RECOMMENDED CANCER, STARVING DIET, MACROPHAGES


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pharma and chemo--sucks

Over a 4-year period for 48 recently approved cancer 35% had significant extension of survival, median life extension for those terminal patients was 2.7 months [not very significant when it takes longer to die], with the longest drug bring 5.8 and the shortest 1 month for the approved drugs, and only 10% improved quality of life, which means that 90% of the drugs approved made quality of life worse.  Very low hurdle for patent of exclucivity.  The worse are the post marketing studies, since they are done to expand the market and for an assortment of other marketing goals—See Ben Goldacre’s Bad Pharma for a reasonable good account of the scientific fraud committed by pharma on an industrial scale (their business model).  But it is much worse than their finding, because the journals, unlike the EMA (European Medicine Agency) which sees the raw data the journals and thus the 5 authors do not see the raw data.  Pharma will not share the raw data—need I say more, but I will.  In a similar study of trials submit to the FDA for which a group of 4 professor received the raw data through the Freedom of Information Act, they found all 74 journal articles which were compared to the published raw data that these articles had deliberate positive bias, and average of 32% (from 11% to 69%).  The study revealed given the universality of positive bias, that this is the way pharma runs trial.  The finding as to bias has a very high probability of applying to the cancer trials.  Given the minimal benefit to terminal patients and the bias, the net benefit has to amount to below zero.  Yes, it gets approved based on secondary endpoint, must commonly the shrinking of a tumor.  The FDA and EMA do not check the journal articles to see if the study submitted to them are then published without bias.  The 32% positive bias is fat greater than the meager benefit on a surrogate endpoint. 

Allow me to explain why shrink a tumor through chemo with few exception is a bad thing. Most types of chemo cully from the cancer tumor the weaker cancerous cells, thereby leaving the more vigorous cells, secondly most chemotherapies weaken the immune cells, thereby reducing the effectiveness of the system that has evolved to limit tumor growth, destroy tumor cells, and thereby prevent metastatic spread and locally invasive growth.          

http://www.bmj.com/content/359/bmj.j4530?utm_medium=email&utm_campaign_name=201710278&utm_source=etoc_daily

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

1.       Courtney Davis, senior lecturer1,

2.       Huseyin Naci, assistant professor of health policy2,

3.       Evrim Gurpinar, MSc candidate in international health policy 2,

4.       Elita Poplavska, assistant professor3,

5.       Ashlyn Pinto, MSc candidate in global health2,

6.       Ajay Aggarwal, academic clinical oncologist5

 

1.       Correspondence: C Davis courtney.davis@kcl.ac.uk

  • Accepted 28 September 2017

Abstract

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.

Design Retrospective cohort study.

Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.

Main outcome measures Pivotal and post-marketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs.

Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent post-marketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%).

Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

Introduction

Before new prescription medicines are allowed onto the market, they must be tested in studies and show, to the satisfaction of drug regulatory agencies, that their benefits outweigh the harms of drug toxicity. The most informative and valuable studies are those providing robust evidence from well designed randomised controlled trials that a new drug has a significant effect on outcomes that are important to patients and that the magnitude of those effects, compared with other treatment options, are clinically meaningful. Although the goal of cancer treatment is to improve the quantity and quality of life,123 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4567891011 or quality of life46111213 in all settings, and two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low.814Moreover, there is growing concern that the benefits offered by many new treatments for cancer—often discussed and promoted as “breakthroughs”15161718—are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs.1920212223 Consequently, there have been calls to raise the evidence bar for market authorisation of new cancer drugs.152123242526

No recent studies have systematically examined the evidence base and magnitude of benefit for cancer drugs approved by the European Medicines Agency (EMA).272829 Available data from the US show that only a small proportion of cancer treatments approved by the US Food and Drug Administration (FDA) unequivocally show benefits on survival or quality of life.30 The applicability of this evidence to the European context, however, is not clear. Recent FDA-EMA comparisons show differences in regulatory decisions, route of approval, and availability of cancer drugs that could have important implications for clinical practice and patient safety.3132333435 In particular, regulatory provisions for expediting drug development and approval differ between the US and the EU,32 with EU regulation being more restrictive in scope.36 This could lead to divergent outcomes between the two regions.

The proportion of cancer drugs approved by the EMA without any demonstrable benefits on survival or quality of life is not known. In addition, whether treatments approved without evidence of benefit on survival are subsequently shown to improve survival or quality of life in postmarketing studies has not been characterised.

