China, with its huge population and its position as the second-largest pharmaceutical market in the world, should be poised to become a world leader in clinical trials for new drugs and devices. But it isn’t quite ready for that.
Problems with protecting clinical trial participants, inadequate clinical trial infrastructure, and poor transparency make China an unreliable country in which to conduct a clinical trial. As a clinical research professional with more than a decade of global industry experience, I’ve seen clinical trials conducted in many countries but have yet to work with a U.S. company that has opted to conduct a clinical trial in China.
Protecting human subjects is a fundamental part of clinical trials. When deciding where to conduct one, pharmaceutical and medical technology companies must select countries that have adequate protections in place. China has had issues and challenges with protecting human subjects for years. A historical lack of clinical research infrastructure in China has led to problems adhering to Good Clinical Practice, the international gold standard for maintaining ethical and quality standards in clinical trials.
As an example, nearly all clinical research sites in China are hospitals, as there are no private practices. Because of that, clinical trial participants are treated exactly the same way as regular patients. That’s a problem because study staff — who are regular hospital employees — don’t have experience complying with Good Clinical Practice, putting the trial’s integrity, not to mention patient protection, at risk.
Another concern is the transparency of clinical research. Several documented cases of falsified or fraudulent clinical data have emerged from China in the past few years. That prompted China’s Food and Drug Administration (CFDA) to launch an initiative in 2015 to inspect more than 1,600 new drug applications that were pending approval. This initiative uncovered a mass of inauthentic data, and the CFDA was forced to withdraw or reject around 90 percent of those applications. Since then, the CFDA has required applicants to include a self-inspection report for each clinical trial. That should help minimize fraudulent data and increase transparency.
Despite new Chinese laws and regulations aimed at improving the conduct of clinical trials and protecting trial participants, issues with quality, proper oversight, and adherence to these protections still remain.
On the surface, the current protections appear to be in line with the Good Clinical Practice guidelines established by the International Conference on Harmonization. But a closer look reveals some big differences in the way these laws are followed. For instance, the new laws generally aren’t enforced, and there are no detailed guidelines for ensuring informed consent, an essential part of clinical trial participation.
China recently joined the International Conference on Harmonization as a regulatory member. According to the U.S. FDA, China has pledged “to gradually transform its pharmaceutical regulatory authorities, industry, and research institutions to implement the international coalition’s technical standards and guidelines.”
The Good Clinical Practice guidelines, while helpful in standardizing the ethical oversight of clinical trials, can be subject to interpretation. When implementing these guidelines in problematic countries such as China, trial sponsors must go above and beyond to ensure adherence and responsibility for the ethical conduct of their trials. Recent regulations have put more layers of oversight in place, including the pledge by China to implement International Conference on Harmonization recommendations, but we have yet to see if this will have any real effect on the overall quality of clinical trials being conducted there.
Part of the issue is that clinical trial investigators have substantial power in Chinese society, and they are the ones who are relied upon to interpret the regulations. CFDA officials, instead of acting as overseers, typically follow the investigators’ interpretation.
On paper, the protections of clinical trial participants that China has put in place are becoming more and more sufficient. And its membership in the International Conference on Harmonization and pledge to enact its Good Clinical Practice guidelines should help improve protection of human research subjects. Yet the actual implementation of these protections, laws, and regulations remains inadequate.
If a U.S. pharmaceutical company asked me today if it should conduct a clinical trial in China, I would say no. How I would answer next year, or the year after, will depend on whether China can improve its protection of human clinical trial participants, increase transparency, and establish a clear delineation of clinical research infrastructure.
China could someday become a global clinical trial mecca. But it has a lot of work to do before that happens.
Anne Poli is a senior consultant with expertise in clinical trial management at Halloran Consulting Group in Boston.
Last August, National Securities Corp analyst Jonathan Aschoff was bullish on Avenue Therapeutics Inc (ATXI.O), a fledgling biotechnology company with no revenue and one drug in clinical trials. In a research note posted on National’s website, he rated the newly listed stock a “buy” and predicted that the share price would more than double in a year.
National Securities analyst Jonathan Aschoff’s note initiating coverage of Avenue Therapeutics with a “buy” recommendation did not explicitly disclose that his employer and Avenue were owned by the same company.
Nearly a year later, Avenue shares are down 36 percent, at about $4.
A few months earlier, Aschoff had waxed equally optimistic about another biotech venture, Checkpoint Therapeutics Inc (CKPT.O), with several cancer drugs in various stages of development. He predicted the share price would rise from $10.75 to $18 in a year. It is now around $2.60.
National Securities analyst Jonathan Aschoff’s note initiating coverage of Checkpoint Therapeutics with a “buy” recommendation did not explicitly disclose that his employer and Checkpoint were owned by the same company.
Then in September, he recommended Mustang Bio Inc (MBIO.O), which is working on a drug to treat brain cancer. He forecast a 12-month increase in the share price from around $12 to $21. That stock is now at $6.62.
National Securities analyst Jonathan Aschoff’s note initiating coverage of Mustang Bio with a “buy” recommendation did not explicitly disclose that his employer and Mustang were owned by the same company.
