From: Karl Schwartz [karls@lymphomation.org]
Sent: Monday, September 08, 2003 10:14 AM
To: fdadockets@oc.fda.gov
Subject: 2003P-0274/CPI

September 8, 2003

 

RE:  2003P-0274/CP1  
Tier 1 Initial Approval Program to Expedite the Availability of Lifesaving Drugs (Petition)   Citizen Petition of the Abigail Alliance and the Washington Legal Foundation 

 

Mark McClellan, MD, PhD
Commissioner
Food and Drug Administration

Dear Dr. McClellan,

I am the president of Patients Against Lymphoma, and serve as a patient consultant to the FDA.  My comments, however, represent only my personal perspectives, which I believe to be relevant because of my training and seven-year support of patients living with lymphatic cancers and their treatments.  

I wish first to express my deep sympathy with the needs of patients that have led to the Petition  I recognize as legitimate the desire for patients to have autonomy and to have access to investigational treatments.  Facing death, a patient will want to try an unproven path over a path proven to fail.  In a similar vein, it can be argued that it's illogical to try first what is both toxic and ineffective before trying some investigational agents. 

However, I have concerns with the Petition. I will start with the proposal to allow for Tier 1 approvals based on preliminary Phase I or II study outcomes.  Initially, the idea might sound good to patients, but in practice it is likely to have the following important and undesirable consequences:

         There will be increased risks to patients using Tier 1 approved drugs. Statistically, most drugs that complete Phase I will be judged not suitable for approval.  Adding to the risks for patients would be that treating physicians, instead of trained investigators, would monitor patients receiving new and poorly-characterized drugs in local centers, perhaps without adequate resources and time. 

         It will be more difficult to assess the merits and risks of tier 1 approved drugs in these less controlled settings.  This could slow the pace of approval and thereby inadvertently harm the larger patient community who must wait for full approval before having access.

         It proposes a commercial solution while making only modest recommendations for enhancing the compassionate use program, which we address below.  

         It does not adequately speak to the potential downside of reducing standards of evidence, which can undermine the public confidence in marketed drugs and confusion about which drug is best and how it is best administered.   For example, if three new therapies gain Tier 1 approval for a condition, which of these is best, safest, or most dangerous?

         It does not adequately address how the sponsor can collect adequate and reliable data in post-marketing studies in order to establish safety and efficacy after provisional approval.   

         It can have negative effects on the completion of formal clinical trials by distracting the sponsor from the primary goal of winning full approval, and by confusing patients as to why they should enroll in a study for a treatment thats already approved and can be purchased by some patients.  

         We can expect that insurance companies will not reimburse patients for provisionally approved treatments, which is required in order for sponsors to recoup investments and become profitable.  

         The proposed solution would exclude the majority of patients, who will be unable to pay for Tier 1 drugs out of pocket. 

         Even if the petition changed FDA policy, drug sponsors may not participate or may be less inclined to develop new drugs because of the following concerns. 

o        The program would be complex and distract from the more profitable and therefore primary objective of winning full approval  required for insurance reimbursement. 

o        Concerns about litigation resulting from adverse events that are more likely to result when going too fast with a new drug (about which less is known in less controlled settings). 

o        Adverse events in less controlled settings could be considered as increasing the risk of not winning full FDA approval. 

o        Producing drugs on demand in small orders can be much more expensive. It would be difficult to predict manufacturing requirements in practice, and difficult for FDA to confirm good manufacturing practices. This could further delay or compromise winning full approval.

 

Compassionate Use Reform - Access is Not Working
The Petition proposes a commercial solution while making only modest recommendations for enhancing the compassionate use program. 

The compassionate use program is not accessible and when implemented often amounts to too little too late. It requires the cooperation and consent of the drug sponsor, the treating physician, the FDA, and an IRB.  The majority of patients are not aware that the program exists, and treating physicians are unlikely to inform patients or make compassionate use recommendations.  Getting all the parties to cooperate takes considerable time, energy, persistence and luck.

In advance of approval of a CU protocol many important questions can be raised. Has the requesting patient and/or physician done their homework?  Is it the best treatment option?  Is someone failing to recognize that its time to let nature take its course?

How sensible the decision is depends on the type of cancer, the previous treatments, the health of the patient, the mechanism and safety profile of the investigational agent, and whether the potential to help is reasonably established by some preliminary data - and perhaps if the therapeutic target is relevant to the cancer.  

I think its self-evident that a functioning compassionate use program is needed for cancer patients because all too often standard therapies are not effective, and all too often cancer patients are not eligible for clinical trials.  

Here are some well-known reasons patients cannot enter clinical trials they desire: 

  a.. The appropriate study might not be offered locally and travel can be a hardship or impossible. 
  b.. Target enrollment numbers in many phase I and II studies are small. 
  c.. Study criteria exclude many from participation. 
  d.. Studies are typically designed to treat patients in narrowly defined diagnostic and treatment settings, based on calculations on the fastest way to win approval. Large numbers of patients with similar diseases, who could reasonably try the protocol, are often excluded.
About eligibility criteria for compassionate use protocols: 
(in addition to being ineligible for a clinical trial)

  a.. Omit Desperately ill and having immediately life-threatening disease  as requirements for eligibility.  These are inappropriate criteria for access to CU protocols.  This status implies advanced disease and a circumstance where no therapy no matter how advanced is likely to benefit the patient. That said, with the improving specificity and better toxicity profiles of many emerging treatments its reasonable to expect that it will be appropriate to administer CU protocols, increasingly, even to patients with rapidly declining health and end-stage disease. 
Instead, the criteria for eligibility should be the following for patients who have life-threatening cancers and are not eligible for clinical trials:

  1.. When standard therapies are toxic and have demonstrated little or no ability to benefit patients for a given cancer. 
  2.. When the patient is refractory to standard treatments. 
  3.. When an investigational agent is established to be significantly less toxic than standard treatments and has a potential advantage that does not preclude the latter use of toxic standard treatments.  