We sought to systematically evaluate the evidence base for all new drugs and new indications for the treatment of solid tumours and haematological malignancies approved by the EMA in the five year period 2009-13. We determined the proportion of drugs with demonstrable benefit on survival or quality of life over available treatment options or placebo, both at time of approval and in the postmarketing period. In addition, we used a validated scale to evaluate the magnitude of benefit of drugs in our sample showing a significant improvement on survival in the treatment of solid cancers.

Methods

Cohort of cancer drugs approved by EMA 2009-13

We searched the publicly available EMA database of European Public Assessment Reports using L01-04 ATC codes to identify “antineoplastic and immunomodulating” agents for solid tumours and haematological malignancies authorised from 1 January 2009 to 31 December 2013. Consistent with previous research,30our study period ended in 2013, which allowed adequate time for the completion of randomised trials in the postmarketing period. We excluded paediatric indications, indications for the treatment of benign tumours, supportive treatments, and generic products (fig A in appendix). Authorised indications for each drug were identified by searching the EPAR document “Procedural steps taken and scientific information after authorisation.”

We distinguished between different types of regulatory approval. A “first marketing authorisation” indicates that the drug is a new active substance, approved onto the EU market for the first time. An “extension” to a marketing authorisation is when a marketed drug is approved for use in a new patient population, new combination, new line of treatment, or new type of cancer. By law, a “regular marketing authorisation” should be based on comprehensive evidence of quality, safety, and efficacy. “Conditional marketing authorisations” can be granted for drugs intended to treat patients with seriously debilitating or life threatening diseases and are expected to fulfil an unmet medical need. Conditional approvals are granted on the basis of less comprehensive data than required for a regular marketing authorisation, and companies are required to generate additional evidence in the postmarketing period.36 “Orphan drug” designation is granted for the treatment of rare cancers. We also categorised indications according to cancer site and stage of disease (specifically whether treatments were to be used in a curative or non-curative setting).

Middle section of about 20 pages was not copied

Comparison with other studies

Apolone and colleagues27 evaluated the evidence base for new cancer drugs approved by the EMA in the period 1995-2004. In that 10 year period the EMA authorised 14 anticancer drugs for 27 indications. An important difference between their earlier study and the present one is that the earlier cohort includes only drugs to treat solid tumours. Nevertheless, our findings indicate some improvements in the quality of the evidence base supporting new oncology drugs. For example, drug uses authorised in the study period 2009-13 were more likely to be supported by trials that included overall survival as a primary endpoint (26% v 8%), and by randomised trials (88% v 66%). There has been a substantial increase in the number of approved treatments for solid tumours compared with the earlier period—an average of 12 a year for 2009-20 compared with three a year for 1995-2004.

In contrast with recent studies focusing on a subset of oncology drug approvals in Europe,3233 we included all authorised oncology indications regardless of route of approval and systematically analysed survival and quality of life benefits. We also relied exclusively on evidence generated from randomised controlled trials. We did not therefore accept mathematical models considered by health technology assessment bodies such as the National Institute for Health and Care Excellence.81 There is continuing debate around the validity of simulation models that extrapolate findings from short term trials.8283 Our analysis is the first to investigate whether drugs that did not show a survival benefit at the time of approval in Europe are subsequently shown to improve survival or quality of life in follow-up randomised controlled trials once drugs are on the market.

Study limitations

There are several limitations to this study. Firstly, there were several cases in which results reported in the EPARs were ambiguous or incomplete. When difficulties in interpretation occurred, we ensured our determinations were consistent with the EMA’s conclusions. Following this approach, we determined that significant survival benefits had been shown at time of market authorisation for vinflunine (in transitional cell carcinoma) and trastuzumab (in neoadjuvant breast cancer), despite uncertainty regarding the reported statistical analyses. When the EMA’s opinions on specific questions were not clear or not available, we adopted a generous approach that favoured the drug. For example, we credited panitumumab with showing a survival benefit in the postmarketing period on the basis of an “exploratory” analysis.84

There was also considerable variation in the reporting of quality of life endpoints in both the EPARs and the medical literature. Significant results might have been shown for isolated parameters or single subscales only, and it was not clear whether a net quality of life benefit had been shown. Nor was it consistently reported whether or not the magnitude of improvement was such that it would be considered clinically meaningful for patients. Consequently, we might have overestimated the proportion of drugs that offer benefits on survival or quality of life and the clinical meaningfulness of these. Our findings, however, are consistent with recent findings from the US.3085

Secondly, we did not consider the appropriateness of clinical trial design, including whether a treatment administered in the control arm of a study was optimal or even informative. This is an important study limitation, which again means we might have overestimated the benefits offered by the drugs in our sample. For example, the control arm of the pivotal trial to support approval of ipilimumab for metastatic melanoma was an experimental treatment. Similarly, the pivotal trial to support lapatinib in combination with trastuzumab for patients with metastatic breast cancer used lapatinib monotherapy as the comparison—a treatment acknowledged in the EPAR to be “without established efficacy.”86 Although this trial design failed to isolate the effects of the test drug, the EMA nevertheless concluded that the reported benefit in survival was clinically relevant and could be attributed to the combination.