What Aschoff did not mention in any of these bullish notes: His employer, National Securities, is owned by the same company that controls Avenue, Checkpoint and Mustang. That company is Fortress Biotech Inc FBIO.N, the brainchild of longtime biotech entrepreneurs Dr Lindsay Rosenwald and Michael Weiss.
In September 2016, Fortress acquired a controlling stake in National Securities’ parent, National Holdings Corp (NHLD.O). The deal solidified an unusual relationship that dates to 2010, when Rosenwald and Weiss, through an investment fund they control, invested $3 million in National Holdings.
Owning National gives Fortress an in-house underwriter and a private sales force of about 700 brokers – nearly a third of whom have been flagged by regulators – to help it raise money for its stable of nine ventures that are developing new drugs or treatments.
If this setup seems like a conflict of interest, that’s because it is one: National brokers are required under U.S. regulations to ensure that they promote investments deemed appropriate for their clients – the same clients to whom they are marketing securities in their parent company’s ventures in biotech, a notoriously high-risk sector.
“I’ve never seen a firm that needs to raise a lot of capital acquire a brokerage for that purpose,” said Benjamin Edwards, an associate professor of securities law at the University of Nevada, Las Vegas, echoing nearly a dozen other experts in corporate finance and securities law whom Reuters interviewed for this article.
Since coming under Fortress’s umbrella, National brokers, with an assist from analysts like Aschoff, have helped raise at least $240 million from thousands of individual investors across the United States to fund Fortress or its related biotech companies, according to data from National. And U.S. Securities and Exchange Commission (SEC) filings show that Fortress-related deals are in the works to raise as much as an additional $125 million.
OUT IN THE OPEN
While Aschoff did not disclose the relationship in the analyst notes, National discloses the conflict of interest in prospectuses for securities offerings it underwrites for Fortress, in keeping with U.S. regulations.
The Financial Industry Regulatory Authority (FINRA), the watchdog funded by the industry it monitors, approved National’s application for ownership change when Fortress acquired it, as required under U.S. regulations. FINRA declined to answer questions about the deal, saying it does not discuss specific firms.
The SEC did not respond to requests for comment. The agency asked Avenue for greater disclosure of its connection to National in the lead up to the biotech firm’s initial public offering last year, but ultimately allowed it to raise money through the investment firm, filings show.
Still, “naïve investors may not even know the connection. Most small investors don’t read the prospectus,” said Roni Michaely, a professor of finance at Cornell University. “If you are selling your own company, you want to sell it at the highest possible price. This is a situation that is very troublesome. … Personally, I wouldn’t touch (the offerings) with a 9-foot pole.”
In an interview with Reuters, Weiss, executive vice chairman of Fortress, said: “We over-disclose. We tell everything. We are the most honest management team ever to walk through this biotech business.” Weiss served as chairman of the National Holdings board from shortly after Fortress acquired a controlling stake in the company until he resigned in June.
A National executive acknowledged on Dec. 4, 2017, that Aschoff’s research notes did not disclose the relationships between Fortress and its cash-raising subsidiaries on one hand and National on the other. In an email Weiss forwarded to Reuters, the executive said National republished the notes in September last year to correct the omission.
However, the notes as they appeared on National’s website in December did not contain such company-specific disclosures. The notes have since been removed from the site.
National on June 5 this year denied that the notes ever lacked proper disclosure, pointing to nonspecific boilerplate language in them that says: “One or more directors, officers, and/or employees of NSC (National Securities Corp) and its affiliated companies, or independent contractors affiliated with NSC may be a director of the issuer of the securities mentioned herein.”
Even with that general disclosure, “it does not eliminate the conflict of interest,” said Michael McMillan, director of ethics education at the CFA Institute.
In most cases, a firm will suspend analyst coverage of a company if a potential conflict of interest arises between the firm and the covered company, McMillan said. Fortress’s ownership of National, he said, raises questions about the ability of its analysts to remain independent and objective.
On May 15, more than a year and a half after Fortress acquired its controlling interest in National – and as Reuters continued to make inquiries about the relationship – National posted on its website a page titled “Meet our Majority Shareholder, Fortress Biotech.”
In a section on potential conflicts of interest, National says it and Fortress “have built a unique model that inherently aligns Fortress’ business objectives with the financial interest of National’s clients.” The company says it is “proud” of the Fortress-affiliated deals it has handled since the acquisition. It notes that those are a fraction of the total of $2.835 billion in deals National has closed during the same period.
BROKERS WITH A PAST
In June 2017, Reuters reported here that 35 percent of National’s brokers – more than three times the industry average – had a history of regulatory run-ins, legal disputes or personal financial difficulties that must be disclosed to investors under FINRA rules, based on a Reuters analysis of the regulator’s data. A fresh analysis encompassing disclosures from 2000 through June 2018 found that the proportion still hovered at 30 percent.
National executives said the Reuters analysis did not adequately reflect efforts to implement “a new culture at National” – an effort that has included removing 298 brokers since shortly after Fortress bought the company. National also questioned the value of including regulatory disclosures from more than a decade ago, and it pointed out that the firm itself hasn’t been hit with any regulatory sanctions since 2015.
