New Anticancer Drugs: Reliably Assessing “Value” While Addressing High Prices

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors argue that high prices of oncology drugs are influenced by the high cost of drug development, slow regulatory processes for marketing new oncology drugs, and inadequate cost-effectiveness thresholds. The authors suggest that regulations need to be changed to accelerate the commercialization of oncology drugs and advocate for faster funding by being willing to pay higher prices. The authors emphasize the need for a shift in the current system to enable quicker access to effective therapies for lethal diseases like certain types of cancers.

However, the high costs are also due to a perception of the value of these oncology drugs that is too high and based more on expectations than on the real value based on clinical evidence. In addition, there are other factors that increase the cost of 'these drugs as marketing strategies and the value of pharmaceutical companies' shares and the return of profits to shareholders. On the other hand, the advantage of the standard thresholds of the QUALYs is to treat and analyze all diseases equally. Establishing different standard thresholds for different diseases can generate inequities within the public health system. It is essential to consider a holistic approach that takes into account not only the clinical evidence but also the broader economic and ethical implications of drug pricing and access.

Here are the key points for consideration and potential questions for the authors:

1. Value perception and drug pricing: The article emphasizes the impact of high drug prices on oncology drugs, attributing it to factors such as high development costs and slow regulatory processes. However, it would be beneficial to further explore the influence of value perception, marketing strategies, and shareholder interests on drug pricing. How do these factors contribute to the pricing strategies of pharmaceutical companies, and what measures can be taken to ensure that drug prices align with their true value based on clinical evidence?

2. Regulatory framework and drug development costs: The proposed changes in regulation to expedite drug commercialization raise questions about the potential trade-offs between faster access to treatments and ensuring patient safety and efficacy. Could the authors elaborate on the specific regulatory reforms they recommend and how these changes would impact the overall drug development process, including clinical trial requirements and post-market surveillance?

3. Cost-effectiveness thresholds and QALYs: The discussion on cost-effectiveness thresholds and the use of QALYs in assessing drug value is crucial. However, it would be valuable to explore alternative approaches to evaluating the value of oncology drugs, considering the diverse nature of cancer treatments and patient populations. How can the current cost-effectiveness frameworks be adapted to better reflect the unique challenges and benefits of oncology therapies?

4. Ethical and societal implications: The ethical considerations surrounding drug pricing and access to essential medications are paramount. It would be insightful to delve into the societal impact of high drug costs on healthcare systems, patient outcomes, and healthcare equity. How can the balance between profitability and public health be achieved, ensuring that patients have equitable access to life-saving treatments without compromising financial sustainability?

5. Author clarifications: Seeking clarification from the authors on the rationale behind their proposed regulatory changes, the evidence supporting the relationship between regulatory processes and drug development costs, and the considerations taken into account when determining cost-effectiveness thresholds for oncology drugs would provide a deeper understanding of the article's arguments and recommendations.

By addressing these points, the article can be strengthened to provide a more comprehensive analysis of the challenges and potential solutions related to oncology drug pricing and access.

Comments on the Quality of English Language

The quality of English language in the paper requires:

Minor editing: There are areas where improvements in clarity, coherence, or grammar are needed to enhance the overall readability and professionalism of the paper. Conducting a thorough review for minor edits can help improve the quality of English language in the document.

Author Response

Reviewer #1. We would like to thank the reviewer for their helpful suggestions. In answer:

Comment #1: “However, the high costs are also due to a perception of the value of these oncology drugs that is too high and based more on expectations than on the real value based on clinical evidence. In addition, there are other factors that increase the cost of 'these drugs as marketing strategies and the value of pharmaceutical companies' shares and the return of profits to shareholders. On the other hand, the advantage of the standard thresholds of the QUALYs is to treat and analyze all diseases equally. Establishing different standard thresholds for different diseases can generate inequities within the public health system. It is essential to consider a holistic approach that takes into account not only the clinical evidence but also the broader economic and ethical implications of drug pricing and access.”

We have expanded the section on other factors that increase drug prices. (See response to comment #2).

To further expand on the topic of misperceptions about drug value, we have added the following in the section on “Hazard ratios and relative vs absolute gains”: “As noted earlier, misperceptions that a drug’s value is higher than it really is might result in paying too much for it, but misperceptions that a drug is less valuable than it actually is can also be problematic. Excessively negative misperceptions based on flawed interpretation of clinical trial data may result in useful drugs being discarded.  Some authors [135, 140, 141] may undervalue the benefits of effective new therapies by inadequately considering the impact of crossover and long post-progression survival on OS absolute gains and hazard ratios.”

