> FDA & Drug Evaluations
Itemizing Opportunities and Challenges
& Proposals | Timeline for FDA Policy | Discussion
Evaluation Guidance Papers | Perspectives
on the Drug Evaluation System
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
Endpoints in Oncology
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
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.
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
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
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
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." -
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
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
"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.
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 )
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
A tragedy motivated
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
Advocate pressure leads to relaxation of formal approval standards
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
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
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
approving harmful drugs (i.e., thalidomide) than by failing to approve beneficial drugs
(i.e., Idiotype vaccines).
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
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.
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.
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
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
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
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
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.
not attempt to prove survival benefit for indolent cancers.
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
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.
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
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
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
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.
FDA Drug Evaluation Guidance Papers
FDA: Clinical Trial and Human Subject Protection - Web
FDA: ICH-Guidance on General Considerations for Clinical Trials - PDF |
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
Perspectives on the Drug Evaluation System
The FDA view on
non-inferiority trials - PDF
FDA ODAC Discussion - FDA.gov MARCH 12, 2003
PURPOSE: (1) to review past accelerated approvals; (2) discuss the current progress of associated Phase IV commitments; and (3) solicit input for improving the accelerated approval process.
Benefit vs. Risk: How the FDA Approves New Dugs - MDAdvice.com
Drug Approval Over regulation Article - by
Michael R. Ward
Drug Development: Who Knows Where to Time Goes (fdli.org)
FDA: From Test Tube to Patient - PDF
Issues Surrounding The Drug Approval Process With The
FDA - Pharma
Understanding Clinical Trials From The Patient's
Patty Delaney (FDA)
Tufts Center for the Study of Drug Development Impact Report
| PDF | PDF-Help
Other Tufts CSDD Impact Reports: Web
Will FDA Relinquish the "Gold Standard" for New Drug
Approval? by Jennifer Kulynych, PhD - PDF