(Im)Patient Side of Drug Development

The public thinks that medical research is funded to make people’s lives better by producing patient outcomes that improve health in a seamless process of harmony and data sharing, from discovery and development through delivery of care. If only it worked this way. It frequently seems like the “system” focuses on everything but better patient outcomes.

Medical research has made progress in many health conditions and diseases and patients appreciate that. Each new improvement, however, comes with costs to the patient community and to individual patients. There are more survivors in some types of cancers now than in previous decades, but the new “chronic disease” focus from cancer research is not what they expected. Cancer patients are faced with long-term consequences, just as patients with diabetes, Parkinson’s and many other illnesses have discovered [1].

The public believes in the traditional “goal” to “cure” diseases and medical conditions, but when they become patients, they learn that the “goal” has virtually nothing to do with the way the health-care or research systems actually work (at least in the United States). Fear mixed with hope is too often replaced by confusion and mistrust. Whether or not a patient is presented with positive or negative odds (statistics) for his/her medical condition, there is little help in applying those averages to a given patient’s personal situation. Being a patient is not for the weak of spirit—it often turns into a lifelong endurance race.

There is no time to mince words about the problems in medical research. Far too many people believe in conspiracy theories regarding drug development, which are regularly reinforced through online outlets [2]. These perennial doubts are fueled by the unfortunate fact that most patients face at some point in their medical experience—they are merely the last consideration in how research is done, and how health care is actually organized [3].

It is clear in 20+ years of working with government, academia, industry, and the medical research community that the drug development process is far too fragmented and complex for anyone to actually create conspiracies that keep effective treatments from patients. It seems far more likely that those in the development process are focused on misguided priorities and incentives that end up putting patients last in line. There also is no “evil” person who works in the milieu, intentionally misdirecting promising leads, but researchers in academia and industry work within systems that clearly put self-interest ahead of solving problems for human beings. It is past time to fix these fundamental problems and build a cohesive and comprehensive medical research system based on patient needs, and that will produce partnerships that profit from providing significant value to patients’ lives.

What’s Wrong with This Picture?

Current drug and device development rarely create the kind of patient outcomes that most people are looking for as they search for relief and cures. The public continues to believe in medical research and supports continued government funding as well as payments for treatments in the hope that people will be healthier and can avoid life-threatening illnesses.

Recently, cracks in the ivory towers have publicly exposed the underbelly of drug development with issues like reproducibility [4] and scientific misconduct [5]. Drug development seems driven by fame and money (instead of patients) for investigators, institutions, and companies. Patients and the public expect this mind-set from companies, but are becoming increasingly repulsed by its reality in academia and from their own clinicians [6]. While people are rightfully outraged, these problems are by-products of a broken research system.

The thing we call a medical research “system” really isn’t, starting with the traditional chasm between discovery research and health delivery. This is easily illustrated by the fact that most patients don’t know what clinical trials are, or how research has improved overall health or the condition of their greatest concern [7].

The current research system is made up of a conglomeration of disparate pieces, many of which perform with competing goals (both explicit and implicit), and with virtually no purposeful connections. Main players include those in academia and industry members, along with government servants and clinicians who perform clinical trials in both academia and local communities.

Where are patients in the development process? They are paternally held up as the ideal, like mom and apple pie, but when the development process itself is examined, there has traditionally been no place for them. Patients who enroll in clinical trials are thought of as a means to an end, and their needs are trumped every time by narrow scientific questions, the quest for “significant” p-values that add publications to curriculum vitae and market share.

This perspective, developed over a 20-year period of working within the research system, may sound harsh to some, but until the research system bases drug development on science advances and patient needs, no amount of systemic tweaking will move the fragments onto the right track. It will take true partnership with a surprising stakeholder list and patient-focused expertise to resolve development barriers that keep us from producing relevant and timely solutions for people. This becomes critical with the implementation of the Affordable Care Act (ACA), which stresses a “values-based” payment system and Accountable Care Organizations (ACOs) [8].

