[Ip-health] Size of trials by status (S or P) - Some 2004 FDA and Parexcel data compared

[James Love]

Joe,

What Michael Palmedo reported were the number of patients in clinical
trials referred to by the FDA in a new drug approval, in the
"clinical trials" section of the approval letter.   His reason for
focusing on this is given below.  But first, let me note the following.

These are not "CPTech numbers."  They come from the FDA.  The numbers
are not "estimates,"  but rather the numbers reported by the FDA as
the evidence the drug is safe and effective  (assuming Michael reads
the FDA letters correctly).  Allow me to explain one reason we are
interested in the data.

Relative size of trials:  As you know (but did not really address
below), Michael was asked to look at the "relative" size of trials
between standard and priority drug approvals.  We are interested in
this issue for the following reason.  We want to know if company R&D
investments are directed at priority or non-priority medicines.
Relatively smaller trials would suggest (all other things being
equal)  investments in clinical trials for priority products may be
smaller than investments in trials for "standard" drugs.

I asked Michael about the issue of other trials not reported on the
Clinical trials section of the FDA approval letter, but sometimes
reported elsewhere.  This was his reply:

--------------Michael Palmedo quote----------
"There are two parts of the FDA labels that typically include
patients in clinical trials - the Clinical Trials section and the
Adverse Reactions section. At one point I tried to incorporate the
adverse reactions section, but found that this approach was
problematic as well. For starters, it does not include control
groups, so it too gives incomplete information. It often gives a
higher number than the Clinical Trials section, but not always, and
it sometimes gives a lower number. Sometime it gives estimates
instead of numbers "Approximately 2,000" or "more than 1500." So if
you take the highest number off the label for one drug, and then
compare it to the highest number on other labels for other drugs, you
are comparing:
- full numbers of patients from a specific subset clinical trials
- the number of patients in an unknown number of trials (maybe all
the trials, maybe not) minus the control groups
- vague estimates"
--------------end quote-------------

Michael said he wanted to "keep the comparisons apple-to-apple" using
what seemed like the most important data, the trials cited as the
main basis for the FDA approval.

You are correct, if Michael presents this data, he (we) should always
mention that these data under-report the total number of patients,
and be clear that the data is only that reported in the Clinical
Trials section of the FDA approval.  With this explanation and
context, it is interesting to compare the size (apple to apple) of
trials for priority and non-priority products.   The numbers of
patients in the trials for the priority products have been
considerably *lower* than for standard products.

With respect to the trials not included in the FDA section on
clinical trials for a particular approval, there are, as we have both
noted, different possible explanations as to what they may represent,
including unreported (small) Phase I trials, trials not considered
scientifically important on that indication, trials on the same drug
for a different indication (which may or may not receive a priority
status), or a variety of situations where people get drugs for
compassionate use (sometimes as part of a 'trial' that mostly yields
info on adverse effects), or for some trials that some might call
"seeding" trials, and may have a marketing purpose.

All of this being said, I don't see any reason not to look at, report
and think about the data from the FDA approval letters under the
clinical trials section, and to use this data to examine certain
issues, such as the one that Michael was asked to look at.

We are also keen to look at other data on clinical trials, including
data that would shed light on the questions of relative sizes of
trials for priority and non-priority drugs/indications, as well as
other issues.

There are also a set of interesting questions on the optimal number
of patients in studies to establish safetey and efficacy of products,
and the ways people might distinguish between what is needed for
science and health policy, and what might be done with marketing
purposes in mind -- an issue that many big drug companies have raised
in various reports in the news media, such as the ones reported below:


From: Evidence Regarding Research and Development Investments in
Innovative and Non-Innovative Medicines, September 2003. (footnotes
renumbered)

5.1 Pharmacoeconomic Analysis in Clinical Research

When commercial interests perform research, the research program is
influenced in many ways, including areas where marketing objectives
influence the choice and design of studies.  There exists
considerable confusion and some controversy over the actual cost of
performing clinical trials; but there is general agreement that
spending on clinical trials has increased sharply in the past fifteen
years.  In their study of 1996-1998 new drug approvals, Tufts
researchers Kaitin and Healy described the underlying reasons for the
increases in the costs for pre-approval trials as follows:

