Cancer is the second leading cause of death in the United States, right on the heels of heart disease.
In developed countries, the general consensus is that if you do not die of heart disease, then the next likely event is cancer.
In fact, most health experts expect that everyone will eventually develop, and likely die of cancer or a related complication—provided nothing else happens before then.
As a condition that is bound to haunt a significant proportion of the population, we have been searching for cures for cancer for hundreds of years.
So far, the earliest documented cases of cancer were made over 3,500 years ago. The first causes of cancer and anti-cancer therapy were also found over 200 years ago.
However, over 200 years later, exactly how effective are our drugs?
Effectiveness of Drugs
From 1991 to 2019, mortality rates from cancer fell by 32% as cancer survival rates increased.
Drug regulatory agencies may drive the idea that these rates are dropping due to the approved pharmaceuticals on the market, yet studies suggest that we have to thank early prevention, detection, and improved cancer care organizations for increased survivability.
It should be noted that early prevention, detection, and other methods are also not perfect. They can cause overdiagnosis and overtreatment.
Additionally, some cancers progress slowly, and patients will have a longer survival period, which increases the numbers.
In that case, how effective are cancer drugs?
A study evaluated 85 cancer drugs approved from 2006 to 2018.
The study examined the drugs’ response rates (RRs), a measurement that quantifies how well the patient’s tumors respond to the drug.
The authors found the median RR was 41%, meaning that, at the median, only 41% of patients’ tumors responded to the drug. Breaking the results down, of these 85 approved drugs, 14 (16%) had an RR less than 20% and almost half (47%) had an RR less than 40%.
Another study evaluating 207 anti-cancer drugs approved between May 2016 to May 2021, found that 14% of these novel drugs replaced approved drugs in first-line of care.
This indicates that the 14% of novel drugs approved over 5 years, replaced standard lines of treatment.
However, the majority of the novel treatments were only approved add-on treatments (29%) which complemented the main treatment or as alternatives (42%) to the standard treatment.
Therefore, most novel cancer drugs are complementary, rather than a treatment that overturns the standard regime. The authors stated that while complementary treatments can be beneficial, the addition of another drug to the regime also generates more cost for patients.
Further, studies on newly-launched cancer drugs found that newer drugs tend to be more dangerous than standard lines of treatment.
Newly-approved drugs are either novel (a new molecules or acting on a new pathways) drugs or a generic version of a previously branded or patented product.
The majority of drugs approved by the FDA are generic drugs.
In 2021, the FDA gave 776 full or tentative approvals to generic applications (pdf) and approved 50 novel drugs.
Though generics make up the majority of newly approved drugs, researchers say physicians generally recommend patients to avoid newly-released generic drugs within the first five to seven years of release.
This is because generic drugs are not tested for safety, only for bio-similarity to the branded drug already on the market: such as the absorbance rates, the concentration of the active compound, and so on.
Generally these drugs are just as safe as the branded version, and are also significantly cheaper.
However, considering that more than 80% of the United States’ pharmaceutical active ingredients are manufactured in developed countries, including India and China—where regulation of pharmaceuticals is less stringent—this puts drugs at risk of tampering and contamination.
The Food and Drug Administration (FDA) has also previously banned generic medications manufactured at several Indian sites.
In contrast, novel drugs will generally go through a more stringent approval process; tested for safety and efficacy as part of the approval process.
However, novel drugs are not without risks either.
Many studies have found that though novel drugs are usually more effective, they are also more likely to be toxic.
A 2012 study found that novel drugs often come with increased risk of morbidity and toxic death. The authors speculated that clinical trials for drugs often enroll patients with good performance status and few comorbidities, and these trials would inevitably show lower toxicity results and improved efficacy in healthier patients.
However, in reality, drugs may often be prescribed to cancer patients with weaker constitutions, and studies have shown direct evidence that toxicity in clinical trials underpredicts real-life toxicity.
Transparency, Data Protection, and Intellectual Property
The pharmaceutical and regulation sector is entrenched in intransparency and corruption.
Many research and media reports blame the lack of transparency, undisclosed clinical data as a sickness endemic to the oncology drug industry as well as the pharmaceutical sector in general.
In many cases, it is true: only a small number of people have the data and it can even be difficult for insiders to access critical clinical data.
However, the delicate balance between data transparency, compliance to data protection laws, and the need to protect intellectual property has made full disclosure of clinical data trials difficult.