Also, at the end of the section on “government willingness to pay”, we have added the following:

“While the above points could be used to argue that the value of a QALY should be higher for orphan diseases and uncommon malignancy subtypes than for common diseases and for lethal diseases than for nonlethal diseases, some observers might argue that this would not be equitable, and that the same value per QALY should be applied in all situations.

However, applying the same value per QALY in all situations would be substantially different from what Canada does in other healthcare and social situations. For example, each of polio vaccinations, blood transfusions, appendectomies, renal dialysis, heart transplants, or bone marrow transplants can save lives, but there are marked differences in costs for these procedures, and Canadians do not question this. Similarly, there are marked differences in the cost to save a life through preventative measures such as car seat belts and airbags, road maintenance, workplace safety regulations, proper disposal of radioactive waste, etc [99], and Canadians do not question this. The amount of income tax paid annually is not the same dollar amount across all Canadians nor the same percent of income, and most Canadians do not question this. Hence, there is no indication that society demands a standard cost per QALY for all situations, nor should it. As outlined above, such an approach would unjustly disadvantage many Canadians with lethal and/or uncommon diseases. It is important to take into consideration not only the cost per QALY, but also the broader economic and ethical implications of drug pricing and access.”

It is inherently evident that cancer is a special disease.  This is implicitly recognized by the public and governments.  Unlike other illnesses, there exist mandatory cancer registries nationally and special provincial agencies exist to manage cancer programs.  Few other diseases are so immediately threatening to life and limb.

Comment #2: “Value perception and drug pricing: The article emphasizes the impact of high drug prices on oncology drugs, attributing it to factors such as high development costs and slow regulatory processes. However, it would be beneficial to further explore the influence of value perception, marketing strategies, and shareholder interests on drug pricing. How do these factors contribute to the pricing strategies of pharmaceutical companies, and what measures can be taken to ensure that drug prices align with their true value based on clinical evidence?”

We have added the following:

 “Factors driving high drug prices: As recently reviewed [3], several factors are driving high therapy prices. These include “personalization” of therapies (ie, only using the therapy in a subpopulation of patients who have characteristics that potentially predict the therapy will be effective). This results in a relatively small market size. Hence, more may be charged for each patient treated so that drug development costs can be recouped.

There are also several factors that distort market forces. These include “comparative pricing” and “charging what the market will bear" (since one company is successful in setting a record price for a new drug, another company selects a similar high price for their unrelated new drug), marketing approaches by drug companies, the presence of oligopolies (with relatively few companies responsible for most new drugs), factors impairing competition between drugs, misperceptions about a drug’s efficacy, lobbying by pharmaceutical companies, factors that limit the impact of generic drugs, and restrictions on drug imports [3].

Another factor is that in 2003, the American government passed The Medicare Prescription Drug, Improvement and Modernization Act [1]. This law specifically blocked Medicare from negotiating with a manufacturer on drug prices. Consequently, US Medicare (but not other branches of the US government) had to accept the price proposed by the drug manufacturer. This is a key reason that American drug prices are the highest in the world [3]. These high American drug prices tend to drag up worldwide prices. Recent initiatives to bring down US drug prices also might help reduce drug prices elsewhere, although they could potentially slow access to new therapies by reducing the incentive to invest in new drug development [4, 5].”

Please also see the answer to comment #4 below.

Comment #3: “Regulatory framework and drug development costs: The proposed changes in regulation to expedite drug commercialization raise questions about the potential trade-offs between faster access to treatments and ensuring patient safety and efficacy. Could the authors elaborate on the specific regulatory reforms they recommend and how these changes would impact the overall drug development process, including clinical trial requirements and post-market surveillance?”

The regulatory changes we would propose are outlined in Table 1, and follow from our expanded description of the underlying problem. (See comment #6 below). We would be happy to add further details if needed.

With respect to the increased need for post-marketing surveillance, we have added the following to the end of the section on high drug development costs:

“The approaches we advocate would mean the availability of less data at the time of drug approval. This unequivocally would increase risks, but the rapid availability of effective new therapies is highly important to patients with lethal diseases. To ensure both safety and efficacy of the therapy, this would make post-marketing surveillance even more important than it currently is [46]. The rapid migration to electronic medical record systems means that artificial intelligence could prove to be a very valuable tool in generating real world evidence as a cornerstone of this post-marketing surveillance.”

