|
Past Issues
Volume 20, numbers 1, 2, 3
January – March 2006
The End of Early Access?
Is there still a need for expanded access to experimental drugs?
A Look Back at Early Access
Activist documents from 1991 and 1997
The Down Side of EAPs
Research sites howl over administrative burdens
Ethical Review of HIV Research Studies
IRBs are one of the watchdogs of HIV research
Strenghthening Health Systems
Universal Access to ARVs will depends of building capacity
Where are the Women?
GMHC Action Center members call for more inclusive research
Uncertain Future for Early Access?
By Bob Huff
In the bad old days—before effective combinations of HIV
medications dramatically rolled back the tide of suffering
and death from AIDS in this country—informed patients-turned-activists
helped institute a revolution in drug development that allowed
people with no hope to obtain promising new antiretroviral
(ARV) drugs before the FDA had approved them. Initially called
"parallel track"—because it was a separate way to simultaneously
access drugs outside of ongoing clinical trials—early or expanded
access programs (EAPs) became an expectation with every new drug.
The first parallel track program for ddI in 1990 enrolled over
20,000 people to receive the drug for up to 12 months before it
was finally approved in late 1991. There may well be hundreds or
thousands of people alive today because early access to ddI or
another drug gave them a six-month reprieve that kept HIV at bay
long enough for something else to come along.
But the ddI experience showed that early access to experimental
drugs could also give an early warning about uncommon adverse events
that are only noticed after a large number of people have taken the
drug. Because the ddI access protocol called for fairly rigorous
safety reporting, the several cases of fatal pancreatitis identified
let doctors know that this was something to watch out for once the
drug hit pharmacy shelves.
Beyond addressing the humanitarian need for rapid access to new
lifesaving drugs and offering an early look at safety data in a relatively
large patient population, early access also gave drug makers a head start
in building the market for a new drug. Because doctors and patients were
already using the drug when FDA approval came and the company could begin
charging money for it, the time required to achieve market acceptance—and
profitability—was dramatically shortened. For people with HIV, their
doctors, and the drug companies, early access programs were a win-win-win
situation.
If there was one downside it was that patients chasing the
next new drug were burning though their options as fast as HIV
could develop resistance to each single active agent added as
monotherapy or, when its companion drugs had already failed,
virtual monotherapy. Even after combination therapy was recognized
as the way to go, it was several years before industry and the
HIV medical community generally accepted that the only safe way
to add a new drug was to be sure that it was supported by other
active agents in the rest of the regimen. Tragically, many expanded
access participants from the 1990s are today resistant to nearly
all of the 20-plus approved HIV drugs. Many still worry that early
access to the next promising drug is all that can rescue them from
the brink of runaway HIV infection.
When treatment activists meet with drug companies about an
ARV in development, planning for an expanded access program is
always near the top of the agenda. From the mid-1990s forward,
treatment activists have consistently demanded that EAPs be made
available to "any patient unable to construct a viable treatment
regimen." Most companies eventually adopted this broad and rational
criterion, although many initially limited expanded access eligibility
to people with very low T cell counts—those most in need—due to a
limited supply of drug or perhaps too sparse data safety. One continuing
community complaint is that EAPs sometimes open too late to offer a
significant advantage to many people—sometimes beginning enrollment
only a few months before approval. Typically, people receiving a drug
for free through an expanded access program will continue to receive
it for a few months after approval until a stable method of reimbursement
is established.
Ten years after the advent of truly effective antiretroviral
therapy and 15 years after parallel track, there are emerging signs
that expanded access programs may no longer be filling the need they
once did, and that the burden of running these programs may be forcing
some doctors in large clinics and research sites to say "no thanks"
to early access.
Early access programs are actually formal studies conducted
under FDA-approved protocols. Participants must be informed
about the risks of taking the experimental drug and they must
give their written consent. The protocols are vetted by ethical
review boards and the data may be monitored by safety review
committees. Patients give blood samples and are examined according
to the protocol. All adverse events—whether considered caused
by the drug or not—must be reported to the FDA, the ethical
review boards, and to every investigator using the drug, whether
in a clinical trial or through an EAP.
In 2005, one new protease inhibitor, Aptivus (tipranavir),
was approved, and in 2006 another new protease inhibitor, Prezista
(darunavir), was approved in June. Each of these drugs were available
to patients before approval through expanded access programs that
ran in parallel with the main clinical trials designed to support
approval. In an attempt to roll back the window of early access
earlier still, Open Label Safety Studies (OLSS) allowed a small
group of the most desperate patients to obtain drug under very
strict protocols before the large clinical trials had even finished
enrolling. After a few months the entry criteria were relaxed a
bit and the drugs became available to a broader group through
conventional early access protocols.
Despite what was thought to be an urgent need for a new protease
inhibitor with activity against PI-resistant HIV, enrollment in the
tipranavir EAP was dissappointing, with less than 1,000 patents
having enrolled by the time of approval. Many observers thought
this low enrollment for a badly needed new drug may have been due
to concerns about liver toxicity associated with tipranavir and
with the fact that another new drug with a better safety profile,
darunavir from Tibotec, was making rapid progress towards becoming
available in its own EAP.
But reports about Tibotec's experience with darunavir suggest
that something else may be going on. Early access to darunavir
began in the fall of 2005 through an OLSS before opening up to
a wider group with an expanded access protocol in October 2005. There
was a lot of positive buzz about darunavir (TMC114) because it
seemed to be very effective, minimally toxic (compared to tipranavir),
and because the FDA had given it an extraordinarily fast track
based on data from Phase II trials. Yet at the time of approval
in June 2006, perhaps only 800 people had taken advantage of early
access to darunavir. Was it that patients were finding all the
drugs they needed elsewhere? Or were the barriers to running an
expanded access protocol becoming too great for the research sites
that traditionally enroll most patients in EAPs?
The industry has estimated that there may be over 120,000
patients on a third or fouth regimen in 2006 and that 45,000
of these will switch therapies during the year. So if only 10%
of those switching went to an EAP for a new drug, that would
suggest enrollment numbers could reach several thousand.
With evidence accumulating that staying on a failing regimen
may have benefits, and with several new drugs in the development
pipeline, it may be that patients and doctors aren't feeling a
desperate need to switch and are deciding to wait until they can
put together a potent regimen that will last. Perhaps the tide
of multidrug resistance due to serial monotherapy has crested.
In 2006, several new expanded access programs are expected
to open as the pipeline surges with the first of a new wave of
drugs. Pfizer's entry inhibitor, maraviroc, Merck's integrase
inhibitor, MK-0518, and Tibotec's NNRTI, TMC125 may soon be
in competition for research sites and patients—not only for
expanded access, but for pivotal clinical trials as well. Will
the network of experienced research sites have enough time and
staff to handle all of the clinical trials—for which they are
reimbursed—and still have the capacity to host more than one
unfunded expanded access program? Perhaps another reason that
expanded access programs are falling by the wayside is because
so many promising new drugs are becoming available through
clinical trials. In late May 2006, Gilead Sciences announced
that it had met Phase II enrollment targets for its new integrase
inhibitor ahead of schedule and was closing the study to new
patients. Larger, Phase III trials for Merck's similar compound
are also said to be enrolling swiftly.
