In 2006, in the midst of a growing opioid epidemic, the FDA approved the new narcotic painkiller Opana.
It was a familiar drug.
Under the name Numorphan, it had been abused in the 1960s and 1970s
until it was removed from the market. When injected, the drug is 10
times as potent as morphine.
And now there is a familiar problem.
Known generically as oxymorphone, the FDA approved the new version of
the drug -- made by Endo Pharmaceuticals -- in 2006 as both an
immediate-release and extended-release pill. Then in December 2011, the
agency approved a new abuse-deterrent version -- but users have been
able to foil the anti-injection mechanism and have been shooting up
Opana.
In addition to overdose risk, abuse of Opana by injection has been tied to a recent outbreak of HIV in rural Indiana as well as a surge in hepatitis C infections in several Appalachian states.
It also has been associated with a blood-clotting disorder and permanent organ damage -- a problem that didn't occur with injection abuse of generics and the earlier version of the drug.
When Opana was approved, it joined more than a dozen other narcotic painkillers on the market.
"There certainly didn't seem to be a need for it," said James Roberts, MD,
a professor of emergency medicine at Drexel University College of
Medicine in Philadelphia. "There are plenty of narcotics around for pain
relief."
As Numorphan, the drug's popularity among addicts was due to its quick and sustained effect, according to the 1974 report "Drugs and Addict Lifestyle" by the National Institute on Drug Abuse.
The report said the drug -- which carried a street name of "blues"
-- was used primarily by white males and highlighted 309 Philadelphia
area addicts who were interviewed about their Numorphan abuse in 1970.
Many of the addicts said they preferred the drug over heroin.
Originally approved in 1959, FDA records indicate the pill form of
Numorphan was taken off the market in 1979 for what is described as "commercial reasons." Its intravenous and suppository formulations were allowed to remain on the market.
In an email, FDA spokesman Eric Pahon said opioids, including Opana,
are important medications for the treatment of pain, when used properly.
"The FDA is concerned about the misuse and abuse of prescription
opioids, which is a serious public health challenge, and is working in
many ways to help prescribers and patients make the best possible
choices about how to use these powerful drugs," he said. "We must
balance this effort, however, with ensuring prescribers and patients
maintain access to these medications and a variety of treatment options
are available."
Opana ER generated 756,000 prescriptions and sales of $385 million in
2013, according to data supplied by IMS Health, a drug market research
firm. Since 2009, its annual sales have ranged from $246 million to $640
million.
In an email, Endo spokesperson Heather Zoumas Lubeski said the drug
"was approved by the FDA based upon its demonstration of safety and
effectiveness in clinical trials and its successful submission of an
application for approval."
Meetings Impact Approval?
A Milwaukee Journal Sentinel/MedPage Today examination found
oxymorphone's re-appearance on the market followed a pattern identified
in past investigations, including cozy relationships between regulators
and drug company executives and the use of questionable clinical
testing methods allowed by the FDA.
Endo was a frequent participant at meetings of an organization funded
by pain drug companies that brought together pharmaceutical executives
and federal regulators during the 2000s, records show.
The group, known as IMMPACT, was the subject of a 2013 Journal Sentinel/MedPage Today investigation.
The story highlighted how federal health industry officials, members
of academia, and executives of companies that make pain drugs held
private meetings at expensive hotels at least once a year beginning in
2002, according to emails obtained through a public records request.
Each year, a handful of drug companies paid up to $35,000 each to
send a representative to the meetings where they could discuss clinical
trial design with FDA officials.
The arrangement was criticized as appearing to be pay-for-play
connection between regulators and companies anxious to get products onto
the multibillion-dollar-a-year pain market.
In 2014, two U.S. senators wrote to the medical school dean at the University of Rochester demanding financial records related to the IMMPACT meetings. A researcher at the school was a co-founder of the group.
