Abigail Alliance
May 14, 2003
Page 1
Abigail Alliance for Better Access to Developmental Drugs
501 (C3) non-profit incorporated in Virginia
1518 North Buchanan StreetArlington, VA22205
703-525-9266 cell: 703-963-2518
Board of Directors: Doug Baxter: David’s Father, Cancer Advocate, Gene Krueger: Abigail’s Step Father, Cancer Advocate, Anne Agnew: Booz Allen Hamilton, Prince Agarwal: University of Virginia,Cynthia Small: Charter One Mortgage
The letter presented below was sent to FDA Commissioner Mark McClellan on March 14, 2003 in response to a communication from the Marti Nelson Cancer Foundation (MNCF). The Abigail Alliance for Better Access to Developmental Drugs and the MNCF agree that cancer patients and patients suffering from other life-threatening diseases need and deserve increased access to investigational drugs; however, we differ on the scope of the changes needed to make this goal a reality. The Abigail Alliance has encountered overwhelming support for “Tier 1” from cancer patients, advocacy groups and many others with a stake in the issue for one reason; it will work for patients. MNCF’s letter to Dr. McClellan explained some of their concerns that we think were based on an incomplete understanding of the “Tier 1” concept but nonetheless deserved a response. The responses provided below address not only the MNCF concerns, but clarify why “Tier 1” is needed and why less complete proposals are unlikely to make a difference for cancer patients. In summary, we think the MNCF’s concerns are unfounded, but we welcome their interest in the issue and their ongoing parallel efforts to achieve our common goal of helping patients with life-threatening diseases that have run out of approved treatment options.
Frank Burroughs
President, Abigail Alliance for Better Access to Developmental Drugs
May 14, 2003
Dear Respected Colleagues,
The Abigail Alliance for Better Access to Developmental Drugs feels compelled to respond to the letter sent to Dr. Mark McClellan, FDA Commissioner, signed by Nancy Roach of the Marti Nelson Cancer Foundation (MNCF) regarding the Abigail Alliance initiative ‘Tier 1 Initial Approval’ (Tier 1). First, the Early Conditional Approval (ECA) concept most often referenced in MNCF’s letter was replaced in February by ‘Tier 1 Initial Approval’. Tier 1 is materially different from ECA, and was found interesting enough by the FDA to merit a meeting requested by Senior Associate Commissioner Bill Hubbard and a written response from newly appointed Senior Associate Commissioner for External Affairs Peter Pitts.
The Abigail Alliance for some time has been close allies with MNCF and we remain so. Both organizations have and continue to work for and stress efforts for more expanded access programs and compassionate use of promising new cancer drugs and other drugs for life saving illnesses. The Abigail Alliance respects differing opinions and thoughts. We are also strong believers in the importance of good dialog.
We think the letter demonstrates a misunderstanding of the purpose, objectives, and details of Tier 1. The new initiative has received high-profile support in the national press and is now being considered by some influential members of Congress. Our comments on your letter are presented below. We have included the headings from your letter to organize our responses.
Safety
Tier 1 requires safety and dosing data sufficient to at least support beginning a Phase II clinical trial in which hundreds of patients will be administered the new drug subject to informed consent. Tier 1 does not require that a request for approval be made after completing only a Phase I study. Tier 1 approval could be sought at any time prior to receiving either accelerated or full approval. Completion of a Phase I trial would generally be the earliest point at which Tier 1 approval could be granted, subject to the standard of safety data sufficient to support a Phase II or III trial and preliminary evidence of effectiveness based on responses that can only be explained as a result of a patient receiving the treatment. A careful reading of the brief Tier 1 document would have revealed these conditions for obtaining Tier 1 approval.
When patients have run out of approved options in their fight for life and are facing a near-certain risk of death from their diseases, a risk to benefit evaluation that recognizes the risk they face from their diseases is the justification used for allowing much of the clinical testing conducted on human beings, and for allowing access through compassionate use and expanded access programs (EAP). If a drug is safe enough to give to patients in a Phase II clinical trial, it is safe enough to give to patients facing the same risks as those who gain entry to the trial. The FDA and Congress have already decided that access under these conditions is appropriate, and it is routinely allowed. Tier 1 also requires informed consent, just as those obtaining a drug in a clinical trial, an EAP, or through compassionate use are required to give their informed consent. The FDA currently approves early access to new drugs outside clinical trials when approving expanded access programs or compassionate use. In reality, expanded access programs and compassionate use are often non-existent, and almost never large enough to accommodate all, or even most, who seek access. In fact, Tier 1 intentionally presents nothing new with respect to the level of safety and effectiveness data required in FDA’s current policies for allowing access to investigational drugs. Consequently, we do not understand the position regarding safety in your letter. If your stated concerns are valid, then exposing hundreds of patients to new drugs in Phase II clinical trials, in EAPs, or through compassionate use is also unacceptable and should be stopped. The Abigail Alliance, the FDA, Congress, oncologists, and practically every one else with an interest in this subject think access to investigational drugs is appropriate for patients with life-threatening diseases with unmet needs and no approved options. Tier 1, like all the existing programs to provide investigational drugs to patients that need access, also relies on these existing inherently correct judgments.
