Impact of Systemic Delays for Patient Access to Oncology Drugs on Clinical, Economic, and Quality of Life Outcomes in Canada: A Call to Action

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

The authors present a targeted literature review assessing the “Impact of Systemic Delays for Patient Access to Oncology Drugs on Clinical, Economic, and Quality of Life Outcomes in Canada: A Call to Action”.

Overall, the TLR is timely, has substantial clinical importance from a health policy perspective, and is well-written.

My primary comment concerns the Results section (3.1).  In this section, the authors describe their search results, indicated that “56 unique records were included in the TLR. Two types of treatment delays were identified in this literature review: individual delays (e.g., time from cancer diagnosis to the start of treatment already accessible) and delays due to approval or reimbursement processes. Most delays identified in the TLR were individual delays (n=52).”

The records assessing individual delays were not fully assessed other than the following statement: “the great majority of studies reported the impact of delayed access to treatment on clinical outcomes, more specifically OS (n=43), PFS (n=10), and mortality (n=16). Most studies reported shorter treatment access delays between 0 and 3 months (n=47) and between 3 and 6 months (n=17) since they focused on delays in individual timelines (e.g., delays between diagnosis and the beginning of an already accessible treatment due to hospital chair time), which are shorter than those associated with process delays due to cumbersome reimbursement and approval.”

As the stated purpose of this LTR is to assess the “Impact of Systemic Delays for Patient Access to Oncology Drugs”, I do not see any reason to include the individual delay reports in the LTR, other than indicate that the majority of records regarding delays were “individual delays”.

I suggest modifying the manuscript to address this issue.  Otherwise, the Results section is misleading (56 vs. four records analyzed).

Author Response

Thank you for this suggestion. We totally agree that the objective of this article is not regarding the individual delays and thus, these articles should have been excluded. To address this issue, we have modified the methodology and the results of the review. An exclusion criterion was added regarding the type of delays described in the article (individual versus systemic delays).

Reviewer 2 Report

Comments and Suggestions for Authors

 

Deepening knowledge of systemic problems in Canada's cancer medication access process is the goal of the submitted inquiries. They examine how delays affect patient outcomes, the economy, and people's quality of life while contrasting the Canadian system with those across the world. These inquiries also look at provincial differences, the particular difficulties with the regulatory and reimbursement systems, and possible solutions. To fully address the complex challenges influencing cancer treatment in Canada, the focus also includes the importance of early access programs, provincial financing decisions, and the use of real-world data in analyzing regulatory consequences.

 

1.          In Canada, what are the main causes of the systemic delays in patients' access to cancer medications?

2.          What effect do these drug access delays have on Canadian cancer patients' clinical outcomes?

3.          Could you provide more details about the financial effects of Canada's delayed access to cancer medications?

4.          How might cancer patients' quality of life be impacted by delayed medicine access?

5.          What particular difficulties exist in Canada's procedures for public reimbursement and medication approval?

6.          In comparison to other nations, how long does Canada take to grant access to drugs?

7.          What changes are recommended to improve the effectiveness of the systems for health technology evaluation and drug regulation?

8.          How does the Patented Medicines Prices Review Board function within the framework of the approval of drugs?

9.          Could you elaborate on how patients' access to novel cancer therapies is affected by Health Canada's regulatory approval?

10.      Which Canadian provinces have different access to cancer drugs?

11.      What is the impact of individual delays on cancer treatment in Canada, from diagnosis to treatment initiation?

12.      What conclusions did the targeted literature review (TLR) reach about the issue of delayed access to cancer treatment?

13.      might you talk about the global partnerships that might enhance Canada's drug approval procedure?

14.      How important are the early managed access initiatives in other nations?

15.      How do individual Canadian provinces choose how much money to allot for pharmaceuticals?

16.      What are the suggested ways to enhance Canada's access to cancer drugs?

17.      In particular, what is the effect of the drug availability delay on metastatic and curative cancer settings?

18.      What patterns and trends exist in Canada when it comes to the approval of novel cancer treatments?

19.      Could you talk about how real-world data is used to evaluate the effects of regulatory delays?

20.      What effects do Canada's protracted medication access procedures have on the prognosis and available treatments for cancer patients?

 

Comments on the Quality of English Language

The paper has a generally good command of the English language, with suitable terminology, clear and cohesive sentence structures, and effective delivery of difficult medical and policy-related ideas. The writers have done a good job of communicating the importance and severity of the problems related to Canada's delayed access to cancer medications. Even if the majority of the language is formal and fitting for a scientific journal, readers of varying skill levels may nevertheless understand it. A professional tone is created by the thoughtful use of technical phrases that don't overwhelm the reader.