Comment #4: “Cost-effectiveness thresholds and QALYs: The discussion on cost-effectiveness thresholds and the use of QALYs in assessing drug value is crucial. However, it would be valuable to explore alternative approaches to evaluating the value of oncology drugs, considering the diverse nature of cancer treatments and patient populations. How can the current cost-effectiveness frameworks be adapted to better reflect the unique challenges and benefits of oncology therapies?”

In the Discussion, we have added the following:

“The quest has been to find a single metric that defines the value of a new anticancer therapy. This would greatly simplify the decision on how much to pay for the therapy. However, the bottom line is that no such gold standard metric exists. Any metric that we might choose will have intrinsic limitations, and trying to designate one as being our gold standard will have a high potential to result in very flawed decisions.

We must weigh all the data together, including OS half-life gain, OS hazard ratio, proportion of patients with prolonged OS, PFS gain (if crossover, long post-progression survival or short follow-up distort OS outcomes), level of certainty in the outcome, Bayesian “prior probabilities” that might support our view on the therapy, impact in distinct subpopulations and in disease that is resistant to other therapies, single agent response rate and duration of response, proportion of patients with prolonged responses, the improvement in response and duration of response when the new agent is added to a standard therapy, therapy toxicity and convenience and ease of administration, availability of alternatives, impact on other components of the healthcare system (eg, hospital beds and emergency departments), etc. Then once we have made our decision and negotiated a price, this must be regularly renegotiated as we assess real world evidence derived from patients who have received the therapy.

In negotiating the price, we must also be willing to pay a “premium” for a therapy that is beneficial in a lethal or orphan disease.

While doing this, we must work to correct factors that impede competition, and we must do everything feasible to make new drug development cheaper and faster. If it is cheaper and faster, that will increase the options available to us, and help bring down therapy prices while speeding development of even better therapies in the future. The rate of progress against cancer has been unprecedented. By far the biggest threat to sustained progress is the rapidly rising cost of new drug development and the potential inability of governments to afford the new therapies that are discovered [3]. It will be a pyrrhic victory if government attempts to cut drug prices do so at the cost of marked slowing of research and progress [4].

Comment #5: “Ethical and societal implications: The ethical considerations surrounding drug pricing and access to essential medications are paramount. It would be insightful to delve into the societal impact of high drug costs on healthcare systems, patient outcomes, and healthcare equity. How can the balance between profitability and public health be achieved, ensuring that patients have equitable access to life-saving treatments without compromising financial sustainability?”

Under the “Pharmaceutical company potential actions and reactions” section, we have added the following:

“Cancer is the leading cause of death in Canada. In 2021, the total economic burden of cancer in Canada was more than CAD $26B (USD $19B), yet patented oncology drugs accounted for only 1.3% of national health expenditures [83]. It is anticipated that this will increase. Pharmaceutical spending accounted for 18.2% of Canadian healthcare spending in 2010, but had fallen to 14.5% by 2022 [123].  Similarly, the amount spent on patented medicines in Canada was 0.75% of GDP in 2002, peaked at 0.83% in 2009, then fell to 0.76% by 2021 [124]. However, sales of oncology drugs increased from 8.4% of patented medicine costs in 2012 to 23.9% in 2021 as the number of patented cancer medicines went from 56 to 113 and sales went from CAD $1.379B (USD $1.02B) in 2012 to CAD $4.172B (USD $3.09B) in 2021 [124].  With increasing availability of effective new drugs, it is anticipated that this could rise substantially over the next few years and that this will put increasing pressure on the healthcare system.”

In the Discussion, we have added:

“While the overall cost of pharmaceuticals as a percent of healthcare spending is not rising, and while the cost of patented drugs as a percent of GDP is not increasing, oncology drug sales as a percent of patented medicine sales is increasing rapidly [123, 124]. The good news is that these new medications have resulted in substantial improvements in outcomes for cancer patients [3, 169]. The bad news is that with the rate of development of these effective but expensive new medications, we will not be able to continue to afford them unless something changes [3].”

Comment #6: “Author clarifications: Seeking clarification from the authors on the rationale behind their proposed regulatory changes, the evidence supporting the relationship between regulatory processes and drug development costs, and the considerations taken into account when determining cost-effectiveness thresholds for oncology drugs would provide a deeper understanding of the article's arguments and recommendations.”