Manufacturing Quality Standards
The MNCF letter raises the issue of manufacturing quality and cites examples of problems that have occurred in other countries that would not occur in the U.S. Tier 1 does not address or relax manufacturing standards, and is not intended to allow manufacture and distribution of improperly or unsafely manufactured drugs. Standards for manufacture of drugs in Tier 1 programs would be subject to manufacturing controls at least as stringent as those imposed for pilot manufacture of drugs for clinical trials, EAPs and compassionate use. It appears that the concern about manufacturing has no connection to our Tier 1 proposal, which is silent on the subject and would therefore not affect existing controls.
Had we received this comment from MNCF earlier, we might have included a provision to clarify that an appropriate level of manufacturing controls would apply to drugs marketed under Tier 1.
Impact on Development of Effective Treatments
A concern regarding impacts on the drug development system is raised in your letter. Tier 1 is clearly explained as being a restricted approval that requires continued clinical trials and pursuit of accelerated or full approval. It appears that the problems referred to in MNCF’s letter are based on the problems that have arisen with completion of Phase IV trials after accelerated approval. Accelerated approval is, effectively, full approval with respect to marketing which has created a problem in completing clinical trials. The problem has arisen primarily from FDA Phase IV clinical trial design requirements that make them impossible to complete, and even in some cases unethical, when the drug is also available with no restrictions outside the trial. The key differences with Tier 1 are that it is a true “restricted” marketing approval that will leave in place substantial financial incentives to continue pursuit of accelerated or full approval, and the requirement that the patients receiving a Tier 1 drug will be those that are unable to get it through enrolling in a clinical trial.
The second point made in the letter on this subject is that some drugs that show preliminary evidence of safety and efficacy later do not show sufficient safety and efficacy for approval. We believe this point is irrelevant to any discussion of access to investigational drugs. MNCF supports EAPs and compassionate use which are equally affected by the same uncertainties. Patients seeking access to investigational drugs, and who will seek access to Tier 1 drugs, will be doing so because the treatments with well proven safety and efficacy (i.e., approved drugs) are not appropriate for them. In most cases, they will have already tried and failed treatment using those drugs. Patients seeking treatment in an EAP, and patients, who will seek treatment with Tier 1 drugs, will for the most part be “experienced” patients that will thoroughly understand that they are asking to be treated with a partially-proven drug.
The argument that Tier 1 will delay and impair the development of new drugs is simply not supported by logic. Just the opposite is likely to occur. Tier 1 would generate resources in the form of income and capital for research and development, especially for small innovative pharmaceutical and biotechnology companies, most of which are now relying solely on investment, an exceedingly uncertain source of funding. It is important to note that it is the small, innovative biotechnology companies that are developing most of the truly new approaches to cancer treatment emerging today, and many of those companies do not yet have approved products to fund their development programs. Moving a new drug from the laboratory to the clinic costs hundreds of millions of dollars. Tier 1 would create a limited source of revenue through restricted marketing for drug developers and would also generate investor interest in development programs. These companies are now encouraged by organizations like MNCF and the Abigail Alliance to create EAPs and provide their drugs to as many patients as they can, but they are usually unable to justify the expense of implementing access programs, or are willing to conduct only very small programs (e.g., Erbitux). Tier 1 creates several incentives for companies to include an access program in their development plans to be conducted in parallel with clinical trials. The main incentive is that the Tier 1 program will generate revenue to offset some of the costs of the development program.
The letter raises concerns that the public would perceive Tier 1 approval as being the FDA’s “gold star approval” standard, thus misleading people to think that a Tier 1 approval is something other than a restricted, preliminary approval. While it is true that many people will not take the time to thoroughly understand the meaning of any type of FDA approval, patients seeking the drug will be required to read and sign an informed consent document that clearly explains the partially-proven nature of the treatment they are seeking. In keeping with existing practice, the physician also will explain these facts to the patient. The tiered approval approach built into Tier 1 was selected to clearly convey that there would be three levels of approval with Tier 1 being the most restricted, based on the least amount of evidence, and limited only to those that can not be successfully treated with drugs approved under Tier 2 (accelerated approval) or Tier 3 (full approval). As is clearly explained in the initiative, Tier 1 is designed to spur broader early access to investigational drugs to better help cancer patients and others with life threatening illnesses that need more options in their fight for life. This is not a difficult concept to explain or understand, and most Americans with an interest will readily understand it.