If the number of people who can benefit from early access
has declined, the sense of desperation for people who truly have
no treatment options has not lessened. If the large, geographically
diverse, expanded access program is becoming a dinosaur, then
treatment activists, drug companies, and the FDA need to agree
on creative new ways to get experimental drugs to those in need
without strangling patients in red tape. One proposal is for
a streamlined individual treatment IND—a protocol for a study
of one—using a simple, standard, web-based form, and a central
ethical review committee, that can offer early access to a
new agent based on a doctor's medical judgment—not on his
capacity for battling bureaucracy.
Whether they serve the numbers they once did or not,
sponsors are unlikely to stop planning for EAPs. Community
pressure for continuing the programs remains consistent—and
there will always be some patients for whom they are
lifesaving. But simply offering an expanded access protocol
to ordinary treating physicians gives companies a valuable
chance to educate HIV doctors about a new drug or a new drug
target prior to approval. In the win-win logic of expanded
access, this is an advantage that will likely keep EAPs part
of the HIV landscape for the forseeable future.
History of Antiretroviral
Expanded Access Programs
(EAPs) in the United States |
|
| Drug |
Dates of EAP |
Pts in EAP |
Approval Date |
| Zidovudine (AZT) |
198687 |
4,804 |
March 1987 |
| Didanosine (ddI) |
198991 |
~22,000 |
October 1991 |
|
Zalcitabine (ddC) |
199092 |
6,705 |
June 1992 |
| Stavudine (d4T) |
199294 |
12,561 |
June 1994 |
| Lamivudine (3TC) |
199395 |
29,430 |
Nov 1995 |
| Saquinavir (SQV) |
1995 |
2,200 |
December 1995 |
| Indinavir (IDV) |
1995 |
1,500 |
March 1996 |
| Ritonavir (RTV) |
1995 |
2,000 |
March 1996 |
| Nevirapine (NVP) |
1996 |
421 |
June 1996 |
| Delavirdine (DLV) |
199697 |
1,527 |
April 1997 |
| Nelfinavir (NFV) |
199697 |
3,100 |
March 1997 |
| Efavirenz (EFV) |
199799 |
8,281 |
September 1998 |
| Abacavir (ABC) |
199798 |
<5000 |
December 1998 |
| Amprenavir (APV) |
199899 |
2217 |
April 1999 |
| Kaletra (LPV/r) |
199900 |
~2,400 |
September 2000 |
| Tenofovir (TDF) |
2001 |
3,111 |
Ocober 2001 |
| Enfuvirtide (ENV) |
200203 |
~3000 |
March 2003 |
| Atazanavir (ATV) |
200203 |
3610 |
June 2003 |
| Tipranavir (TPV) |
200405 |
972 |
June 2005 |
| Darunavir (DRV) |
200506 |
~800 |
June 2006 |
June 1991: Access vs. Answers
ACT UP/New York, Treatment and Data Committee
"There is, to be sure, an incredible irony in all this. Sick gay
men, abandoned by a president who refused publicly to acknowledge their
disease on all but one occasion, provided the shock troops to move
forward his administration's deregulatory drug control program."
Harold Edgar + David Rothman
"The ddI expanded access program saved my life."
A Person With AIDS
In the past year and a half, more than 20,000 people have
received ddI through expanded access programs. Meanwhile, clinical
trials of ddI have enrolled faster than trials for any other
comparable antiviral therapy tested by the AIDS Clinical Trials
Group (ACTG). This doesn't mean that tensions between the need
to adequately characterize a new therapy and the need to provide
treatment to people at high risk for severely debilitating disease
and death have been resolved. Some activists continue to complain
that the ddI expanded access program is overly restrictive and
demand the drug's approval before clinical trials have been
completed. Many doctors and regulators who have seen Bristol
Myers-Squibb's NDA application have expressed doubt about the
quality of the application.
This experience has initiated a debate about the importance
of "Access vs. Answers," as though there were an essential conflict
between allowing people for whom no approved therapy exists to
access promising unproven medications and the conduct of sound
scientific research on those medications. This is more a sign
of the intellectual poverty of regulators, scientists and AIDS
activists than an indication of any real dichotomy. The regulation
of AIDS drugs, like the treatment of AIDS, must build on its
experience; we must incorporate knowledge gained from the ddI
experience into future attempts to resolve regulatory and trial
design issues.
The need for ethical, well-designed trials that provide clear,
quick answers has never been more pressing. Some have suggested
that validation of new therapies takes so long as to be virtually
useless. However, we cannot allow this crisis to eliminate requirements
for sound efficacy evaluation. It is grossly unethical to require
PWAs to make treatment decisions in an informational vacuum any
longer than is absolutely necessary. While the FDA is often unresponsive
and painfully slow, deregulation promises nothing more than a
capitulation to life-or-death treatment decisions based on "drug
of the month" anecdotes, an unacceptable solution to many of us
who are fighting for our lives.
The unrecognized benefit of Expanded Access programs is
that they provide the equivalent of a Phase Four post-marketing
study coterminous with the randomized Phase II efficacy trials—generating
invaluable insights into the patterns of use and real-world
toxicities likely to be encountered when the drug is taken by
its intended population, with all its diversity and
heterogeneity. While the FDA might be understandably reluctant
to approve a drug which has only been taken by the small number
of people in a controlled Phase II trial, proof that the drug
is safe in a broad swaths of the real-world HIV population
would provide significantly greater confidence, thus supporting
an NDA.
The key to achieving faster drug development in AIDS lies
not in an exclusive focus on Expanded Access or Parallel Tracks,
but rather on their integration into an enlightened program of
rapid, flexible, humane and attractive clinical trials.
The activists, regulators, and statisticians have provided
the tools. It is up to industry, now, to use these tools to
devise not only better treatments and prophylaxes, but a cure
for AIDS within this decade.
1997: Whatever Happened to Expanded Access?
The PWA Health Group Newsletter
In 1996, expanded access has all but disappeared. Why? AIDS
hadn't changed, lots of drugs were in the pipeline, and company
profits were climbing. In fact, the more money drug companies
made, the smaller and shorter the programs got. In 1996, marketing
replaced compassion for PWAs with no other options. Companies
designed programs as public relations stunts, getting their brand
name out, not the drug. How could they offer lotteries for
life-saving drugs?
Like it or not, drug companies are not the same as
other corporations. They are part of our health care system.
They make products that can save lives. They have a responsibility
to society, not just their investors. All over the world, drug
prices are regulated, preserving both profit and access. But
not in the US, where government officials support corporate
health over public health. Expanded access is a real way for
companies to honor their community role, offering hope and
collecting critical safety data. Expanded access programs are
not required. They cost money. In 1989, the urgency of PWAs
pushed companies to be generous. AIDS in 1997 is just as
urgent. Once again, we need to organize, get noisy and push
for fair, early access for all of us who need this chance.
|
The Down Side of Expanded Access Programs
A Site Management Perspective
By Harry C.S. Wingfield
Expanded access programs allow patients to add a promising
new drug to their antiretroviral (ARV) regimen months before
the drug is expected to be approved. For people with few treatment
options, expanded access programs can be lifesavers. For the companies,
the programs offer a head start in developing a market for the drug
as key physicians become familiar with the new product.