We have rewritten the portion of the paper on high drug development costs and have described these in much greater detail, as follows:

“High drug development costs: A particularly important factor is that the cost of bringing a new drug from discovery to approval is rising much faster than inflation [6, 7]. While estimates of drug development costs vary, it is clear that they are very high, particularly for anticancer drugs [8]. It cost an average of USD $4M to bring a new anticancer drug from discovery to marketing in the 1960’s [9]. By the 1980’s, this had increased to USD $230M [9], and by 2013, the estimate had risen to USD $2.9B [6]. These drug development costs eventually must be recovered from sales of approved drugs if investment in new drug development is to continue.

While bringing down drug development costs would not be sufficient to bring down drug prices, it is an essential prerequisite [3].

High drug development costs are driven by essential but excessively burdensome clinical research regulation [3, 10] which is “harmonized” internationally [11]. This harmonization has the advantage that it means clinical research data generated in one country can be used for approval of the drug in a different country, but it has the disadvantage that it means major changes cannot be made to clinical research regulation without international agreement.

With respect to individual regulatory factors driving high drug development costs, it can take years [12] for the costly preclinical toxicology assessments that may be required by regulators before clinical trials can be launched but that add little value [10]. Preclinical toxicology assessments generally predict the obvious (eg, the drug will cause neutropenia) or miss toxicities ultimately found to be important in humans or predict toxicities that end up not being a problem. They rarely give a vital forewarning about a toxicity that is both unexpected and important [10].

The greatest potential value of preclinical toxicology assessments is to determine the “rodent LD10” (ie, the drug dose that is a lethal dose, or LD, for 10% of rodents). It generally is safe to initiate human clinical trials with 10% of the rodent LD10 [13, 14].

If patients are to be selected for a trial based on a biomarker, then a biomarker test that is certified according to the Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) must first be developed. The requirement for CLIA certification of a screening test can delay trial initiation by a year or more and can cost $100K before it is even known whether the test might predict drug efficacy [15]. A more rational strategy would be to initially use a much less expensive research laboratory test, and only invest time and money in perfecting and certifying the test if the preliminary data suggested that it would be useful.

Multiple additional bottlenecks and barriers markedly slow clinical trial activation while increasing costs and adding little value [16, 17]. There is an excessively high administrative burden interacting with Institutional Review Boards (IRBs) [18], and IRB approval of a study can take far too long [19]. The entire IRB approach needs a very major overhaul [20].

In addition to trial activation requiring IRB approval, the majority of study amendments also require IRB approval, even if changes are minor and unlikely to negatively impact patient safety or study scientific conclusions. Approval of amendments can take several months or more and in some cases can cost hundreds of thousands of dollars [21].   

Trial eligibility criteria are irrationally restrictive [22, 23], with fewer than 5% of North American adults with cancer able to participate in a clinical trial [24], despite a majority being willing to participate if given the option [25]. Until the late 1990’s, a trial’s Principal Investigator (PI) could grant an exception to the eligibility criteria and permit entry of a patient on a trial if there was no good clinical or scientific reason to exclude them. This generally is no longer allowed, but it makes little sense to not allow it if the patient’s participation would be unlikely to risk their safety or the conclusions of the trial [23].

Overall, the complexity of cancer clinical trials is rising rapidly [26]. For example, by 2011-2015, there was an 88% increase in the number of data points that were required per patient on a trial compared to 2001-2005 [27]. Typically, a large amount of expensive data must be collected during a clinical trial, but much of this information may add little value and may never be needed or used [28, 29].

Involvement of a Clinical Research Organization in a trial can substantially increase the amount of expensive but unimportant data collected [3, 28]. With the large amount of unimportant but “required” data that must be collected, the overwhelming majority of random FDA audits identify at least some deficiencies [30]. It is almost impossible to completely avoid error when required to collect an unnecessarily huge amount of unhelpful data.

Increasing trial complexity has meant an increase in research trial staffing requirements [31] and in mandated procedures and patient visits [32].  Increasingly complex privacy restrictions have also increased clinical research costs and barriers [33, 34].  The average cost to a sponsor for a patient on a phase III trial rose from around USD $26,000 in 2006 [10] to USD $41,413 by 2015-2017, and was as much as USD $75,000-$90,000 in some studies [35, 36]. Inflation [37] would have accounted for only $4,953 of that $15,400 average cost increase.