  NOTE: This last criterion could be most appropriate and best applied when there is no need for an immediate treatment response  the patient is not desperately ill  such as when in watchful waiting status. 
 

A Proposal for Optimizing the Compassionate Use Program
(for cancer patients in need who are ineligible for clinical trials.)  

The proposed changes to compassionate use (CU) in the Petition do not go far enough, in my view, to address the inability of the program to deliver appropriate investigational therapies in a timely manner. 

For example, its widely acknowledged that access to CU protocols is mainly restricted by the drug sponsors declining to make the drug available, and not by existing FDA guidelines. This key problem was not addressed by the petition.  

Recommendation for optimizing the CU program: 

         Set up an NCI-directed panel to create CU trial protocols in anticipation of needs that utilize promising new agents, or new uses of existing agents, that appear promising for patients in a variety of treatment settings. The panel should include experts in the field, in consultation with patient advocates and treating oncologists, with the primary goal of designing protocols that address unmet needs.

NOTE: The selection of an investigational agent for a CU protocol will be seen as an indicator of the potential of the therapy to benefit patients, and therefore sponsors who have confidence in their agents will be likely to welcome the program.

         The program should be conducted by the NCI and funded by both public and commercial monies.  

         The program will require that drug sponsors provide investigational and approved drugs to the NCI for CU studies, as part of deal for the promise of patent protection for drugs that win approval. 

Would an expanded CU program harm accrual in clinical trials?  

o        By definition, a CU protocol is open to patients who are not eligible for other studies. Unlike the present program, CU protocols will be better powered than individual INDs, and they will be structured like formal studies to provide credible data.  Administrators can also refer patients to formal studies for the agent when openings exist.

 What would be the benefits of providing ready-to-use CU protocols?

o        These protocols may help some patients who have failed standard treatments, and they will provide meaningful rationally-selected alternatives to the often-heard refrain that There is nothing more that we can do for you. You should get your affairs in order. 

o        They will investigate promising protocols in settings that are not currently explored in our commercially driven system;  for example, frontline biological approaches for indolent cancers.

o        They can be rationally designed and selected by experts to treat many patients, instead of being selected by treating physicians for individual patients in crisis.  

o        They can be administered on a timely basis  unlike single-patient INDs that take months to apply for and will require the cooperation and consent of the drug sponsor, the treating physician, the FDA, and an IRB. 

o        They will be available to more patients, not just the patients who have the ability, resources and information necessary to apply for single-patient INDs.

 

Safeguards Against Misuse
We must recognize that giving patients the freedom to try experimental therapies when trials are not available is not necessarily in their best interest. Inherently, for new drugs, less is known and significant dangers can exist.  The outcomes could conceivably be worse than had nothing been done. New is not always better. These attempts may increase mortality, pain and suffering, or both in some cases.  However, this is true for any clinical trial for cancer and should not be used as a rationale not to provide rationally selected investigational treatments to patients ineligible for trials. 

Existing safeguards against misuse need only to be applied:  It's the duty of the treating physician, the principle investigators, and in some cases the patient's guardians, to thoroughly inform the individual about the potential risks and benefits of a proposed treatment, and to fully describe and compare it to any viable alternatives.  These safeguards should apply to the initiation of any treatment  be it investigational or standard, be it in a formal study or for compassionate use. 

We also need to help patients and caregivers to recognize that sometimes  when the cancer is advanced and health has been compromised by treatment and disease  additional efforts will do more harm than good, and allow these individuals to die with dignity and help instead to minimize pain and suffering.

 

In conclusion, these two important goals must not be considered mutually exclusive:

  a.. Applying the best possible evidence-based standards to ensure that patients have reliable information about the risks and benefits of marketed treatments for given conditions, and increasing incentives for companies to develop new therapies to meet our needs.
  a.. Providing cancer patients with every reasonable chance to improve their survival and quality of life.
A planned and optimized CU program will be able to provide meaningful safety and efficacy data. It will be much easier to make CU protocols available to patients in a timely manner.  These changes should not influence accrual in similar formal clinical trials.  The current CU program helps very few and teaches us less.  We think that the well-intentioned Petition breaks more than it fixes. We think the correct remedy is not to weaken the evidence-based evaluation system, but to ensure that additional CU or expanded access protocols are developed and are offered when early evidence suggests that an investigational protocol has the potential to help cancer patients in need. 

 

Karl Schwartz
Patient Consultant to the FDA

President, Patients Against Lymphoma
www.lymphomation.org

1305 Mason Avenue
Staten Island NY 10306
718-980-0635
KarlS@lymphomation.org