Current Drug Development Roles

There are differences between “industry” (a community of biotech, device, and pharmaceutical companies) and “companies” which patients usually see as drug developers. “Academia” applies to the field of education, while “universities” or “institutions” are organizations where individual “academic” investigators and clinicians are housed, as opposed to “community” clinicians in private practice (who also play a pivotal role in drug development). Likewise, collective “patients” are different from each individual experience, and “patient advocates” in this chapter refer to those who represent the collective patient viewpoint.

The role of academia often appears early and late in drug development. Academic scientists produce leads. Miscommunication often starts when they claim to have found the “answer” in their publication—discovery is only the beginning of the quest and must be validated to be useful. Institutions quickly use the potential promise to negotiate intellectual property (IP) agreements when companies follow up on the lead. This role developed as a result of the Bayh–Dole Act in 1980, which has now outlived its usefulness [9]. While some academics are interested in preclinical development, they rarely possess the skills, or work in an institution that has the capacity to perform this step. Academic clinicians sometimes get involved in early-phase clinical trials. More complexity surfaces when completely different institutions and investigators are involved in this developmental stage. Negotiations between institutions and companies start over with each trial, and create headaches and time warps for all [10].

Clinicians from the community are also involved in drug development, primarily by opening up clinical trials in their private practices and collectively enrolling the majority of patients who participate in those trials [11]. Very little credit is given to them, but they contend with daily pressures of conflicting messages, multiple regulations, unmet medical needs, staff for clinical trials and data, cost containment, and doing no harm to their patients. Their voice must be included in improvement efforts. Even their efforts could be more focused by enrolling most of their patients, instead of a small minority.

Industry develops new products in (hopefully) ethical and safe ways so that they can market drugs and devices after achieving Food and Drug Administration (FDA) approval on what the product label can say. While discovery used to take place in companies, most now rely on academia for drug leads. These leads come to their attention through publications and personal relationships, and are then pursued with investigators and institutions. Once contracts are signed, experimental results must be replicated before preclinical development starts. Most leads end here due to failure to reproduce, which creates little value and much disappointment for all, including patients [12]. For the minority of leads that show promise, companies then prioritize the agents they will follow, based on market share and other feasibilities. Preclinical experiments with cells and animals focus on toxicology, chemistry, and production. FDA applications are produced before clinical trials are planned. Project managers implement these steps and identify clinicians to conduct the first trials while progressing through the approval process.

Government agencies provide supportive research infrastructure, funding, and protect patient safety and efficacy. Key entities include the FDA for drug and device development, formal guidance, and label approval for new products before they can be marketed. The Office of Human Research Protections (OHRP) regulates how those who receive federal funds conduct clinical trials through approvals of informed consent forms that must be given to prospective research participants. The Office of Civil Rights (OCR) plays an indirect role in research through its Health Insurance Portability and Accountability Act (HIPAA) regulations on patient privacy. The National Institutes of Health (NIH) not only fund much of the discovery work done in institutions, they also review proposals in federally funded institutions for preclinical and clinical research, guide investigators on regulatory requirements, and contract with some companies to test new agents and sometimes hold Investigational New Drug applications (INDs). Some NIH institutes approve protocols, produce informed consent templates, and provide Central Institutional Review Board (CIRB) approvals before trials can be opened. The loop is closed with NIH consensus panels on specific diseases, dissemination strategies produced with funds from the Agency for Healthcare Research and Quality (AHRQ), and a public health focus from the Centers for Disease Control and Prevention (CDC). See Table 37.1 for more information.

Patients play a critical role in the development process that is rarely acknowledged in a meaningful way. Without actual patients, no clinical trials would complete their objectives, and yet the system treats them as “human subjects,” with the similar regulatory language that governs lab animal safety [13]. Today’s patients consider themselves “research participants” and no longer accept antiquated mind-sets. The latest buzz words in medical research call for more “patient-centeredness” or attention to “patient outcomes.” It is now time to turn these concepts into more than standard rhetoric or press release material.

Industry and Company Mistakes

Companies changed their focus many years ago from “creating solutions for patients” to maximizing profit through mergers, acquisitions, and blockbuster drugs (not effective therapies). Many turned their backs on past industry founders and the ways they reaped their rich rewards for risk-taking approaches. Since then, risk-averse behavior is the norm, and potential markets rule, often independent of demand or promising scientific leads [14]. The results—recent polls show that industry executives are now regarded as greedy tycoons who focus on short-term self-interest, not far removed from those who caused the global banking crisis [15].