“We’ve worked so hard at changing the culture,” said Michael Mullen, National Holdings’ chief executive officer and a longtime business associate of Rosenwald.
In 2002, FINRA accused analyst Aschoff of falsely claiming to be a medical doctor to obtain inside information about a drug development program at an unidentified publicly traded company. Aschoff, working for B. Riley FBR Inc at the time, agreed to a $10,000 fine and a two-week suspension without admitting or denying wrongdoing.
In a statement provided by National, Aschoff acknowledged the incident and declined to comment on it further.
A former National broker told Reuters he learned he was raising money for the National parent’s biotech ventures only after several months of recruiting investors for Mustang Bio. When he asked his supervisor about potential conflicts, he said, “I was told to stop asking questions and get back to dialing.”
Weiss said he found “it hard to believe that there is a broker at National who … did not read anything in the prospectus that says that Fortress has a majority interest in National.” He said National brokers recruited mostly accredited investors – individuals who under U.S. law meet certain minimum wealth requirements – for Fortress deals.
National brokers, Weiss said, sell Fortress deals because the investments make money for brokers and clients alike.
UNUSUAL STRUCTURES
For outside investors, Fortress’s ventures not only carry the typical risks of a long-shot biotech bet; they also come with unique conditions that can put outsiders at a disadvantage relative to the parent company.
For one thing, the upside potential for outside investors is damped by covenants between Fortress and its offshoots that favor Fortress with equity awards over time.
Fortress also treats the cost of acquiring drug-development rights as debt owed by its startups, and that debt is repaid from money raised from sales of the startups’ shares. Fortress ventures have paid at least $5 million under such arrangements across two deals, SEC filings show. The amounts may seem small, biotech analysts and investors said, but they allow Fortress to shift costs onto outside investors.
“It’s a very sweet deal for Fortress,” said Erik Gordon, a professor at University of Michigan’s Ross School of Business. “I think someone could see it as either very smart or very tricky.”
Weiss and Rosenwald acknowledged the unusual nature of the equity awards, but said that by pricing stock offerings at low valuations, they mitigate the impact of the dilution. In addition, they said, many investors don’t plan to hold the stock long enough for the dilution to hit them very hard.
Rosenwald and Weiss together owned 30.5 percent of Fortress as of March 31. For the past three years combined, each was paid $1.6 million in Fortress-related compensation and $5.6 million in stock awards, according to SEC filings.
As for National, its investment banking revenue surged more than 25 percent to $44.6 million in fiscal 2017 from a year earlier, thanks in part to fees from Fortress-related offerings, according to a Reuters review of SEC filings. And National’s brokerage operation collects commissions on Fortress-related shares sold to investors.
“Retail investors need more protections than institutional investors,” and the complex structures of Fortress deals “do the opposite of that,” said Les Funtleyder, a portfolio manager at E Squared Capital Management. “That’s compounded by the fact that biotech, because it’s so risky, isn’t really appropriate for retail investors to begin with.”
In an interview, Rosenwald argued that “if anybody thinks that Fortress is getting too good of a deal from the (subsidiary) companies … then you can go out and buy Fortress stock.” Those shares are down 35 percent, at $2.25, since April 2015, when publicly listed Coronado Biosciences, a failed venture, was renamed Fortress and became an incubator for Rosenwald and Weiss biotech ventures.
The structure of Fortress’s deals, Rosenwald said, doesn’t eliminate all risk for the parent company and its executives. Fortress covers overhead costs for its ventures, he noted, including office space, management, human resources and legal advice, amounting to millions of dollars a year. Some of that, however, is repaid to Fortress through fees charged to each company. Fortress said it holds $30 million in direct investments in the ventures, and Rosenwald is an Avenue investor.
However, the biggest risk for Fortress “is reputational,” Rosenwald said. “You’re allowed to fail in biotech. If they all fail, that’s horrible.”
EASING PAIN
Failure is common in biotech. Lead times are long. Startups burn through cash and usually have no revenue. Treatments that show early promise can blow up in late-stage trials. Nine times out of 10, according to a 2016 study by a group of biotech industry organizations, ventures do not achieve the ultimate goal: U.S. Food and Drug Administration approval of a new drug or therapy.
But while payoff is rare, it can be huge. That’s why the sector typically attracts venture capital funds and other “smart money” investors who are willing to take on more risk than most.
Over the past two decades, Rosenwald and Weiss have, together and separately, launched more than 50 separate biotech firms. Most of their ventures have conformed to the industry norm, failing to receive FDA approval.
They’ve had rare successes, too, such as Cougar Biotechnology Inc, which was developing prostate cancer drug Zytiga when Johnson & Johnson bought the company for $1 billion in 2009. The purchase price represented a 16 percent premium to the company’s market value at the time. Zytiga received FDA approval in 2011.
Whether a venture succeeds or fails, Fortress has found a way to boost the benefit and trim the risk for itself relative to the retail investors who help fund its ventures. That innovation was on display recently with Avenue Therapeutics.
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In 2015, Fortress, then still known as Coronado Biosciences, created Avenue to develop for the U.S. market an intravenous formulation of the synthetic opioid Tramadol to treat pain in patients after surgery. The drug is already sold worldwide in oral form, and outside the United States for intravenous use.