Patient safety has been the major rationale given for this increased regulatory stringency. However, as trial costs and complexity have increased, there has been negligible meaningful impact on patient safety, but at the very high cost of an estimated $2.7M per life-year saved by this increased regulatory burden [10]. Overall, clinical research regulation is both essential and well-intentioned, but it currently is not cost-effective. The approaches used are not evidence-based and result in clinical research costs that are much too high. This inevitably contributes substantially to high drug prices [3].

Expensive new medications are usually paid for by governments or insurance companies.  The number of new drugs developed would plummet if patients had to pay full price out-of-pocket since few could afford it. Hence, there would be insufficient sales to generate the profits needed to drive the research innovation needed for progress.

However, drug development costs are a direct function of regulatory processes and requirements. The more cumbersome and complex, the longer it takes and the more the drugs cost to develop. Hence, an alternative scenario would be the evolution of a simpler regulatory environment which would permit rapid, less expensive drug development. The governments that bear the burden of paying high drug prices have it within their power to lower these prices by rectifying markedly cost-ineffective clinical research regulation [3].

There have been attempts to improve the current situation [38-43], but we need to go much further. As briefly summarized in Table 1, there are several feasible steps that could be taken to markedly cut drug development costs without unreasonably jeopardizing safety or data integrity. These recommendations are derived from a Life Saving Therapies Network modified multi-round Delphi study involving 70 Canadian, European and American patient advocates and experts in drug development, ethics, oncology, and regulatory and legal processes [44], and from related prior publications [3, 10, 44-47].

Please also see the answer to comment #4 above.

Comment #7: “Minor editing: There are areas where improvements in clarity, coherence, or grammar are needed to enhance the overall readability and professionalism of the paper. Conducting a thorough review for minor edits can help improve the quality of English language in the document.”

We have extensively edited the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

I read with interest the paper titled "New anticancer drugs: bringing down prices while reliably assessing “value”"

My first comment is to simplify the way the paper is written: eg, in the first lines of abstract "Countries face challenges in paying for new drugs. High prices are driven in part by exploding drug development costs. Development costs, in turn, are driven by essential but burdensome regulation. Burdensome regulation also delays drug development. Delays can translate into thousands of life-years lost." - too many sentences and too repetititive, since one sentence start with the ending idea of the previous sentence. 

References should be provided in the rules of the journal. Please check: mdpi.com/journal/curroncol/instructions#references

"The speed with which COVID vaccines and AIDS therapies were developed indicates this is possible if governments prioritize it." - well, even the idea is true, when you prioritize time over safety, there are a lot of information missing from clinical trials, that should not be abandoned. For sure developing a vaccine is different of developing an anticancer drug, and so its safety profile. When COVID vaccines came to market, no toxicological studies were provided for long time, pregnancy, childbirth, and so on and so on. This should be discussed.

Again, in the introduction a lot of small sentences, that seems no sense:

- "Estimates of drug development costs vary"

- "Few could afford it." - the paper should be extensively rewritten and go to proofreading before resubmission. 

Why having 2 topics "High drug development costs" and "Factors for High drug development costs" - My suggestion is to merge and simplify the text.

Some values are presented in Euro, others in dollars. You need to choose one and when other is provided, atual currency should be provided. 

You provide Table 1 as recommendations. Reccomendations of who? Based in what data? Validated by who (a Delphi panel, a Focus group). If not validated with a proper methods, or if not involve a specific organization, this is more a letter of intentions or dreams, than reccomendations. Most of them doesn't provide any reference, and those that provide, provide random numbers of references, (3, 7 is ok, but then with 128, 189, 130, since the last reference on text was 7. The references in the table should follow the same order than the manuscript. 

Some topics are redundacts like those: 

"International “harmonisation” of clinical research regulation: 

Currently, rules governing clinical research oversight are “harmonised” internationally. The governments that bear the burden of paying high drug prices have it within their power to lower these prices by rectifying markedly cost-ineffective clinical research regulation. However, this will require international collaboration." - What you conclude? The need of harmonization that it's already implemented? Collaboration already exists, all guidelines of ICH are made in collaboration. 

Althrough the topic is relevant and some of the information could give the reader a good perspective, the paper is titled to be related to "New anticancer drugs", however the overall paper is superficial on that topic. In order to have a smooth paper to be published, extensive editing and rewriting should be performed. 

Comments on the Quality of English Language

Extensive rewriting should be performed. The paper have very small sentences along the entire manuscript and the ideas are not well connected. 