Author Response

Deepening knowledge of systemic problems in Canada's cancer medication access process is the goal of the submitted inquiries. They examine how delays affect patient outcomes, the economy, and people's quality of life while contrasting the Canadian system with those across the world. These inquiries also look at provincial differences, the particular difficulties with the regulatory and reimbursement systems, and possible solutions. To fully address the complex challenges influencing cancer treatment in Canada, the focus also includes the importance of early access programs, provincial financing decisions, and the use of real-world data in analyzing regulatory consequences.

1. In Canada, what are the main causes of the systemic delays in patients' access to cancer medications?

This was addressed in the manuscript:

“Canada has one of the most complex and rigorous drug approval and public re-imbursement processes”

“Consequently, patient access to innovative drugs is usually greatly delayed due to the sequential federal and provincial processes in regulatory and reimbursement review”

2. What effect do these drug access delays have on Canadian cancer patients' clinical outcomes?

In the manuscript, few examples were reported based on the 4 articles included from the TLR:

“In the study by Uyl-de Groot, (…) The analysis showed that the delay in patient access to ipilimumab (melanoma) and abiraterone (prostate cancer) have led to a potential loss of more than 30,000 life years.

Finally, the impact of delays for NSLSC patients was assessed in the study by Vanderpuye-Orgle. (…) The analysis demonstrated that in Canada, reviews of NSCLC drugs took a medium of 216 days and delays for the three drugs evaluated ranged between 5 and 94 days at Health Canada, 0 and 80 days at CADTH/pCODR and 12 and 797 days in Canadian provinces. Consequently, 6,400 patients may have been affected, totalling a loss of up to 1,740 per-son-years of life.”

3. Could you provide more details about the financial effects of Canada's delayed access to cancer medications?

 

We believe this is beyond the scope of our review and not really possible to determine since estimates based on list price would be grossly incorrect and true negotiated prices are confidential.

Only one article was retrieved in the review assessing the economic impact of systemic delays in oncology drug access (study by Vanderpuye-Orgle). A sentence was added in the manuscript to describe the economic impact results described by this study.

4. How might cancer patients' quality of life be impacted by delayed medicine access?

We believe this was addressed in the manuscript:

“QoL is also affected detrimentally by delayed access to new treatments which could better control disease and improve, prevent, or delay serious cancer symptoms. Time is of the essence for our patients. Delays in access are especially tragic considering the increasing effectiveness of new breakthrough therapeutics, unfortunately remaining inaccessible to patients in need”

5. What particular difficulties exist in Canada's procedures for public reimbursement and medication approval?

We believe this summarized at length in the introduction:

“These disparities between Canada and other countries are partly attributable to complex, overlapping sequential multi-step regulatory and funding processes involving federal, provincial and private authorities (Health Canada, PMPRB, HTA organizations (CADTH and INESSS), pCPA, and different provincial and private payers”

6. In comparison to other nations, how long does Canada take to grant access to drugs?

From the manuscript:

“Unfortunately, Canada is one of the countries with the longest delays in drug access, with a median time from marketing authorization to public reimbursement for oncology drugs of 581 days compared to 382 days for 20 comparable countries”

7. What changes are recommended to improve the effectiveness of the systems for health technology evaluation and drug regulation?

Recommended changes:  Faster speed for existing processes.  Beyond the scope of our review (about the impact of existing delays) but government agencies and Ministers are accountable to make their processes serve Canadian patients effectively — while the system if fragmented due to our Constitution and division of responsibilities, it is the joint responsibility of federal and provincial agencies to better cooperate, avoid duplication, streamline processes and adhere to reasonable performance standards so lives can be saved.  Suggestions summarized in 4.2 Potential Solutions of the manuscript.

8. How does the Patented Medicines Prices Review Board function within the framework of the approval of drugs?

PMPRB:  Their function (dysfunction) is also the subject of many other publications and federal governmental task forces.  The impact of their delays is our concern, but their complex functioning would be beyond our scope here. From the manuscript:

“A federal agency called the Patented Medicines Prices Review Board (PMPRB) ensures that the prices of patented drugs are not excessive, based on specified regulations”

9. Could you elaborate on how patients' access to novel cancer therapies is affected by Health Canada's regulatory approval?

If Health Canada does not review a drug, or refuses a drug approved elsewhere, then the impacts would be to prevent a patient from benefiting from a treatment that could have a positive impact on his or her health, quality of life and survival.