Thirdly, our ESMO ratings share the limitations of the published studies on which they are based. For example, the magnitude of clinical benefit shown in a particular trial could be inflated by the choice of an inappropriate comparator or treatment in the control arm that does not represent best standard of care.38 Several maintenance therapy trials for metastatic non-small cell lung cancer, for example, have been criticised for flawed study designs that systematically result in substandard care in the control arms.87 In the case of lapatinib combined with tratuzumab, the pivotal study was scored 4 on the basis of a 4.5 month survival gain over lapatinib monotherapy (with no established efficacy).

Fourthly, our findings do not reflect the totality of the evidence base for a specific authorised indication as we did not take account of studies with negative results for the same drug indication if they were not reported as pivotal studies in the EPAR, nor did we take account of the fact that studies with positive results for a particular indication could conflict with negative findings from other studies in the same indicated patient population.

Implications for clinical practice and regulatory policy

Despite the EMA’s statement that overall survival is the “most persuasive outcome” for studies investigating the clinical safety and efficacy of new oncology drugs and new uses of such drugs, European regulators commonly accept the use of surrogate measures of drug benefit as primary endpoints in pivotal trials for both conditional and regular pathways to market authorisation.1188 In addition, any demonstration of a statistically significant difference in survival between treatments, however small and regardless of whether such a difference is clinically meaningful to patients, has recently been accepted as the basis for approving new cancer drugs.89 To a large extent, regulatory evidence standards determine the clinical value of, and the quality of the evidence base for, new oncology drugs. Our study suggests these standards are failing to incentivise drug development that best meets the needs of patients, clinicians, and healthcare systems.15171921

Though surrogate endpoints are argued to have the advantage of allowing quicker drug development and patient access, it is questionable whether studies based on surrogate measures of efficacy provide optimal, or even meaningful, information for patients and clinicians.24 Moreover, our analysis raises the possibility that regulatory and current research practices have created a situation in which critical information about the outcomes that matter most to patients might never be generated once oncology drugs are approved for widespread use. The limited availability of studies showing either benefits to overall survival or quality of life in the postmarketing period underscores the importance of requiring robust evidence of clinical benefit at the time of marketing authorisation.909192

The EMA and other drug regulatory agencies should reconsider when, and to what extent, it is appropriate to approve new cancer drugs on the basis of surrogate endpoints. Furthermore, when gains in survival and quality of life are shown, these gains should be meaningful to patients and clinicians.

Conclusion

Among 68 cancer drug indications approved by the EMA in the period 2009-13, and with a median of 5.4 years’ follow-up, only 35 (51%) were associated with significant improvement in survival or quality of life over alternative treatment options, placebo, or as add on treatment. For 33 (49%), uncertainty remains over whether the drugs extend survival or improve quality of life. Of the 23 drugs with a survival benefit that could be scored with the validated ESMO-MCBS tool, only 11 (48%) were judged to offer a clinically meaningful benefit.

Most new oncology drugs authorised by the EMA in 2009-13 came onto the market without clear evidence that they improved the quality or quantity of patients’ lives, and, when survival gains over available treatment alternatives were shown, they were not always clinically meaningful. Little new information to guide patients, their treating clinicians, or decisions about whether or not to pay for treatments was generated in the postmarketing period. This situation has negative implications for patients and public health.1993 When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined.

What is already known on this topicWhen in the lifecycle of a cancer drug should an improvement in survival or quality of life be demonstrated? Some people argue that these benefits should be clearly evident before marketing. Others, me included, believe that for some indications, including terminal cancers with few treatment options, a drug might receive provisional approval based on surrogate outcomes (such as tumour shrinkage or progression-free survival), with overall survival or quality of life assessed after market authorisation. Although there is no consensus, the one answer that seems absolutely unjustifiable is never. And yet, this is often what happens, according to two recent studies.

