Beginning in 1987, during the AIDS crisis, FDA code has included a set of regulatory provisions for expanded access of yet-unapproved investigational drugs for serious and life threatening conditions (often called “compassionate use”).
For life threatening diseases like ALS, FDA has the discretion to allow such drug access under the following conditions:
a) The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition. And…
b) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated.
In FDA’s 2009 re-codification, expanded access was broken down into three program types, by group size. A patient may now access investigational drugs by filing an “individual patient” expanded access IND (Investigational New Drug filing), or be part of an “intermediate-size” group IND or a “treatment IND” for a large group. However, approval is always at the discretion of the FDA reviewer. And expanded access programs also require significant paperwork by the physician and by an Institutional Review Board (IRB) who must be both aware of the drug and inclined to pursue it. Furthermore, from the perspective of the companies who must agree to provide the drugs, there has been little perceived assurance that adverse events reported during expanded access will not weigh negatively on the likelihood of marketing approval. For these factors and for one or two factors beyond the scope of this paper, very few of the patients suffering from life-threatening conditions actually access investigational therapies through expanded access programs. Over the period from 1986 through 2009, the average annual number of individuals with submitted IND applications was very small. When we add those patients to the miniscule proportion of patients with unmet need who are accepted into clinical trials, it is clear that the vast majority of patients must wait until drugs are approved before access is possible.
One doesn’t get far in his investigation before hearing the same tired arguments against expanded access that have been lobbed up for years. “We don’t know for sure that the drug will work,” “we still need more evidence that the drug is safe,” or “we’re not sure it’s appropriate for every patient.” Such facile comments are maddening to rational patients of quick-killer diseases who, under the advice of their doctors, choose to explore options that may offer a different path than their disease’s 100% mortality rate. The negative arguments beg the question of really how serious the patient outcome would be in the absence of treatment, a question to which, in the case of ALS, we already know the answer.
Maybe the most dangerous argument offered against early patient access rests on the notion that expanded access programs are a threat to good science. Some researchers, especially those disconnected from the personal impact of the disease they are studying, actually believe this, and would rather not see the topic considered at all. The most logical of their fears is that expanded access programs could compete with clinical trials for participants. We must consider the dilemma that arises when dying patients weigh the 100% likelihood of receiving the actual drug in an expanded access program against a significant chance of receiving placebo if they participate in a randomized controlled trial. If nothing else, this situation might underscore the questionable ethics behind randomized controlled trials (RCT) in deadly diseases with unmet medical need: To show relative efficacy, placebo group members will do we as we expect untreated patients to do: they will get worse and maybe die before the trial ends. And to keep patients interested in this lottery, we must eliminate the possibility of getting the drug through other means such as expanded access.
We think that’s a false choice, and we think that medical ethics demand that the clinical community regard current patients as more than expendable soldiers in the process of proving clinical efficacy. Patients CAN be allowed to pursue life saving treatment WITHOUT compromising ongoing clinical development of the drug. Expanded Access programs can be made to first enroll those patients who are ineligible for clinical studies; in most ALS trials that is patients with less than 70% of normal forced-vital capacity breathing performance, patients that use bi-pap, cpap, or fully assisted ventilation, patients who first presented symptoms more than three years ago, or patients over 80 years old. Virtually every “late stage” ALS patient will be regarded as ineligible for trial, but thousands of early stage patients are also unable to participate in clinical trials due to lack of timely awareness, distance from the trial site, or simply a limited number of slots to fill in the trial. How about trial participants who did well in their 6 month treatment regimen but then have no more drug supply? And, the unfortunate patients who spent 6 months of their shortened lives in the placebo arms of non-crossover trials? Drug access for these classes of patients would not affect concurrent clinical development.
In 2009 FDA added the following requirement to Expanded Access authorization guidelines:
c) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.
This language leaves a lot of room for the irresponsible arguments against expanded access that have long been left unexamined.
But the fact remains, expanded access programs can be undertaken in a way that does not interfere with clinical development and may actually accelerate it.
ALS Treat Us Now pursues three things: expanded access, accelerated approval, and real patient advocacy.
Our mission is to enable ALS sufferers to gain immediate emergency access to potentially life extending investigational drugs.
The best opportunity we have to achieve this lies in making expanded access programs (EAP’s) a commercially feasible option for drug makers. Doing so requires coordination with FDA reviewers, the ALS clinical community, and patients themselves. But in today’s landscape, it mostly requires a well planned fiscal program to ensure that what we propose aligns with the drug companies’ fiduciary requirements to their shareholders. Patients cannot ask a commercial company to do good, if doing good loses them money.
Our expanded access campaign includes charitable funding to cover the program’s administration, clinical oversight, liability, and product manufacture expenses. Some of these costs must go through the drug company and some can be jointly operated or independently contracted. With sound financial management, an Emergency Treatment Fund can be used to defray the variable costs incurred, without the risk of spending it on the company’s fixed costs or other areas not directly associated with emergency treatment.