Also, as mentioned in the manuscript, the study by Vanderpuye-Orgle measured the durations and outcomes of regulatory and reimbursement reviews of NSCLC drugs in Canada. The analysis demonstrated that in Canada, reviews of NSCLC drugs took a medium of 216 days and delays for the three drugs evaluated ranged between 5 and 94 days at Health Canada, 0 and 80 days at CADTH/pCODR and 12 and 797 days in Canadian provinces.

10. Which Canadian provinces have different access to cancer drugs?

We thank you for this question. While CADTH processes and joint price negotiations with PCPA are intended to reduce disparities, each province or territory has it’s own formulary for funded drugs and criteria for funding. 

However, because this article has a Canadian perspective, the purpose was not to compare each province, but to emphasize on the Canada’s public drug reimbursement timelines, more specifically for cancer drugs. Furthermore, several steps in the approval and reimbursement process are common for each province, namely Health Canada’s regulatory approval, PMPRB’s control of prices, the assessment by HTAs (CADTH and INESSS) and pCPA negotiations.

11. What is the impact of individual delays on cancer treatment in Canada, from diagnosis to treatment initiation?

The purpose of the article was to assess the impact of systemic delays for patient access to oncology drugs on clinical, economic, and quality of life outcomes in Canada. After a suggestion by a reviewer, we have adjusted the methodology and the results of the review by including only articles reporting systemic delays in the TLR, to reflect the objective of this article.

12. What conclusions did the targeted literature review (TLR) reach about the issue of delayed access to cancer treatment?

From the manuscript:

“The results of this TLR highlighted the outcomes impacted by delayed access to oncology drugs, the majority of which were clinical outcomes (e.g., life years lost, OS, and PFS). It is conceivable that delays associated with the lengthy drug approval and reimbursement processes will have an even greater impact. This was specifically analyzed in the four articles included in this review.”

13. might you talk about the global partnerships that might enhance Canada's drug approval procedure?

This was addressed in the Discussion, section 4.2 Potential solutions, in which international collaborations is suggested and in which examples of these collaborations are described.

14. How important are the early managed access initiatives in other nations?

Examples mentioned in the manuscript (Discussion, section 4.2 Potential Solutions):

“The European HTA regulation will be adopted in a stepwise approach, starting in 2025 onwards where all new cancer medicines and advanced therapy medicinal products will be commonly assessed, while the final HTA appraisals and the subsequent reimbursement decisions remain within the responsibility of each jurisdiction. From 2028, orphan medicinal products will also be included in the mutual clinical assessment. This promising initiative will allow a more efficient assessment for the most innovative medicines.

Another example is the BeneluxA initiative, which comprises five countries (Belgium, the Netherlands, Luxembourg, Austria, and Ireland) and has the objective to improve access to innovative medicines at an affordable cost[26,27]. The different activities of this initiative include information sharing (re-use of HTA reports) and collaboration with mutual recognition of national HTA assessments.

Australian HTA Reform aims to reduce the time to treatment access for Australian patients and to increase the commercial attractiveness of Australia as a first launch coun-try for new medicines, ensuring that its assessment processes keep pace with rapid advances in health technology[28]. The HTA Review will run for 12 months, until December 2023 with recommendations to be implemented within 12 months (December 2024).”

15. How do individual Canadian provinces choose how much money to allot for pharmaceuticals?

We thank you for this question. However, because this article has a Canadian perspective, the purpose was not to compare each province, but to emphasize on the Canada’s public drug reimbursement timelines, more specifically for cancer drugs. Thus, a comparison of each provincial budget would not address the objective of this article.

16. What are the suggested ways to enhance Canada's access to cancer drugs?

This was addressed in the Discussion, section 4.2 Potential Solutions of the manuscript.

17. In particular, what is the effect of the drug availability delay on metastatic and curative cancer settings?

This was not particularly assessed in the manuscript, as the articles presented did not separate their results according to the disease stage. However, we believe that treatment access delays have an impact for, in both the metastatic setting (given their reduced or limited life expectancy) and the curative setting (where adjuvant medicines improve the chance of cure). Indeed, as mentioned in the manuscript, Section 1. Introduction, a treatment delay as short as four weeks can increase cancer-related mortality.

18. What patterns and trends exist in Canada when it comes to the approval of novel cancer treatments?

We thank you for this important, and we believe it was addressed in the manuscript in the “Discussion section 4.1. Call to Action”.

19. Could you talk about how real-world data is used to evaluate the effects of regulatory delays?

The TLR did not retrieve any article using real-world data to evaluate the impact of systemic delays in oncology drugs access.

20. What effects do Canada's protracted medication access procedures have on the prognosis and available treatments for cancer patients?