Author Response

Reviewer #2. We would like to thank the reviewer for their helpful suggestions. In answer:

Comment #1: “My first comment is to simplify the way the paper is written: eg, in the first lines of abstract "Countries face challenges in paying for new drugs. High prices are driven in part by exploding drug development costs. Development costs, in turn, are driven by essential but burdensome regulation. Burdensome regulation also delays drug development. Delays can translate into thousands of life-years lost." - too many sentences and too repetitive, since one sentence start with the ending idea of the previous sentence.”

We have extensively revised the manuscript and have lengthened several of the short sentences.

Comment #2: “References should be provided in the rules of the journal. Please check: mdpi.com/journal/curroncol/instructions#references”

References have been revised according to Current Oncology rules.

Comment #3: “’The speed with which COVID vaccines and AIDS therapies were developed indicates this is possible if governments prioritize it." - well, even the idea is true, when you prioritize time over safety, there are a lot of information missing from clinical trials, that should not be abandoned. For sure developing a vaccine is different of developing an anticancer drug, and so its safety profile. When COVID vaccines came to market, no toxicological studies were provided for long time, pregnancy, childbirth, and so on and so on. This should be discussed.”

We have added the following to the end of the section on high drug development costs:

“The approaches we advocate would mean the availability of less data at the time of drug approval. This unequivocally would increase risks, but the rapid availability of effective new therapies is highly important to patients with lethal diseases. To ensure both safety and efficacy of the therapy, this would make post-marketing surveillance even more important than it currently is [46]. The rapid migration to electronic medical record systems means that artificial intelligence could prove to be a very valuable tool in generating real world evidence as a cornerstone of this post-marketing surveillance.”

Comment #4: “Again, in the introduction a lot of small sentences, that seems no sense:

- "Estimates of drug development costs vary"

- "Few could afford it." - the paper should be extensively rewritten and go to proofreading before resubmission.”

We have extensively edited the manuscript to decrease the number of short sentences.

Comment #5: “Why having 2 topics "High drug development costs" and "Factors for High drug development costs" - My suggestion is to merge and simplify the text.”

These sections have been combined.

Comment #6: “Some values are presented in Euro, others in dollars. You need to choose one and when other is provided, actual currency should be provided. ”

We have included a conversion to USD for each entry of CAD or Euros.

Comment #7: “You provide Table 1 as recommendations. Recommendations of who? Based in what data? Validated by who (a Delphi panel, a Focus group). If not validated with a proper method, or if not involve a specific organization, this is more a letter of intentions or dreams, than recommendations. Most of them doesn't provide any reference, and those that provide, provide random numbers of references, (3, 7 is ok, but then with 128, 189, 130, since the last reference on text was 7. The references in the table should follow the same order than the manuscript.”

We have removed the references from the upper part of the table since we have now included far more detail (with references) in the text under “high drug development costs”. Remaining references are now in their proper order.

As the source of the recommendations, we have added the following to the section on high drug development costs:

“These recommendations are derived from a Life Saving Therapies Network modified multi-round Delphi study involving 70 Canadian, European and American patient advocates and experts in drug development, ethics, oncology, and regulatory and legal processes [44], and from related prior publications [3, 10, 44-47].”

Comment #8: “Some topics are redundant like those: 

"International “harmonisation” of clinical research regulation: 

Currently, rules governing clinical research oversight are “harmonised” internationally. The governments that bear the burden of paying high drug prices have it within their power to lower these prices by rectifying markedly cost-ineffective clinical research regulation. However, this will require international collaboration." - What you conclude? The need of harmonization that it's already implemented? Collaboration already exists, all guidelines of ICH are made in collaboration.”

We have removed the separate section on harmonisation, and have added the following under “high drug development costs”:

“High drug development costs are driven by essential but excessively burdensome clinical research regulation [3, 10] which is “harmonized” internationally [11]. This harmonization has the advantage that it means clinical research data generated in one country can be used for approval of the drug in a different country, but it has the disadvantage that it means major changes cannot be made to clinical research regulation without international agreement.”

Comment #9: “Although the topic is relevant and some of the information could give the reader a good perspective, the paper is titled to be related to "New anticancer drugs", however the overall paper is superficial on that topic. In order to have a smooth paper to be published, extensive editing and rewriting should be performed.”

We have changed the title to “New anticancer drugs: reliably assessing “value” while addressing high prices” and have extensively rewritten the paper.

