The 21st Century Cures Act may help solve many problems, but ignores others

Authors (alphabetical): Gregory Conway, Eric Lumsden, Spencer Todd & Benjamin Wolfson

I. Introduction

One of the biggest challenges facing the scientific community is in the field of biomedical research and development. At a recent symposium discussing translating research into effective treatments, the idea of an ‘Innovation Gap’ was introduced. Companies continue to increase the amount of money spent to develop drugs but production has remained at a consistent level (Figure 1). It is becoming more expensive to develop drugs, and companies are becoming reluctant to take on that challenge. This has a downstream effect, where companies will only research and study drugs they are certain will be effective. Diseases with less research or no known mechanism of action (e.g. neurological disorders) are ignored, as companies worry that development will be too difficult. If a disease is rare and affects few people, companies decline the chance to fund drug discovery as they know the final product would not be cost-effective. And it is becoming increasingly common for companies to release exciting new drugs, only for them to be so expensive as to be cost-prohibitive to the patient. All of these issues are causing holes in what the health care world can treat and cure. As a response, politicians worked in a bipartisan fashion to pass the 21^st Century Cures Act, hoping to expand biomedical research and expedite the process of moving drugs and treatments from the laboratory to the hospitals.

Figure 1 While the price of drug development has increased (red line) the number of products the FDA has seen to market has plateaued (blue bars). NME is New Molecular Entities, WW R&D is Capitol invested in Research and Development. Figure from Applied Clinical Trials Online <http://www.appliedclinicaltrialsonline.com/disruptive-technologies-breaking-down-barriers-drug-development>.

As with any bill, the Cures Act makes compromises, and it is important to understand the consequences of these compromises. Does it do enough in alleviating certain research risks? What are the health risks following these accelerated procedures? Are there omissions that will need to be addressed in the future? What follows is a dive into the bill that discusses its strengths and weaknesses from the viewpoint of research scientists. We will discuss the pros and cons, and possible room for improvement.

II. On risk and the innovation gap

A major goal of the 21^st Century Cures Act is to begin to address the innovation gap present in the biomedical industry and help bring to market new treatment options for a multitude of diseases. One objective of the legislation, according to Rep. Fred Upton (R-MI), is to add to the 500 existing treatments for 10,000 known diseases [1]. In an effort to fund high risk/high reward research and spur the development of new, breakthrough treatments, the Cures Act allocates $4.8 billion to fund three special projects—the Precision Medicine Initiative ($1.4 billion), the “Cancer Moonshot” ($1.8 billion) and the BRAIN Initiative ($1.56 billion) [2]. Additionally, the Act establishes prize competitions in areas of research where funding has been relatively small [3]. These efforts are reminiscent of the Human Genome Project, a similar, large scale initiative supported by the government that led to great breakthroughs in research and medical care. The 21^st Century Cures Act also hopes to entice innovative, young individuals to pursue research through a loan repayment program and earmarking 35% of funds from the Cures Act for early stage investigators3. These incentives are greatly needed given that twice as many investigators over the age of 65 have R01 grants, compared to those under 36 [4].

In theory, the Cures Act should have a significant impact on the innovation gap; however, several details of the Act remain unclear. First, it is unknown how the NIH and FDA will define high risk research. Given the stated goals of the Act, NIH and FDA will likely prefer funding research with a rapid translational path. However, given that it can take several years to truly understand the long-term impact of research endeavors, [5] prioritizing rapid projects may come at the expense of traditional projects that could have a more substantial impact on medical care in the long-term. Therefore, it will be important that the Cures Act is supplemental, not detrimental, to more traditional research that may be low risk but could have an even higher reward. Additionally, while the Cures Act focuses on innovation, it does little to address the risk such research places on the careers of individual researchers. Future promotions and grants are often determined by a researcher’s publication record. An investigator that pursues a high risk project that fails and is unpublishable could have their career stall or potentially end. Therefore, to truly incentivize early stage investigators to pursue these high risk projects it will be necessary for Congress, funding institutions, and Universities to work together to provide some sort of safety mechanism or special recognition for individuals with grants provided under the Cures Act. As translational researchers, we look forward to seeing how the 21^st Century Cures Act is operationalized and hope that the Act will be able to deliver on its promise to bring new, innovative therapies to patients.

III. On intellectual property and incentivization

The 21st century cures act has been charged with decreasing the time that therapeutics take to get to market for rare and threatening diseases. Exactly how the bill will accomplish this is still being picked apart by experts. In one section the Act makes it cheaper and easier for drug manufacturers to approve new therapeutic uses for already approved FDA drugs [6]. Drugs that reach the end of their 20 year patent exclusivity are open to having generics made as long as those generics show “bioequivalence” for their therapeutic target. However, repurposing these drugs to target a new patient population, disease, or method of treatment is open to a “method of use” patent. This allows protection giving the manufacturer exclusivity to sell that drug for that use for 20 years. However, this doesn’t mean doctors will not prescribe patients cheaper generics for “off-label” use [7], [8]. The Act aims to speed this approval process as repurposing of drugs is much cheaper than producing new chemical entities since their clinical profiles are known.