We calculate that a modestly sized Emergency Treatment Fund could fully sponsor a pilot program of 50 initial participants for a 6 month period on one of the three aforementioned ALS drugs. After covering the program’s own fixed costs, our funding can be used very efficiently and without the dilution from new overhead expenses. With minimal supplemental fundraising, the Emergency Treatment Fund could cover the addition of hundreds if not thousands more patients in a way that could
sustain treatment for a long time.
An essential fact is that none of the three investigational ALS drugs is expensive to manufacture. This allows us to focus our fundraising requirement on the setup, administrative offset to the company, and the underwriting required to commit a contract manufacturer to a number of “batches” of product. Ongoing costs of the drug and its administration are passed on to the individual patients in the program.
This means that our early financial partners can enable thousands of patients to access ongoing potentially life saving treatment with a one-time grant to the fund.
The second opportunity for early drug access is Accelerated Approval. Treat Us Now seeks to assist drug makers who choose to apply for early marketing approval based on a weight of evidence standard in consideration of the enormous unmet medical need in diseases like ALS. 1997 FDAMA included mechanisms for early conditional “Accelerated Approval” for such quick killer diseases, but to date these mechanisms have only been applied to antiretroviral HIV drugs and to a handful of cancer drugs. We think this can be improved, and we want to offer our organization’s resources to ALS drug sponsors who pursue early approval.
Our third campaign is Real Patient Advocacy. It is rare in a disease like ALS to have a patients’ foundation that is actually run by current patients and those who are close to them. With the shortened lifespans and progressive physical debilitation of ALS, that’s not a surprising fact. But we are an exception. We believe that the historical roadblocks to patients’ drug access are ready to fall, and the patients behind this effort are committed to expediting that process. Our family members that do not have the disease –some of whom are on our steering committee- have also pledged to continue our unique mission, on behalf of real patients who continue to fight for their lives.
More remarkable than the ALS community’s dearth of actual patients at the forefront is the apparent inability of larger ALS organizations to simply advocate for patients who are still living and who are seeking disease modifying treatment. Nearly every message board and support group of knowledgeable ALS families is dominated by the frustration patients have in not having a large organization that truly speaks for them. We would like to help ALSA and MDA adopt policies that benefit not just their research partners, support groups, and palliative care programs, but also to benefit the part of the community that is struggling to find near term treatment options. We continue to reach out to these larger organizations because they are the ones that receive the lion’s share of charitable support, and because much of that money is intended to improve patient outcomes.
In its Patient Advocacy campaign, Treat Us Now will continue working with clinical researchers, regulators and drug sponsors to promote ethical trial design. That means finding ways to ensure all trial participants have access to the investigational drug that is being studied. This can be achieved in crossover studies and/or follow-on expanded access programs. It is also can be done by questioning the need for large placebo arms, given the immense amounts of clinical data from placebo groups of previous ALS studies. Also, the inability to properly stratify treatment arms in a heterogeneous disease raises doubts about the statistical value of a parallel control arm. We want to make sure ALS does not fall victim to a cult-like devotion to randomized controlled trials (RCT), because, in many cases there are more appropriate alternatives.
In addition to our work within the ALS community, ALS Treat Us Now intends to remind policy makers in the Capitol and at FDA that dying patients are not well served when regulatory conditions deny them the opportunity to pursue proven-safe treatments that may help them survive. At the time of this writing there is great need to support the pro-patient legislative measures that may be included in PDUFA V. And by pro-patient, we mean initiatives that will restore dying patients’ right to express their own preferences for risk and hope, and not tighten drug accessibility. This is yet another area where the ALS community’s voice has been completely absent.
Our founders and steering committee believe there are really two unmet needs in ALS: First is the medical need patients have for potentially effective treatment; and the other is the lack of focused initiatives to give current patients as a great a chance at survival as possible. It must be made clear that ALSA, MDA, and other groups like ALS Guardian Angels do great work that helps patients in many ways. But when it comes to near term treatment access there is a void. ALS Therapy Development Institute must also be commended for their pioneering work to identify clinical drug candidates; we collaborate with a small handful of commercial venture teams that are working to bring those candidates into clinical development. Our task is to put those drugs into the hands of patients who, with their doctors’ advice, have made the decision to try them now, while they still have a chance at benefiting from them.
1. Shuren J. 2009. Final Rules for Expanded Access to Investigational Drugs for Treatment Use and Charging for
Investigational Drugs., U.S. Dept of Health and Human Services / FDA Federal Register.
2. Code of Federal Regulations, Title 21, Section 312.305
3. Code of Federal Regulations, Title 21, Section 312.310
4. Code of Federal Regulations, Title 21, Section 312.26 (since re-rewritten)
http://edocket.access.gpo.gov/cfr_2003/aprqtr/pdf/21cfr312.36.pdf pp. 65- 66