Expanded access programs are conducted as research protocols
in clinical settings and must be approved by the FDA and by ethical
review committees or institutional review boards (IRBs). An expanded
access program site may be located in a local doctor's office or a
large university HIV research clinic (which is where I work), yet
each must adhere to the regulatory agency's requirements for record
keeping and safety reporting. While small clinics and independent
physician researchers may use a single national IRB for ethical
oversight, universities typically host a local IRB that must approve
all human research conducted at that institution.
Clinical research sites typically get little if any funding
from drug companies to run expanded access programs for investigational
HIV drugs, yet these projects probably consume more site staff time
than most conventional research studies. A few busy research sites,
particularly those associated with large universities, have recently
refused to open expanded access programs due to the uncompensated
burdens of administration. If this trend continues, then in the
future there will be fewer opportunities for patients to obtain
access to desperately needed new treatment options.
Study Start-up
Drug companies almost never pay the same start-up fees for
an expanded access study as for a conventional drug development
study. Yet the work at best is equal, and is often more
time-consuming. Any study involving an investigational drug,
even a drug that is very close to FDA approval, requires the
same elements in submissions to the IRB. This includes all
the local required documents, the rewriting of the informed
consent to conform to local regulations and guidelines
(which also must be approved by the sponsor's regulatory
and legal staff before, during and after the IRB approval
process), and the copying and filing of all correspondence
with the IRB and with the sponsor and/or study management.
The drug companies usually want to rush the expanded access
protocol through the IRB submission process. This is admirable,
since it means the drug will get dispensed sooner to people who
need it, but it usually results in sloppier work being done at
all levels, with multiple protocol revisions being necessary. Often
the protocol and/or template consent form will need to be re-written
one or more times because the protocol wasn't thought through
carefully before being released to the sites, or because late
breaking data needs to be incorporated, or because errors were
made that weren't caught in the proofreading process. Each
rewrite results in the sites having to make protocol revision
submissions to the IRB. Revision submissions can be almost as
time consuming and paperwork-generating as initial submissions.
When rushed and/or overworked, contract research organizations
(CROs)—third party clinical trial specialists often hired by drug
companies to actually manage expanded access programs—are more
likely to misplace key documents such as signature pages, original
financial disclosure forms, etc. This means duplicated effort for
the sites if they have to print new forms, obtain new signatures,
and send the signed forms to the sponsor again. Depending on the
form, this may also result in a new IRB submission as well.
My experience at the local level is that the more I am
rushed, the more likely I am to make a typo on a consent
revision or some other form, or to miss one sheet out of
the mountains of papers the investigator is required to
sign. In the world of regulatory compliance, you can't just
put a line through a typo and write the correction above
it with your initials and date. You have to generate a
document highlighting the correction, and generate a clean
document incorporating the correction, and then get this
copied and approved by the sponsor, CRO, and IRB.
The grants and contracts specialist at the research
site has to do the same work for an expanded access study
as for any other study. The host institution will take
the same "overhead" fees from the company's payment. IRB
processing and review fees are the same. Nurses, doctors
and data managers have to do the same preparation in terms
of becoming familiar with the protocol, the study forms,
and the data recording and reporting processes, and must
set up files and notebooks just like they do for any
other study. All this takes time, which costs money.
Running the Study
While drug companies may pay limited start-up costs for
an expanded access study, they seldom pay anything for
the costs of running the study. Again, these costs are
as high if not higher than those for a drug development
study.
Any time a patient with limited treatment options is
enrolled in a study with a new agent, a resistance test
should be done to make sure the patient's virus is sensitive
to the drugs in rest of the ART regimen. If the only active
drug is the investigational agent, then there is a risk of
developing resistance since the patient will be on "virtual
monotherapy." For a salvage study being used for drug
development, sponsors usually pay for this resistance
testing, and occasionally help pay for the optimized
background regimen. For expanded access studies however,
the resistance test must be paid for by the patient. If
the patient has inadequate insurance coverage for this,
the site usually ends up absorbing the cost. If the patient
is unable to pay for the drugs in the new optimized background
regimen, then site staff often ends up spending additional
time to help the person enroll in compassionate use or
the state's AIDS Drug Assistance Program (ADAP).
Another major reason for the increased costs to research
sites offering expanded access programs is the health status
of the patients often enrolling in these studies. In a typical
Phase II or III drug development study, there are tight inclusion
and exclusion criteria designed to ensure the integrity of the
data and protect patient safety by filtering out patients with
very advanced disease. This also means that the likelihood of
a study patient experiencing an adverse event is fairly low,
and usually not expected.
This is not the case for expanded access studies. The
patients who enroll in these studies are often very sick,
to the point that the new drug is their last (but very slim)
hope. The inclusion/exclusion criteria for expanded access
studies are minimal. Patients with high viral loads, low
to non-existent CD4 counts, and pre-existing conditions
are allowed to enroll. Unfortunately, these patients are
easily prone to severe illness. Furthermore, a sick patient
will come to the clinic more often than a healthier patient,
and will require more time from site personnel at every level.
Once a patient becomes a study patient, every adverse
event, every illness, and every lab abnormality, even if
it is obviously related to a pre-existing condition and
not related to the study drug, must be reported to the
sponsor and to the IRB. Moreover, the event usually must
be reported several times, because there are usually follow
up reports generated. It may seem irrelevant to a study drug
that a patient with a pre-existing end-stage brain infection
has a seizure after enrolling in an expanded access study. However,
because there is no way to completely rule out that the drug
did not exacerbate the condition to some degree, the event must
be reported. Every follow up visit, every new lab report, and
every recurrence of the event must be reported again, until
the time when and if the condition is resolved.
In addition, each one of these adverse event reports
then becomes a safety letter that is sent to every other
site using the drug in research. These safety reports must
be filed in each site's regulatory binder and reported to
their IRB, and then documentation of IRB receipt must be
filed and sent to the sponsor. This can result in multiple
shelves of binders full of paperwork. Every on-study serious
adverse event, from every clinic in the world doing research
on the drug, must be filed at every site and reported to
the IRB at every site that is using the drug in any research
project. For example, during the tenofovir (Viread) expanded
access study in 2001, I accumulated 10 full binders of safety
report filings by the time the study closed. For a few months,
I was processing up to 10 or more tenofovir safety reports a
day, spending half my time on it. Most of these were obviously
related to late-stage HIV complications, but since an
association to the drug could not be ruled out, all of the
events had to be reported. For every report and follow-up
report on an adverse event related to pre-existing C.
difficile or seizure disorder, there might be another
report that could lead to a real association of the drug
to a condition like renal disease or bone density problems.
We want to do everything we can to get potential life
saving drugs to patients, but clinics also have to pay the
doctors who diagnose and evaluate the events and the study
staff who have to process the paperwork. In addition, the
lab work for safety labs, if the patient's insurance doesn't
cover it, often must come out of the site's budget. Expanded
access studies often consider safety labs to be part of
"standard of care." They expect reporting of all labs,
including routine viral load, CD4 and CBC counts, but
seldom pay for the cost of these labs.
