“Right to Try” laws have come into fashion with the success of the beautifully crafted and acted Dallas Buyer’s Club. That the movie was simply a movie with significant historical inaccuracies and that demonized the one drug (AZT) in the film that was actually effective at fighting HIV has apparently been lost on policy makers. Several states – some citing to the movie directly – are now pushing forward with legislation to supposedly improve access to investigational new drugs (INDs) for terminally ill patients. These right to try laws have now passed in Colorado, Missouri, and Louisiana and several more states are considering them. Additionally, federal legislation has recently been introduced that would go even further at a federal level.
The basic outline of these laws will be given below, but it’s important to note here that the “right to try” movement has been pushed forward by the Goldwater Institute and it’s model legislation. This is relevant only to the extent that the Goldwater Institute’s understanding of medical science are severely questionable. In their policy report Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment, they state the following:
After the enactment of the FDCA, the FDA began to require pre-market testing for drug safety, however pre-market testing for efficacy was not required until the 1960’s with the passage of the Kefauver-Harris Amendments. The Kefauver-Harris Amendments were enacted as a direct result of worldwide Thalidomide-caused birth defects. Although Thalidomide was sold in 46 countries, it was never approved for sale in the United States due to the FDA’s lingering safety concerns. While over 10,000 children worldwide were born with birth defects attributed to Thalidomide, only 17 of those children were born in the United States, where access to the drug was limited to those patients undergoing the FDA safety trial. The Kefauver-Harris Amendments drastically expanded the FDA’s regulatory authority by requiring drug manufacturers to prove efficacy prior to being approved for sale.
This vast new granting of power was unwarranted. Thalidomide presented a safety problem (over which the FDA already had authority) – not an efficacy problem. As a result of the Kefauver-Harris Amendments, no drug could be sold within the United
States until it had been deemed both safe and effective by the FDA.
In response, the FDA designed a clinical trial process which is substantially the same practice still in place today. During the ensuing 50 years, everything in the medical world — from the way diseases are diagnosed and treated to the way medical records are kept — has been modernized, but the FDA continues to adhere to an approval process that is half a century old.
That the Goldwater Institute would bemoan the requirement that drugs approved for sale actually be shown to be effective is incomprehensible. The safety of drugs is entirely dependent on the efficacy of those drugs. No drug (or herb, or supplement) is completely free of side-effects and safety is always relative to the efficacy of the drug and the reasons for taking it. For example, AZT is a “safe” drug if used in combination with other antiretroviral medications to halt replication of HIV in the body of the person taking it. AZT, however, is not “safe” to take if used incorrectly or in persons who aren’t HIV positive. It does have significant potential side-effects (more limited in the modern treatment era) and can be severely toxic at high doses and is thus not “safe” if not prescribed with a specific purpose. Even at the level prescribed in the early days of AIDS, AZT was “safe” in comparison only to the alternative – but that’s precisely because it did have some demonstrated efficacy at fighting replication of HIV in people taking it and not because it met some universal criteria of “safety” in all persons.
The idea that efficacy shouldn’t be part of the drug approval and regulatory process is – quite frankly – mad.
Nevertheless, motive alone is not a reason to dismiss the validity of these laws which are deeply understandable on a human level. Unfortunately, for individuals facing terminal illnesses, the laws are likely to prove meaningless and instead serve up an array of false hope, confusion, and frustration for what appears to be little more than political point scoring. There’s virtually no reason to believe that these laws will be effective at changing the landscape of access to INDs for terminally ill patients.
The intention of the laws is to make access to INDs available without getting approval from the FDA which proponents of the laws claim is overly burdensome and time-consuming. Yet, the laws fail to meaningfully expand access for a number of reasons:
Miracle drugs essentially don’t exist
The FDA’s compassionate use exemption already provides access, and
FDA’s regulatory limitations remain.
Miracle drugs essentially don’t exist
Medical science is an iterative science. Slow improvements are made as more and more basic research is conducted to determine the causes and treatment pathways for targeted diseases. The statistics for success are damning for those advocating in favor of these laws – despite the language frequently used that these drugs are “potentially life-saving”.
The process of achieving regulatory approval for a new drug requires three phases of clinical trials in humans. Importantly, these all take place after desk science and animal trials have already given an indication that the drugs are likely to prove safe and effective in humans. The three phases are:
Phase I: Very small trials of 20 – 80 people looking primarily for the maximum tolerable dose of the drug for consumption. Phase 1 trials establish initial side-effect profiles for the experimental drug to establish what clinicians should pay special attention to monitoring during subsequent phases of the trial. Depending on the purpose of the drug being investigated, they may or may not even be given to people who actually have the disease the drug is meant to treat. While frequently cited as establishing the safety of a drug, phase 1 trials are essentially indicative of safety, they do not establish safety.
Phase II: Generally larger randomized control trials that sort people into different treatment arms. Phase 2 trials will have 100 to 300 participants spread across a control arm (who would generally receive current standard treatment along with a placebo or just placebo depending on the trial) and several intervention arms at different dose levels of the drug being investigated. The primary end point of phase 2 trials is to determine an initial assessment of the efficacy of the drug along with refining the safety profile.
Phase III: Larger randomized control trials generally consisting of several hundred to thousands of participants. This is where the real science of treatment efficacy comes out. As with the phase 2 trial, participants will be sorted into control and intervention arms, but the primary outcome for the trial is now efficacy with secondary end points consisting of refining the safety profile of the drug.