The first found that between 2008 and 2012 the US Food and Drug Administration approved most uses of cancer drugs without evidence of survival or improved quality of life (67%, 36/54).1 Among the 36 such approvals, only five (14%) uses were shown later to improve survival compared with existing treatments or placebo after a median of 4.4 years on the market.

The linked paper by Davis and colleagues (doi:10.1136/bmj.j4530) extends these findings.2In their study of cancer drugs approved by the European Medicines Agency between 2009 and 2013, 57% (39/68) had no supporting evidence of better survival or quality of life when they entered the market. After a median of 5.9 years on the market, just six of these 39 (15%) agents had been shown to improve survival or quality of life.

 

  • Clinical trials designed to gain regulatory approval for new drugs often evaluate surrogate measures that do not always reliably predict clinically meaningful outcomes like survival or quality of life

  • Recent reviews from the US show that only a small proportion of cancer drugs approved by the US Food and Drug Administration improve survival or quality of life

  • No recent studies have systematically examined the evidence base for and magnitude of benefit for cancer drugs approved by the EMA

What this study adds

  • Most new oncology drugs authorised by the EMA in 2009-13 came onto the market without clear evidence that they improved the quality or quantity of patients’ lives

  • After market entry, cancer drugs rarely show benefits on overall survival or quality of life in randomised trials

  • When survival gains over available treatment alternatives are shown, they are not always clinically meaningful

http://www.bmj.com/content/359/bmj.j4528?utm_medium=email&utm_campaign_name=201710278&utm_source=etoc_daily   BMJ 2017359 doi: https://doi.org/10.1136/bmj.j4528 (Published 04 October 2017)

Editorial

You don’t need to know, according to our broken regulatory system

When in the lifecycle of a cancer drug should an improvement in survival or quality of life be demonstrated? Some people argue that these benefits should be clearly evident before marketing. Others, me included, believe that for some indications, including terminal cancers with few treatment options, a drug might receive provisional approval based on surrogate outcomes (such as tumour shrinkage or progression-free survival), with overall survival or quality of life assessed after market authorisation. Although there is no consensus, the one answer that seems absolutely unjustifiable is never. And yet, this is often what happens, according to two recent studies.

The first found that between 2008 and 2012 the US Food and Drug Administration approved most uses of cancer drugs without evidence of survival or improved quality of life (67%, 36/54).1 Among the 36 such approvals, only five (14%) uses were shown later to improve survival compared with existing treatments or placebo after a median of 4.4 years on the market.

 

The linked paper by Davis and colleagues (doi:10.1136/bmj.j4530) extends these findings.2In their study of cancer drugs approved by the European Medicines Agency between 2009 and 2013, 57% (39/68) had no supporting evidence of better survival or quality of life when they entered the market. After a median of 5.9 years on the market, just six of these 39 (15%) agents had been shown to improve survival or quality of life.

 

Minimal benefit

Three further facts help characterise the current regulatory climate. Firstly, when drugs do offer survival advantages, the gains are often marginal. Fojo and colleagues found that the median improvement in survival among patients treated with 71 drugs for solid tumours was just 2.1 months.3 Davis and colleagues agree. Of the 23 drugs that improved survival, 11 (48%) failed to meet the modest definition of “clinically meaningful benefit” set by the European Society of Medical Oncology.

All three aforementioned analyses123 consider only measured improvements in survival and not mathematically derived or modelled estimates. This is for good reason. Modelled estimates make assumptions to predict survival benefits that might occur during longer follow-up or adjusting for differences in post-study treatment between groups. Modelled estimates are uncertain and seem to be consistently larger than measured gains,4 raising question about their fidelity.

Secondly, the small benefits of cancer drugs typically occur in trials conducted in unrepresentative patient populations—patients who are younger and with less comorbidity than average clinical populations.5 When a marginal drug advantage is applied to a real world population, a small benefit may vanish entirely because of the fine balance between risks and benefits typical of these agents.5

Finally, many of the surrogate outcomes used for drug approval are poorly correlated with survival.6 For others, the strength of the correlation is untested.7 This is true for the FDA’s regular approval pathway as well as the accelerated approval route.6 Notably, regular approvals are not usually coupled to postmarketing requirements for further trials to confirm effectiveness and safety. This means that the surrogate outcome, often unvalidated, may be all we ever have.