In 2007, the Food and Drug Administration Amendments Act of 2007 (FDAAA) gave the FDA more power to require post-approval studies from drug manufacturers.
The regulatory body could also impose monetary penalties if manufacturers are noncompliant.
The FDAAA also required information on the design of all clinical trials, the summary of the results also had to be made public on ClinicalTrials.gov 12 months after study completion, as well as other changes.
However, much of the patients’ data from clinical trials for cancer drugs is not public, despite this legislation.
Studies evaluating transparency for pharmaceutical clinical trials often return with findings that leave much to be desired.
A recent study evaluated 115 anti-cancer drugs and 304 supporting clinical trials launched between 2011 to 2021. The authors found that over half of these pivotally supporting studies (55%) have not made their patient data public. Some of the drugs evaluated in the study are top in the globe for drug sales.
The authors found that of the top 10 anti-cancer medications in global sales, nivolumab (immunotherapy for melanoma), pembrolizumab (immunotherapy for many cancers including melanoma and breast cancer), and pomalidomide (chemotherapy for multiple myeloma) had less than 10% of their data eligible to be made public.
A major reason for controlled access to patient data and clinical study reports is because these data may contain sensitive data, and there are stringent legislations in place to protect such private data.
In 2018, the European Union (EU) enacted the General Data Protection Regulation (GDPR).
The GDPR is a legal standard that protects personal data of EU citizens.
It affects any organization that stores or processes their personal data, even if it does not have a business presence in the EU, encompassing data for health and medical fields, online industries, and many more.
The United States does not have a similar equivalent, though there is the Health Insurance Portability and Accountability Act of 1996 (HIPAA).
HIPAA entails U.S. privacy laws on sensitive health information of patients and consumers. It generally is not applied to pharmaceutical firms, but becomes relevant in clinical studies.
According to the U.S. Centers for Disease Control and Prevention’s website, the two main elements of HIPAA are the Privacy Rule and the Security Rule. These rules require sponsors and controllers of clinical trials (sometimes a contracted third party) to protect participants’ personal health information, and also to restrict access and impermissible usage not under the law.
Though some data may be suppressed due to unfavorable findings, often data is only made accessible to a very small number of people partaking in the research.
This can often leave people working in the firms and in drug development, in the dark.
Many large firms contract third-party research groups to conduct their trials, and this adds layers of complexity on who is able to control, analyze, and process the data.
Not to mention that the risk of intellectual property theft increases as more people are able to access the records. China, India, Iran, and Russia have long histories of intellectual theft, and in the era of technological advancements, these concerns become increasingly relevant.
Thieves of pharmaceutical intellectual data can easily manufacture successful patented products as generics at cheaper prices and reduce the competitiveness of pharmaceutical firms. Theft of these data can also give rise to counterfeit and inferior drugs which can contribute to severe health consequences (pdf).
Expedited Approvals
Though it may seem easy to point the finger at Big Pharma, a study published by BMJ shows that drug regulatory bodies have also added fuel to the production pipeline that is delivering drugs at low clinical values.
Over the years, drug regulators have progressively lowered the bar on data quality for trials.
A study evaluating 188 novel drugs approved by the FDA from 2005 to 2012 found that 30 (16%) of the drugs were approved based on a single pivotal study, 48 (25%) were approved on surrogate markers as the clinical endpoint, and 40 were approved on a single pivotal study that focused on surrogate markers.
Surrogate markers are the easiest markers to use in clinical trials, they are also the most unreliable.
This is because they measure biological signs that may indicate improvements in disease rather than improvements in patients’ symptoms and tumors or reported symptoms by patients.
The FDA has also increasingly given out expedited approvals.
Accelerated approval is supposed to be only granted to drugs that indicate a clinical benefit that gives significant advantage over available therapies. Though it is intended to give patients the best available treatment, the reality is the reverse of such intentions.
Since expedited approval is mostly based on surrogate endpoints, it has a lower data integrity. These drugs are therefore at a higher risk of having lower clinical values.
A 2014 study showed that from 1992, the year accelerated approval processes were enacted, black box labels (side effect warnings) and market withdrawals increased by 35%.
For the many oncology drugs that were fast tracked and approved, many post-market studies show that these drugs have no significant clinical benefit or advantage over available therapies and become a misallocation of money and resources instead.
