Today, the Food and Drug Administration is sharing with the public its decision to allow patients with Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease also known as Lou Gehrig’s Disease, or ALS, to have access to a drug called Iplex under an Investigational New Drug (IND) application. Iplex (mecasermin rinfabate [rDNA origin] injection), is a combination of two substances: human insulin-like growth factor 1 (IGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3). Iplex is approved by the FDA only for the treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. The drug is currently not marketed because of a court order related to patent infringement. Iplex is made by Insmed, a biologics company headquartered in Richmond, Virginia.
The FDA and Insmed have agreed that access to Iplex for investigational use in patients with ALS will occur in two ways under Investigational New Drug applications (INDs):
- Single-patient INDs requesting “compassionate use” of Iplex for treatment of named patients with ALS, received and date-stamped by FDA’s document room by close of business on March 6,
2009, will be allowed to proceed, and Insmed has agreed to supply Iplex to those patients; and
- The remaining supply of Iplex, which is very limited, will be used by Insmed to conduct a clinical trial under an IND in which other patients with ALS who are interested in receiving Iplex treatment will be randomly assigned to receive drug through a lottery system.
All patients who receive Iplex under either a single-patient IND or in the Insmed clinical trial must be adequately informed by their treating physician of the possible benefits and risks of the treatment. To facilitate the informed consent process, FDA is making available other documents, as described below, to ensure that healthcare providers and patients have access to more complete information related to the potential risks and benefits of Iplex treatment.
FDA has agreed to allow Insmed to submit a request for cost recovery under existing IND regulations to offset the costs associated with conducting the planned clinical trial. The physicians who submitted the single-patient INDs for “compassionate use” of Iplex will be asked to participate in the data collection for the Insmed clinical trial in order to maximize the collection of data from the very limited supply of drug.
For further details regarding the Insmed clinical trial, including the process for enrollment into the lottery, contact Insmed at (804) 565-3083 or firstname.lastname@example.org.
Rationale for FDA’s Decision
The FDA’s decision comes after serious consideration of the needs of patients with ALS and the practical limitations posed by the extremely limited supply of the drug. The agency has carefully reviewed all available studies and data on the potential benefits and risks to patients with ALS, as well as the need to have as fair a plan as possible for allocating the limited supply of the drug among the patients who want to receive it.
FDA has received a number of single-patient IND requests from physicians to allow “compassionate use” of Iplex for named patients with ALS. In reaching its decision on permitting investigational use of Iplex in patients with ALS, FDA recognized that solely granting access to the drug under single-patient INDs would rapidly deplete the limited supply of Iplex and make it virtually impossible to conduct a controlled clinical trial. This is critical, because without adequate controlled clinical trials, it is not possible to determine whether Iplex is effective, or harmful, in patients with ALS.
The FDA believes its decision represents the fairest way possible to provide access to Iplex, first, because Insmed does not have enough drug for every patient who may request it and, second, because it is important to maximize what can be learned from the remaining supply of drug in case it does have benefit, and could be further developed for widespread use by patients with ALS.
FDA has attempted to balance the needs of individual patients who are desperately seeking treatment options for this devastating disease with the need to learn if the drug is in fact beneficial, or harmful, in treating patients with ALS. These considerations were weighed over the last few weeks by FDA scientists and physicians, who held a series of meetings with Insmed and internal meetings to discuss the best path forward.
With the intent of being transparent regarding our decision, today we are making public the available information and study findings on the use of Iplex in patients with ALS that served as the basis for our decision.
Approximately 10 weeks ago, the FDA first received requests from physicians requesting access to Iplex for “compassionate use” treatment of named patients with ALS under single-patient INDs. After careful review and consideration, FDA initially denied those requests because the agency was not aware of any data that suggested that Iplex was beneficial in the treatment of ALS. In addition, FDA was aware of data from controlled trials for a very similar drug (IGF-1 or Myotrophin) that failed to demonstrate benefit, and in some trials suggested a worse outcome in patients treated with IGF-1 compared to patients treated with placebo (no treatment). The data for IGF-1 came from four randomized, double-blind, placebo-controlled trials as well as randomized access to IGF-1 through a Treatment IND. Reports of three of the controlled trials of IGF-1 have been published in the medical literature1; the fourth trial and the Treatment IND experience (both of which suggested harm of IGF-1) have not been published but were reported to FDA by the sponsor of the IGF-1 development program. As part of today’s web posting, FDA is making available a summary of the controlled data for the use of IGF-1 in the treatment of ALS.