Better patient value

Taken together, these facts paint a sobering picture. Although we are approving cancer drugs at a rapid pace, few come to market with good evidence that they improve patient centred outcomes. If they do, they often offer marginal benefits that may be lost in the heterogeneous patients of the real world. Most approvals of cancer drugs are based on flimsy or untested surrogate endpoints, and postmarketing studies rarely validate the efficacy and safety of these drugs on patient centred endpoints. Add to this that the average cancer drug costs in excess of $100 000 (75 000; €85 000) per year of treatment, and the conclusion seems that the regulatory system is broken.7

In the US, this broken system means huge expenditures on cancer drugs with certain toxicity but uncertain benefit. The US Medicare programme is legally required to pay for any drug approved by the FDA without negotiation on price.7

In Europe, agencies such as the National Institute for Health and Care Excellence (NICE) exclude from reimbursement drugs that provide only marginal or uncertain benefits at high cost.8 Their decisions are continually subjected to political scrutiny and public criticism. However, it is only because regulators are lax that payers have had to wield the stick.

What can be done? The default path to market for all cancer drugs should include rigorous testing against the best standard of care in randomised trials powered to rule in or rule out a clinically meaningful difference in patient centred outcomes in a representative population. The use of uncontrolled study designs or surrogate endpoints should be the exception not the rule. When surrogates are used, postmarketing studies with clinically meaningful and patient centred outcomes must be started, completed, and published. Patient level data should be shared. Health technology assessment programmes should reject modelled measurements of survival, which may unintentionally incentivise the industry not to conduct trials that evaluate survival directly and rely instead on modelling.

The expense and toxicity of cancer drugs means we have an obligation to expose patients to treatment only when they can reasonably expect an improvement in survival or quality of life. The study by Davis and colleagues suggests we may be falling far short of this important benchmark.

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http://www.bmj.com/content/359/bmj.j4543?utm_medium=email&utm_campaign_name=201710278&utm_source=etoc_daily

Feature      Drug Regulation

Cancer drugs: high price, uncertain value

BMJ 2017359 doi: https://doi.org/10.1136/bmj.j4543 (Published 04 October 2017)Cite this as: BMJ 2017;359:j4543

A study published in The BMJ this week shows how most new cancer drugs are failing to deliver any clinically meaningful benefit. It’s time for Europe to raise the evidence bar before market approval, finds

Deborah Cohen   dcohen@bmj,com

 

Most cancer drugs recently entering the European market do so without clear evidence of extending or improving quality of life, new research published in The BMJ has found.1

The findings raise serious questions about why the current regulatory environment supports the approval of cancer drugs that may leave patients at risk of experiencing toxicity and reduced quality of life without deriving meaningful benefit.

Out of the 68 cancer drug indications approved by the European Medicines Agency during 2009-13, 57% (39) entered the market without evidence of a survival or quality of life benefit. Even when drugs did show survival gains over available treatment options, most of these were not clinically meaningful, researchers found.

Many of the drugs were approved on the basis of surrogate endpoints despite evidence that these are not a reliable indicator of overall survival or quality of life for most cancer treatments.

“When expensive drugs that lack clinically meaningful benefits are approved and reimbursed within publicly funded healthcare systems, individual patients may be harmed, important resources wasted, and the delivery of equitable and affordable care is undermined,” the researchers say.

The study comes at a time when European governments are starting to seriously challenge the high cost of drugs. While it’s hard to know how much healthcare systems are paying for cancer drugs because prices are often negotiated behind closed doors, the total amount spent on cancer care is growing, partly because of the cost of drugs.

Inadequate evidence

The research found that the EMA is basing many approval decisions on uncontrolled study designs or surrogate endpoints, which don’t always translate into outcomes which make a difference to patients.

Some of the cancer drugs were given “conditional marketing authorisations,” on the understanding that postmarketing studies would assess overall survival or quality of life. If the drugs are subsequently found to be clinically ineffective or unsafe, then the EMA can withdraw them. The study in The BMJ identifies 10 drugs approved under these fast track arrangements, but after four years of market entry none of them had good evidence that they either extended or improved life for patients.

Asked to comment on the research by The BMJ, an EMA spokesperson stated that is not agency practice to comment on research it has not seen. This is a topic that it has discussed widely and it welcomes taking part in further debate on the evidence underpinning cancer medicines.

The fact that so many of the new drugs on the market lack good evidence that they improve patient outcomes puts governments in a difficult position when it comes to deciding which treatments to fund.

In 2016, European health ministers issued a statement saying that new medical products “pose challenges to individual patients and public health systems in particular regarding their added value.” This, they said, affects patient access, affordability, and the financial sustainability of health systems.

