By Daniel Tarade
The pharmaceutical industry is said to be a necessary evil. Yes, essential medicines are expensive. But, we are told that is the cost of developing new drugs. Research takes many years, and clinical trials are costly. Ten thousand dollars may seem like an obscene cost for a course of drug, but otherwise the company would not make any money. That is how exorbitant prices are justified. That is how patents are justified. Without these practices, a pharmaceutical company would not make a profit, and they would not develop medicines. Even though many people (or countries) may not be able to afford these futuristic medications right now, the prices will fall in time. When they do, we will all benefit. That is the narrative. While it is true that there is massive private investment into the drug development pipeline, the mythos omits the labour and investment of the public sector. Every drug is developed on the back of fundamental scientific discoveries that are not factored into the equation. In reality, the university scientist sets the stage for big pharma to come in at the last possible moment and steal the profits.
Let’s start by unpacking the current narrative of drug development. A pharmaceutical company can now expect to spend $5 billion for every drug that is approved for use. This estimate is the main justification for the often unaffordable price tag attached to new, life-saving medications. Without profit, how can one expect a private company to invest in the drugs that help everyone? But why does a drug take billions of dollars to develop? The major reason cited by pharma is that most of the drugs they begin developing are neither efficacious, safe, or profitable. Thus, the average cost of drug development includes the ghosts of failed projects. Because private capital is willing to take on this risk, they deserve to make a profit. After all, if private industries were not around, we would never benefit from new medicines. That is the argument I hear over and over again. I hear it from libertarians, and I hear it from scientists. I once had a long conversation with Durhane Wong-Rieger, President of the Canadian Organization for Rare Disorders, following her presentation on how the current drug discovery system fails those who suffer from a rare disease. Because demand is lower, the price is often unaffordable by individuals and unjustifiable in the Canadian universal healthcare system. When I brought up the potential solution of nationalizing pharmaceutical R&D, she cut me off and said it wasn’t possible. That scientists lack the motive to discover new cures if they aren’t to become wealthy in the process. Over the years, the parasitic relationship of pharma has become normalized. We are workers without consciousness of our class.
When we look only at the piles of money invested by pharma, we lose sight of what the public scientist provides to the system. By public scientist, I mean the graduate student, the postdoctoral fellow, the research associate, the laboratory technician, and the professor working at a university or college. These scientists are most often publicly funded and their work enters the public domain. It is in this sector that the most important scientific discoveries of the past hundred years were made. It was not a private company that discovered the nucleus, the mitochondria, or the cell. Pharma did not discover the double helix, or vitamin C, or protein kinases. They did not invent protein crystallography or cryo-electron microscopy. The fundamental discoveries and inventions that form the basis of current biological knowledge and practice were the fruits of the average, government-funded scientist. Scientists operating without a profit motive but driven to explore and improve the world. In many cases, scientists discovered essential medicines in the absence of private investment. Pencillin, insulin, and the polio vaccine sit on the trophy shelf of non-profit science. We have done the hard part. In light of this, why do we let for-profit companies control our drugs.
I want to bring up the case of imatinib to highlight how pharma acts as a parasite, extracting profit at the very last stage of drug development. Imatinib is a veritable cure for chronic myelogenous leukaemia (CML), as disease that kills over 50% of diagnosed individuals treated with conventional chemotherapy.[i] The disease was first described by doctors Rudolf Virchow and John Hughes Bennett in 1845. In 1960, doctors Peter Nowell and David Hungerford made another big discovery. They noted that CML cells taken from patients display a specific chromosomal abnormality. This defect was named the Philadelphia chromosome after the city in which they worked. By 1973, Dr Janet Rowley identified that the Philadelphia chromosome came from the erroneous swapping of bits of chromosome 22 and chromosome 9. A whole cadre of scientists began to unravel the molecular mystery at play. The accepted idea is that the ABL oncogene encoded on chromosome 9 breaks apart and fuses to another gene on chromosome 22 called BCR. This fusion event produces a chimeric protein, termed BCR-ABL, that is more active than ABL and capable of initiating tumourigenesis. Thirty years of work established the BCR-ABL oncogene as the cause of CML and clarified that the protein functioned as a tyrosine kinase (an enzyme that catalyzes phosphorylation of tyrosine residues on proteins; associated with cell growth and division in the case of BCR-ABL). This work was not dispensable but absolutely necessary for any future innovation by a pharma company.
While the investigation into CML and BCR-ABL was ongoing, scientists at Ciba-Geigy (now Novartis) became interested in developing protein kinase inhibitors for cancer treatment.[ii] After all, most of the discovered oncogenes at the time were kinases. They based their designs on kinase inhibitors first discovered by university scientists. One problem Ciba-Geigy had to overcome was to figure out how to screen their chemicals for activity, and these pharma scientists had no successful method to purify protein kinases for experiments. Rather than develop their own techniques, they adopted the methods of Tom Roberts, a scientist at the Dana-Farber Cancer Institute. Further, it was John Kuriyan’s lab, based in Berkeley, that performed the protein crystallography that confirmed how imatinib worked to inhibit BCR-ABL. The biggest contribution came from Brian Druker, scientist at Oregon Health & Science University, who became interested in finding an inhibitor of BCR-ABL after pioneering the use of antibodies to study tyrosine kinase activity.[iii] He described his one goal as finding “a drug company that had a BCR-ABL kinase inhibitor.” Nick Lydon, a scientist at Ciba-Geigy, sent over compounds they had developed. It was Brian Druker who was able to confirm the selective activity of imatinib against CML cells. In clinical studies, funded by Ciba-Geigy, imatinib proved to be even more effective than either could imagine; patients taking imatinib have a 90% cure rate. This story highlights both the power of the scientific method to improve lives but also why scientists need to rethink our relationship with pharma.
