by Navied Akhtar
Navied Akhtar has been accepted as a PhD candidate in the Biomedical Engineering department and is completing an M.S. in biotechnology from UCI. Prior to his scientific training, he completed a B.A. in Political Science from UC Irvine and changed careers into scientific research in 2013. He is currently a member of the Downing Epigenetics Engineering Laboratory and is focused on elucidating the mechanisms involved in cell differentiation and identity.
In modern day medical research, the advent of stem cells has shown immense potential and insight as a means for therapy and information regarding human physiology. Stem cells have been used for crucial therapies such as bone marrow transplants and skin grafts, however their use has not been without question. The ethical dilemmas that arise from the use of stem cells come from philosophical questions of what constitutes a human life and when an embryo can be deemed as a living entity. The answer to these questions guide policy and, ultimately, the amount of funding that is being given to the research of stem cell therapy.
There have been many laws set into place specifically in regards to stem cell research and therapy. Currently, the Dickey-Wicker Amendment, passed in 1995, prohibits the use of NIH funds for creating of human embryos solely for research purposes or for research in which embryos are destroyed. 3 Although this type of research is done elsewhere in the world, the NIH still upholds this ban of funds to this day. States vary in their bans and restrictions on stem cell use. Some states specifically ban human reproductive cloning or ban the use of public money for reproductive cloning, while other states specifically allow therapeutic cloning. 2 These statutes dictate what and how research can be conducted in a given state, and are important for the freedom of what can be researched.
Although there are limitations to how stem cell research and therapies can be deployed, some policymakers feel that stem cells need to be put to use as fast as possible. The REGROW (Reliable and Effective Growth for Regenerative Health Options that Improve Wellness) Act was introduced by Senator Mark Kirk in March of 2016. The REGROW Act aimed to conditionally approve therapeutic products without initiation of large-scale clinical trials. This act would allow phase 3 trials to be circumvented if a particular therapy can show effectiveness in phase 2 trials. 6 The average sample size of phase 2 trials is about 50 while phase 3 trials can grow to as large as 3000 patients. 7 There was an outcry from the scientific community regarding the dangers of the REGROW Act due to concerns that patient safety is being put on hold to allow access to untested medications or treatments. The REGROW Act is still set as “introduced” in the Senate, so no decision has been made as of yet, but there is a new bill that echoes the sentiments of the REGROW Act and poses some of the same concerns: The 21 st Century Cures Act.
The 21 st Century Cures Act is an important piece of legislature that will affect the landscape of scientific research and medicine. The bill aims to accelerate the discovery, development, and delivery of cures to the general public. The bill has been backed by all manner of companies and policy makers, passing in the House of Representatives by 344-77 and in the Senate by 94-5. It allocates 1.75 billion USD for each of the fiscal years 2016 to 2020 for spending by the NIH and Cures Innovation Fund. 500 million of the 1.75 billion dollars will be for the Accelerating Advancement Program, with 35% of the remaining money allocated for early stage investigators, 20% for high-risk, high-reward research, and 10% for intramural research. The Accelerating Advancement Program is the hallmark of the Cures Act, a program that amends Section 506 of the Federal Food, Drug, and Cosmetic Act to allow a surrogate endpoint to approve a therapy for release into a market. In the following five years, the drug manufacturer would have to conduct its own follow up research to ensure the efficacy and safety of the treatment. 1
There is a key amendment in this bill that is crucial to answering the question of whether or not the decision making process of accelerated approval will ensure protection of consumers. This amendment utilizes evidence from clinical experience to “help to support the approval of a new indication for a drug approved under [accelerated approval]” and “to help to support or satisfy post approval study requirements.” The only requirements written in for accelerated approval past a “reasonable likelihood” that there will be clinical benefit, is that one or both of two requirements are met: (1) That the manufacturer conducts studies after accelerated approval to verify the predicted effect on mortality or other clinical benefit and (2) That the manufacturer submits copies of marketing materials for the drug during the preapproval period. 4 The addition of the amendment will allow for what is effectively anecdotal evidence to be used as actual evidence to support the requirement for accelerated approval.
Furthermore, the verbiage surrounding the term “surrogate endpoint” is loose at best. The idea of a surrogate endpoint is to produce a clinically relevant point in which to be able to measure the efficacy and safety of a drug. In the Cures Act, the definition of what constitutes a surrogate endpoint is left rather open-ended. It reads as such: “ The term ‘surrogate endpoint’ means a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement of clinical benefit, and is known to predict clinical benefit and could be used to support traditional approval of a drug or biological product; or is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug or biological product.” 1 It is worrisome to write that this endpoint can be a marker that is not a direct measurement of clinical benefit, but is known to predict clinical benefit. This leaves open a large workaround for accelerated approval of drugs that may have no business being approved.