As an example of the pressures put on health systems, a recent Bristol-Myers Squibb funded analysis compared licensed drugs for six different cancers across Europe and Canada and concluded that reimbursement decisions seem inconsistent. In an accompanying press release, the authors of the analysis stated: “There are potentially 200 000 patients in 12 countries who by licence should have access to drugs but are not getting them because of the reimbursement decision.”

Their underlying premise was that the EMA grants licences to “safe, effective cancer treatments where access to the drug can improve and prolong life” and these drugs should be paid for.2

In the eyes of industry the problem is with national reimbursement, yet the overwhelming picture now, from not only The BMJ study1 but from studies published in Lancet Oncologyand elsewhere, is that cancer medicines are being licensed that do not deliver clinically meaningful benefit.

The BMJ has found methodological problems with trials that EMA has either failed to identify or overlooked (box 1). This includes the trials’ design, conduct, analysis, and reporting.

Box 1: EMA’S questionable practices

Lenience on trial design
  • EMA’s approval of mifamurtide in 2009 for non-metastatic osteosarcoma was on the basis of a pivotal trial that was not designed to evaluate the drug’s clinical efficacy. Instead, the factorial design trial was aimed at independently evaluating the effect of mifamurtide and another agent, ifosfamide. In 2007, the FDA’s oncologic drugs advisory committee raised serious concerns about the study design and choice of comparators and concluded that mifamurtide failed to show substantial evidence of efficacy

  • Pomalidomide was approved by the EMA in 2013 for relapsed or refractory multiple myeloma. The trial supporting this indication compared one group of patients who were randomly allocated to receive pomalidomide in combination with low dose dexamethasone to another group receiving high dose dexamethasone. The company was repeatedly alerted about the unsuitability of the comparator choice for regulatory decision making by the FDA and NICE

Failure to follow its recommendations
  • The main study supporting the EMA’s marketing authorisation of S-1 (tegafur/gimeracil/oteracil) in combination with cisplatin for the treatment of advanced gastric cancer was designed and conducted to show its superiority over 5-fluorouracil in combination with cisplatin. When the trial did not meet its objective, and after it was completed, the sponsor company considered it appropriate to change the primary objective from superiority to non-inferiority. EMA’s guidance from 1999 admitted that “there is ample room for bias” if the non-inferiority margin is chosen after the data have been inspected

Tolerance for questionable analytical practices
  • In 2011, EMA approved bevacizumab as a first line treatment for advanced ovarian cancer. Two pivotal studies supported this extension of bevacizumab’s previously approved indication. In one of these studies, the primary endpoint was initially specified as overall survival but was changed to progression-free survival during the trial, jeopardising a fundamental principle in trial design.

  • Vinflunine was approved by the EMA in 2009 as a second line treatment for metastatic transitional cell carcinoma of the urothelial tract. In its pivotal trial, vinflunine was associated with an overall survival benefit over best supportive care. However, this effect was observed only in the those treated per protocol and not in the intention-to-treat population

  • Trastuzumab received marketing authorisation from the EMA in 2011 for locally advanced breast cancer. The main study supporting this approval measured overall survival as a secondary endpoint. Although the predefined analysis did not show a statistically significant survival benefit, EMA concluded that “the strongest evidence of benefit was provided by overall survival results” on the basis of an exploratory analysis that achieved significance after data were excluded from one of the participating centres “for which issues were raised.” In the five year follow-up of the trial, investigators concluded that the difference between groups in overall survival did not reach significance, probably because of crossover to adjuvant trastuzumab in some patients initially randomised to chemotherapy alone

  • Panitumumab was approved by the EMA in 2011 as a second line treatment for colorectal cancer on the basis of a randomised controlled trial with the coprimary endpoints progression-free survival and overall survival. According to the predefined statistical analysis plan, progression-free survival and overall survival were analysed using a P value of 0.01 and 0.04, respectively.3 At the time of approval, primary analysis showed a borderline statistically significant benefit in progression-free survival, which the EMA did not consider robust. There was no statistically detectable overall survival benefit. However, a later publication in the postmarketing period reported that the final analysis of this trial showed significant improvement in progression-free survival.4 Yet the P value for this analysis was 0.023, which did not meet the investigators’ prespecified threshold.

  • Reporting by Courtney Davis, Department of Global Health and Social Medicine, King’s College, London, and Huseyin Naci, LSE Health, London

Such flawed clinical trials can lead to bias and further difficulties in identifying the true effectiveness. Unless there’s thorough scrutiny of this regulatory evidence after approval, governments may make poor decisions about how to prioritise health budgets.