The bottom line is until the FDA approves a drug, it
can only be accessed through a research study. Even expanded
access studies are by definition research studies, and can
be audited by the FDA just like any other study. Therefore
all the same work must be done to stay in compliance with
Good Clinical Practice, multiplied by the fact that these
studies, by nature of enrolling very sick people, can eat
up a major percentage of the staff's work hours. Since the
expanded access studies are often conducted at the same
time as the FDA submission process, the drug companies often
generate even more regulatory paperwork than normal.
Companies should be willing to pay the sites for the
work they do on expanded access studies. The sad fact is
that some research sites are now declining to participate
in these programs because they are unwilling to take on
the extra burden. It's not that the sites don't want to
help people obtain early access to promising new HIV
drugs; it's that they can't afford to pay the people who
have to perform the significant amount of work involved.
Harry C. S. Wingfield, MFA, is a site regulatory specialist
at a major U.S. clinical research institution.
The Role of IRBs in U.S. HIV Clinical Trials
By Kelly Safreed-Harmon
HIV clinical trials, like other studies that test medical
hypotheses in humans, embody a fundamental ethical tension. The
immediate well-being of clinical trial participants, even those
who might benefit greatly from certain experimental regimens,
is implicitly being weighed against the future well-being of
other unknown people.
Who decides whether the risks to clinical trial participants
are justified by the possible health benefits that they and other
people might experience? According to modern ethical and legal
norms, it is essential for each individual to make his or her
own decisions after receiving accurate information about the
study in question. "Informed consent" refers to the process
through which investigators educate potential participants
about a trial's risks, benefits and objectives. By formally
providing informed consent, people attest to their understanding
and acceptance of what they will be asked to do in the course
of the trial.
Experience has suggested that informed consent by itself
is not enough. Unless he or she happens to possess the relevant
professional background, a person considering a clinical trial
might find it challenging to rigorously evaluate the scientific
underpinnings of the study protocol. And even someone with a
sophisticated understanding of the protocol is still dependent
on the study team to conduct itself with integrity. A study
team that lacks the judgment or knowledge to work in an ethically
sound manner can inflict physical or psychological harm on
even the most educated study participant.
The Emergence of the IRB System
Institutional review boards, commonly known as IRBs, bring
an important form of oversight to the decision-making processes
behind US clinical trials. An IRB is a committee of people who
draw on their various areas of expertise to evaluate study
protocols. According to federal regulations, a clinical trial
cannot be undertaken without IRB approval.
IRBs are created and managed by organizations that
are themselves involved in research, with board members
drawn primarily from within those bodies. Since community
input is recognized as a component of the ethical review
of research protocols, an IRB is required to include at
least one member who is not affiliated with the institution.
(This policy is also intended to serve as a check on the
potential conflict of interest that is created by essentially
asking institutions to monitor themselves in regard to
research ethics.)
Formal systems for protecting research participants
are relatively new in the history of medicine. The first
widely recognized ethical document relating specifically
to studies involving humans was a response to the atrocities
committed by Germany's Nazi regime. Horrifying evidence of
Nazi doctors' widespread experimentation on concentration
camp prisoners gave rise to the 1947 Nuremberg Code. An
American-led military tribunal formulated the Nuremberg
Code in the course of issuing verdicts against 23 Germans
implicated in the experiments.
The World Medical Association introduced a second
influential ethical statement, the Declaration of Helsinki,
in 1964. This document addresses important aspects of human
subjects protections in more specific terms than the Nuremberg
Code does.
The Nuremberg Code and the Declaration of Helsinki
have done much to frame the discourse about how ethical
principles should inform modern medical research. However,
neither is actually a legally binding regulatory document.
Medical researchers and research institutions in the
United States and elsewhere were left to interpret and
act upon the guidelines as they chose.
Research involving human subjects went on with minimal
government oversight in the United States until the early
1970s, when news of the Tuskegee syphilis study marked a
dramatic turning point. In 1972, a front-page New York
Times article revealed that government researchers had
intentionally withheld treatment from a large cohort of
African-American men in a decades-long study of the effects
of syphilis.
When the study began in Tuskegee, Alabama in the early
1930s, no treatment for this disease was known to be widely
effective. In the years following World War II, penicillin
became the standard treatment for syphilis. But the Tuskegee
researchers, seeking to learn more about the natural progression
of the disease, did not offer penicillin to study participants
or inform them of its effectiveness.
Congressional hearings in the wake of this disclosure
led to the passage of the 1974 National Research Act, which
did much to define US regulatory structures and procedures.
The legislation established the Office for Protection from
Research Risks, as well as mandating IRB review of all
research funded by the Department of Health, Education
and Welfare.
Federal Oversight and IRBs Today
More than three decades later, while the regulations
brought into being by the National Research Act have
undergone some revisions, the overall system remains
in place. The Office for Protection from Research Risks
was reorganized as the Office for Human Research Protections
(OHRP) and given broader responsibilities in 2000. OHRP's
authority extends over the research activities of public
and private institutions receiving Department of Health
and Human Services (DHHS) support. (DHHS is descended
from the Department of Health, Education and Welfare.)
Every institution under the jurisdiction of OHRP is
required to either maintain its own IRB or be affiliated
with an IRB. This IRB usually is charged with reviewing
all of the institution's proposed studies involving human
cohorts — not just the studies supported by DHHS.
An IRB is legally authorized to operate when OHRP
has granted it permission to do so by issuing a "federal-wide
assurance" (FWA). The FWA imposes a set of regulations that
specify in great detail how the institution should carry
out research activities that involve humans. For example,
researchers must obtain informed consent from all study
participants and must be able to document this consent.
The FWA serves as the primary enforcement mechanism
in OHRP's oversight system. OHRP has the power to revoke
the FWA of an institution that is found to not be in
compliance with research regulations. If an FWA is revoked,
then the institution must halt its research. The day-to-day
work of conducting studies is actually brought to a
standstill. Also, there is a freeze on funding from
the many federal agencies that have adopted OHRP's
standards. (These include the National Institutes of
Health and the Centers for Disease Control and Prevention.)
While OHRP has never permanently revoked a major
US research center's FWA, temporary revocations have
compelled a number of institutions to overhaul their
research procedures and practices. Johns Hopkins
University, the University of CaliforniaLos Angeles,
and Duke University Medical Center are among the
institutions that have had their FWAs briefly suspended
after OHRP identified major problems with how their
IRBs were functioning.
IRBs have the enormous responsibility of considering
proposed studies from an ethical standpoint, which means
weighing potential benefits of new scientific knowledge
against potential risks to subjects. There may be some
clear benefits to subjects, e.g. medical care; financial
compensation for their time; opportunities to try
experimental regimens that possibly will be more
efficacious than approved regimens. At the same
time—and also of concern to IRBs—there is the potential
for benefits such as those named to serve as undue
inducements. That is, people might feel uneasy about
a trial's drawbacks, but sign up anyway out of a sense
of desperation.
As a check on the judgment of investigators, IRBs
thus are at the nexus of the OHRP system. In the last
several years, a number of widely publicized cases have
shown that clinical trial participants' health—and even
their lives—still can be put at risk, and that their
rights still can be violated, in spite of IRB and OHRP
oversight. These developments have raised questions
about how strong the regulatory system is and whether
individual IRBs are performing effectively.