The letter states, “This form of early conditional approval is likely to impair the progress of clinical trials.” ‘Tier 1 Initial Approval’ very clearly states that access to a drug under Tier 1 Initial Approval would be available only to patients that for one or more of several reasons, are unable to get the drug by participating in a clinical trial. Sponsors seeking Tier 1 initial Approval also will be required to continue diligent pursuit of Tier 2 (accelerated) or Tier 3 (full) approval which would require proceeding with appropriate clinical trials.
It is further stated in the letter that under “Tier 1 Initial Approval’ “…sponsors should be allowed to sell almost anything to patients with terminal disease…” This is a surprising distortion of the clear intent and controls explained in our proposal. ‘Tier 1 Initial Approval’ requires the same evidence of safety and efficacy needed to administer the drug to hundreds of patients in a Phase II clinical trial. The only material difference between the patients receiving a new drug in a clinical trial and those receiving it through a Tier 1 approval is that the latter are unable to participate in the trial. The FDA currently does approve early access when they approve clinical trial protocols, Treatment INDs (expanded access programs) and single-patient INDs (compassionate use). The problem is that these mechanisms generally serve only a small fraction of those in need of the investigational drug.
The letter includes the following text that Tier 1 would put treatments that are not effective on the market “….thus harming an already over burdened health care system.” First, some of the investigational drugs of today will be proven safe and effective and will become the standard of care of tomorrow. EAPs are helpful, but because they have been viewed by industry as pure expenses with no real upside for conducting them, it is necessary for those of us interested in helping cancer patients to look at the reality of asking “for profit” companies to be charitable organizations. They will do it on a limited and sporadic basis, but never to the level needed by those suffering from a wide variety of deadly diseases. Tier 1 acknowledges this reality. Our current system abandons hundreds of thousands of Americans each year that cannot gain entry to an appropriate clinical trial, and for whom there is no other access available in the form of an EAP or compassionate use program. Abandonment of these Americans is unacceptable. We agree that the FDA’s ‘Improving Innovation in Medical Technology: Beyond 2002’ document contains some good ideas, but none that will address the abandonment of so many Americans by our health care system, either now or anytime in the foreseeable future. Incremental changes in the system can do nothing but chip around the edges of this massive problem. Tier 1 is designed to fix it now. If access to clinical trials, and industry participation in EAPs and compassionate use were to double, it would still leave the overwhelming majority of Americans in need of access unserved. It is time to take a step back, take a deep breath, and acknowledge that our current system is not working, and cannot work without major changes. We cannot perpetually work only for future patients. We also have to work effectively for today’s patients.
As the Abigail Alliance brought up in a March 12, 2003 meeting with FDA Associate Commissioner Bill Hubbard and others, there are numerous problems with the health care system in the U. S. Claiming that patients should be denied access to best available care in the form of approved drugs because of an increased cost burden on the health care system is a dangerous concept. Our system has always separated determinations of drug approval from the cost of those drugs, and with good reason. Bringing cost into the approval process will put accountants in charge of approvals. The problems with regulatory access to drugs and the cost of health care are necessarily separate issues that require separate solutions. An example is Eloxatin, the newly-approved drug for colon cancer. The FDA has approved it, and Medicare CMS has indicated that it may not pay for it. If Medicare decides not to reimburse some or all of the cost of treatment with Eloxatin, should FDA withdraw approval? Should FDA have considered this problem before approving Eloxatin and delayed or perhaps denied approval? The answer to both questions is clearly no, and the same logic applies to a concept like Tier 1 approval. Access to partially-proven drugs clearly represents best available care for some patients and should be considered solely on those merits.
Closing Comments
The Abigail Alliance continues to value its relationship with the Marti Nelson Cancer Foundation and others. Again we very much value others input and ideas. This dialog can help us see clearly how best to move forward with ideas to help so many precious people have the best chance possible to fight for their lives.
We are a long way down the road at this point with Tier 1. The idea has gained acceptance and support from a wide cross-section of interested parties, has gotten press coverage and expressions of support from the national media, and has spurred ongoing substantive communications at the highest levels of the FDA and with key members of Congress.