------
Advances in scientific knowledge, the greater complexity of new
products, an increase in the number of pharmacoeconomic studies done
in the pre-market phase, and industry inefficiency are contributing
to an escalation in the size and complexity of clinical trials, and
an increase in research and development costs.[4]
---------

While the first two factors are generally considered positive
developments, there is considerable controversy over the benefits of
designing trials to address pharmacoecononic and marketing issues.
Fred Hassan, then CEO of Pharmacia and PhRMA chair, told McKinsey
Quarterly,"You=92re also dealing with demands for very expensive
outcome trials from various regulators as well as from managed-care
administrators.[5]  In a brochure, Demonstrating Product Potential
for Competitive Advantage,[6] consultant Abt Associates describes the
relationship between marketing and science as follows:

----------Abt brochure---
We understand that the transition from clinical development to
marketplace introduction is critical to the success of any
pharmaceutical, biotechnology, or medical device product.  Our
expertise can enhance your plans for research before, during, and
after market launch. Our projects =97 which range from small-scale
retrospective studies to large-scale prospective registries =97 can be
used to generate greater understanding of the use and value of a new
drug, biologic, or device. This understanding in turn supports its
use by physicians and managed care organizations (MCOs) as well as
appropriate coverage of reimbursement decisions by payors =97 both
public and private.   Abt Associates' skill and experience in post-
marketing evaluations can help sponsors meet the needs of their
marketing and sales teams. Since the 1970s, Abt Associates has
conducted hundreds of prospective observational studies and
longitudinal surveys to determine the value of healthcare products
and services across a wide range of therapeutic areas. We will work
with you to achieve the scientific credibility needed to maximize
your product exposure.
---------------

An undetermined amount of investment in clinical trials, both before
and after product approval, is related to marketing issues.[7]
Consider these quotes from a Wall Street Journal article on clinical
trials:[8]

------WSJ story-----
. . .increasingly, marketing executives are joining research teams
from the start, surveying doctors and consumers and tailoring trials
to win optimal "positioning" in the marketplace. Many of the biggest
trials come not in difficult-to-treat diseases such as cancer, as one
might expect, but in well-established therapeutic areas, such as
antibiotics or blood-pressure drugs, where enormous testing programs
are needed to ferret out small advantages over existing drugs that
can then be highlighted in marketing campaigns.

"The FDA told us that we don't need all these trials" to get
omapatrilat approved for blood pressure, says Hubert Pouleur, Bristol-
Myers's vice president for cardiovascular clinical research. "But
there is a difference between getting a drug approved and having it
be a commercial success. A new drug will be used only if it is a
significant improvement on existing drugs, and to establish that you
need trials that aren't required for approval."

Postmarketing studies, as trials for drugs already on the market are
called, "are billowing out of control," says Eve Slater, Merck's
senior vice president for clinical testing. She decries "a total lack
of science" in some studies. But drug marketers contend they are
helpless to stop the one-upmanship. If a rival mounts a new study
aimed at backing up a sales-expanding marketing claim, "you have to
do it, too, or you are dead in the water," she says.
  ---------------

             Seeding Studies

A particularly controversial mixture between research and marketing
are so-called "seeding studies," which are designed to promote the
use of medicines. [9]

Traditionally, once a product has been launched the company wants to
gain as much market share as possible to gain return on investment.
One way of achieving the involvement of prescribers and patients is
the use of 'seeding' studies. In such trials, the data is often
collected by sales reps rather than Contract Research Organizations
(CRAs) and patient recruitment is often thinly spread over a large
number of sites.[10]  Seeding studies are generally held in very low
esteem, particularly if the company attempts to masquerade them as
Phase IV studies. Some of the characteristics of seeding studies are
listed below:

Characteristics of Seeding Studies
Lack of control group

Inadequate statistical power

Involvement of a large number of study sites, each recruiting only a
few patients

Inappropriate use of sales representatives

Vague safety aim, irrelevant or inappropriate outcomes

Short-term studies with a drug intended for long-term use

Paid for directly by the company's marketing department

One interesting analysis of the role of seeding studies in marketing
was recently published in The Netherlands by the Health Care
Inspectorate.[11]   The 25-page report details a wide range of areas
where research and marketing are blended together, often apparently
in violation of Dutch and European regulations on ethical marketing
practices.  Of particular interest here are some of the discussions
of the practice of using clinical trials as marketing practices.