One response to the latter issue has been the creation
of new agencies to accredit IRB programs. The non-profit
Association for the Accreditation of Human Research Protection
Programs (AAHRPP) has emerged as the central player in the
accreditation movement. Following intensive reviews, AAHRPP
has accredited 35 institutions to date, including Johns Hopkins
University, Stanford University and other research
powerhouses. AAHRPP reports that another 365 organizations
have begun the demanding accreditation process.
The US Food and Drug Administration (FDA) oversees research
separately from OHRP. Any human study of an investigational new
drug (IND) that might become a candidate for FDA approval should
be implemented according to FDA regulations. Generally speaking,
these regulations are similar to OHRP regulations (although from
a legal perspective some of the differences might be considered
significant). The FDA, like OHRP, calls for IRB oversight of all
human research. (If a study of an IND takes place at an institution
that has an FWA from OHRP, then the study falls under the jurisdiction
of both OHRP and the FDA.)
In recent years, private independent IRBs have emerged
as an alternative to IRBs convened by research institutions. A
researcher affiliated with an OHRP-governed institution may have
the option of hiring an independent IRB to review his or her
protocol, providing that the IRB has an FWA from OHRP. Independent
IRBs also review protocols for studies taking place in the private
sector.
Some people have expressed skepticism about the adequacy
of reviews by independent IRBs, which—unlike university and
hospital IRBs—typically do not disclose the names of their
board members. However, by and large, the most prominent
independent IRBs seem to be winning the confidence of the
biomedical and bioethical communities. At least two independent
IRBs have been accredited by AAHRPP so far.
Throughout the 1980s and most of the 1990s, the workings
of the IRB system elicited little public comment. Then in the
late 1990s and early part of this decade, a series of
episodes—including the deaths of patients in three clinical
trials—called into question how well IRBs were meeting their
responsibilities.
Medical journals and the mainstream media served as
vehicles for calling attention to what a 2001 article in
Annals of Internal Medicine called "a crisis in confidence"
in the oversight system. OHRP underwent great scrutiny as
it reviewed and restructured its role. In recent years,
there have been fewer reports of ethical questions or
lapses related to trials conducted in the United States. However,
some highly important concerns remain to be addressed.
Shortcomings of the System: Implications for Researchers
From the standpoint of many clinical investigators, the
ethical review process has changed greatly during the last
several years. OHRP has investigated a relatively small
number of institutions for alleged regulatory violations,
but those cases have encouraged many other institutions
to scrutinize and improve upon how their IRBs operate. This
presumably has resulted in some advances in regard to the
protection of research participants; at the same time it
has added considerable administrative requirements for
both IRBs and investigators.
One of the most common themes to emerge from investigators'
criticism of IRBs relates to the length and complexity of the
review process. As IRBs have become more attentive to the
details of applications—in many cases asking for more
information than in the past—investigators have found
themselves in what may seem like a maze of paperwork. Requirements
for reporting "adverse events"—health issues that develop
for trial participants, and that might be related to the
experimental regimens they are following—add further to
the workload.
Questions have been raised about whether IRBs are
overburdened and insufficiently funded—logical questions,
since it appears as if backlogs at some IRBs have delayed
the review and therefore the implementation of protocols. The
nature of clinical research itself has changed in ways that
affect this already-complicated situation. Far more multi-site
trials are being conducted now than in the 1970s, when the
IRB system took form. Some trials might be staged at two
dozen sites or more. If one IRB requires revisions in the
trial protocol, then the amended protocol might need to
be re-approved by all of the other IRBs.
(Originally, multi-site trials required the review
and approval of IRBs at all trial sites. OHRP and other
federal institutions have made some progress in developing
more efficient ways for multi-site trials to be approved. The
National Cancer Institute, for example, is piloting a
central review system that is designed to supplement
the work of local IRBs. However, many multi-site trials
still undergo full review at each participating institution.)
Another layer of complexity is added when US
investigators want to implement protocols at sites in
other countries. (The investigators are bound by the
regulations of both the US government and the host country
or countries.) Following the appropriate procedures and
documenting the process to the appropriate degree can
be particularly challenging in resource-limited countries,
where a significant number of HIV clinical trial sites
are now found.
Various stakeholders in the clinical research realm,
including research institutions, their IRBs, and the federal
agencies that oversee them, are working to streamline the
administrative processes for clinical investigators. But
the question of how to do this under the federal regulations
inherited from the 1970s, without compromising the quality
of the ethical review process, is a formidable one. (Some
analyses have concluded that a new regulatory system is
in order, but there has not been widespread consensus-building
of the nature that would be required for Congress to create
the necessary legislation.)
Shortcomings of the System: Implications for
Research Participants
While there are concerns about how the regulatory system
affects the pace of research, it is essential to remember
that protecting the well-being of research participants
is the overarching goal. The risks of enrolling in some
types of clinical trials may be quite small, but virtually
no experimental intervention is risk-free. Investigators
have the obligation to minimize the risks as much as
possible, in keeping with the ethical principle that
it is unacceptable to harm current research participants
in the name of acquiring medical information that could
benefit others in the future.
IRBs are charged with ensuring that both the ethical
principles relating to research and the legal regulations
intended to support those principles are honored. It could
be argued that the US IRB system has stood the test of
time in the sense that nothing on par with the Tuskegee
scandal has been observed in the 30-plus years since
then. However, there are various other ways in which
IRBs might not be completely fulfilling their mandate.
The very nature of the IRB system, with internal
ethical review of an organization's research protocols,
creates the potential for conflicts of interest to undercut
the protection of research participants. For example, an
IRB member may feel reluctant to criticize a protocol from
a colleague with whom he or she works closely.
Internal ethical review may also have the opposite
effect. IRB members who are very concerned about protecting
their institution's reputation may steer an overly cautious
course and reject protocols that would impose an entirely
reasonable level of risk on participants.
There is another type of conflict of interest that
warrants scrutiny. In this era of major industry involvement
in research, investigators may have strong financial incentives
for enrolling people in clinical trials. In some cases,
investigators may own stock in or be paid consultants to
companies sponsoring research. In other cases, industry
sponsors may offer payments to investigators who meet study
enrollment goals. There may also be payments made to
non-medical personnel to reward them for recruiting people
for studies.
The presence of financial incentives is particularly
troubling when the setting is the office of a physician
whose patients expect him or her to use the best possible
judgment in the course of providing medical care. Many
people who are unaware of the existence of financial
incentives will assume that their physicians and the
physicians' staff are exclusively concerned with patient
well-being. An invitation to join a clinical trial may
erroneously be interpreted as a suggestion to pursue a
better course of treatment than that which is currently available.
In clinical trials involving financial incentives,
one can speculate that telling people about those financial
incentives might affect their decisions about whether or not
to enroll. Telling them might also affect their relationships
with their physicians, raising questions in their minds about
whether the physicians' clinical recommendations are colored
by self-interest.
It is not known how effective IRBs are at mitigating
the challenges that financial conflicts of interest may
pose for clinical trial candidates. There is significant
variation in the policies that individual IRBs have adopted
in regard to whether or how investigators should acknowledge
having financial stakes in trials.
