiations within 130 days | 41.0% | ||||
| % of time between NOC/c and pCPA outcome within 18 months | 46.3% | 35.2% | |||
DISCUSSION
These results indicate that 82% of the oncology drugs receiving an NOC/c after 2011 and were submitted to CDA. No alternative explanation for a lack of a submission could be found for six drugs.
Less than 50% of the submissions to CDA were made prior to the NOC/c date, although pre-NOC submissions were more likely after 2015. Once submitted, CDA took longer than its commonly stated “typical timeline” of 180 days for 87% of the drugs, but almost 75% were completed within its more realistic nine-month target. The pCPA generally took much longer to decide whether to negotiate with the developer than its target time; only 37% of the oncology drugs had a decision regarding negotiation within 60 days. In addition, just 41% of the negotiations were completed within the pCPA’s target of 130 days.
These results are consistent with an analysis of all reimbursement recommendations for oncology medicines issued by CDA between January 2014 and December 2023 and subsequent pCPA price negotiation decisions and outcomes, which found that CDA’s “typical timeline” of 180 days was not achieved in any review in 2021, 2022 or 2023. 9 In addition, the pCPA’s target of 60 days for deciding whether to negotiate was attained for less than 40% of oncology drugs between 2017 and 2023 and its target of 130 days for negotiations was achieved for only 14.3% of negotiations in 2016, although the rate then gradually increased to 61.5% in 2023.
Delays resulting from reimbursement reviews and price negotiations for oncology drugs with an NOC/c regulatory approval led to the time between NOC/c and final pCPA outcome being close to two years for over 50% of the drugs and almost three years for a quarter of them. These delays are compounded by government drug plans taking further lengthy time periods to decide whether to fund the drugs. The potential benefit to patient access of an expedited regulatory review resulting in an NOC/c is eliminated when extensive delays occur in the reimbursement review and price negotiation processes established by government drug plans.
Many calls have been made for Canada to reduce delays in patient access to new oncology medicines via government drug plans. Canada’s governments have established and control CDA and the pCPA and allowed them to develop procedures without accountable performance targets. Even when drugs have passed through these processes, government drug plans do not automatically list the medicine, leading to further delays. Delays in bringing effective new cancer medicines to Canadians, which may lead to thousands of lives being lost, are unacceptable. 10-21
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