Treatment Access, Health Economics, and the Wave of a Magic Wand
Round 1
Reviewer 1 Report
This is an outstanding and comprehensive analysis of Canadian health care determinants that delay the provision of effective cancer therapies to Canadians with advanced cancers. It is clearly written and well-organized. My only suggestion would to be add a figure or table that illustrates the various steps between drug development and practical availability of cancer therapies for Canadians (Health Canada, CADTH, PMPRB etc).
Author Response
We thank the reviewer for their comments and suggestions. We have now included a figure that illustrates timelines for drug approval and funding in Canada.
Reviewer 2 Report
REVIEW OF PAPER: “TREATMENT ACCESS, HEALTH ECONOMICS, AND THE WAVE OF A MAGIC WAND”
Journal: Current Oncology
Regarding the review of paper " Treatment access, health economics, and the wave of a magic wand", the authors conducted a commentary on the approval of new drug funding by the Canadian Agency for Drug and Technologies in Health (CADTH) as long as the value per QUALY exceeds $50,000. The authors believe that this amount is obsolete since, simply by updating for inflation since the 1970s, it would mean that this amount should be multiplied by a factor of 5.
Title and summary. The title and abstract express well the object of study, objectives, and results of the article.
Structure of the article: The contents are well organized and it includes a theoretical framework of the research problem but at this point, I suggest the authors incorporate some other bibliographic reference that I miss in the text:
Coyle D, Lee KM, Mamdani M, Sabarre KA, Tingley K. Reimbursement-Based Economics--What Is It and How Can We Use It to Inform Drug Policy Reform? Headache. 2015 Jul-Aug;55 Suppl 4:236-47. doi: 10.1111/head.12585. Epub 2015 Jul 14. PMID: 26178290.
Focusing on the opportunity of the study, it must be said that it is useful work since it covers one of the major problems related to the sustainability, access and efficiency of healthcare systems.
Materials and methods.
Regarding the material and methods section, the methodology is tailored to the object of study and the objectives and is explained in a transparent manner while it has been validly applied to guarantee the paper's development.
Development of the paper.
Regarding the opinion of the authors it should be pointed out that the existence of an approved list of reimbursable medicines is regarded as an important tool in improving the quality of care as well as in containing the costs of pharmaceutical care. Experience in many countries, both in Europe and the developing world, strongly suggests that limitation of the range of reimbursed drugs can be achieved without depriving the population of valuable therapeutic opportunities. Norway, for instance, had until a few years ago only 600 drug substances on the market, and achieved the same pharmacotherapeutic results as other countries with many times more registered drugs on sale. In example, according to EU regulations, no restriction on the number of drugs on the market is permitted, and member states have therefore usually followed an alternative course by limiting the list of those drugs for eligible for payment under a national health service or public reimbursement system. From the therapeutic point of view, the selection of drugs available on the market is in most industrialised countries so broad that considerable limitations can be imposed without creating any real threat to patients’ interests. The results justify and relate to the objectives and methods and the results are of sufficient interest.
What is true is that a reference price system will clearly not be applicable to certain highly innovative drugs which are unique in nature and cannot be said to belong to any pre-existing therapeutic group of products interchangeable with them, so this drug will form a class of its own. To ensure fair pricing of such products one will clearly have to adopt other approaches.
These two approaches should also be discussed by the authors.
Discussion.
The discussion appropriately compares the study results with other works, highlighting the main study findings. However, I would propose the inclusion of two bibliographic references in the discussion section:
Bibliography.
The 84% of the bibliography cited in the study belongs to the previous five years.
Overall, it is an interesting study and should be considered for publication in Current Oncology, once the very minor revision proposed have been resolved.
Comments for author File: 
Comments.pdf
Author Response
We would like to thank the reviewer for their helpful comments. As suggested, we have added the reference from Coyle et al, with the statement about decision-making for drug funding that "Various new approaches have been proposed, but there is no perfect method to determine what should and what should not be funded."
We have also added the statements "Rapid access is particularly important for effective new agents that are the first in their class. In this situation, there may be no reasonable alternatives. If a new agent is a “me-too” drug that works in the same way as a currently available agent and does not have any obvious advantages, rapid access may be a less pressing issue."
We have also added "It could be particularly challenging to decide on a reasonable price for a new drug if the agent is highly innovative and meets an unfulfilled need.".
Reviewer 3 Report
Many thanks for asking me to review – this is a very informative with lots of opinion. Overall, I think this would be a good addition to this special edition, and as the authors mention, a follow-up to other submitted work in this edition. I do note 11 self-citations.