The blockbuster model produced maximum short-term rewards, but it appears to be over [16]. Companies mistook successful blockbusters as a marker of their own business acumen rather than low-hanging fruit, and started picking markets instead of scientific leads. Unfortunately, focus on short-term gains allowed a financial viewpoint to take hold, reducing expenditures and following market parameters instead of biology. Many promising biotech agents were also bought and shelved to eliminate even the hint of competition that might affect their “cash cows” [17].

For some reason, the patent clock was initially ignored, reminiscent of attitudes in the 1920s. Companies hired lawyers to protect the status quo and many new products became “me-too” drugs [18]. Powerful lobbies pressured FDA to not only reduce bureaucracy, but to lower safety and efficacy standards [19]. Meanwhile, marketing departments created demand out of vapor with “direct-to-consumer” advertising, offering great promise with very little value attached [20].

Refreshing exceptions exist, but headlined breakthroughs such as Herceptin® and Plavix® lose their luster after being touted as innovations, decades after their market release. For over 15 years, emerging science has focused on genomics, but cells also live in dynamic environments that affect their functions as well [21]. Myopic focus on genes, spurred by a desire for simplicity by companies and lucrative grant funding for academics, has produced disappointing progress for patients. At best, even drugs like Gleevec® that target a single gene will eventually stop working in the human body [22] (Box 37.1).

All of these tactics are concerning, and public and patient trust has been shaken, even without much knowledge about (1) dogged resistance to publishing all clinical trial results and sharing data [23]; (2) ghost writers and scientific misconduct accusations [24]; (3) trials closed and agents eliminated without warning instead of appropriate go/no go decisions before enrolling trial participants [25]; and (4) outdated study designs and lack of pharmacodynamic (PD) analysis [26].

Another concern is the alarming number of rescinded drug approvals due to trial methods that do not produce better drugs. According to Outterson et al., “Among the 61 New Molecular Entity (NME) approved antibiotics, 26 were withdrawn (43%), a rate far higher than was observed among non-antibiotics (13%)” [27]. A sample of these drugs is included in Table 37.2. This acute situation should be more alarming than the impending health crisis we may face, as evidenced by this excerpt from the National Physicians Alliance and Public Citizen’s Health Research Group, “The consequences of inappropriate trial designs in the setting of life threatening diseases are even more severe—death from ineffective treatments when effective therapies exist. FDA has released warnings regarding [antibacterial] drugs [like Tygacil®] that have increased deaths in serious and life-threatening diseases when approved through non-inferiority trials using outcomes other than mortality” [28].

Successful campaigns that scare everyone about super-resistant bugs have worked well, but old research methods that focus on bugs in a test tube and healthy patients will not lead to better patient outcomes, even if FDA eliminated all requirements [29]. This is similar to the reliance cancer research has toward cell lines, and both disease fields rely on mouse models that often cannot truly emulate the human body. Additionally, manufactured markets accelerate mistrust and prove to patients that their well-being is not a priority. Was it really a surprise that studies show potential health concerns for men taking drugs to eliminate “low T”? [30]. As Yogi Berra opined, “It’s déjà vu all over again” when you consider historic health risks for women who take hormone replacement therapy [31].

Even marketing finesse cannot justify the questionable “value-based pricing” tactics of some companies [32]. Their justification of the “value to society” for drugs like Avastin® has created an avalanche of exorbitant drug prices in the United States (but not in other countries) and extreme ill will with patient communities and the public. Even after skillful lobbying, the FDA rescinded approval for metastatic breast cancer, citing lack of efficacy and concerns about toxicity [33]. Though the value proved low in this case, the pricing model remains, bankrupting some families who pay a hefty penalty for hope [34]. Many feel totally comfortable equating this highly aggressive economic model with the “Robber Barons” of yesteryear [35].

Academic and Institutional Mistakes

Unfortunately, the feudal structure still used by most academic institutions has morphed into a culture of ego-driven departments and labs that often reward those who excel at gaming the system instead of fostering teams who build on scientific findings [36] (Box 37.2).