Sen. Joe Manchin (D-W.Va.) and Sen. David Vitter (R-La.) wrote that
they were "deeply troubled by allegations that the FDA gave
manufacturers of prescription drugs the opportunity to pay thousands of
dollars to the University of Rochester Medical Center for the privilege
to attend private meetings with FDA officials."
FDA spokesman Pahon said it is misleading to imply that the IMMPACT
meetings were private meetings between FDA officials and members of
industry.
Though the meetings were invitation-only, he said, they were attended
by a variety of government officials, academics, and pain advocates.
"These were large scientific meetings at which the outside experts
almost always outnumbered the attending companies," he said. "We are not
aware of any separate, private meetings between FDA and pharmaceutical
companies during or as a result of IMMPACT meetings."
He said the meetings had no bearing on the approval of Opana and did
not include the discussion of any particular product or the standards
for FDA approval of pain products.
Stacking the Deck?
The IMMPACT meetings helped develop a new approach to winning approval of drugs known as enriched enrollment.
The approach allows drugs companies to weed out people who don't
respond well to a drug or who can't tolerate taking it before an actual
clinical trial for the drug begins.
Independent doctors say that approach makes it much more likely a
drug will be found effective and possibly win FDA approval. It's also
cheaper for drug companies to conduct such trials.
Critics say the approach essentially stacks the deck in favor of the
drug. More importantly, experts say, drugs tested that way are not
likely to reflect what will happen when a medication gets on the market
and is prescribed for large numbers of people.
When Endo tried to get Opana approved in 2003, the FDA said the drug
didn't appear effective enough in clinical trials. It also raised safety
concerns after several postoperative pain patients overdosed on the
drug and had to be revived with naloxone.
So Endo conducted new clinical trials using enriched enrollment.
In those trials, only the patients who initially responded to the
drug were entered into a randomized, controlled trial, where they were
given either Opana or a placebo. The idea is that the drug's effects can
be clearly demonstrated in comparison with placebo because it is
already known to work for all of the patients.
The results of those trials helped get the drug approved by the FDA
in 2006. But the FDA's own medical review of the drug acknowledged that,
given the enriched study design, "one could argue that the results may
not be generalizable to the wider chronic pain population."
"The FDA should be in the business of requiring high-quality evidence and not short-cut evidence," said Lewis Nelson, MD,
a medical toxicologist at NYU Langone Medical Center. "Unfortunately,
they're under pressure to make pharmaceuticals available to the general
public."
Nelson said the enriched trials "find the people who are most likely to respond to a drug and not suffer from side effects."
"I don't think enriched enrollment studies are truly valid," he added.
FDA spokesman Pahon said companies use a variety of strategies to
select those in the general population in which the effect of a drug can
be more readily shown.
He would not say whether the FDA encouraged Endo to use enriched enrollment for Opana.
"You'll need to FOIA [apply under the Freedom of Information Act to see] those pre-approval meeting minutes," he said.
Opana is not the only opioid approved using enriched enrollment. In 2013, drugmaker Zogenix used the strategy to win approval for Zohydro, a high-dose, hydrocodone-only drug that was originally approved without any abuse-deterrent mechanisms.
| Medpage Today
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A cancer cell containing the nanoparticles. The nanoparticles are
colored green, and have entered the nucleus, which is the area in blue.
Credit: M. Welland
has been successfully tested by scientists.
The ground-breaking technique could eventually be used to treat glioblastoma
multiforme, which is the most common and aggressive brain tumour in
adults, and notoriously difficult to treat. Many sufferers die within a
few months of diagnosis, and just six in every 100 patients with the
condition are alive after five years.
The research involved engineering nanostructures containing both gold
and cisplatin, a conventional chemotherapy drug. These were released
into tumour cells that had been taken from glioblastoma patients and
grown in the lab.
Once inside, these "nanospheres" were exposed to radiotherapy. This
caused the gold to release electrons which damaged the cancer cell's DNA
and its overall structure, thereby enhancing the impact of the
chemotherapy drug.
The process was so effective that 20 days later, the cell culture
showed no evidence of any revival, suggesting that the tumour cells had
been destroyed.