Discrepant standards for the informed consent process
constitute another major area of concern. There is relatively
little empirical evidence to help investigators and IRBs
identify best practices in regard to seeking informed consent
from research participants. A three-page informed consent
form describing a study's goals, risks and benefits might
be considered too detailed by one IRB, but not detailed
enough by another. The language in an informed consent
form is supposed to be tailored to the literacy level of
the intended audience, but deciding whether the form will
succeed in conveying key information can be a subjective
process.
From the research participant's standpoint, this means
that enrolling in a study may involve receiving an informed
consent form that is too complicated to understand. Alternately,
the informed consent form may have been simplified to the
point that it leaves out significant information. In either
scenario, someone might be in danger of signing an informed
consent form and undergoing an experimental treatment without
fully understanding the risks.
In summation, there is more than one way to characterize
the US regulatory system for protecting human subjects. Reasonable
arguments could be made for the effectiveness of the system,
especially as it compares to the regulation of clinical research
in many other countries. On the other hand, the US regulatory
system could also fairly be described as very much of a
work-in-progress in some regards. There are shortcomings
that urgently need to be addressed by both the biomedical
field and those outside of the field who have taken on the
charge of advocating for patients' interests.
It is important for the HIV/AIDS community to understand
how IRBs are entrusted with safeguarding key components of
the system, and to more broadly understand the roles of all
major stakeholders in the ethical review process. Doing so
will enable individuals to become more informed participants
in HIV clinical trials. Just as importantly, it will ensure
that the community as a whole has a voice in some of the
most vital ethical issues of our era.
What We Can Do: The Public's Role in Promoting
Ethical HIV Clinical Trials
Clinical investigators, institutional review boards
and federal overseers are not the only parties responsible
for ensuring that research participants' right and interests
are protected. It is vitally important to recognize that
we — people living with HIV and their allies and
advocates — should also take an active role in the
ethical dimension of the clinical research enterprise.
Before enrolling in a clinical study that is affiliated
with an academic research center, consider this advice:
- Carefully read the informed consent form. Do not sign
it unless you are sure that you understand the contents,
which should address the goals, risks and benefits of the
study in understandable language. You might want to take a
few days — or more — to thoroughly review the form and to do
research about the medications and procedures being used in the trial.
- Providing informed consent is a process, not a simple
act of signing a document. This means that the potential trial
participant should have the opportunity to discuss any concerns
directly with the study investigator. Clinical trial managers
and other staff members may have a role in educating people
about trials, but they cannot substitute for the medical
professionals who are charged with safeguarding your health.
If you feel unsatisfied about your communication with the
study investigator or other members of the study team, this
might be a warning sign.
- Confirm that the study has been reviewed and approved
by an institutional review board (IRB) that is registered
with the Office for Human Research Protections (OHRP). If
this is not stated directly in the informed consent form,
then ask the study staff. They should be able to provide
you with the name of the IRB, as well as the IRB's Federalwide
Assurance number. (OHRP assigns a unique number to each
Federalwide Assurance that it grants.)
- If you want to assess the situation more rigorously,
you can ask the investigator if the IRB that reviewed the
study expressed any concerns before approving it. You can
also ask the study team or the IRB itself for a copy of
the meeting minutes documenting the IRB's consideration
of the study.
Some industry-sponsored trials are not affiliated
with academic research centers, in which case the IRBs
approving the trials may be operating under less
scrutiny. In those situations, you may want to take
the these measures:
- Ask the study team if its IRB is accredited by the
Association for the Accreditation of Human Research Protection
Programs (AAHRPP), or is in the process of applying for
accreditation. AAHRPP sets high standards and conducts
rigorous reviews of applicant organizations. IRBs that
seek accreditation are likely to be committed to doing
their job effectively.
- Ask if the clinical trial has been registered in
the US government's official clinical trials database
(www.clinicaltrials.gov). The study team should be able
to provide a database registration number. If the trial
is not registered, this possibly raises questions about
the commitment and professionalism of the study's leaders
and sponsors.
-
Kelly Safreed-Harmon |
Universal Access to ARVs
Requires Stronger Health Systems
By Rebecca Pointer, Rene Loewenson, Gregg Gonsalves
From EQUINET, June Newsletter
When the United Nations General Assembly met in
June to review progress in tackling the AIDS epidemic
it was reminded by civil society globally of the commitment
made to ensure universal access to treatment for AIDS by
2010. This commitment has greatest resonance in sub-Saharan
Africa where AIDS-related mortality is highest.
Two years ago, in June 2004 the regional EQUINET
conference of civil society, state, academic and parliamentary
delegates resolved that the health challenges in east and
southern Africa demanded health systems that are universal,
comprehensive, equitable, participatory and publicly
funded. This also has urgency in a region where poverty
is undermining progress in meeting the most basic Millennium
Development Goals.
How do these two sets of imperatives relate to each
other? Do they reinforce each other or are they competing
for policy attention and resources? Does giving urgency
to addressing the right to treatment for AIDS boost or
weaken efforts to rebuild fragile health systems? This
was the focus of debate at a meeting in Cape Town in
early May 2006 that gathered international AIDS activists,
people living with HIV and AIDS (PLWHA), and health
activists. The meeting was organized by Gay Men's Health
Crisis (GMHC) with support from the Rockefeller
Foundation, and focused on "Identifying public policies
for scaling up antiretroviral therapy (ART) and
strengthening health systems in developing countries."
The gathering of AIDS and health systems activists
itself signals a widening social debate on health and
health systems, raising the social, economic and political
profile of health after decades of market reforms that
have undermined equity and solidarity in health and that
have weakened public health systems. It builds on new
and increased resources that AIDS brings to health
systems, and a growth in social movements for health
that can strengthen relationships between health services
and communities.
Delegates recognized that access to treatment for
AIDS is a right, and so too is access to essential
health care. An advocacy and public policy agenda that
recognizes both of these rights of necessity calls for
health — systems friendly, people (especially
PLWHA) — driven approaches to the establishment,
scale-up and long-term sustainability of AIDS treatment
programs. There has been past debate on whether the
speed of responding to treatment rights compromises
this goal of building sustainable systems. The AIDS
epidemic is an emergency and the level of avoidable
infection and death calls for measures to bring HIV
prevention and AIDS treatment services rapidly to
community levels. At the same time it is a chronic
long-term issue that calls for sustainable systems
and measures beyond emergency responses.
How can this be achieved? The meeting reinforced
the more general call within the region for people-centered
health systems. The role people play in decision making
in the health sector is important, and often weakly
recognized. Specific measures were called for to
remedy this.
For example, it was proposed that decision-making
structures and processes include the active participation
of PLWHAs, their communities, health care workers and
other stakeholders from civil society. However, the
governance of the health sector is weak in many countries
and the acceptance of the role of civil society is
contentious for many governments, thus making real
participation a challenge in most settings. In order
to pave the way for greater involvement, this participation
needs to be backed by regulatory frameworks, guidelines,
clear policy messages from governments and effective
mechanisms and processes to manage this engagement,
including for transparently managing conflicts in the
interests and priorities of different groups.
Delegates agreed that involvement in decision
making and delivery raises a corresponding obligation
of PLWHAs and communities to be literate on both HIV
prevention and AIDS treatment and on how health systems
work. Building on community-based AIDS treatment
literacy, health systems literacy is needed to build
community knowledge on public health, and the health
systems through which prevention and treatment are
delivered. Just as AIDS treatment literacy has become
a vehicle for mobilizing communities around rights
of access to ART, so health systems literacy should
be a tool to mobilize communities around their
collective rights to health and health care.