From the manuscript:

“International regulatory collaborations between Canada and other countries exist, such as Project Orbis, an international partnership designed to give cancer patients faster access to promising cancer treatments [21,22]. Canada has joined the U.S. Food and Drug Administration and other international regulators to collaborate in such joint drug re-views for cancer, rare diseases, and conditions with limited treatment options, allowing for simultaneous review and earlier approval of these medications. However, such initia-tives appear insufficient to overcome systemic delays, as only 28% of drugs approved by Health Canada qualified for faster regulatory review from these programs, compared to 82% in the United States

Comments on the Quality of English Language：The paper has a generally good command of the English language, with suitable terminology, clear and cohesive sentence structures, and effective delivery of difficult medical and policy-related ideas. The writers have done a good job of 3 communicating the importance and severity of the problems related to Canada's delayed access to cancer medications. Even if the majority of the language is formal and fitting for a scientific journal, readers of varying skill levels may nevertheless understand it. A professional tone is created by the thoughtful use of technical phrases that don't overwhelm the reader.

We thank you for this comment.

Reviewer 3 Report

Comments and Suggestions for Authors

The work does not provide any new information regarding the topic of the work beyond what has already been published as items 13-16 of the cited literature. Additionally, the co-author of the work is the co-author of one of the 4 works analyzed in the study, which is the main source of the most important data from the point of view of the topic of the work.

Author Response

Thank you for your comment. We believe that this article is different than that of the 4 published articles analyzed. Indeed, in addition to addressing the problem of the systemic delays in cancer, this article is suggesting potential solutions, which were not addressed in the 4 articles of interest. Furthermore, with a call to action, this strongly and clearly encourage the government to take action on this important issue. Our article adds perspective by adding context (introduction and discussion), demonstrating the paucity of research globally into the question compared with “individual delays” (scoping review), discussing the models used elsewhere and suggestions for urgent process change.

Reviewer 4 Report

Comments and Suggestions for Authors

I find this article very interesting and highly important, especially the recommendation for international collaborations to expedite the approval of life-saving medications for cancer patients.

General note: It seems unprofessional to submit a paper for review with comments in the margins.

I know that Canada has a public healthcare system. Are private health insurances common in Canada that could expedite purchasing medications privately? Of course, after the medications are approved by the Canadian Health Ministry.

Finally, I recommend the authors to add a PRISMA diagram to the paper.

Author Response

I find this article very interesting and highly important, especially the recommendation for international collaborations to expedite the approval of life-saving medications for cancer patients.

General note: It seems unprofessional to submit a paper for review with comments in the margins.

Thank for this remark, we have deleted the comments in the margins.

I know that Canada has a public healthcare system. Are private health insurances common in Canada that could expedite purchasing medications privately? Of course, after the medications are approved by the Canadian Health Ministry.

We appreciate this question. According to the Conference Board of Canada, while there is an important percentage of Canadians who are covered by private payers, many patients in Canada do not have access to a private health insurance plan and this cannot be relied upon for access. Also, most senior patients (65 years and older) are covered in the public. Private insurance is available for some Canadians but only 30-45% of the population affected by cancer (often older) and it has limitations.  Many plans now use the slow CADTH HTA approval process before considering adding drugs on to their formularies and will not cover drugs not approved by Health Canada or CADTH. A sentence was added in the conclusion of the manuscript.

Finally, I recommend the authors to add a PRISMA diagram to the paper.

We thank you for this suggestion, a PRISMA diagram was added to the paper.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The points raised together highlight the necessity of conducting further study on the regulatory and economic effects of delayed access to cancer drugs, as well as the significance of looking into other analytical techniques given the secrecy of drug pricing. Future research on the consequences of access delays in various cancer situations, such as metastatic and curative scenarios, is encouraged by the questions posed. Real-world data is also suggested to be incorporated for a more precise evaluation of regulatory procedures. Furthermore, they advocate for a closer look at the regional variations in Canada's medication approval and subsidy processes and emphasize the importance of incorporating global case studies into the assessment of early managed access programs. These indicate thorough research paths meant to enhance our comprehension and control over cancer medication accessibility.

1.         For financial effects (Question 3): "Can you clarify which alternative methods or data sources future studies might employ to indirectly assess the economic impact of delayed access to cancer medications when direct pricing data is not available?"We want to see a debate about other analytical techniques that may be applied even in cases when medicine price is private.

2.         How might future research be designed to specifically capture the differential impacts of treatment access delays on metastatic versus curative cancer settings?" refers to the differentiated affects by illness stage (Question 17).We would welcome more investigation into study approaches to distinguish the impacts of delays in various stages of cancer in the future.