Envision a scenario in which a stem cell therapy is developed that shows some kind of promise in curing a disease. The Cures Act would allow for a fast track for FDA approval of this therapy to be released to the public for use. This therapy could then be used moving forward to treat this disease, and society is made more robust and effective because of this act. The fact that there are likely to be stem cell therapies that will have been proven safe which can be released to the public more quickly is the main draw of the Cures Act. Lives would be changed for the better, and much more quickly, than without the Cures Act. This is the most ideal case that the act can provide, but what of the other side of the coin?
There are countless stories of why having a phase 3 trial and taking the time to know the outcome of a treatment on a larger sample size of patients is of paramount importance. The story of Tysabri is just one of the many. Tysabri is a monoclonal antibody developed to treat Multiple Sclerosis in an otherwise treatment resistant population. Tysabri’s phase 2 trials were conducted on 213 patients, while the phase 3 trial was conducted on 2113 patients. None of the phase 2 trials produced fatalities linked to the use of Tysabri. In the phase 3 trial however, three patients developed progressive multifocal leukoencephalopathy (PML), inflammation of the white matter of the brain, due to JC virus and ultimately passed away from the symptoms. 8,9 There is no known cure to JC virus, but it is usually cleared by the host’s immune system and is asymptomatic, unless the patient is immunocompromised. Tysabri comes with a strict warning on the box and from medical practitioners that developing PML is a risk, and although the drug is effective in treating Multiple Sclerosis, it is not used as the first line of defense against the disease. The phase 3 trial provided evidence for an estimate of 1 in 1,000 patients developing PML from JC virus. 10
Now, imagine if the Accelerated Approval Program was in full effect before the release of Tysabri. Phase 2 clinical trials showcased Tysabri’s efficacy and safety, and there was more than enough evidence to prove it is “reasonably likely” that this drug works. Tysabri would have been an excellent choice to be fast tracked and approved given the Cures Act verbiage. The aftermath of releasing Tysabri to the market would have been catastrophic since the impact of the JC virus was not known until phase 3 trials. Any individual that was immunocompromised would be at an extremely high risk for activation of JC virus and PML. Even with the knowledge from the phase 3 clinical trials, 517 cases of PML were reported from 130,000 people being treated with the medication in phase 4 studies. 10 How many of the immunocompromised population would develop these symptoms from JC virus without the knowledge from the phase 3 trials? Thankfully, we will never have to know the answer to that question, but it begs the question of who will be held responsible for such catastrophic consequences in the face of an accelerated approval drug? Now how does this scenario change if a stem cell therapy was being utilized?
In regards to stem cells and regenerative medicine, there is no information that directly addresses these types of therapies in the 21 st Century Cures Act. The use of stem cells is already in a highly controversial position and fast tracking experimental therapies that only anecdotally show positive results could be detrimental to the acceptance of stem cell research and therapies in the future. There is evidence of unregulated stem cell therapies leading to development of cancer at the site of treatment. What if in a certain subpopulation, the application of a stem cell therapy would yield a similar result as that of Tysabri? Those who are at odds with the use of stem cells could portray the use of stem cells as therapy as inherently dangerous, and extend it to the thought that it is a waste to even fund it. The Cures Act provides very little gain for the field of stem cells, and the framework provides a lot to lose.
The greatest unknown is that if a therapeutic treatment is fast tracked and turns out to have a dangerous consequence; will the blame be placed on the scientists, legislatures, industry, or the treatment itself? Could we see stem cell therapies be preemptively fast tracked without checking for safety leading to cancers or fatalities in a large population? Would the stigma of stem cell therapy then change because stem cell therapies are seen as dangerous and highly experimental? We approach a slippery slope at this point because there are too many unknowns, but history has shown us that it is neither policy makers nor the pharmaceutical industry that gets the blame in cases such as this. The only way stem cell research and therapy can make it through with this new bill enacted, is that the process for accelerated approval be strict and have the safety of the consumer in mind before all else.
- H.R.6 – 21 st Century Cures Act. H. Rept. 114-190. The Library of Congress. Retrieved 12/6/16
- National Institute of Health, Stem Cell Policy. https://stemcells.nih.gov/policy.htm Accessed 12/6/16
- P.L. 104-99 H.R. 2880. The Library of Congress. Retrieved 12/6/16
- Title 21-Food and Drugs. Chapter 9-Federal Food, Drug, and Cosmetic Act, Subchapter V-Drugs and Devices, Part A-Drugs and Devices. 21 USC 356 Retrieved 12/6/16
- Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC). NIH Categorical Spending. Report.nih.gov Published February 10, 2016
- S. 2689 – REGROW Act. The Library of Congress. Retrieved 12/6/16
- Ye, Fei. Design and Analysis of Phase III Clinical Trials. Presented on June 19, 2008.
- O’Connor et al., Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis. Multiple Sclerosis. 2005 Oct; 11(5):568-72
- Hutchinson, M. Natalizumab: A new treatment for relapsing remitting multiple sclerosis. Therapeutics and Clinical Risk Management. 2007 Jun;3(2): 259-268
- MS Research Update 2015. Multiple Sclerosis Association of America: Tysabri. Accessed 12/6/16