Avenue, with no revenue and only the one drug in its pipeline, went public last summer. Fortress hired Oppenheimer & Co as lead underwriter for the IPO – a role that includes conducting due diligence on the deal and the issuing company. In an unusual move, two-thirds of the Avenue shares offered were allotted to National.
“The deal from the beginning was designed to be a National-led transaction for our clients,” Weiss said. “We hired Oppenheimer … to satisfy the regulatory requirements.”
Oppenheimer declined to comment.
The IPO raised nearly $38 million. That was already much less than the $50 million Fortress had initially hoped to raise, according to SEC filings.
Avenue soon afterward paid out $6.6 million, or 17 percent of the IPO proceeds. More than $3 million went to cover Fortress’s debt from buying the rights to IV Tramadol. The rest repaid a line of credit that Fortress had provided to Avenue.
With that debt repaid, outside investors are now bearing most of the cost of developing IV Tramadol and carrying the most risk if Avenue fails.
Typically, biotech companies hold little debt, if any, when going public so that shareholders are protected from undue risk if the company struggles to bring its product to market, several biotech investors told Reuters.
For Fortress, debt is part of the formula. “We are using debt as Fortress’s balance sheet grows. We prefer not to,” Rosenwald said. “We will probably stop using debt soon.”
Further, the founders agreement between Fortress and Avenue gives the parent company the equivalent of 2.5 percent of Avenue’s outstanding shares each year, plus additional shares equal to 2.5 percent of any equity or debt financing.
That provision would benefit Fortress, relative to outside investors, should Avenue succeed and the shares take off. Over, say, 15 years, the annual transfer alone would dilute the value of outside investors’ holdings in Avenue by nearly a third.
Rosenwald told Reuters that over such a 15-year span, he and Weiss would “add so much value to these companies that the little bit that keeps us interested financially will be a decimal point.”
Avenue’s Tramadol formulation is now in late-stage clinical trials, and the company expects to apply for FDA approval by the end of 2019.
“I have never seen a structure like this one before,” said Funtleyder, the E Squared portfolio manager. “We would need a really good reason to participate in something like that and probably wouldn’t on principle because there are so many other investments that don’t have this kind of baggage.”
The founders agreement also calls for Avenue to send Fortress 4.5 percent of net sales each year, if Avenue begins producing revenue.
The annual 2.5 percent equity transfer is contained in the founders agreements between Fortress and nine ventures, according to SEC filings.
One of them is Checkpoint Therapeutics, whose shares began trading on Nasdaq last June, just after Aschoff published his “buy” recommendation. Another is Mustang Bio, whose shares began trading on Nasdaq in August last year.
Mustang is in the early stages of developing several immunotherapy products to treat cancer. In a July 2017 appearance on the Fox TV network morning show “Fox & Friends,” Rosenwald and Mustang’s CEO talked about the potential of one of those drugs to help U.S. Senator John McCain, who had recently been diagnosed with a lethal brain cancer.
“It’s early clinical trials,” Rosenwald said during the broadcast. “We have to prove the effectiveness.”
A year ago, National completed a private placement of Mustang shares, raising $95 million, according to SEC filings. National’s fee came to 10 percent, or $9.5 million. An additional $2 million paid Fortress’s debt from licensing fees.
Caelum Biosciences, another company with the same founders agreement, is in the early stages of developing a treatment for a rare immune-system disorder called amyloidosis. National raised $9.9 million for the company through the sale of convertible notes to around 170 investors, earning nearly $1 million in commissions, SEC filings show.
ALL IN THE FAMILY
In 1987, Rosenwald, who holds a medical degree from Temple University, started working at D.H. Blair & Co, a Wall Street boiler room that a New York state judge likened to a criminal enterprise and that was led for decades by Rosenwald’s father-in-law, J. Morton “Morty” Davis.
In 2000, several executives and employees were charged in New York state court with 173 counts of securities fraud, among other violations. Two years later, the firm and three officers, including two of Rosenwald’s brothers-in-law, pleaded guilty to and were convicted of three counts of violating state securities law. (One brother-in-law served time in prison; the other got probation.) Neither Rosenwald nor Davis was charged.
Rosenwald had already left to launch his own small brokerage, Paramount BioCapital, in 1991, he said. Weiss came on board in 1994. Paramount functioned much as National does now, raising money for Rosenwald startups in biotech.
In 2009, FINRA records show, the regulator determined that in two deals for Rosenwald-controlled biotech companies, Paramount had failed to meet the requirement that it hire an independent underwriter “to protect investors from purchasing shares at an unfair price.” FINRA also found that Paramount had failed to obtain approval to issue initial public offerings.
Paramount paid a fine of $20,000, without admitting wrongdoing.
Rosenwald said that the people involved “are no longer working with us,” and that the violations were “minor technical infractions” not worth fighting.
The following year, Opus Point Partners, an investment fund controlled by Rosenwald and Weiss, invested $3 million in National. Opus and National then formed OPN Capital Markets, a boutique investment bank focused on the healthcare industry. Rosenwald shuttered Paramount.