Comment #10: “Extensive rewriting should be performed. The paper has very small sentences along the entire manuscript and the ideas are not well connected.”

We have addressed sentence length and have extensively rewritten the paper.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

In my opinion, the article is biased and lacks a critical perspective on the issue. According to the authors, the problem of the significant increase in the costs of oncological drugs is only attributed to development costs influenced by excessive regulation. Therefore, the authors suggest that loosening regulatory processes in marketing and financing, along with higher QALY values for oncological drugs, would solve the problem. I believe this is a partial view of the problem, which is more complex, and fails to critically address the commercial strategies of pharmaceutical companies, which are also a key factor in the increase in the prices of oncological medicines. Nonetheless, the authors have every right to express their opinion, which does not align with mine. 

The final sentence of the abstract is not very appropriate for a scientific article. My suggestion is to change the sentence. For example, "Addressing these disparities demands urgent reform."The final sentence of the abstract is not very appropriate for a scientific article. My suggestion is to change the sentence. For example, "Addressing these disparities demands urgent reform."

I have no further comments.

Author Response

We would like to thank the reviewer for their helpful comments. In reply:

Comment #1: “In my opinion, the article is biased and lacks a critical perspective on the issue. According to the authors, the problem of the significant increase in the costs of oncological drugs is only attributed to development costs influenced by excessive regulation. Therefore, the authors suggest that loosening regulatory processes in marketing and financing, along with higher QALY values for oncological drugs, would solve the problem. I believe this is a partial view of the problem, which is more complex, and fails to critically address the commercial strategies of pharmaceutical companies, which are also a key factor in the increase in the prices of oncological medicines. Nonetheless, the authors have every right to express their opinion, which does not align with mine.”

Reply: We completely agree with the reviewer that clinical research costs are only part of the problem and addressing them would not by itself solve the problem. However, we feel that it is an urgent part of the problem, and that most other steps will have minimal impact unless we do address drug development costs.

We have reworded the section as follows: “While bringing down drug development costs would not be sufficient to bring down drug prices, it is an important component [4]. Increasing personalization of therapy will continue to create an upward pressure on drug prices since personalization means a smaller market size from which drug development, production and marketing costs may be recouped [5]. Irrespective of any other factors driving high drug prices, if governments take actions that bring revenues from drug sales down to levels lower than what it costs to develop these drugs, then private investment in drug development would be expected to decrease substantially or stop [4].  

Since drug development costs have been rising much faster than inflation [11, 12] and since there has been no concerted effort to address this, we believe that tackling high drug development costs constitutes an important opportunity that ultimately could help make a major difference in drug prices. The other factors driving high prices would still need to be addressed, but governments and companies would have more room to maneuver if drug development costs were much lower [4]. Regulation is highly important, and the objective would not be to weaken regulation but instead to make it more cost effective.”

Comment #2: “The final sentence of the abstract is not very appropriate for a scientific article. My suggestion is to change the sentence. For example, "Addressing these disparities demands urgent reform."The final sentence of the abstract is not very appropriate for a scientific article. My suggestion is to change the sentence. For example, ‘Addressing these disparities demands urgent reform.’”

Reply: As per their suggestion, we have replaced the last sentence of the abstract with: “Addressing these disparities demands urgent reform.”

Reviewer 2 Report

Comments and Suggestions for Authors

I read with interest the reviewed version of the paper titled "New anticancer drugs: bringing down prices while reliably assessing “value”". 

From my point of view, the comments that arose in the previous revision were not performed properly. 

In the last revision, it was suggested that the writing must be clear and simplified. Still, there are a lot of parts in the manuscript that are badly written with small and biased sentences. Add connectors as "which", "this", "and" or "but" to connect sentences, did not clarify the meaning of the sentences. The entire manuscript should be rewritten in a proper way. 

- Abstract ends with this sentence "This must change". This is, from my point of view improper sentence to add in a scientific article.

- I consider that paper should be written in passive voice. The use of "we" is unnecessary. 

- the introduction have only 4 lines? Please clarify why one of the main chapters in a paper is so small. 

- As I mentioned previously in my first revision, there are multiple sentences that need references. Examples: 

line 47 - "Countries differ in how much they are willing to pay for a new drug." where are the references?

line 48 - "New therapies are expensive, and prices are rising rapidly."

line 71 - "These high American drug prices tend to drag up worldwide prices"

Small sentences still remains. In the new text, there are multiple. Examples:  Line 55 - This results in a relatively small market size.  