The desire to move at "AIDS speed" has led to
vertical programming to meet short-term demands,
and delegates at the meeting agreed that some
verticality is needed in the short term in response
to the epidemic. However vertical programs can only
sustain the long-term, lifetime delivery of ART if
they are integrated within the wider health system.
The issue of vertical programming and the integration
in health systems is not unique to AIDS, and affects many
other disease-based programs. The resources flowing to
AIDS programs gives it specific prominence, however, as
the positive and negative systems effects can be
pronounced. This issue naturally arose in the dialogue:
delegates at the meeting recommended that plans for AIDS
treatment programs need to assess which components can
be immediately integrated into general health systems
and which require vertical implementation in the short-
to medium-term. Delegates also raised the need for plans
to be set up front for how all vertical components will
be integrated into the health system in the medium- and
long-term. Whether initial decisions are made to vertically
implement certain components of AIDS treatment programs
or to immediately integrate these components into general
health systems, delegates raised the need to recognize,
monitor and address problems that might arise from whatever
approach is adopted.
As the meeting noted, this calls for national information
systems and research that is able to identify these effects. It
also calls for policy processes that are responsive to
this information and flexible enough to rapidly correct
problems.
EQUINET has raised that fair financing and valuing of
health workers is central to rebuilding national health
systems in the region. These issues were also central in
the dialogue at the meeting.
The absolute shortage of trained health care workers,
at crisis levels in some African countries, is now a major
impediment to treatment access, and needs short-term action
linked to long-term measures. Health systems and AIDS
activists agreed on this. Efforts by some governments in
east and southern Africa to tackle this issue were noted,
and need to be supported, spread, and backed by consultation
with health workers. This calls for targets for training
and employing health workers, new resources to employ and
pay incentives to retain health workers and removal of
any international finance institution conditions or fiscal
restraints that undermine the application of these
measures. The meeting delegates expressed frustration
at the slow pace of global discussions and measures to
cancel debt, mobilize aid and lift fiscal restraints to
support these health system measures, relative to the
speed with which these resources are needed.
The meeting agreed that a point of synthesis of
all these points is that of support for bottom-up
district level planning as this brings communities
and health service providers together around priority
health needs, including AIDS treatment. A number of
key features were raised, for example:
- bottom-up level district planning that involves communities
in a substantive way;
- respect for district planning by governments,
international agencies, non government organizations
and donors;
- ensuring free access to AIDS treatment (and
primary health care services) at point of service
and addressing other barriers to accessing care,
such as transport to health services;
- resource allocation systems that are responsive
to district planning.
To this we may add ensuring that health workers at
district and primary health care levels are adequate,
valued and retained, including ensuring their own access
to AIDS treatment, strengthening district-level health
information and planning systems and revitalizing and
resourcing the community health worker and primary health
care approaches that strengthened the interface between
communities and health services.
Finally, the stewardship of global public health, AIDS
programs and health systems, needs independent and rigorous
external monitoring.
The promises made at the 2001 UNGASS were largely
promises broken and the new promises made at the 2006
UNGASS in New York need to be held open to greater
scrutiny in the years ahead. Stronger mechanisms for
monitoring of good practices and stewardship in health
at global, regional and country level must be established
and led by institutions from developing countries.
The dialogue at the meeting in Cape Town provided
a useful opportunity to identify shared goals and paths
to strengthening health systems and ensuring universal
access to AIDS treatment. It now provides a useful
"watching brief" for health systems activists and AIDS
activists to see how far the dialogue at UNGASS addresses
our shared expectations.
EQUINET, the Regional Network on Equity in Health in
Southern Africa, is a network of professionals, civil
society members, policy makers, state officials and others
within the region who have come together as an equity
catalyst, to promote and realize shared values of equity
and social justice in health.
www.equinetafrica.org
Reports From the 7th
HIV Pharmacology Workshop
By Polly Clayden
HIV i-Base
Effect of Pregnancy on
PK of Protease Inhibitors
Previous studies investigating the pharmacokinetics (PK) of
protease inhibitors (PIs) show reduced exposure during
pregnancy. M. Regazzi and coworkers from a multicenter
cohort in Italy evaluated nelfinavir and lopinavir plasma
levels in a group of HIV-positive pregnant women after
receiving multiple doses.
A group of 29 women in the 3rd trimester of pregnancy
were selected from an ongoing national surveillance
study. All women achieved steady-state plasma concentrations
while on a HAART regimen containing nelfinavir (1250 mg
BD, n=20) or lopinavir/r (400/100 mg, BD, n=9).
Nelfinavir samples were obtained pre-dose (Ctrough)
and 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose. For
lopinavir, Ctrough and 3 hour plasma samples were
obtained. The results were compared to results from a
control group of HIV-positive non-pregnant women
(nelfinavir: n=21; lopinavir: n=12).
Additionally, the investigators evaluated placental
transfer in a subgroup of 6/20 mother/infant pairs receiving
nelfinavir and 6/9 receiving lopinavir/r by comparing
drug concentrations in samples collected at delivery.
They found median nelfinavir PK values were: AUC
(012h) 25.76 mcg.h/mL (range: 12.61-42.74) in pregnant
women vs. 32.49 mcg.h/mL (range: 19.1663.81) in controls
(p<0.05). CL/F was significantly higher in pregnant women
than in controls, 48.5 L/h (range: 29.3- 99.1) vs. 38.5
L/h (range: 19.665.2), but the difference did not remain
after CL/F was adjusted for patient weight. Additionally,
median Ctrough was significantly (p<0.01) lower in pregnant
vs. controls, 0.8 mcg/mL (range: 0-2.6) vs. 1.5 mcg/mL
(range: 0.5-4.9). In the 6 women evaluated at delivery,
the median plasma concentration was 0.15 mcg/mL (range:
0-1.82) and 3 women (50%) had undetectable levels.
Median lopinavir Ctrough levels were similar in
pregnant women and controls: 4.3 mcg/mL (range: 3.08.3)
and 5.2 mcg/mL (range: 0.316.0). Only 1/9 pregnant women
had Ctrough level below the recommended lopinavir target
of 4.0mcg/mL. The median C3h was significantly lower
(p<0.01) in pregnant women: 4.2 mcg/mL (range: 2.29.7)
vs. 9.8 mcg/mL (7.020.5). At delivery the median lopinavir
concentration was 0.22 mcg/mL (range: 06.8), with 5/6
women having levels below 4.0mcg/mL. No measurable nelfinavir
or lopinavir or nelfinavir and concentrations were found
in any of the cord blood samples.
The investigators concluded that HIV-positive pregnant
women receiving nelfinavir without any concomitant PIs
frequently show subtherapeutic levels of nelfinavir in
late pregnancy. They found that lopinavir showed better
PK, with similar Ctrough levels in the two groups.
They wrote, "The difference between the two drugs
in achieving therapeutic levels may be explained by
the inclusion of ritonavir in lopinavir regimen. Nelfinavir
and lopinavir did not cross the placenta to an appreciable
extent and thus should not be expected to provide any
direct protection for the newborn."