National took up where Paramount left off, handling a private placement and later serving as co-lead underwriter for the IPO of Ventrus BioSciences, a Rosenwald venture that was developing treatments for gastrointestinal ailments.
A month after the December 2010 IPO, National analyst Jason Kolbert published a research report with an enthusiastic “buy” recommendation. “Bet the horse, bet the jockey!” he wrote. The report did not disclose the connection between National, Rosenwald and Ventrus.
Kolbert did not respond to requests for comment.
Representatives for National and Fortress pointed out that the note included boilerplate language stating: “One or more directors, officers, and/or employees of NSC and its affiliated companies, or independent contractors affiliated with NSC may be a director of the issuer of the securities mentioned herein.”
Ventrus raised $65 million through the private placement, IPO and several follow-on offerings. Over the next two years, Ventrus’s stock rose from a $6 initial offering price to as high as $21 as investors awaited news on the hemorrhoid ointment, the anal fissure cream and the incontinence gel the company was developing.
As underwriter, National – including its many brokers with FINRA flags – was key to promoting the shares. In one case Reuters found, 17 separate purchases of Ventrus stock were among 38 unauthorized trades a National broker made on a single client’s account between May 24 and July 26, 2012, according to the complaint filed by FINRA. The broker, Glenn McDowell, was permanently barred from the securities business. National fired McDowell in January 2013.
Reuters was unable to locate McDowell.
On June 25, 2012, Ventrus announced that it would abandon development of what had been its most promising product – the hemorrhoid ointment – after it failed its final clinical trial. The share price plunged more than 50 percent in a day. In February 2014, the anal fissure cream failed a key clinical trial, and the stock plunged 63 percent.
A few months later, Ventrus merged with Assembly Biosciences, a small biotech with no ties to Fortress.
Though Rosenwald said he “lost millions” on Ventrus, he, Weiss and other National executives described Ventrus as a success because investors who got out of the stock at the right time made a profit.
Researchers have developed a novel test that rapidly distinguishes between type 1 and type 2 diabetes. This new method and a second study revealing gaps in care for women with gestational diabetes were presented today at the 70th AACC Annual Scientific Meeting & Clinical Lab Expo, and could improve treatment for patients with all diabetes types across the board.
One major issue in diabetes care today is the difficulty in distinguishing type 1 diabetes from type 2. Type 1 and type 2 diabetes require very different treatment plans, but up to 15% of diabetic young adults are wrongly classified and treated, which can lead to dangerous complications. Another challenge in diabetes care is preventing type 2 diabetes in women who have had gestational diabetes. Because half of women who have had gestational diabetes go on to develop type 2 diabetes, guidelines encourage these women to undergo diabetes testing six weeks after giving birth so they can receive preventive treatment if they are at risk. It is unknown, however, how consistently this follow-up testing is performed worldwide.
Correctly Diagnosing Type 1 and Type 2 Diabetes
A research team led by Mark Latten of Randox Laboratories and Richard Oram, MD, of the University of Exeter Medical School in the U.K., has developed a new test intended to diagnose type 1 diabetes more effectively. The test, named the Type 1 Diabetes GRS array, screens for 10 heritable mutations associated with a predisposition to type 1 diabetes, and combines the measurements into a genetic risk score. In an initial validation study, the researchers analyzed 259 DNA samples with the GRS array and an established genetic testing method, and found that the GRS array successfully detected the same combinations of the 10 mutations in the samples compared with the established method. This indicates that the test could serve as a vital tool for preventing the misdiagnosis of diabetes patients.
“No one has, to date, used the known strong genetic risk of type 1 diabetes to distinguish type 1 from type 2,” said Oram. “Our assay could be used alone, or in combination with clinical features and autoantibody testing to improve classification of diabetes at diagnosis, and therefore make sure people get on the right treatment.”
Preventing Diabetes in Women Post-Pregnancy
A research team led by Lucius Imoh, MBBS, of Jos University Teaching Hospital in Nigeria, set out to determine how many women undergo recommended postpartum glucose testing six weeks after birth. The study followed up with 58 women who were diagnosed as having gestational diabetes or overt diabetes during pregnancy to determine their post-pregnancy testing status.
While many of the women had undergone some form of follow-up testing, only 4 of the 58 were tested with an oral glucose tolerance test (OGTT)-;the gold standard for diagnosing type 2 diabetes-;six weeks after delivery, and eight had no form of glucose testing whatsoever. Furthermore, only 28 of the women had been advised to undergo OGTT after delivery, a sobering finding that indicates inadequate referral for postpartum care was the norm in the study group.
“Our study draws the attention of clinicians and laboratorians to the current state of vagueness in postpartum testing,” said Imoh. “It calls attention to this missed opportunity for assessing and preventing diabetes mellitus and cardiovascular diseases in women with gestational diabetes.”
Altogether, this underscores the need for labs and clinicians to work together to improve postpartum glucose testing in developing countries such as Nigeria, so that type 2 diabetes onset can be prevented in more women worldwide.
Bariatric surgery was associated with a five-fold decrease in the risk of hormone-related cancers but twice the risk of colorectal cancer, researchers found.
