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Advocacy > FDA & Drug Evaluations

Itemizing Opportunities and Challenges


Introduction & Proposals | Timeline for FDA Policy | Discussion Points  
FDA Drug Evaluation Guidance Papers | Perspectives on the Drug Evaluation System

Introduction & Proposals

The goal of this text is to identify how to meet our common goal of getting better therapies to patients in urgent need of new treatments as fast as we can responsibly do so. To meet this goal we propose the following interim steps:

  • Endpoints in Oncology  FDA
  • FOCUS ON THE MEANING OF CLINICAL BENEFIT: Patient representatives and drug sponsors must  understand the criteria and rationale for the current FDA definition of "substantial evidence" of clinical benefit in clinical trials so we can make responsible recommendations.  See Perspectives on the Drug Evaluation System and Lets be realistic below.
  • GET EXPERTS TO MEET: Seek guidance from the experts and the FDA about responsible alternatives or amendments to the current system. Patient input has been lacking, but the FDA patient consulting program is an encouraging step forward.  We also need to call for proactive meetings of all parties (FDA, academia, commercial drug sponsors, and patient advocates) to develop better clinical trials designs, and more efficient ways of evaluating clinical benefit of new drugs.  Also see More cancer subtypes will not help and When a Patient Speaks - FDA.gov 
  • VALIDATE & USE BIOMARKERS: Identify ways to validate and use biomarkers (indirect evidence of drug activity or improvement in quality of life) in order to infer clinical benefit of new cancer drugs. These markers may also help to complement standard statistical findings, and enable the use of smaller trials that can be carried out faster.  See Questions about biomarkers below.
  • CREATE INCENTIVES FOR DRUG DEVELOPMENT: The expense and risks of developing new cancer drugs are enormous. It is therefore vital to ensure that incentives are provided so more companies take this risk; increasing patent life for new drugs that meet urgent needs, for example.  See High Costs of Developing Drugs below. 
  • ENSURE THAT SAFETY IS FACTORED INTO BENEFIT ASSESSMENTS: Ensure that safety is included in the statistical calculations of determining clinical benefit. For example, enable the approval of drug A that is safer (i.e., transitory instead of enduring toxicity) than available drugs even if it produces fewer responses.  
  • ENSURE THAT DRUG RESISTANCE IS FACTORED INTO BENEFIT ASSESSMENTS: Include in the evaluation of clinical benefit the beneficial property of some new drugs that do not undermine the optimal use of subsequent treatments.  For example, vaccines that activate innate immunity will not cause drug resistance, but the opposite is not true and can preclude the use of future vaccines.
  • FLEXIBLE CRITERIA FOR CLINICAL BENEFIT: Ensure that safer drugs that successfully target pro-cancer mechanisms have a clear path to accelerated approval, even if the clinical activity  is modest or the benefit is to a subset of patients.
  • HARMONIZE RESEARCH AND TREATMENT OBJECTIVES:  Ensure that clinical trials are designed in ways that attract patients. Cancer patients seek trials as treatment, so designing studies that harmonize treatment and research goals will move the research forward and provide the chances for improved outcomes that patients with incurable cancers deserve.   See Patient Perspective in Clinical Trial Design
  • PROVIDE INCENTIVES FOR PTS TO PARTICIPATE IN TRIALS:  Pts who participate in studies provide a great service to our society. Presently, a small number participate; and those that do do so because available treatments are inadequate and toxic. Instead of praise and reward, participants may receive insurance denials for coverage of associated tests. Participants with indolent disease will get frequent exposures to CT scans well beyond what's called for in normal practice.  Consider that many experts believe that a key to the successful management of indolent lymphomas is the creative sequencing  and combination of  treatments not typically applied in study settings . Also see Why Patients Don't Participate in Clinical Trials
    • PROPOSAL: Create incentives for the collaboration between the industry and the NCI to set up Expanded Access and Compassionate Use programs for new drugs judged to have a potential to help patients in end stage disease. 
      Appropriate Compassionate Use protocols should be waiting to receive patients in advance of the individual emergencies that happen again and again.
    • PROPOSAL: Use MRI instead of CT scans to minimize risks of developing secondary cancers, and pass legislation that requires the government to pay for tests associated with clinical trials.  Note:  It's not uncommon for pts with indolent NHL to receive 20 full body CT scans in a few years if they participate in more than one trial.  See FDA 
  • DO NOT LOSE SIGHT OF THE URGENCY: Balance the requirements of science in the evaluation of drugs with a deep appreciation of the circumstances of the patient.  We cannot always wait for all the evidence to be in, particularly when the new treatment has a better safety profile and preliminary evidence shows it has potential. As an example, we believe it's reasonable to license immune-based therapies that safely induce an immune response against tumor antigens because the mechanism of active immunity is so well established. Also see Urgent need below.
  • LEARN FROM THE PATIENTS: Make the changes necessary to ensure that all cancer patients have an opportunity and a desire  to participate in clinical trials. See Why Patients Don't Participate in Clinical Trials
  • CREATE A MORE TRANSPARENT SYSTEM:  It's only possible to improve the drug evaluation system if we can see the process and identify the mistakes made --i.e.,  poor study design or reporting, FDA policy or the application of policy. See Drug Application Transparency and It's not just the FDA below.

