Date: Mon, 31 Oct 94 10:34:05 -0500 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD#138 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#138, 31 October 1994) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ----- == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. The ALS Digest is == == published (approximately) weekly. Currently there are == == 370+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. FDA RESPONDS (1) ===== FDA RESPONDS ========== Date : Mon, 24 Oct 1994 22:04:58 -0400 >From : JACKN74940@aol.com Subject: FDA RESPONDS RESPONSE TO SENATOR WELLSTONE OF MINNESOTA: QUESTION 1 - received in Wellstone's office Sept and I received it October 22: This is in further response to your letter of April 4,.1994, on behalf of Mr. Jack Norton of Andover, Minnesota, regarding access to investigational drugs for the treatment of Amyotrophic Lateral Sclerosis (ALS). Mr. Norton asked the following Question: 1) In the response your office provided, "FDA has long supported the idea of expanded access to investigational drugs in the case of life threatening diseases without alternative therapies." They go on to say there are several mechanisms to allow for this. So the question remains why don't we have access to these drugs on a compassionate basis? FDA RESPONSE: FDA has indeed provided a variety of mechanisms to facilitate the use of investigational products outside of a clinical study, when appropriate. It is up to the sponsor, however, to decide to make a product available through one of those mechanisms. For example, the treatment IND, the mechanism with the greatest ability to enhance availabilty, applies only when the drug is "promising" and when there is sufficient evidence of safety and effectiveness to support such use in a serious disease. Ordinarily, some controlled clinical trial data would need to be developed in order to determine this. The sponsor would then need to seek an expanded access program. To date, no development programs for drugs to treat ALS have meet the treatment IND criteria. END OF FDA RESPONSE. My inital response to their response - what does promising mean - they can't have it both ways. The FDA must define promising! They require absolute data on efficacy and yet when the drug is promising is to me when animal data shows it arrests the disease. What does sufficient evidence of effectiveness mean? The regs say "may be effective". Why would any drug company request expanded access if the amount of analysis needed to get market approval is the same as offering expanded access? Drug sponsors can offer life saving experimental drugs in phase III and no earlier than phase II. How many times has the FDA encouraged drug sponsors to submit IND applications for expanded access? Further comments? Question 2) What is the FDA doing to provide that access? FDA RESPONSE : FDA is willing to work with a product sponsor on a case by case basis in arranging expanded access and has provided a variety of mechanisms which a sponsor may use (i.e., through a Treatment Investigational New Drug application [Treatment IND], single-patient IND, dose comparison trial, and/or open protocol study), as discussed in our previous letter. It is up to the product sponsor, however, to utilize those mechanisms. FDA does not have any statutory authority to require a sponsor to develop a particular product, to develop a product to treat a certain disease, or to make a product available to patients outside of a clinical study. END OF FDA RESPONSE. My response - The FDA has a regulation authorizing expanded access - last year we started discussions that led to a draft legislation to compel all drug sponsors to offer expanded access for any drug trials that were FAST TRACK! Question 3) They further state that the "FDA does not have the authority to compel a sponsor to submit an application" for compassionate access. Why did the FDA allow a clinical trial to go on when there was no provision for compassionate access? FDA RESPONSE : FDA receives its authority from statutes enacted by Congress. FDA does not have the statutory authority to require a product sponsor to make a product available to patients outside of a clinical trial. Compassionate access is not a required element of a clinical trial according to the law. END OF FDA RESPONSE. My response to the FDA - they set the stage by encouraging drug sponsors to offer expanded access, at least remind them when they seek protocol approval. The clearest point to all of this is that the FDA will only pursue compassionate access if given the authority by Congress! It is not a required element of a clinical trial according TO LAW! The law must be changed. For those of you on a single drug trial, what will you do when Phase II or III of a combo trial is nearing completion and you want Compassionate access. What about you 28,000 that were not given the CHOICE to take an experimental drug, are you happy that the FDA is hiding behind Congress and the Drug Sponsors are not interested in proving effectiveness until a trial is over? Remember the reg says "may be effective". Question 4) What is the FDA recommending should be done to encourage the offering of life saving drugs on a compassionate basis? FDA RESPONSE: We believe that the terms "compassionate use" or "compassionate basis," which are not FDA terms, relate to making an unapproved drug or biologic available to patients outside of a clinical trial through means of a Treatment IND as discussed in items 1 and 2 above, or to individual patients on a case by case basis. FDA is not the drug developer or drug owner and has no legal basis for compelling a manufacturer to provide any of its investigational products to a particular patient or patients. FDA does, however, encourage use of the treatment IND mechanism for promising agents and has published in its regulations the legal mechanisms for a manufacturer to provide its investigational products to the physicians of patients for treatment use. If a physician can arrange for the manufacture to provide sufficient quantities of the product for the patient's therapy, FDA will work with the physician to determine if the regulatory conditions permit the submission of a single patient IND application and will assist the physician in filing the IND submission as necessary. END OF FDA RESPONSE. My response - the FDA knows perfectly well what compassionate access means, and they should use the terms that best describes Humane treatment not scientific apathy toward the living. Again with the FDA has no legal basis for compelling....I asked them what they would recommend and they talk about what doesn't work now. If I was thinking of a good way to logjam their office I would have each of you get a single patient IND and date stamp it, copy your Senators and start asking for the drug of choice. You may need to get your neuro involved, but the first one done should copy the rest of us! A public refusal to offer an individual's neuro the drug should be publicized in light of the fact that FDA regs allow for it in Phase III and no earlier than Phase II! Comments? Question 5) Who made the decision to sanction placebos? FDA RESPONSE: No one individual "sanctioned" the use of placebos in clinical trials of ALS, but the