In a national, population-based cohort study, 8,794 patients who underwent bariatric surgery for obesity had a decreased risk for cancer of the breast, endometrium, and prostate (odds ratio [OR] 0.25, 0.21 and 0.37, respectively), compared with 8,794 matched controls who did not have surgery.
The study showed that gastric bypass was associated with the largest risk reduction for all three hormone-related cancers (OR 0.16), followed by sleeve gastrectomy (OR 0.21), and gastric banding (OR 0.34), said Sheraz R. Markar, MBBChir, PhD, of Imperial College London, the United Kingdom, and colleagues.
“There was a five-fold reduction in the incidence of hormone-related cancers following bariatric surgery, particularly in patients who had undergone gastric bypass or sleeve gastrectomy,” the study authors reported online in the British Journal of Surgery. “However, it must also be noted that there was a three-fold reduction in the incidence of hormone-related cancers after gastric banding.”
Although only gastric bypass was associated with a significant reduction in the risk of prostate cancer (OR o.22), it was also associated with more than twice the risk of colorectal cancer (OR 2.63), the study showed. “Longer followup after bariatric surgery strengthened these diverging associations,” the researchers wrote.
The study did not show that bariatric surgery was associated with a reduced risk of esophageal cancer. “The statistical power for assessing the risk of esophageal cancer was low due to the low incidence of this cancer,” the study authors said.
Hormone-related cancer as well as colorectal cancer and esophageal cancer have all been associated with obesity, defined as a body mass index (BMI) of 30kg/m2 or higher, they noted. Bariatric surgery for obesity “is the only evidence-based treatment that offers substantial and long-lasting weight reduction in severely obese individuals.”
“I think this is an important study,” said Samer G. Mattar, MD, president of the American Society for Metabolic and Bariatric Surgery (ASMBS) and medical director, Swedish Weight Loss Services in Seattle, Wash., when asked to comment.
“The study is meticulously designed, takes advantage of a very large administrative database, and confirms what we’ve known for several years,” said Mattar, who was not involved in the study. “This is a great information for all providers since bariatric surgery is about so much more than losing weight. It’s about improving overall health, and protection from obesity-related disease.”
Bariatric surgery offers protection against primary cancers and increases survivorship in patients who have already been diagnosed with cancer, he said. “Those who lose weight live longer.”
Mattar pointed to previous research out of McGill University Health Center in Montreal, Canada. A 2008 study showed that bariatric surgery significantly reduced the number of physician/hospital visits in obese patients with any cancer diagnosis compared to controls with cancer who didn’t undergo bariatric surgery. In 2009, the same research group published a second study providing evidence that the sustained, long-term weight loss achieved through bariatric surgery significantly reduced the relative risk of death from almost all obesity related diseases.
“We used to wait for 5 years after a cancer diagnosis to perform bariatric surgery,” Mattar told MedPage Today. “Now we operate right after treatment for acute cancer, especially in patients with breast or endometrial cancer.”
The finding that bariatric surgery was associated with an increased incidence of colorectal cancer also confirms what has been observed before, said Mattar. More study is needed to determine the mechanisms behind this, he added. “We need more data in order to make recommendations on more frequent colonoscopy.”
Although the overall incidence of esophageal cancer was low in both the bariatric surgery and control groups, Mattar noted that the study data did not distinguish between esophageal squamous-cell carcinoma and esophageal adenocarcinoma.
When asked to comment, Eric Velazquez, MD, assistant professor of clinical surgery and interim director of the bariatric and metabolic surgery program at Temple University Health System in Philadelphia, Pa., said more clinicians need to be speaking to potential candidates about bariatric surgery.
The effects of weight loss surgery on comorbid conditions such as type 2 diabetes, hypertension, and metabolic syndrome have been well proven, added Velasquez, who was not affiliated with the research. “Now we have studies showing us risk reduction of hormone-related cancers in patients after bariatric surgery but still less than 2% of the population that qualify for bariatric surgery seeks the type of treatment. We as providers should do more in educating the population and our colleagues in the benefits of bariatric surgery.”
For the study, the researchers used national data (1997 — 2012) from England’s Hospital Episode Statistics database on 716,960 patients diagnosed with obesity. Propensity matching on sex, age, co-morbidity, and duration of followup was used to compare cancer risk among patients who had undergone bariatric surgery and those who hadn’t.
In both groups, the median age was 42 years, 80.4% were female and 64.8% had no co-morbidities. The median length of followup was 55 months.
Gastric bypass was performed in 4,978 (56.6%) while 2,957 (33.6%) underwent gastric banding and 859 (9.8%) had a sleeve gastrectomy.
Since obesity was coded as a co-morbidity, participants’ exact weight and BMI data were not available, the study authors pointed out. As a result, they could not make a correlation between BMI changes after surgery and cancer risk.
“However,” they said, “as the direction of change in hormone-related and colorectal cancer were opposite and strong, an underlying difference in BMI or co-morbidity between the comparison groups is unlikely to be the primary driver for the changes in cancer incidence observed.”
Similarly, there were no data on potential confounding factors such as smoking, high alcohol intake, and low physical activity for propensity matching, the researchers noted.
Funding for this study was provided by the National Institute of Health Research and the Karolinska Institutet. Dr. Markar and study co-authors reported having no conflicts of interest.