Line 87 and repeated in line 89 - that it means

Line 96 - Reference 10 - I've consulted the paper cited. No information was found about the unexpected and important toxicity not found, that you cited. 

In the middle of the paper, Canada started to be the center of the discussion. Why that? Until that point, no information that the focus will be Canada was provided. The perspective paper is related to Canada? If yes, Title and abstract must refer to Canada. If not, no need to refer canada anywhere. Also, an objective for the paper will be good.

Author Response

We thank the reviewer for their extensive assessment of our paper and for their very helpful suggestions. In reply:

Comment #1: “In the last revision, it was suggested that the writing must be clear and simplified. Still, there are a lot of parts in the manuscript that are badly written with small and biased sentences. Add connectors as "which", "this", "and" or "but" to connect sentences, did not clarify the meaning of the sentences. The entire manuscript should be rewritten in a proper way.”

Reply: With respect to use of short sentences vs longer sentences, we appreciate the reviewer’s perspective, but we have elected not to extensively change sentence structure. Some readers prefer shorter sentences, and some prefer longer sentences.

Comment #2: “- Abstract ends with this sentence "This must change". This is, from my point of view improper sentence to add in a scientific article.”

Reply: We have replaced that sentence with: “Addressing these disparities demands urgent reform.”

Comment #3: “- I consider that paper should be written in passive voice. The use of "we" is unnecessary.”

Reply: We appreciate the reviewer’s thoughts on this, but since this is a “perspective” piece, we feel that it is appropriate to use “we”, and we have elected not to change this.

Comment #4: “- the introduction have only 4 lines? Please clarify why one of the main chapters in a paper is so small.”

Reply: We have expanded the introduction.

Comment #5: “- As I mentioned previously in my first revision, there are multiple sentences that need references. Examples: 

line 47 - "Countries differ in how much they are willing to pay for a new drug." where are the references?

line 48 - "New therapies are expensive, and prices are rising rapidly."

line 71 - "These high American drug prices tend to drag up worldwide prices”

Reply: References have been added for lines 47 and 48 and in several other areas of the manuscript.

In addition, in several areas of the manuscript we have tried to clarify areas that are based on our opinion by adding terminology such as “We anticipate that…..”, “We feel that….”, “We believe that….”,   “From our perspective….”, or something equivalent,

We have changed the wording for line 71. We have changed “These high American drug prices tend to drag up worldwide prices” to “If some purchasers of a product are willing to pay a very high price, then this may set the price bar higher, and a lower initial price may bring the overall global price bar down. It has been proposed that high unregulated initial American drug prices tend to drag up worldwide prices [4].”

Comment #6: “Small sentences still remains. In the new text, there are multiple. Examples:  Line 55 - This results in a relatively small market size.”

Reply: Please see our reply to comment #1. For this particular example, we have restated this as follows: “This results in a relatively small market size [5]. If only a small proportion of the population have the characteristic known to be required for therapy efficacy, then relatively few patients will be treated.”

Comment #7: “Line 87 and repeated in line 89 - that it means”

Reply: We have deleted the second “it means”

Comment #8: “Line 96 - Reference 10 - I've consulted the paper cited. No information was found about the unexpected and important toxicity not found, that you cited.”

Reply: We appreciate the reviewer drawing this to our attention. We have replaced the reference for the last sentence of the paragraph and have changed the sentence to “There are few examples of them giving a vital forewarning about a toxicity that is both unexpected and important [4].”

Comment #9: “In the middle of the paper, Canada started to be the center of the discussion. Why that? Until that point, no information that the focus will be Canada was provided. The perspective paper is related to Canada? If yes, Title and abstract must refer to Canada. If not, no need to refer Canada anywhere.”

Reply: We have included in the abstract that “Canada is used as an example to illustrate how “incremental cost effectiveness ratios” (ICERs) based on measures such as gains in “quality-adjusted life-years” (QALYs) may be used to determine a drug’s value, but are often problematic, imprecise assessments.”  

In the introduction, we have added: “Canada is used as an example to illustrate potential limitations in health technology assessments (HTAs). How approaches to deciding on a drug’s value can impact access to a drug in both Canada and elsewhere are also discussed.”

Comment #10: “ Also, an objective for the paper will be good.”

Reply: In the introduction, we have added: “The objectives of this manuscript are to address why new anticancer drugs are so expensive and why current approaches to deciding on a drug’s value can be problematic.”