A recent review to drugs going through clinical trials shows that success is relatively rare:
For oncology drugs – which are frequently cited as the basis for wanting to expand access by right to try advocates – the success rate is a mere 4.5%, and those are mostly drugs that show only marginal additional benefit over existing standard of care. They’re not the life-saving drugs we’re looking for. For drugs that show amazing benefit, the FDA already has processes that enable fast-tracking of drug approval. By fast-tracking approval, drugs can circumvent the need for phase III trials and proceed straight to market. As David Gorski wrote on Science Based Medicine:
The entire justification for “right to try” laws also seems to rest on a misperception that there are “miracle drugs” out there that we will have to wait years for because the FDA is too slow to approve them. However, if there really were such a “miracle drug” that was amazingly effective compared to anything we have now, a large randomized phase III trial would not be necessary to detect its efficacy. Indeed, its efficacy could show up in even a small phase I trial or, at the latest, in phase II trials. There’d be examples of clinical trial subjects demonstrating amazing tumor shrinkage or even outright cures. In reality, we don’t see these things in phase I trials, because there are no miracle drugs, at least not yet (if there ever will be).
This is where the selling of the right to try laws has been disingenuous and shameful. Advocates of these laws frequently make claims along the lines that if INDs were made available to these patients, countless lives could be saved. The reality is much different.
The FDA’s Expanded Access exemption and regulatory limitations remain
Separate from the above, these laws don’t truly fix anything in the process. The FDA implemented expanded access exemptions more than 20 years ago to enable patients to access INDs prior to them gaining final FDA approval. That process is outlined on the FDA’s website along with the form and instructions for how to apply.
The process first requires that the patient’s physician reach out to the drug developer to determine whether they are willing to provide it. No data exists for how many people attempt get access to INDs but are initially rebuffed by the manufacturer before ever applying to the FDA. However, we do have data on the number of applications that are submitted to the FDA. In 2013, 977 applications were made to the FDA, of which 974 were approved. While likely rare, there are emergency allowance procedures that allow for these exemptions to be granted by phone.
The requirements for the FDA’s Expanded Access program are substantially similar to those in the right to try laws. Patients must still show that they have a terminal illness, that they have considered all available approved drugs, and that their physician is on board. The FDA additionally assesses whether there’s sufficient safety and efficacy indications that warrants providing the drug and that providing the drug won’t undermine on-going clinical trials.
These are precisely the same requirements that drug companies are likely to continue to require even under these new right to try laws. Under the right to try laws, drug companies have no additional incentive to provide the drugs. They are allowed only to provide the drug for free or to provide it at cost to the patient (which is likely the be very high). Even from a publicity perspective, the drug companies know the chances of success are infinitesimally small and that even marginal benefits are unlikely to be remembered or identified when a patient eventually dies. Regardless of the circumstances under which it was provided, it’s bad publicity to have patients dying on one’s investigational drug.
Proponents of these laws claim that the FDA process is too slow and cumbersome, but outside of a few heartbreaking anecdotal stories – where the delays may not have even been the result of the FDA – they have not presented any systematic evidence that these laws actually solve any of the procedural problems or would shorten the time frames in any meaningful manner. Even the paperwork requirements that are claimed to be overly burdensome – the patient’s medical history, diagnosis, prior treatment attempts and results, and a treatment plan – are the same paperwork that any reputable pharmaceutical company would demand prior to providing access to their investigational drug. It’s simply implausible to believe – and dangerous to desire – that drug companies acting under these right to try laws remove any of this oversight from the process of approving access.
FDA’s regulatory limitations remain
Perhaps most importantly is that it is virtually impossible to see these laws as actually expanding access. The FDA prohibits the sale or provision of unapproved drugs unless exemptions are granted through the FDA process. The legal space has been filled at the federal level and state laws simply cannot legally preempt the FDAs regulatory authority in this manner. While the proposed federal legislation would resolve that conflict, the chances of it passing this congress are minute.
In the meantime, while there are potentially a few micro-pharmaceutical companies that may be able to avoid FDA’s regulatory authority by only acting within state borders, it is virtually impossible to imagine large pharmaceutical companies being willing to provide INDs to patients in violation (or at least in conflict with) federal law simply because the state law says that it can. Even for those micro-companies, it’s unlikely – rightly or wrongly – that they would risk upsetting the FDA by circumventing federal regulation.
If these laws have little chance of actually expanding access, the question comes back to why they are being advocated at all. I think the explanation lies partly in the fact that there are real world horror stories of patients fighting through terminal diseases and that experience is – speaking from personal experience – truly heart-wrenching. Watching one’s family member face a terminal diagnosis when something – anything – might possibly be done is possibly the most human of responses. We should not and cannot forget that in this debate. Unfortunately, these laws as proposed don’t lead anywhere but to false-hope.
I do believe there is also a deeper political intention here that is highlighted by where I started this post. Reading the Goldwater Institute’s policy paper reveals a desire to undermine the FDA’s entire regulatory authority on clinical trials. Certainly, much should be done to bring down the costs of conducting the full range of clinical trials and to speed the drug approval process. However, returning to an era – as hinted at by the Goldwater Institute – where the reliability of the clinical trial process is lessened and that enables minimally restricted utilization of medications that haven’t been proven to be either safe or effective is not sound policy.
The views reflected in this expert column are those of the individual authors and do not necessarily represent those of the O’Neill Institute for National and Global Health Law or Georgetown University. This blog is solely informational in nature, and not intended as a substitute for competent legal advice from a licensed and retained attorney in your state or country.