Reviewed by Henry A. Solomon, MD, FACP, FACCClinical Associate Professor, Weill Cornell Medical College and Dorothy Caputo, MA, BSN, RN, Nurse Planner
“I feel dizzy” is a common complaint in the ER and triage nurses sometimes use the shorthand “IFD” when describing the patient’s complaint. Finding a diagnosis for this vague symptom can be challenging. One thing the nurse can do to speed up the process is to drill down to a more firm description than dizziness.
Dizziness is a complaint that can include four separate symptoms, sometimes overlapping. A careful history will reveal one or more of these: vertigo, disequilibrium, presyncope, or light-headedness.
Vertigo
Vertigo is the feeling that the room is spinning. Often, there is a false sense of movement. Sometimes vertigo is accompanied by nausea, vomiting, sweating, and/or nystagmus. It gets worse when the patient’s head is moving. The question the nurse can ask the patient to differentiate vertigo from other forms of dizziness is, “Do you feel like the room is spinning or moving around you?”
Vertigo has relatively few causes. Benign paroxysmal positional vertigo (BPPV), Meniere’s disease, and labyrinthitis are the most common. Less common are brain tumors, brain injury, stroke, multiple sclerosis, and migraine. You can see that they divide into central and peripheral causes: those that are central involve the brain, and those that are peripheral come from the middle ear.
Anything that causes inflammation in the structures surrounding the organs of balance can lead to vertigo. Often the patient will have a cold or sinus problems. Tinnitus, hearing loss, and feeling of fullness in the ear can accompany vertigo. There is a rapid compensatory process when things go wrong with the organs of balance. Usually the course is self-limiting and resolves within a few days.
BPPV is caused by loose granules of calcium carbonate moving in the semicircular canal. It can be diagnosed with the Dix-Hallpike test and can sometimes be effectively treated with repositioning movements called the Epley maneuver. BPPV does not present with hearing loss.
Meniere’s disease involves episodic vertigo along with hearing loss and a sensation of fullness, usually in one ear. There are few treatments, and the disease is poorly understood. The course can last from 5 to 15 years before the episodes stop, and the patient is left with mildly disturbed balance and decreased hearing.
Labyrinthitis is believed to be caused by a viral infection of the inner ear and can result in permanent symptoms of dizziness.
Disequilibrium
Disequilibrium exhibits itself in the patient’s gait. A stumbling or shuffling gait can be a sign of stroke, a life-threatening emergency that calls for immediate activation of the emergency medical system.
Other causes are Parkinson’s disease and peripheral neuropathy. Alcohol and drug intoxication frequently lead to disequilibrium. In older people, poor vision can accompany disturbances in gait, leading to falls. Use of benzodiazepines and tricyclic antidepressants can also increase the risk of falls in the elderly.
Presyncope
Presyncope is a problem of circulation and is most commonly described as feeling like one is going to pass out without actually losing consciousness. It’s either a pump or fluid problem and exhibits as orthostatic hypotension. When the patient stands up, he or she gets dizzy. It can be caused by dehydration (fluid problem), arrhythmias, myocardial infarction (pump problem), multiple medications, or debilitating illness. The nurse should ask the patient if he or she gets dizzy when standing up from a sitting position.
Asking the patient a few extra questions and taking a careful history can assist the healthcare provider in making a diagnosis. The word dizziness alone is not a very good descriptor of this problem, so drill down a little.
Spencer Miller, RN, is an emergency room nurse who has worked at various hospitals in Florida, Georgia, and California. This story was originally published by Minority Nurse, a trusted source for nursing news and information and a portal for the latest jobs, scholarships, and books from Springer Publishing Company.
The Centers for Disease Control and Prevention says a pill known as pre-exposure prophylaxis, taken daily, reduces the risk of getting HIV from sex by more than 90 percent and among people who inject drugs by more than 70 percent.
However, the CDC estimated in March that slightly more than 8 percent of the estimated 1.1 million Americans at substantial risk for HIV filled prescriptions for PrEP in 2015.
“Part of the problem with the uptake is people don’t know about it, so they don’t know to ask, medical providers might not be knowledgeable about it, and anecdotically we know many medical providers are uncomfortable talking to patients about their sexual histories,” said Shawn Lang, deputy director of AIDS CT, a statewide coalition of AIDS-based organizations based in Hartford.
“We have a chance to change the course of this epidemic with a one-a-day pill and I think the beauty of PrEP is, when you’re on it, you see your doctor once every three months,” he said.
Marianne Buchelli, health program supervisor at the state Department of Public Health, said in an emailed statement that the department does not yet have accurate statewide statistics on the use and cost of Truvada, a drug manufactured by Gilead Sciences and the only commercially available form of PrEP.
“There’s a lot that needs to be done on the medical provider side of this,” Lang said.
Tom Butcher, the local project director of the Ryan White CARE Act program, which provides HIV/AIDS services for low-income people in New Haven and Fairfield counties, said he takes PrEP, which is made easier because he attends a gay-oriented health care practice, something he says are “few and far between.”
“They’re for white, privileged guys like me, for the most part,” he said.