Unrealistic expectations

Perhaps most importantly, however, the fact the drugs have been given the imprimatur of regulatory approval may cause patients and doctors to have unrealistic expectations about their benefits and harms.

According to Richard Sullivan, professor of cancer and global health at King’s College London and director of the Institute of Cancer Policy, doctors cannot be expected to be gatekeepers. In many cases across Europe new cancer medicines with low clinically meaningful benefit continue to be prescribed.

“They may inappropriately script cancer drugs because of patient and family pressure; a lack of understanding of how new complex therapies work; or because of the culture of medical oncology in the absence of multidisciplinary decision making,” he says. “If patients are not offered alternative modalities, including palliative care, in end-of-life settings then the risk of inappropriate or futile treatment with chemotherapy and immunotherapy increases.”

Sullivan says the processes that allow a drug to be funded in national health services across Europe vary in their robustness and due diligence around judging clinical evidence. Some health technology assessment bodies view themselves as secondary gatekeepers to stop use of drugs that the EMA has licensed without evidence of benefit (box 2).

Box 2: EMA under scrutiny

Some aspects of the EMA’s regulatory process are coming under scrutiny—not least the scientific advice offered companies seeking approval for their drugs. According to Guido Rasi, EMA’s executive director, early dialogue with medicine developers allows the agency to give scientific advice and help with protocols to “provide methodological direction and discourage the production of irrelevant or substandard data.”5

Currently, the scientific advice EMA gives is not publicly available, preventing its assessment. Some advocacy groups have reported that attempts to access such information have been thwarted by commercial confidentiality.

People both currently and formerly involved with EMA have told The BMJ that manufacturers see presubmission processes as a way to lobby the agency, repeatedly asking the same question until they get the answer they want, and this may affect various aspects of trial design, conduct and analysis.

In July this year Emily O' Reilly, the European Ombudsman, launched a “strategic inquiry” into EMA’s processes.

Although she recognised that “these activities help the development and availability of high-quality, effective and acceptably safe medicines,” such “activities may pose some risks.”

She noted that the EMA sees presubmission meetings as a way to “enable medicine developers to establish contact with the agency staff who will be involved with the application.”5

The case of cancer drugs also raises question about inconsistency between funding and licensing decisions in Europe. One suggestion has been for the EMA to work alongside the organisations carrying out health technology assessments, which countries use to help decide whether to pay for a treatment.

On paper, joining up the EMA with health technology assessment might seem a quicker way of getting drugs to patients. But concerns are being raised that EMA standards might actually erode those applied by some health technology bodies. More importantly, perhaps, is that decisions about pricing and reimbursement should also be related to the gross domestic product of countries, which differs greatly across the EU. Differential pricing would not be possible if assessment was linked with EMA approval.

Furthermore, members of some health technology bodies say they are currently a barrier against poor regulatory decisions and worry that EMA’s “regulatory capture”—whereby 89% of the agency’s budget comes from the drug industry fees—may come to thwart their independence.6

For example, the EMA approved vinflunine as a second line treatment for metastatic transitional cell carcinoma of the urothelial tract in 2009 (box 1) on the basis of a potentially biased analysis. But the UK National Institute for Health and Care Excellence (NICE) was less convinced, implying the evidence used for regulatory approval did not show the drug to be effective, and didn’t recommend it.

Although the exact reasons for rejection aren’t always clear, an assessment body analysis obtained by The BMJ shows that health technology assessments in most European countries have also taken a less favourable view of vinflunine than the EMA.

For patients, approval of such drugs may lead to unrealistic expectations, fuelled by patient organisations . In response to NICE’s decision, Action on Bladder Cancer, a charity supporting patients and promoting research, wrote to the agency to complain that: “Patients with metastatic bladder cancer are disadvantaged by the lack of a second line treatment option. Study 302 is the first trial to show a survival benefit and we feel that vinflunine should be available for this relatively small group of patients.”7

Uncertainty is compounded by unproved drugs being used as comparators. Despite the questions around vinflunine , for example, it is now being used as a comparator in trials for new drugs. On its website, the patient charity Fight Bladder Cancer has highlighted an ongoing study of a drug called PDL3280A for patients with advanced or metastatic bladder cancer.8 This, they say, compares chemotherapy with either paclitaxel or vinflunine. But regulatory sanctioning of a comparator that lacks robust evidence of efficacy, means the cycle of weak evidence and uncertainty continues.