A BMJ report released in July 2021 found that around half (112) of 253 drugs approved through FDA’s accelerated approval have yet to prove their clinical effectiveness. The accelerated pathway allows drugs onto the market before efficacy has been proven in laboratory tests. But as a condition of this approval, manufacturers must conduct post-approval studies—also known as phase IV confirmatory trials—to “verify the anticipated clinical benefit,” wrote the author of the press release.
Since the FDA introduced the expedited approval pathway in 1992, only 16 drugs have ever been withdrawn.
In some cases, confirmatory trials were never done.
Not only are some drugs granted accelerated approval ineffective, a JAMA report found that, from 2017 to 2019, Medicare spent $569 million (inflation adjusted) on 10 expedited-approved cancer drugs that were later found to have no benefit to overall survival.
Another study found that in 2019, Medicare spent at least a total of $1.8 billion on medications that went through accelerated approval, which later showed no clinical benefit.
Meanwhile, the FDA has also become increasingly less rigorous with their market withdrawal decisions.
Some FDA withdrawals are not based on post-market problems, but are rather based on a “guilty until proven innocent” procedure, according to a report by Lachman Consultants (pdf).
“If the FDA feels an applicant’s processes, adherence to processes, or reputation is not pristine, the FDA will require additional support to prove lack of ‘guilt’. Many recalls are now based on ‘lack of assurance’ of GMP (good manufacturing practices), as opposed to the finding or likelihood of defects,” the authors of the report wrote.
Such is the FDA’s blundering acts of a market takedown of JUUL in June 2022 over lack of evidence of product safety, only to lift the ban a month later after pressure from the public and legislators.
Though this example is irrelevant to the oncology industry, it reflects the rigorousness of FDA’s decision-making across market approvals and withdrawals.
Pharmaceutical Patents
Patents, the exclusivity to manufacture and use a pharmaceutical agent, provide high profits for pharmaceutical firms.
90% of drugs fail in clinical studies, so patents maintain the competitiveness of pharmaceutical firms by preventing the theft of intellectual property and give revenue flow to finance research and development (R&D).
Since chemical products like pharmaceutical agents can be easily reverse engineered by basing it on the drug’s trials and research studies, trade secret laws cannot provide very meaningful protection.
Patents also come with negative consequences: including high market prices and overpromotion of patented drugs, as well as extension of successful patented products through evergreening (patenting “new inventions” that are really just slight modifications of old drugs).
Once a patented drug receives approval from regulators, firms will begin to see returns from their investments in R&D, since the marginal cost of its production and distribution is often quite low. However, in the United States, where the price is mostly regulated by the market, “pharmaceutical firms may set prices that vastly exceed the cost of production and distribution, arguing that these high margins are needed to offset R&D costs,” the authors wrote.
Further, there are also costs that companies need to consider to register and maintain a patent. At minimum, companies will need to pay for administering a patent system for their agent, for litigation costs associated with determining the validity of a contested patent, for rent-seeking conduits to maintain or extend patents, for account costs that were misallocated during research and development, for engaging in cartel-facilitating conduct (such as striking a deal with other generic pharmaceutical companies to not make a generic version of the drug until a certain date), and so on.
Legislative efforts to control drug prices have often been met with industry objections that those efforts would lead to less cutting-edge technology. Though there is no question that some of the patent-generated revenues are reinvested in R&D for new drugs, companies also spend very substantial amounts—often even more than R&D—on advertising and promoting patented drugs.
Data from a study evaluating drug launch prices found that the median launch price in 2021 is 85 times higher than the price in 2008. The study included both patented and generic drugs, though novel drugs —especially novel drugs for rare diseases and cancer—were the most expensive.
“Manufacturers of new molecules have more freedom to launch at higher prices because they are less constrained by public expectations of what the price should be,” said Prof. David Ridley, health economist, in 2021. Further, firms with highly profitable drugs may engage in evergreening by extending the patent.
The FDA gives a patent term of 20 years from the day the company applies for a patent on the molecule and before they start R&D. Therefore, once the drug makes it into the market, the patent period is significantly less than 20 years.
However, a report found that highly profitable drugs often had a patent term of 38 years, suggesting a monopoly. The general reason for such extension is often “improvement” reasons, meaning that the companies are looking to further develop and improve the drug. Though not all improvement patents are done with the purpose of extending the patent for profits, the authors suggested that it can be excessive and undermine innovation in the industry.