Butcher said a young, low-income black man in Connecticut may not have the same access, opportunities or knowledge base as someone like him.
“It’s up to the providers to understand that young man, to do a sexual assessment, to create an environment where that young man would feel safe to say he’s a gay man and ‘This is the kind of sex I enjoy,’ and let’s talk about risk,” he said.
Cost barriers
According to the state DPH statistics, in the four-year period after the federal Food and Drug Administration approved Truvada in 2012, the number of annual new infections in Connecticut has not gone down substantially — from 294 in 2012, to 269 in 2016.
However, even with that decline, massive racial gaps exist. According to state data, from 2012 to 2016, the rate of newly reported HIV infections in black residents of Connecticut fell from 36.4 per 100,000 people to 32.8, a number that eclipses the 3 in 100,000 white people newly diagnosed with HIV in 2012, which fell to 2.7 in 2016. In Hispanics, the rate fell from 18.2 per 100,000 in 2012 to 17.1 in 2016.
Young black and Hispanic men who have sex with men and trans women are “really the bullseye of all of this,” Butcher said.
Additionally, Butcher said federal funding is often allocated to areas where the need is greatest, so if Connecticut were to begin cutting into its rate of new diagnoses, it would also see its budget for prevention services and care slashed.
“It’s leaving Connecticut residents behind and putting us behind the eight ball,” he said.
Although the drug price-tracking website GoodRx estimates that 30 pills of Truvada costs about $1,600, a group of activists penned an op-ed in the New York Times arguing that the generic drug in other countries costs $6 for a month’s supply. Activists also argue that, since public funding from the National Institutes of Health largely funded the development of Truvada, Gilead Science’s patent on the drug is unethical and has transformed a drug with potential to end an epidemic into a luxury.
Gilead Sciences reported $5.6 billion in revenues in the second quarter this week, with a net income of $1.8 billion. The company, which markets 25 products, saw its revenue exceed Wall Street expectations, but stock prices fell as the company failed to surpass revenues in prior years. Gilead CEO John Milligan recently announced his resignation after 28 years, saying in a statement that it was a mutually agreed-upon decision with the company’s board of directors.
Butcher, who works with a low-income population — which qualifies for the Ryan White program once they are already infected — said Gilead’s patient assistance programs, including co-pay coupon programs and patient support programs, help to offset costs and make the drug affordable.
Gilead did not return a request for comment Friday.
A spokesman for U.S. Sen. Chris Murphy, D-Conn., said the senator is “aware of the pricing issue with these and other drugs” but has not had any letters or complaints from Connecticut patients about Truvada.
“(C)urrent federal HIV Prevention funding through the Centers for Disease Control(CDC), prohibits the purchasing of PrEP medications. This is the barrier. People who don’t have insurance or have the type of insurance that will not cover the medication due to cost, are the populations that the Department is planning to focus more on in the future,” Buchelli wrote in an email. “Despite this, DPH has concentrated on raising awareness about PrEP, how to access it, and last year piloted several programs with the goal of assisting people to access PrEP services regardless of insurance.”
The DPH announced a public health initiative in June to target new infections in the five municipalities with the largest number of new HIV infections — New Haven, Bridgeport, Hartford, Waterbury and Stamford — called “Getting to Zero.”
“The Commission aims to engage with consumers and providers to determine how to most effectively use those tools to reach the G2Z goals of no new HIV infections, no AIDS-related deaths and no more AIDS-related stigma and discrimination. The Commission is focused on learning what barriers exist to ending the epidemic,” said Buchelli, of the DPH. “Using a data-driven process, the campaign is focused on three populations at greatest risk (young men of color who have sex with men, African American/Black women and Transgender Women). The Commission is currently conducting listening sessions with the various groups in each city as well as with other consumers and providers of prevention services.”
According to DPH statistics, the number of new diagnoses in New Haven has not exceeded 40 annually since 2010, but it did not go below 29 between 2011 and 2016. It’s a noticeable decline from the first year of data, where there were 103 reported new diagnoses, a number which didn’t fall below 60 until 2007. In Bridgeport, the annual number of new diagnoses has mostly been level this decade, hovering between 26 and 45, although there were 119 new diagnoses in 2002.
The decline is more noticeable in Hartford, which reported 26 new diagnoses in 2016, down from 43 in 2012 when Truvada was introduced to the market, and from 164 in 2002.
Getting the word out
Lang, of AIDS CT, said the Getting to Zero initiative’s commission, which includes stakeholders local to several communities, can be valuable assets in the fight against new infections.
“We like having more tools in our toolbox,” she said. “I think a lot of people don’t even know about (PrEP).”
Butcher said he spoke to a young gay man in New York City who said he was aware of PrEP because of the prevalence of advertisements on the subway. Lang said she saw a commercial on television for PrEP and felt surprised and excited at seeing the drug discussed on a mainstream platform.
In fact, Gilead launched its first branded ad for PrEP in 2016, four years after its version of the drug was approved. That year, it spent $450,000 advertising Truvada, mostly to gay black and Latino men, transgender women and couples in which only one of the partners has a positive diagnosis for HIV/AIDS, according to MM&M. By comparison, the company spent $101 million in 2016 advertising its hepatitis-C treatment.