Urgent need: Cancer patients need new therapies urgently, as over 500,000 patients lose their battle with cancer each year. According to FDA Commissioner David A. Kessler, M.D., "We cannot wait for all the evidence when people are suffering and dying from a devastating disease. But, we must ensure that all the evidence we need eventually does get collected."   Are we waiting too long to acknowledge valuable agents?  Are we are being too careful in assessing risks? 

There are no conspiracies: There are current differences in opinion on how best to evaluate new drugs, but I believe that all the parties are sincere and want to do what is best. A member of NHL-info said it well: "Not only politicians, regulators, scientists, doctors and pharmaceutical officers get cancer, but their parents, siblings children, grandchildren and best friends - so we have an interested majority in any group you can think of - and we have to work the system by speaking up, being active and letting them know that we care and that we expect them to do their best to deal with this devastating plague in our society."   - Leonard R.

Let's be realistic:  It's not easy to bring therapies from the lab to patients.  It's important to test (when possible) new compounds in animals. It takes time to identify the best doses and scheduling of agents and to determine safety.   It's important that therapies actually work and that their benefits outweigh their potential to do harm. It's also important that products can be manufactured safely and consistently.  It's vital to evaluate the overall value of new drugs, both alone and with other agents.  It's clear that the role of the FDA is essential in this process and that progress has been made.

  • FDA New Drug Development Timeline (chart) PDF | PDF-help

  • See Testing Drugs in People by Ken Flieger, FDA
    Very good and readable background material.

  • See Tufts Center for the Study of  Drug Development Impact Report - Web | PDF | PDF-Help
    "Approval phase for new drugs drops by 30% between '93-'95 and '96-'98," but we can and must do better.

It's not just the FDA. The FDA does not test new drugs or design clinical trials.  Their job is to evaluate the data and ensure that it is not tainted and the benefits of the new agent outweigh the risks.  Therefore, drug sponsors also have an essential role in the process. For example, clinical trials must be well-designed so that the data generated results in unbiased and meaningful information that can lead to drug approval. 

Also see
Some Terms & Abbreviations - ebem.org | Why Patients Don't Participate in Clinical Trials - PAL 

Send information/comments to KarlS@lymphomation.org 

-Karl Schwartz (Patient Consultant, FDA ODAC )

Timeline of legislative events that shape current FDA policy.

To understand the present regulatory environment, we've provided an outline of key legislative events.