Major Comments:
The only major comment I have is that the authors state that more speed and access to new therapies is needed. However, I do think some greater acknowledgement of the risks of this approach is required. For example, in the continued approval of immune checkpoint inhibitors (initially approved by accelerated approval on surrogate end points) which have failed to demonstrate efficacy (https://jamanetwork.com/journals/jamaoncology/fullarticle/2781606). This could potentially lead to ineffective costly oncology drugs being on the market which may need reimbursement and can be very problematic to withdraw without the manufacturers consent (https://www.bmj.com/content/374/bmj.n1959 ). A further interesting point to discuss may be the recent approval of aducanumab in the US by accelerated approval in Alzheimer’s disease (https://www.ejcancer.com/article/S0959-8049(21)00529-3/fulltext) which is likely to further impact approval problems in oncology and would be timely to discuss if the authors felt appropriate.
Minor comments
- The authors mention they will talk about the delay of access of Canadian patients to effective new therapies but say they will discuss ‘just a few of them’. I agree it’s a large topic but I think a brief mention of the non-discussed factors with an appropriate reference would be useful signpost for readers.
- The authors discuss ‘breakthrough drugs’ but I think greater context and information is needed here – I assume they refer to drugs granted FDA breakthrough designation and if so greater information about this pathway should be provided. I also find that ‘RCTs are not needed’ is quite a strong statement and not really validated by the reference. Are the authors referring to drugs granted FDA accelerated approval status and then require further confirmatory trials are needed, allowing earlier patient access to innovative treatments?
- I think the confidential pricing aspect is very informative and feel some comparison with other healthcare systems may be interesting. For example, the UK (https://pubmed.ncbi.nlm.nih.gov/33212235/ )has similar confidential pricing schemes which are never revealed publicly so it is difficult to gauge the impact.
- I think the authors should be more descriptive here with the facts purported by PMPRB ‘Spending in 2013 was particularly low and spending in 2017 was particularly high. In their public presentation,PMPRB displayed the difference between 2013 and 2017 as an indication of skyrocketing expenditure on patented medications. They failed to disclose the fact that these two yearswere both outliers!’ If they have the data then it would be better to state this information for each year and allow readers to make up their own mind. If the information is not available, then they should describe this. I also wonder if the authors have been in touch with the PMPRB and asked for further clarification on this point, may be more sensible than waiting to ‘hear from them’ in this article.
- I think the point about COVID vaccine is a little mute and did not really cause much delay in regulatory approval (https://jamanetwork.com/journals/jamanetworkopen/article-abstract/2781352 ) which I think shows HC’s was able to prioritise approval. In fact companies engaged with HC earlier in the development than other regulators such as FDA and EMA which I think needs acknowledgement.
Author Response
We thank this reviewer for their very helpful comments and suggestions.
- Reviewer comment: The only major comment I have is that the authors state that more speed and access to new therapies is needed. However, I do think some greater acknowledgement of the risks of this approach is required. For example, in the continued approval of immune checkpoint inhibitors (initially approved by accelerated approval on surrogate end points) which have failed to demonstrate efficacy (https://jamanetwork.com/journals/jamaoncology/fullarticle/2781606). This could potentially lead to ineffective costly oncology drugs being on the market which may need reimbursement and can be very problematic to withdraw without the manufacturers consent (https://www.bmj.com/content/374/bmj.n1959 ). A further interesting point to discuss may be the recent approval of aducanumab in the US by accelerated approval in Alzheimer’s disease (https://www.ejcancer.com/article/S0959-8049(21)00529-3/fulltext) which is likely to further impact approval problems in oncology and would be timely to discuss if the authors felt appropriate.
Answer: We have added the following: “With accelerated access through approaches such as “breakthrough therapy” designation, there is always some risk that subsequent trials may fail to confirm that the therapy offers sufficient benefit to justify ongoing access. If this happens, the therapy may be withdrawn from the market after discussion between regulators and the pharmaceutical company, or regulators may unilaterally rescind approval.9
In other cases, a therapy may remain approved despite failure to meet its primary endpoint in subsequent trials because of other benefits that are thought to be useful.9 For example, in many tumor types, immune checkpoint inhibitors appear to be of marked benefit in one patient subpopulation and of little benefit another.10 Consequently, a comparison to other therapies may fail to reveal a survival benefit in the overall population, but ongoing access might be considered important because of the unequivocal benefit derived by a substantial subpopulation of the patients. ”
We elected not to discuss aducanumab since it is not directly relevant to oncology.
- Reviewer comment: The authors mention they will talk about the delay of access of Canadian patients to effective new therapies but say they will discuss ‘just a few of them’. I agree it’s a large topic but I think a brief mention of the non-discussed factors with an appropriate reference would be useful signpost for readers.