References:
- Regazzi R, Villani P, Floridia M et al. Effect of
pregnancy on protease Inhibitors (PIs) pharmacokinetics
in HIV-1 infected women. 7th International Workshop on
Clinical Pharmacology of HIV Therapy, 2022 April 2006,
Lisbon. Abstract 27.
- Khuong-Josses M-A, Boussaïri A et al. Nelfinavir plasma
concentrations in 40 pregnant women. 13th CROI. Abstract 707.
- Stek A, Mirochnick M, Capparelli E et al. Reduced
lopinavir exposure during pregnancy: preliminary pharmacokinetic
results from PACTG 1026. XV Intl AIDS Conference, Bangkok. Abstract
LbOrB08.
- Lyons F, Lechelt M, Magaya V et al. Adequate trough
lopinavir levels with standard dosing in pregnancy. 13th
CROI 2006, Denver. Abstract 709.
- Mirochnick M, Stek A, Capparelli E et al. Adequate
lopinavir exposure achieved with a higher dose during
the third trimester of pregnancy. 13th CROI, Denver.
Abstract 710.
Relationship Between Nevirapine Concentrations and Virological Failure
in a Clinical Setting
Previous studies have reported high frequency of sub-optimal
nevirapine Ctrough levels but no guidelines have suggested a
way to manage these patients. Should a clinician confirm the
inadequate concentration on another sample because of high
intra-patient variability or increase nevirapine dose?
N. Machefert from the Centre Hospitalier Universitaire,
Toxicologie et Pharmacocinétique, Poitiers, France and
coworkers performed a retrospective assessment of the
risk of virological failure in a clinical setting for
patients having one or more sub-optimal nevirapine
Ctrough (<3 ug/mL). Additionally, the study
was to determine the extent of the intra-patient variability
among this group.
The authors evaluated 38 patients receiving standard
nevirapine dose as part of their antiretroviral regimen. Nevirapine
Ctrough concentrations were determined from 245
samples collected at each clinic visit throughout the course
of their treatment. Viral load and adherence, recorded at
each clinic visit, were also evaluated. Virological failure
was defined as >1000 copies/mL. The number of patients with
one or more Ctrough <3 ug/mL were compared to
the virological failure group.
Patients received nevirapine for a mean of 700 days;
8/38 patients had virological failure. There was an average
of 6 Ctrough measurements available per
patient. The investigators found 24/ 38 (63%) patients
had at least one inadequate Ctrough during the
course of their treatment. 7/8 (88%) patients had more than
one inadequate Ctrough in the viral failure group
vs. 9/30 patients in the group without virological failure,
p=0.01. Additionally 6/8 patients in the virological group
were considered as non-adherent (confirmed by undetectable
plasma concentration measurement during the course of
their treatment).
They reported that the intra-individual variability
was significant with a mean value of 35% [range: 5200%]
in all patients but only 20% [range: 545%] excluding
non-adherent patients. The investigators wrote, "This
study confirms the high frequency of inadequate Ctrough
in clinical settings and suggests that only patients exhibiting
more than one inadequate NVP Ctrough are at risk
of virological failure. In routine practice, before nevirapine
dosage adjustment, inadequate Ctrough should be
confirmed and adherence should be assessed."
Machefert N, Dupuis A, Le Moal G et al. Relationship
between nevirapine concentration and virological failure
assessed in a clinical setting. 7th International Workshop
on Clinical Pharmacology of HIV Therapy, 2022 April 2006,
Lisbon. Abstract 70.
Using Enzyme Inducers to Reduce the
Half-life of Nevirapine
Several studies have reported the development of resistance
to nevirapine even after taking a single dose of the drug,
which is commonly used in the resource-limited setting for
the prevention of mother to child transmission. This is
likely due to the long half-life of nevirapine that results
in the drug being found in blood for many days after taking
the one dose.
A poster from Rafaella L'homme and coworkers from the
Radboud University Nijmegen Medical Centre presented findings
from a study exploring the novel strategy of using enzyme
inducers to reduce nevirapine half-life and thereby reduce
the risk of developing resistance.
This small study evaluated the use of several different
strategies including using carbamazepine, phenobarbital,
phenytoin, St. John's Wort tea, retinyl palmitate and
beta-carotene, and cholecalciferol.
This was a phase-I single-centre, open-label, 2-period,
9-group, PK study. A single 200 mg dose of nevirapine was
administered to 36 HIV negative non-pregnant women in both
period 1 and 2, blood samples were taken twice weekly for
21 days. In period 2 additional interventions (single-dose
carbamazepine, phenobarbital or phenytoin; phenytoin for 3
or 7 days; St Johns Wort, vitamin A or cholecalciferol for
14 days) were administered to all participants except for
the control group. The primary end point was the ratio of
nevirapine half-life in period 2 to nevirapine half-life
in period 1.
Three of the interventions resulted in the half-life
of nevirapine being significantly reduced. These included
a single 400mg dose of carbamazepine (p=0.002), once a day
184mg phenytoin for three days (p=0.001) and once a day
184mg phenytoin for seven days (p=0.002). The half-life
of nevirapine was reduced by 35.3%, 38.2% and 35.9%
respectively. This resulted in a 4.58.8 day reduction
in time to when nevirapine could not be detected in
blood. The other five interventions had no effect on
the nevirapine half-life.
These interventions now need to be studied in the
real world setting to determine if this will lead to a
decreased risk of developing resistance to nevirapine
among pregnant women taking single dose nevirapine to
prevent HIV transmission to their newborns.
L'homme R, Dijkema T, A. van der Ven A et al. Enzyme
inducers reduce nevirapine half-life. 7th International
Workshop on Clinical Pharmacology of HIV Therapy, 2022
April 2006, Lisbon. Abstract 5.
More Women Needed in Clinical Trials
Statement by the GMHC Action Center
To Whom It May Concern:
We are a group of women and men living with HIV
who are concerned about the limited amount of information
available on the effects of HIV drugs on women. We believe
that research on women should be a high priority but that
too many barriers prevent women from joining research studies.
In a survey of our Action Center members we find that
women are willing to join clinical research studies but
often run into problems that prevent them from participating.
- Enrollment restrictions on women of childbearing
age. It seems that this is often used to exclude all women,
including those who are unable to have children and women
who are willing to use contraception. We find that if you
have been rejected once you feel you are not wanted in any study.
- Women are especially concerned about unknown side effects
that can hurt their bodies.
- The doctors and nurses who run clinical trials often
don't explain what they are doing and seem unwilling to
answer questions.
- Informed consent forms do not tell the whole story and
can be hard to read. We need people at the research sites who
are willing to talk through the study and patiently answer questions.
- We think that a clinical trial that was especially
designed for women with HIV would be very attractive because we
would feel more comfortable that our needs will be looked out for.
In conclusion, we are worried that not enough research
is being done on the effects of HIV drugs on women. We are
willing to participate in research on HIV drugs. But when
we try to join clinical trials we are often made to feel we
are not eligible — or not wanted — when our
questions go unanswered.
Thank you for your attention to this important issue. We look
forward to an answer to our concerns.
GMHC Action Center
Treatment Research Group
© 2006 Gay Men's Health Crisis
|
home 