Food and Drugs Act
"This first drug law required only that drugs meet standards of strength and purity. The burden of proof was on FDA to show that a drug's labeling was false and fraudulent before it could be taken off the market." - FDA
 "Elixir of sulfanilamide killed 107 persons, showing the need to establish drug safety before marketing and to enact the pending food and drug law."  - biomed.tamu.edu 
Federal Food, Drug, and Cosmetic Act (FDCA) further defines and expands role of FDA, includes requirement of manufacture to prove the safety of a drug before it could be marketed
Prior to 1962 . . .
. . . No efficacy standards exist. Consumers had basically no guarantee that drugs they purchased would work as advertised.  (Many drugs were proven ineffective when efficacy was required retroactively)
A tragedy motivated
 an FDCA 
Efficacy standards begin here: "News reports on the role of Dr. Frances O. Kelsey, an FDA medical officer, in keeping thalidomide off the American market aroused public interest in drug regulation."  - biomed.tamu.edu 
Kefauver-Harris Drug Amendments of the FDCA mandated that manufactures provide evidence of safety and effectiveness. Rationale: promoted "harmless and ineffective drugs can displace proven drugs.  Society would be injured by flood in market marketplace of little understood and  ineffective drugs.
Orphan Drug Act 
"Orphans" are drugs and other products for treating rare diseases. They may offer little or no profit to the manufacturer, but may benefit people with the rare diseases. To foster orphan product development, this law allows drug companies to take tax deductions for about three-quarters of the cost of their clinical studies. Firms also are given exclusive marketing rights for seven years for any orphan products that are approved. - FDA
Late 1980s
Advocate pressure leads to relaxation of formal approval standards at agency
Prescription Drug User Fee Act:  agreement to incorporate tough performance deadlines for decisions on NDA in exchange for fees from drug sponsors. Dramatically improves performance
FDA Modernization Act of 1997 (details): Section 112 " mandates the Agency to facilitate the development and expedite review of drugs and biologics intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Fast track adds to existing programs, such as accelerated approval, the possibility of a “rolling submission” for a marketing application. An important feature of fast track is that it emphasizes the critical nature of close early communication between the FDA and sponsor to improve the efficiency of product development."  FDA
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Discussion Points

A complex system: FDA regulations are complex and include lengthy interpretations.  Resubmission of applications by investigators are common at many stages in the process.  Unnecessary resubmissions and reviews can add years of delay for each drug. Delays cost lives and contribute to patient suffering.  Delays also add to costs.  A delay of one month can cost many millions of dollars.  More importantly, the prospect of delays increase the risks of investing in cancer drug research and discourages creative initiatives.

FDA drug approval standards may be too stringent: While progress has been made with the passage of PDUFA and FDAMA, dramatic examples of success exist (see AIDS example, above), it appears to the patient community that the FDA will tend to error on the side of caution, perhaps because the agency is more harmed politically by approving harmful drugs (i.e., thalidomide) than by failing to approve beneficial drugs (i.e., Idiotype vaccines).  

Bureaucratic delays: The FDA is a large institution with a broad range of responsibilities.  They may be under-funded and require reorganization to adjust to the increased demands caused by explosion of information about cancer and new therapeutic targets. Importantly, the important work of education and proactive guidance for drug sponsors is not covered by user fees that fund the bulk of FDA activity.

High costs makes investment risky: It costs over $500-800 million to develop a single drug for commercial availability in the U.S.  Many promising therapeutics are not evaluated because potential sponsors deem it too risky to fund the testing process.

New therapies have poor odds for success: Only one of every 50,000 drugs initially screened actually becomes an approved medicine.  Some of these compounds may be quite useful either alone or in combination with other agents.

Current evaluation methods take a long time: It now takes from 10 to 15 years to test drugs before they can become available to patients. However, it takes as little as one year to determine the safety of a drug.  The majority of time and capital is spent on the assessment of clinical benefit.

Shortages of capital and trained people: There is a shortage of adequately trained clinical investigators and research nurses.  Money is needed to fund studies and attract talent.