In addition to repurposed drugs, the legislation also streamlines and expedites the review process for precision medicines and other “qualified indications” like cancer that the FDA deem important. This is an obvious follow up to the Cancer Moonshot initiative that President Obama signed into order. Precision medicine is defined as medical care based on a particular patient populations genetic or molecular makeup. Expediting the approval of this class of drugs is a progressive move to improving personalized medicine and should be celebrated as therapeutics in gene therapy and modified stem cell therapy are rapidly progressing.

Unfortunately, this Act does not comprehensively repair existing or future issues in incentivization and patent reform. Many professionals fear that since the America Invents Act (AIA) switched to a “first to file” patenting system, we have entered into a patenting atmosphere that hinders innovation for those with less dispensable capital like the young entrepreneur [9]. It appears that small start-up biotech companies tend to make up the lion’s share of innovative, high-risk/high-gain therapeutics being brought to market while larger pharmaceutical companies tend to focus on “safe bets” [10]. One way of possibly bridging the innovation gap from this perspective is to provide cheaper patent applications and financial incentives for small companies with high-risk/high-gain products. Additionally, one must always be cautious when speeding the regulatory process as the lessened safety requirements inevitably lead to higher risk in patient populations.

IV. On concerns surrounding patient safety

Some of the greatest concerns from groups advocating against the 21^st Century Cures Act focused on the effects that the act would have on patient safety. Key functions of the Cures Act were to increase the speed with which drugs and medical devices could reach the market, ideally to increase the treatment options for patients and improve medical outcomes. However, critics believe that these changes will have the opposite effect.

The most widely criticized sections dealt with the mechanisms regulating approval of new drugs and medical devices. The drug development process is complicated, and on average it takes over 10 years and 350 million dollars for a drug to make it from the laboratory bench to patients. This includes 3 rounds of clinical trials which establish the drug’s safety, effectiveness, and the likelihood of adverse reactions [11]. Throughout this process and despite this high cost, only 1 in 10 drugs makes it from the first stage of clinical trials to being approved by the FDA [12].

During the drafting of the 21^st Century Cures Act, lawmakers worked to identify mechanisms that would speed up the development process of both novel drugs and medical devices. In the signed bill, this is largely done through several new regulations easing the approval process. To improve the clinical trial process, the Act promotes the use of Adaptive Clinical Trials, where the end of a clinical trial can be modified based on ongoing results such as expression of previously defined biomarkers or reduction in tumor size. This makes the clinical trial more flexible, saving money and time. However, depending on how the adaptive trial is performed, there can be negative consequences. Adaptations may be based on biomarkers that are poorly defined, or an end point which may result in positive results in the clinical trial but insignificant effect for the patient.

The Cures Act also changes what can be accepted as evidence by the FDA. While previously the three stages of clinical trials were required, the Cures Act makes it possible for non-clinical data or data from small, early stage trials to be acceptable in certain cases. Moreover, the FDA can consider evidence from case studies or medical journals, which may be largely anecdotal. While these would aid in the drug review process, their inclusion weakens the FDA’s ability to insure that all new drugs are safe. Finally, the Act allows device companies to make changes to devices without informing the FDA or proving that the new device is safe and effective. This may allow manufacturers to more rapidly improve pre-existing devices, it also increases the risk associated with the use of said medical devices.

Critics of the act argue that these provisions are shortcuts in drug development that result in an “inject and see” model [13]. Instead of definitively showing that drugs are effective and safe, it would allow pharmaceutical companies to rapidly produce new drugs, with the risks falling on the patients. However, patients who support the bill see it another way. When there are no other options, they are more willing to take risks as they have less to lose. This patient population wants more leeway to try new medical treatments which might save their lives when all else is lost. However, this population is commonly recruited for clinical trials, and allowing them to use drugs that have passed FDA approval but not been well tested may decrease the number willing to participate in clinical trials. A drug approved by the FDA may be less safe than a drug in a stage three clinical trial, and patients taking the drug outside of the structure of a clinical trial will not produce as much data that could be used to inform future treatments.

It remains to be seen what affect the Cures Act will actually have on drug and medical device development, and whether it will have negative ramifications for patient health. While there is a definite appeal to speeding up the FDA approval process, it cannot be done in a way that puts the risk on the patient. The most important way of preventing this is insuring that patients are informed before they consent to drugs that may be higher risk due to a less rigorous investigative process, and to continue to create high quality, effective drugs through the clinical trial model.

V. On omissions and issues warranting consideration

While the 21^st Century Cures Act was intended to be a step forward, some aspects ignore revolutionary therapies. The most exciting (see also innovative, cutting edge, has the highest potential) is work with stem cells.