While further work needs to be done before the same technology can be
used to treat people with glioblastoma, the results offer a highly
promising foundation for future therapies. Importantly, the research was
carried out on cell lines derived directly from glioblastoma patients,
enabling the team to test the approach on evolving, drug-resistant
tumours.
The study was led by Mark Welland, Professor of Nanotechnology and a
Fellow of St John's College, University of Cambridge, and Dr Colin
Watts, a clinician scientist and honorary consultant neurosurgeon at the
Department of Clinical Neurosciences. Their work is reported in the
Royal Society of Chemistry journal, Nanoscale.
"The combined therapy that we have devised appears to be incredibly
effective in the live cell culture," Professor Welland said. "This is
not a cure, but it does demonstrate what nanotechnology can achieve in
fighting these aggressive cancers. By combining this strategy with
cancer cell-targeting materials, we should be able to develop a therapy
for glioblastoma and other challenging cancers in the future."
diagram showing the composition of the nanosphere. Credit: M. Welland
Used on their own, chemotherapy drugs
can cause a dip in the rate at which the tumour spreads. In many cases,
however, this is temporary, as the cell population then recovers.
"We need to be able to hit the cancer cells directly with more than
one treatment at the same time" Dr Watts said. "This is important
because some cancer cells are more resistant to one type of treatment
than another. Nanotechnology provides the opportunity to give the cancer
cells this 'double whammy' and open up new treatment options in the
future."
In an effort to beat tumours more comprehensively, scientists have
been researching ways in which gold nanoparticles might be used in
treatments for some time. Gold is a benign material which in itself
poses no threat to the patient, and the size and shape of the particles
can be controlled very accurately.
When exposed to radiotherapy, the particles emit a type of low energy
electron, known as Auger electrons, capable of damaging the diseased
cell's DNA and other intracellular molecules. This low energy emission
means that they only have an impact at short range, so they do not cause
any serious damage to healthy cells that are nearby.
In the new study, the researchers first wrapped gold nanoparticles
inside a positively charged polymer, polyethylenimine. This interacted
with proteins on the cell surface called proteoglycans which led to the
nanoparticles being ingested by the cell.
Once there, it was possible to excite it using standard radiotherapy,
which many GBM patients undergo as a matter of course. This released
the electrons to attack the cell DNA.
While gold nanospheres, without any accompanying drug, were found to
cause significant cell damage, treatment-resistant cell populations did
eventually recover several days after the radiotherapy. As a result, the
researchers then engineered a second nanostructure which was suffused
with cisplatin.
The chemotherapeutic effect of cisplatin combined with the radiosensitizing effect of gold nanoparticles
resulted in enhanced synergy enabling a more effective cellular damage.
Subsequent tests revealed that the treatment had reduced the visible
cell population by a factor of 100 thousand, compared with an untreated
cell culture, within the space of just 20 days. No population renewal
was detected.
The researchers believe that similar models could eventually be used
to treat other types of challenging cancers. First, however, the method
itself needs to be turned into an applicable treatment for GBM patients.
This process, which will be the focus of much of the group's
forthcoming research, will necessarily involve extensive trials. Further
work needs to be done, too, in determining how best to deliver the
treatment and in other areas, such as modifying the size and surface
chemistry of the nanomedicine so that the body can accommodate it
safely.
Sonali Setua, a PhD student who worked on the project, said: "It was
hugely satisfying to chase such a challenging goal and to be able to
target and destroy these aggressive cancer cells.
This finding has enormous potential to be tested in a clinical trial in
the near future and developed into a novel treatment to overcome
therapeutic resistance of glioblastoma."
Welland added that the significance of the group's results to date
was partly due to the direct collaboration between nanoscientists and
clinicians. "It made a huge difference, as by working with surgeons we
were able to ensure that the nanoscience was clinically relevant," he
said. "That optimises our chances of taking this beyond the lab stage,
and actually having a clinical impact."