More cancer subtypes will not help: New diagnostic techniques will define subcategories of cancers, which will reduce the pool of eligible patients and thus make accrual in trials more difficult.  Current methods of evaluating efficacy requires the evaluation of large numbers of patients for long periods of time.

There are more ideas than resources: An explosion of new and highly specific therapeutics are emerging as a result of insights about cancer and cancer-host interactions.  This will place an enormous burden on the FDA to evaluate these agents in a timely manner, and require creative solutions to evaluating the safety and efficacy of new treatments. 

Transparency in the drug evaluation and application process: The law that requires non-disclosure of agency decisions should be amended. The policy is in place, we're told, to protect trade secrets. But, we have doubts that publicly identifying reasons for delays or denials, such as problems with toxicity, manufacturing, or clinical outcomes, really compromises trade secrets. Greater transparency would enable advocates and drug sponsors to make informed contributions to the process; drug sponsors will be able to learn what succeeds, what fails, and why. For example: If delays are caused by a sponsor's inability to manufacture consistent product, is it productive for cancer pts to blame the FDA for foot dragging? Conversely, if a delay is from questionable agency policy, how can we redress that policy unless we see it applied?  Finally, we will all gain by learning from the mistakes made in the process, such as what constitutes a flawed trial design, or how the FDA defines substantial evidence of effectiveness in particular cases. 

Commentary on Transparency:
  • Statement by Jane E. Henney, M.D. Commissioner of Food and Drugs Food and Drug Administration before the Committee on Health, Education, Labor and Pensions United States Senate October 21, 1999 - FDA


Questions about statistics and biomarkers: Is the FDA providing guidance about how biomarkers might be validated as future endpoints to show clinical benefit?  Have drug sponsors or the NCI asked the FDA for such guidance or made proposals?  Who is most likely to conduct such studies (NCI/Drug sponsors)  What would such a study entail, and do you see signs that they have begun or are likely to begin soon?

Question about statistics and historical controls:  How many pts would need to be enrolled in a non-randomized trial in order for the time to progression outcome data to have statistical significance -- assuming a good deal of retrospective data exists for standard treatment?

Question about statistics and drug safety profile: Is the relative safety of a new drug and properties related to drug resistance included into statistical assessments of clinical benefit?

Question about statistics and biomarkers measured in a given study: What if biomarkers correlate with effectiveness in a given study. Can that correlation be used to support the finding of clinical benefit?  If such a correlation is established, can sponsors who produce new agents that use the same mechanism of action use that marker as evidence of clinical benefit?

Question about statistics and chance:  We understand that measures of response can be misleading in a study. That said, is it true that for some cancers, placebo or chance cannot account for verifiable responses to treatment in a study?  If true, do statistical methods incorporate this perspective, or do all studies of all drugs for all conditions use the same assumptions about chance and placebo effects?  Can a new drug that has less but significant clinical benefit --compared to standard treatments -- still readily win approval if it's toxicity is less, or that benefit applies to some patients refractory to all standard treatments?

PROPOSALS: (Under Construction)

To expand the definition of clinical benefit to include tumor stabilization, improvements quality of life, modest activity if the agent has reduced or transient toxicity and/or the new agent does not impair the pts ability to benefit from other treatments.  Tumor regression, delayed time to progression, tumor stabilization, immune responses, can all be valid endpoints, especially when therapies are less toxic. 

To identify and validate surrogate biomarkers that infer clinical benefit.  This may aid in the identification of safer drugs that may not kill tumors but, instead, prevent tumor growth. Candidate Biomarkers include: LDH, gelectin-3, BCL-2, VEGF, bFGF, copper/zinc ratio, or some combinations of these markers.

Acknowledge the limitations of single-agent studies. A one-punch prize fighter will not win many battles.  Cancer cells are adaptable and therefore it is unlikely that any single agent will improve survival.  