people responsible for reviewing the protocols considered the design appropriate. Controlled clinical trials using placebos have been conducted to evaluate the safety and effectiveness of investigational products, including drugs intended for life threatening diseases, for decades. History has shown that with rare exception of drugs that profoundly improve a disease, efficacy can best be demonstrated by placebo controlled trials. A clinical trial group usually includes standard therapy, rather than a placebo, when such a treatment is available. Such a trial may either establish superiority of the new therapy or establish therapeutic equivalence. For ALS, there is no known effective treatment, and so a trial comparing an investigational product with a single therapy is not possible. We do not at this time believe that historically controlled trials in ALS will provide a meaningful answer. A therapy with a dramatic effect, such as reversing the progress of the disease or completely halting the progression, could be identified in such trials. However, lesser, still valuable effects could be missed in such a design which would be devastating for patients who currently have no available treatment. This is a matter is that is being discussed in the scientific community. It is important to keep in mind that for many products currently under study for treatment of ALS, such as Ciliary Neurotrophic Factor (CNTF) and Brain Derived Neurotrophic Factor (BDNF), there was little information about the effect on humans prior to the current trials. While there were studies in animals prior to the current clinical trials, experience has shown that animal data do not guarantee human efficacy or safety, and it should not be presumed that they will prove effective in humans. In fact, the recent announcement by Regeneron concerning its decision to discontinue development of CNTF because of serious side effects and lack of effectiveness in preventing the progression of ALS emphasizes the need for placebo controlled trials. If the trial had been conducted without a placebo control, it may have taken much longer to discover the lack of benefit from the product. END OF FDA RESPONSE My response - "No one individual Sanctioned the use of Placebos ... but people responsible for reviewing thought it appropriate" - I want their NAMES! I will be clearer next time! The light of day will shine on this despicable practice. They are right in saying it is a matter being discussed in the scientific community - and amongst the victims they have scarificed on the altar of lazy science! I about gagged when they pointed to the Regeneron study. 7 of the 9 months of data showed improvement of those patients haiving side effects, but because the study was designed for 9 months the whole period of time was to be considered. You could have measured against low and high doses at intervals rather than scarificing victims on the altar of lazy science. The FDA reinforces LAZY SCIENCE. We should have History controls as mentioned by The Western ALS alliance and statistician COX 1980- in his paper on history controls- " ...other things being equal the arguments for concurrent controls are overwhelming, BUT when the number of available patients is limited, or when relatively large quantities of high quality recent historical data are available, critical use of the historical data instead of or as well as concurrent controls may be WISE. Further empirical evidence on the stability of comparisons involving historical controls is desirable. NO, the FDA has INSTITUTIONAL BIAS as stated by Marlene Hafner of the FDA and Drug sponsors have not alternative tools to measure effectiveness - no surogate markers, electronic measurements or existing data base ... LAZY SCIENCE = DEAD ALS VICTIMS ... comments? Question 6. In a recent Newsday article, 1 March, FDA officials say that the agency has come up with ways to expand access and even bypass a placebo trial. According to Dr Robert Temple, a director for drug evaluation for the FDA, a company he would not identify is now testing an ALS drug without a placebo, instead comparing a low and high dose of the drug. I would like to know the name of the drug company and why the FDA refuses to tell who it is? FDA RESPONSE: We are not aware of any manufacturer who has actually conducted such a study, although one had planned to do so. The company's plans changed because of results of ongoing studies. FDA regulations on confidentiality under 21 CFR 601.51 would prohibit us from disclosing information about such a trial if it had not previously been publicly disclosed or acknowledged. In addition, the sponsor in question was already carrying out a placebo controlled trial. The planned dose-response study was to be available only for people too advanced to be eligible for the placebo controlled trial. END OF FDA RESPONSE My response: I assume they changed their minds because of the FDA's narrow view of success in the Regeneron study - Instead of acknowledging side effects , which were not as severe as radiation or chemotherapy, and noting improvement after the side effects diminshed, the FDA refused to consider the 7 months of good data. THe FDA did not encourage the drug sponsors to allow ALS victims too advance for the trials the CHOICE to take experimental life safe drugs! If the FDA encourages, drug sponsors will submit expanded access.! Comments? FDA COMMENTARY TO MY LETTER TO SENATOR WELLSTONE: - received October 22, 1994. I hope that this clarifies FDA's position . I am sorry that Mr. Norton has been unsatisfied with our previous correspondence. We are genuinely concerned with the needs of people with ALS, and are committed to working with manufacturers seeking to develop products to treat this terrible condition. We sympathize with Mr. Norton's desire to receive any product which might benefit his condition, and understand his concern that products which might be of benefit be available to other people with ALS. But Mr. Norton needs to understand where FDA's authority begins and ends. FDA has the authority to ensure that clinical studies are conducted in a manner which will provide adequate evidence of effectiveness and safety prior to product approval, and to grant product approval based on an assessment of data from clinical studies, along with other information. WE DO NOT HAVE THE AUTHORITY TO COMPEL A SPONSOR TO PROVIDE A PRODUCT TO PATIENTS OUTSIDE OF A CLINICAL TRIAL. - (my emphasis) END OF FDA RESPONSE. My Response: When is adequate evidence obtained? At trials end? What happened to expanded access when a drug "may be effective" not proven effective? These are in the regulations. This can be done in Phase III and no earlier than Phase II. Are these just idle statements to be ignored by INSTITUTIONAL BIAS? I wonder which Senators had the wording for expanded access inserted in the regulations thinking the FDA would encourage there use and not be subverted by innuendo and waiting us out? Apparently, we need to get Congress to write the law "Compelling Compassionate Access" - comments - discussion....one more time into the breech.....Ours just to Do or Die! The Quest Continues Jack Norton Bob - feel free to reprint -- Angus I am going back after them === end of als 138 ===