Answer: We have changed the wording as follows: “However, various factors delay access of Canadian patients to these effective new therapies. The most important factor that causes delays is the time required for clinical trials that are needed to demonstrate drug efficacy. Also contributing to the delays are the time required for Health Canada review and approval of the drug and the time required to determine whether and how the drug will be funded. ”
- Reviewer comment: The authors discuss ‘breakthrough drugs’ but I think greater context and information is needed here – I assume they refer to drugs granted FDA breakthrough designation and if so greater information about this pathway should be provided. I also find that ‘RCTs are not needed’ is quite a strong statement and not really validated by the reference. Are the authors referring to drugs granted FDA accelerated approval status and then require further confirmatory trials are needed, allowing earlier patient access to innovative treatments?
Answer: We have changed the wording as follows: “Fortunately, if early clinical experience with a new drug indicates that it is highly effective, it may be made available to patients without the prerequisite of further trials. It may be approved rapidly in the United States through the FDA’s “breakthrough therapy” designation10 or in Canada by Health Canada’s “Notice of Compliance with Conditions” designation.11 This expedited approval may be conditional on further trials being performed subsequently.
Rapid access is particularly important for effective new agents that are the first in their class and that provide benefit to patients with lethal diseases like metastatic cancers. In this situation, there may be no reasonable alternatives. If a new agent is a “me-too” drug that works in the same way as a currently available agent and does not have any obvious advantages, rapid access may be a less pressing issue.”
- Reviewer comment: I think the authors should be more descriptive here with the facts purported by PMPRB ‘Spending in 2013 was particularly low and spending in 2017 was particularly high. In their public presentation,PMPRB displayed the difference between 2013 and 2017 as an indication of skyrocketing expenditure on patented medications. They failed to disclose the fact that these two yearswere both outliers!’ If they have the data then it would be better to state this information for each year and allow readers to make up their own mind. If the information is not available, then they should describe this. I also wonder if the authors have been in touch with the PMPRB and asked for further clarification on this point, may be more sensible than waiting to ‘hear from them’ in this article.
Answer: We have changed the wording to state the following: “In presentations to the Canadian public, PMPRB has argued that price controls are necessary to contain rising drug expenditures.53 On slide 34 of their presentation, they pointed out that health care spending in Canada is rising as a percent of GDP. To support their claim that tighter controls on patented medicine prices are needed, they also stated that “Patented drugs account for an increasing share of health care spending: 7.5% in 2017, up from 6.3% in 2013.” 53 However, there is a catch. According to the PMPRB’s own published data, spending on patented medications as a percent of GDP remained relatively constant from about 2002 to 2019.17 There were a few minor aberrations over that time period. From Figure 3c of their publication,17 patented medicine sales as a percent of GDP peaked at 0.79% in 2004 and was 0.75% in 2019. The lowest it went from 2004 to 2019 was 0.71% in 2013, and the highest it went was back up to 0.78% in 2017. Spending in 2013 was particularly low and spending in 2017 was particularly high. In their public presentation,53 PMPRB displayed the difference between 2013 and 2017 as an indication of skyrocketing expenditure on patented medications. They failed to disclose the fact that these two years were both outliers! We wonder whether they were deliberately trying to dupe a naïve Canadian public. Or perhaps they simply do not recognize the problem with their analysis. ”
We have already met with them and talked to them. They had no credible explanation for any of their stances, so we do not anticipate one here.
- Reviewer comment: I think the point about COVID vaccine is a little mute and did not really cause much delay in regulatory approval (https://jamanetwork.com/journals/jamanetworkopen/article-abstract/2781352 ) which I think shows HC’s was able to prioritise approval. In fact companies engaged with HC earlier in the development than other regulators such as FDA and EMA which I think needs acknowledgement.
Answer: We have changed the wording as follows: “Attempts at government price controls also often result in end runs and “special considerations” for politically powerful interest groups. These ultimately result in higher prices rather than lower prices.63 The Covid vaccine may be a case in point. Initially, there was no plan for Covid vaccines to be exempted from the planned new PMPRB rules. However, an exemption for these vaccines was negotiated, and the vaccines rapidly became available to Canadians. Cole Pinnow from Pfizer Canada indicated that Pfizer might not have moved forward with their Covid vaccine as rapidly as they did in Canada without this exemption. They had lots of other countries eager to buy it if Canada didn’t want it. 64 Was this an empty threat by Pfizer or was it reality? We may never know, but we do know that an exemption was granted, and that such exemptions are typical of the end runs and special considerations that so frequently castrate government attempts at price controls.63 The Canadian public has no idea how much these vaccines are costing us.”