To rapidly approve safer therapies even if they show modest activity, such as endogenous compounds like endostatin, and autologous vaccines so they may be used by patients in need and more rapidly combined with other agents.  

To increase patient participation:  Seek informed patients to participate in the design of clinical trials and sensitize investigators to the needs of patients when designing studies.  Simplify consent forms and case report forms. Provide objective education about the merits of new trials. Require insurance providers to pay for related tests. Provide travel and lodging support, and require government reimbursements for associated tests. 

To not attempt to prove survival benefit for indolent cancers.  While proving survival benefit is important, it's also very difficult to prove when treating indolent cancers in which life expectancy can range from five to twenty years. Patients who progress while participating in a study will cross over -- use numerous treatments that will confound the survival assessment. Patients may avoid participating in studies that do not offer a crossover provision in some cases. 

To make the drug evaluation system more transparent.  More individuals will be willing to invest in companies developing cancer drugs when they know what the board of directors knows and at the same time.  Patients will have more confidence in the clinical trial system when they have access to real outcome and side effect data instead of press releases that may contain biases.  

To apply drug evaluation policy in ways that protect incentives to develop new drugs:  When two similar drugs are in the Accelerated Approval path, the approval of the first should not adversely affect the approval of the second as this policy will reduce incentives to develop new agents.   

To support novel statistical study designs and procedures to improve the efficiency of clinical trials of novel agents. This will reduce the risks of investing in cancer drug research and encourage more creative initiatives.

To specify early stopping criteria to terminate studies of toxic or ineffective agents.  This will direct funds and talent to more productive areas.

To support advocacy efforts with Medicare and third-party medical insurance providers to ensure patient access to participation in Phase I, II and III clinical trials of innovative cancer therapies.  This will save insurance providers money in the long run as better and safer therapies will reduce costs.  It must be cheaper to treat patients right the first time, and not have to treat the side effects of toxic therapies, for example. 

To encourage development of new methods to determine optimal dose:   "We need new rules for this age of molecular therapeutics, Druker suggested. The most efficient method for setting trial doses may be to base ranges on insights gleaned from molecular biology rather than to base doses on older procedures developed when less information was available."

To learn from our successes and test therapies on untreated patients:   Three factors were important for the success with STI571, said Druker. First, the disease involved a discrete molecular abnormality. Second, clinicians have a reliable and straightforward method of identifying eligible patients (STI571 might not work on the 5% of CML patients that don't carry the Philadelphia chromosome). Third, treatment is possible in the early phase of the disease, before secondary molecular defects have accumulated. 

Utilize Fast-track (Accelerated Approval): This FDA provision can expedite the review of drugs and biologics intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. One "unmet need" of low grade lymphoma patients is the availability of novel treatments that controls or regresses the disease while minimizing the following:  

  • Damage to normal cells and organs, including immune function. It is not uncommon for patients to succumb to infection that results from depressed immune function -- a side effect of the majority of standard treatments for cancer.
  • Drug resistance.  A drug with even limited efficacy can be extremely valuable when it does not preclude the patient from benefiting from subsequent treatments. Chemotherapy drugs often regress tumors, but they are not curative and can contribute to producing surviving cells that are more aggressive and resistant to future treatments. 
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FDA Drug Evaluation Guidance Papers

  • FDA: Clinical Trial and Human Subject Protection - Web
  • FDA: ICH-Guidance on General Considerations for Clinical Trials - PDF | PDF-Help
  • FDA: ICH-Guidance on Statistical Principles for Clinical Trials -  PDF | PDF-Help
  • FDA: CDER Drug Approval Application Process - Web
  • FDA: Providing Clinical Evidence of Effectiveness for Human Drugs and Biologic Products PDF | PDF-Help
  • FDA: Fast-track - About-Web | Guidance for the Industry - PDF | PDF-Help
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Perspectives on the Drug Evaluation System

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For all medical concerns,  you should always consult your doctor. 
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