In 2012, Senator Mark Kirk from Illinois drafted a bill, which was not introduced to the Senate until March of 2016 [14], that would provide the FDA with authority to skip clinical trials for stem cell therapies. Instead of the lengthy Phase 3 trials, the FDA could simply use surrogate endpoints to determine the effectiveness of these treatments [15], the negatives of this approach being discussed above. As this bill has only been referred to committee and not debated nor amended, the topic of stem cell therapies was ignored in the 21^st Century Cures Act. While the safety of the Regrow Act needs serious consideration (see Section IV), there are other factors surrounding stem cells that need consideration. Currently the FDA requires that all stem cell therapies be approved prior to use [16], including using a patient’s own stem cell therapies in their own bodies [17]. It is unreasonable to expect an individual to undergo the lengthy and expensive process of drug approval for cells that exist within their own body. Critics of the Regrow Act say that the proposed work-around may be even more cumbersome, but that’s a different discussion entirely. However, these issues could have been addressed in the 21^st Century Cures Act, but were instead ignored.

Many critics argue that while the bill has the word ‘cure’ in the title, the focus on finding cures is much too strong [18]. Obviously, the more cures for diseases and disorders the better; but what about prevention? There is not a single mention of preventative medicine in the Cures Act. Given that many pharmaceutical lobbyists helped get the Cures Act passed [19], [20], it is not much of a surprise that the focus is on curing disease rather than prevention. While the economics of prevention are up for debate (some believing it will cut costs while others are unsure) [21], preventing diseases should still be a major part of our healthcare system.

Finally, while the bill does allocate five billion dollars in appropriations for the NIH to meet the act’s goals, the money is not only pulled from a public health program laid out in the Affordable Care Act, but must be approved every year [22]. In the current political climate, it is unsure how long the approvals will continue.

VI. Conclusions

The 21^st Century Cures Act was written with the assistance of 1,455 lobbyists from 400 different companies, universities and other organizations. According to the Center for Responsive Politics, this was one of the most lobbied bills of the 114^th Congress [23]. Due to the intense level of participation by lobbyists, increased scrutiny is needed to determine the actual effects of the bill for both the public and the research community. It is important to determine what effects will be purely beneficial for the pharmaceutical industry, and what positive effects will be seen in the research community and for patients. While no bill is perfect, Congress should focus on helping all their constituents, not just those in Industry. While the increased funding to the NIH and other members of the public research community will be of great benefit, we have to hope that Pharmaceutical Companies will use the lower FDA restrictions to produce more drugs that are effective or find successful alternative uses for currently-employed drugs, and not just to raise their profits by releasing large numbers of ineffective drugs that push the risk onto the American people.

[1] http://time.com/3904400/rep-fred-upton-health-care/

[2] http://www.cbsnews.com/news/21st-century-cures-act-congress-health-care-passed/

[3] https://www.congress.gov/114/bills/hr6/BILLS-114hr6rfs.pdf

[4] http://www.pnas.org/content/112/2/313.abstract

[5] http://www.sciencemag.org/careers/2012/08/gambling-transformative-research

[6] http://www.fr.com/wp-content/uploads/2017/01/21st-Century-Cures-Act-No-Cure-for-an-FDA-Patent-Bias.Mahn_.Bloomberg.Jan2017.pdf

[7] https://www.pharmafocusasia.com/strategy/new-patents-old-drugs

[8] http://www.pharmacytimes.com/publications/issue/2011/june2011/old-drugs-are-new-again-

[9] https://www.law360.com/privacy/articles/662730/coons-calls-for-aia-overhaul-to-lower-patent-kill-rate-

[10] http://fortune.com/2016/05/13/big-pharma-biotech-startups/

[11] https://www.drugs.com/fda-approval-process.html

[12] Hay, M., Thomas, D. W., Craighead, J. L., Economides, C., & Rosenthal, J. (2014). Clinical development success rates for investigational drugs. Nature Biotechnology, 32(1), 40–51. http://doi.org/10.1038/nbt.2786

[13] https://www.wired.com/2016/12/future-regenerative-medicine-inject-see/

[14] https://www.congress.gov/bill/114th-congress/senate-bill/2689

[15] https://www.statnews.com/2016/11/30/stem-cells-cures-act/

[16] http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194655.htm

[17] http://rickjaffeesq.com/2016/05/04/stem-cells/

[18] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554930/

[19] https://www.drugwatch.com/2016/12/08/21st-century-cures-act-benefits-big-pharma/

[20] http://www.businessinsider.com/what-is-the-21st-century-cures-act-winners-losers-fda-approval-congress-2016-12

[21] http://www.reuters.com/article/us-preventive-economics-idUSBRE90S05M20130129

[22] http://fortune.com/2016/11/30/house-passes-21st-century-cures/

[23] http://www.npr.org/sections/health-shots/2016/11/25/503176370/legislation-that-would-shape-fda-and-nih-triggers-lobbying-frenzy

S.O.A.P.

SOAP (Student Organization for Advocacy and Policy) is a group of students and post-docs at the University of Maryland, Baltimore committed towards engaging scientists in policy and advocacy.