3.         "How could subsequent studies incorporate real-world data to better evaluate and understand the consequences of regulatory delays in cancer drug access?" is the question for the use of real-world data (Question 19).Future research should focus on figuring out how to include real-world data so that the effects of regulatory procedures may be evaluated more precisely.

4.         "In terms of financial impact, could other alternative data be used to indirectly assess the economic consequences of delayed access to cancer medications?"Given the scarcity of direct medication pricing data, we strongly recommend investigating alternate analytical approaches.

5.         "Regarding the discussion on early managed access programs and global collaboration, could specifically case studies or data from other countries be integrated to illustrate how such initiatives have successfully (or unsuccessfully) reduced the approval times for cancer drugs?" Incorporating case studies or global data would significantly improve our comprehension of early access initiatives' efficacy.

6.          "Considering that the article does not delve deeply into the specific differences in drug approval and subsidy across Canadian provinces, can you suggest further research to fill this gap?" A more thorough analysis of Canada's interprovincial differences may yield insightful information on the regulatory and reimbursement systems.

7.          "How can future research improve the clarity of reporting on the different outcomes for treatment delays in metastatic versus curative cancer settings?"A major addition to the subject would be the establishment of approaches to discriminate the influence on various stages of cancer.

Author Response

1. For financial effects (Question 3): "Can you clarify which alternative methods or data sources future studies might employ to indirectly assess the economic impact of delayed access to cancer medications when direct pricing data is not available? “We want to see a debate about other analytical techniques that may be applied even in cases when medicine price is private.

Future studies may employ the following sources of indirectly assess the economic impact of delayed access to cancer medications: inpatient admission costs, lost workforce productivity costs for patients and caregiver, costs for home care, costs for palliative and hospice care.  The analytical techniques used to assess the economic impact of these will vary depending on the source and complexity and is beyond the scope of this paper.

2. How might future research be designed to specifically capture the differential impacts of treatment access delays on metastatic versus curative cancer settings?" refers to the differentiated affects by illness stage (Question 17).We would welcome more investigation into study approaches to distinguish the impacts of delays in various stages of cancer in the future.

Exploring study approaches to assess the differential impacts of delays in treatment access in metastatic vs curative cancer is outside the scope of this paper. However, we can expand to say the following: Delays to treatment access in the curative and metastatic settings may arise from similar barriers but result in very different impacts on outcomes. This area requires further research. 

3. "How could subsequent studies incorporate real-world data to better evaluate and understand the consequences of regulatory delays in cancer drug access?" is the question for the use of real-world data (Question 19).Future research should focus on figuring out how to include real-world data so that the effects of regulatory procedures may be evaluated more precisely.

Future studies may incorporate real-world data, such a post marketing data, to better understand the real world survival gains from new treatments, and thereby better understand the detrimental impacts of delays to such treatments. National and international databases should be created to capture both survival and quality of life outcomes.

4. "In terms of financial impact, could other alternative data be used to indirectly assess the economic consequences of delayed access to cancer medications? “Given the scarcity of direct medication pricing data, we strongly recommend investigating alternate analytical approaches.

Please see the response to question 1, which I believe satisfies this question as well.

5. "Regarding the discussion on early managed access programs and global collaboration, could specifically case studies or data from other countries be integrated to illustrate how such initiatives have successfully (or unsuccessfully) reduced the approval times for cancer drugs?" Incorporating case studies or global data would significantly improve our comprehension of early access initiatives' efficacy.

It does seem that Germany's early access program does speed time to market (TTM). According to one study, the average TTM in Europe amounted to 398 days (range 17–1187 days). In general, patients in Germany, the UK, and Austria had the most rapid potential access, with averages of 17, 22, and 31 days, respectively. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464890/

See also : Bussgen (2023) in which authors evaluated the causal effect of HTA based regulation on access to pharmaceuticals by using the introduction of Germany’s HTA system (AMNOG) in 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060338/

The results showed that the introduction of AMNOG consistently reduced the magnitude of the decrease in launch delay in Germany compared to the comparator countries (staggered difference-in-difference: + 4.31 months, p = 0.05).

6. "Considering that the article does not delve deeply into the specific differences in drug approval and subsidy across Canadian provinces, can you suggest further research to fill this gap?" A more thorough analysis of Canada's interprovincial differences may yield insightful information on the regulatory and reimbursement systems.

Further research into the specific processes undertaken by each Canadian province or territory and their correlation with speed of access may help ensure that best practices are shared across the country.

7. "How can future research improve the clarity of reporting on the different outcomes for treatment delays in metastatic versus curative cancer settings? “A major addition to the subject would be the establishment of approaches to discriminate the influence on various stages of cancer.
   
   Please see the response to question 2, which I believe satisfies this question as well.