In addition, although it was not a basis for the denial of the single-patient IND requests, FDA also noted in those denials that the only way to determine if Iplex was beneficial or harmful in the treatment of ALS was to conduct a controlled clinical trial similar to those conducted for IGF-1. Given the variable natural history of ALS, it is not possible to interpret anecdotal experience that may arise from uncontrolled treatment use of the drug, such as was requested under the single-patient INDs. FDA’s regulations on access to investigational drugs for treatment use acknowledge this limitation and, in general, there is an expectation that a drug will be under development and adequate data will be available to evaluate the drug’s safety and effectiveness before single-patient access under an IND is granted. Finally, FDA was concerned that due to the devastating nature of the disease and lack of existing treatments, demand for access to Iplex under single-patient INDs might become widespread, and that such access to the drug would impair the ability to conduct a proper clinical trial to determine if the drug was beneficial or harmful in the treatment of ALS. This concern was cited in our communications to the physicians who submitted the single-patient INDs. We also made clear in those communications that we would welcome the opportunity to work with the ALS community to develop a controlled clinical trial of Iplex for ALS. These concerns over single-patient access became more acute when we subsequently learned, as discussed above, that the supply of the drug is very limited.
As FDA continued to receive requests for access to Iplex after the initial denials of the single-patient INDs, we continued to evaluate the data and pursued several actions in parallel.
First, FDA was aware of reports that Iplex was being made available for treatment use in Italy under a court order. FDA contacted its counterpart agency in Italy to request information about that program and to inquire about any data that may have been collected from that experience. FDA learned that more than 100 patients with ALS had received court-ordered treatment in Italy, and the agency received a summary report of the data provided to the Italian government by Insmed in March 2008. FDA reviewed that report, and while the data were not interpretable with regard to determining any benefit of Iplex in the treatment of ALS, the data were useful in that no serious, immediate drug-related toxicities were apparent (noting that these uncontrolled data are not interpretable for the potential adverse signals of increased mortality that were seen in the IGF-1 studies as reported above). Insmed has agreed to allow FDA to make a summary of the Italian data available to the public as part of today’s announcement. FDA believes that access to these data, along with the summary of the available data on IGF-1, will allow physicians and patients to make better informed decisions about the use of Iplex.
FDA is also making available unofficial English translations of publicly available documents from the Italian government’s review of Iplex for the treatment of ALS. FDA believes that these documents are useful in further providing context to the Italian government decisions regarding the use of Iplex, and may serve to clarify any confusion about access to Iplex in Italy.
- Italian Ministry of Health Paper on Treatment of ALS with Iplex (unofficial English translation)
- Agenzia Italiana del Farmaco Paper on Treatment of ALS with Iplex (unofficial English translation)
FDA also initiated a series of meetings with Insmed to determine their plans for the commercial development of Iplex for treatment of ALS, their inventory of drug and planned manufacturing activities, and their interest in opening an IND to conduct a controlled clinical trial of Iplex in ALS. Those meetings were very informative and productive, and led to today’s statement regarding plans for access to Iplex under INDs.
The FDA understands that ALS is a fatal disease with limited to no treatment options. We are very sympathetic to the desperate situation of patients with this terrible disease, and their families, and we remain committed to facilitating the development of effective drugs to combat ALS. Sometimes therapies that appear promising in the preclinical phase (before studies in humans) do not lead to benefits in patients. Such early promise was not born out by controlled clinical trials for IGF-1 and for another product called recombinant human ciliary neurotrophic factor (rhCNTF)2, which showed no benefit and appeared to increase mortality in controlled clinical trials.
The FDA is mindful of the need to strike a balance between access to unproven therapies for patients with limited treatment options, and the ethics of subjecting those patients to drugs with unacceptable risks or unconfirmed benefits. Today we have chosen a means to provide access to Iplex to as many patients as possible, consistent with all of the considerations discussed earlier.
We will continue to work closely with Insmed on its clinical trial and will keep the public informed about its status. We also are very interested in having discussions with any other companies or physicians who would like to explore development of therapies to treat ALS.
1. Neurology 1997;49:1621-1630; Neurology 1998;51:583-586; Neurology 2008;71:1770-1775
2. Ann Neurol 1996;39:256-260