No one wants to say no to a cancer drug

Vinflunine isn’t an isolated example of questionable decision making. In 2011, the EMA licensed panitumumab in combination with other drugs as a second line treatment for colorectal cancer. This was despite the agency questioning whether the primary analysis showing a borderline statistically significant benefit in progression-free survival was robust (box 1). Indeed, the EMA initially rejected the drug but later reversed its opinion.9 In the words of one EMA adviser who spoke to The BMJ, however, “no one wants to say no to a cancer drug.” When NICE invited Amgen, panitumumab’s manufacturer, to submit evidence for approval to use on the NHS, the company declined to do so. They intimated that there wasn’t sufficient evidence to determine the cost effectiveness. Again NICE didn’t recommend it.10

Most European funding bodies have also turned down panitumumab for second line treatment for colorectal cancer. However, the published study does not reflect the questions over the statistical analyses, concluding that panitumumab “significantly improved” progression-free survival and there was “a trend toward” improved overall survival.4

Subsequent hype and misleading reporting can put pressure on governmental bodies to reimburse a drug. Health technology assessors are in an invidious position—if they refuse to reimburse and a drug later turns out to be an important therapeutic advance, then patients have lost out because of the delay. If they reimburse and the drugs later turn out to be ineffective, have no clinically meaningful effects, or not to be cost effective then patients may have been unnecessarily subjected to toxic drugs and scarce healthcare resources have been wasted.

The combination of this hype coupled with underlying concerns about the quality of trials can cause confusion. In England, pomalidomide, an immunomodulatory drug for refractory multiple myeloma wasn’t available, then was, then wasn’t, then was again.

The drug was approved by the drug regulators both in Europe and the US despite questions over trial design (box 1).

Correspondence between the FDA and Celgene, the trial sponsor, shows the US agency cautioning the company that its choice of comparator was unsuitable for regulatory decision making.1112 The FDA ultimately ignored its own advice and approved the drug regardless. The EMA approved it several years later.

When NICE rejected the drug for use in the NHS because of the poor comparator, Celgene claimed that it was chosen only after consulting with the regulators. Pomalidomide subsequently went onto England’s Cancer Drugs Fund, an extra source of funding, only for budgetary constraints eventually leading to it being removed in 2015. It was one of 17 drugs for 23 different indications to be included in the cull.13

The delisting prompted both companies and charities to call for all interested parties to work together to find a better solution for patients, putting pressure on NICE. Noticeably, however, this did not necessarily include better evidence generation and better oversight from the EMA.

“This has been a unilateral decision by NHS England. What is missing is a willingness for all stakeholders to take part in collaborative discussion and work together,” Wim Souverijns, general manager at Celgene UK and Ireland, said. “There is a role for companies to put pressure on stakeholders, including NICE and NHS England, to point out the implications of these changes.”13

This pressure may have worked for patient access and cost purposes. In 2016—after the company offered a confidential discount—NICE approved the drug because it then became cost effective. But that does not mean the evidence of efficacy is robust; other European countries continue to deem it not worth paying for.

Regulator fit for purpose?

The inability of EMA to uphold its current policies on drug approval has implications for patients and budgets, and the scientific advice the agency gives is coming under increasing scrutiny (box 2).

The example of bevacizumab (Avastin) is a cautionary tale about how well the EMA can monitor, evaluate, and learn about products even after they are on the market. Yet the agency wants to push ahead with a programme allowing quicker access to drugs with immature data.14

In June 2011, the FDA announced it had revoked bevacizumab’s indication for metastatic breast cancer because it “has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that [it] will either help women with breast cancer live longer or improve their quality of life.”15

But the drug is still licensed in Europe for metastatic breast cancer; the EMA withdrew the licence for only some uses. It said this was because the available data on use in combination with paclitaxel have “convincingly shown [the drug] to prolong progression-free survival of breast cancer patients without a negative effect on the overall survival.”16

Again the EMA’s decision caused challenges for funders. Bevacizumab was rejected by NICE and was one of the most requested drugs under the Cancer Drugs Fund.17

It was another of the drugs delisted in 2015, leading to disappointment of patient groups. “People with incurable breast cancer can only watch from the sidelines as life-extending treatments are debated again and again and vital options disappear,” the charity Breast Cancer Care said in a statement.18 But patients will continue to have their hopes dashed if regulators approve drugs using designs that are not methodologically rigorous.

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As required by law, I am not recommending that the public do as I do.  I am only setting out why some scientist subscribe to a different theory of cancer and its treatment, and what I would do based on their theory.  See your physician for medical advice.