-------Netherlands analysis----
Expenditure on combined scientific and marketing studies are
sometimes included under expenditure for research and development and
clinical studies and not in the marketing plans.. . . All studies
(including Phase IV studies) must meet the criteria set out in the
Medical Research Involving Human Subject Act. These tests must be
checked by a medical ethics committee.  Exposing people to non-
scientific studies using medicinal products is unethical.
Findings

In some cases the marketing plans refer to designations which fall
under the phase IV study, such as value-added projects, post
marketing surveillance (PMS), seeding trials, phase IV study,
clinical trial and study.  . .  The objectives of the phase IV
studies described in the plans show that influencing prescriptions
for the product being promoted and building up relationships with the
doctor are mentioned in 48 of the 71 surveys (68%).  There are no
specific study objectives in the remaining 23 surveys.  In addition
to money, incentives in kind offered to doctors including
sphygmomanometers, hand-held computers etc. are mentioned... The
designations in the studies suggest that they could be described as
scientific studies. The fact that no specific study objectives were
mentioned in some of the studies leads us to assume that the
execution of the study is not a prime objective.  The question is how
the medical-ethics committees have interpreted their tasks in these
cases. This is all the more so in those cases in which the marketing
plans have explicitly mentioned influencing prescriptions as an
objective.  Presenting these forms of influencing as research can be
seen as socially unacceptable and unethical. It undermines the
public=92s trust in healthcare. The articles in the Medicinal Products
Advertising Decree are not legally geared towards tackling this.
----------------

Another section of the Dutch Health Care Inspectorate report
describes other research-related activity that have marketing
objectives.

-------
Investigations by the Inspectorate have revealed that about 50% of
refresher courses for GPs are sponsored and/or organised by the
pharmaceutical industry.  The pharmaceutical industry often
determines who is invited, thus creating restricted access for the
profession as a whole. Because the topics are generally determined by
the pharmaceutical industry, the course programmes are more likely to
be supply-oriented rather than demand-oriented.  The question is
whether the needs of public health are served by this situation.
About NLG 18,000,000, or about 11% of the total [marketing] budget,
is spent on promotional meetings which are often not accredited.
These meetings are made attractive to the target group by linking
them to attractive locations and/or events. The objectives mentioned
in the plans include persuading doctors that the medicinal product in
question is the best, increasing the number of patients treated, and
encouraging or influencing doctors to participate in phase IV studies.
-------

[4] Kaitin Healy, page 2.
[5] Catherine George and J. Michael Pearson, "Riding the pharma
roller coaster," The McKinsey Quarterly, 2002 Number 4.
[6] http://www.abtassoc.com/Page.cfm?PageID=3D6300, Demonstrating
Product Potential for Competitive Advantage.
  [7] For recent examples of studies designed to achieve marketing
purposes, see: http://www.biospace.com/news_category.cfm?
CategoryID=3D25&SR=3D1
[8] Robert Langreth, "Drug Marketing Drives Many Clinical Trials,"
Wall Street Journal, November 16, 1998.
[9] La Puma J. Physician rewards for postmarketing surveillance
(seeding studies) in the US. Pharmacoeconomics 1995;7(3):187-90.
Steven Piantadosi, Clinical Trials: A Methodologic Perspective, John
Wiley and Sons, New York, 1997.
[10] http://www.pmlive.com/archive.cfm?
&ArticleID=3D175&back=3D-1&print=3D1, Clinical Trials: Part Two: Marketing
and Clinical Trials.
[11] Health Care Inspectorate, Marketing plans for medicinal products
available on prescription only: the current situation, The Hague,
July 2001, second revised edition.



---------------------------------
James Love, CPTech / www.cptech.org / mailto:james.love@cptech.org /
tel. +1.202.332.2670 / mobile +1.202.361.3040

"If everyone thinks the same: No one thinks."  Bill Walton