Imatinib made its clinical debut in 2001. When introduced to market, a year-long course of drug cost $21,000 USD. Since then, the cost has not decreased. Instead, the price increased 10-20% a year and peaked at $146,000 a year. Even the introduction of a generic form in 2016 did not provide an immediate respite. Due to the Hatch-Waxman act, the company that first filed to bring generic imatinib to market had 180 days of market exclusivity and sold a course for $140,000. As these patents expired, the cost of imatinib did fall to $9000 and $8000 for branded and generic imatinib, respectively. But, these medical costs are destructive, in particular because a patient with CML needs take imatinib for life to prevent recurrence. As wryly noted in an article about how Novartis manipulated the market to maintain high drug costs, the author describes imatinib as “a miraculous drug that results in a normal functional lifespan in most patients with CML who can afford and comply with the treatment and who are monitored optimally [emphasis mine].” Even in a country with universal healthcare like Canada, the cost of generic imatinib costs the government $10,000 a year. But, the Supreme Court in India did deny Novartis a patent extension in 2013 for a slight modification of imatinib. The decision allowed the continued production of generic imatinib, which still costs less than $1000 a year. In response, Novartis threatened that future innovation in India will be discouraged. The same argument resurfaces. Pharma companies threaten to pull the carpet out from under our feet; allow us to profiteer or else suffer pestilence.
Why do we accept that pharma is the central player in drug development? They did not discover cancer, or CML, or the Philadelphia chromosome, or oncogenes, or kinases, or chemotherapy, or kinase inhibitors, or BCR-ABL, or protein crystallography, or kinase purification methods, or kinase detection methods. Ciba-Geigy developed a panel of potential kinase inhibitors and held it hostage. Brian Druker describes how even before he validated the use imatinib as a potential therapeutic for CML, “it was already patented against any tumor in a warm-blooded mammal.”[iii] After winning the prestigious Lasker award, Brian Druker pleaded that scientists aught to give in to pharma. That if we try to negotiate for royalties or control, it will delay and impede clinical development of drugs. That we need to “never forget…the 1.5 million individuals diagnosed and the 500,000 who die of cancer each year and are in desperate need of better therapies.” Druker recognizes that publicly-funded scientists are necessary for the fight against cancer. That is why he called on the government to fund a massive cancer genome sequencing project that would cost $1 billion. Druker also recognizes that pharma is the gatekeeper. There is no mechanism in our society for clinical drug development independent of pharma. They have latched their tentacles to the distal end of the drug pipeline.
Other models of drug development are shaking up the industry for their ability to develop drugs at a tenth the cost of traditional pharma. A non-profit organization, called Drugs for Neglected Diseases initiative (DNDi), brings new drugs to the clinic at cost of $110-170 million. This is a fraction of the cost that it take for-profit pharma to do the same job. How do they make this work? One, they develop drugs against diseases endemic to the poor global south. There they face little competition, and these fatal diseases with few treatment options are low hanging fruit. You do not need to design a clinical trial with tens of thousands of patients because clinical improvements are more clear when you start with a poor baseline. Otherwise, they use the same strategies of big pharma. They contract companies to conduct high-throughput screens of drug libraries. They collaborate with university and government scientists. Yet, at the end of the day, they are non-profit and develop drugs that are necessary even if if the target demographic cannot afford expensive medications. After Gilead Sciences brought a hepatitis C drug to market, many other for-profit companies abandoned their own projects even though there were concerns that the drug may not be effective against all strains. The lack of further innovation also allowed Gilead to charge $74,000 USD for a course of drug. Thus, DNDi is taking up the charge in developing affordable hepatitis drugs by working on those projects abandoned by for-profit companies. The same phenomena is happening with antibiotic development to fight against new drug resistant bacteria. Most pharma companies have abandoned their antibiotic research programs because they are not profitable enough. Yet, almost a million people are already dying each year due to drug-resistant bacteria. The World Health Organization is now tasking DNDi with developing new drugs that will be affordable. The model works. For now, pharma is willing to collaborate with DNDi because they are not trying to develop the cholesterol, heart, diabetes, and cancer medications that are so so profitable. But, once the non-profit model of drug development is expanded, big pharma will fight to maintain control. Despite the battle on the horizon, we cannot relent in our mission to seize control of drug development. Because the current process is not working.
Scientists are capable of developing drugs ourselves. In fact, scientists, whether working at a university or pharma company, create most drugs. All scientists working in private industry received their training in university labs. Much like drug development, pharma plays little role in training scientists, but instead they sponge up human resources at the last stage when they would indeed be capable of working in the non-profit sector. Pharma companies only exist because our governments have allowed private interests to leech off of public scientific progress. We can do it ourselves and we can do it better.
[i] Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 112(13), 4808-4817.
[ii] Lydon, N. (2009). Attacking cancer at its foundation. Nature medicine, 15(10), 1153.
[iii] Druker, B. J. (2009). Perspectives on the development of imatinib and the future of cancer research. Nature medicine, 15(10), 1149.