Financial Gains Taint Debate About Nutritional Supplements

Laird Harrison

November 14, 2016

SAN FRANCISCO — Accusations of conflict of interest, the challenges of interpreting biostatistics, and a lack of definitive data are all fueling the controversy surrounding the benefits of nutritional supplements in age-related macular degeneration, leaving clinicians and their patients without clear answers.

Now, one of the researchers who challenged the benefits of supplements in patients with age-related macular degeneration has added a new twist.

Results from a new study indicate that "individuals without AMD and high genetic risk may benefit from the antioxidant formulation," said Carl Awh, MD, an ophthalmologist in private practice at Tennessee Retina in Nashville.

These assertions have roiled the profession because the stakes are so high. In the United States alone, around 1.75 million people have age-related macular degeneration (Arch Ophthalmol. 2004;122:564-572).

Dr Awh presented the results from the new study at the American Society of Retina Specialists (ASRS) 2016 Annual Meeting earlier this year.

The study that started the debate — the Age-Related Eye Disease Study (AREDS) — showed that nutritional supplements slowed age-related macular degeneration in the moderate stage of the disease (Arch Ophthalmol. 2001;119:1417-1413).

It led both the National Eye Institute (NEI) and the American Academy of Ophthalmology (AAO) to recommend the supplements in this population.

Previous research by Dr Awh's team suggested that thousands of people with intermediate macular degeneration are buying supplements that won't help them and thousands of others are taking supplements that can harm them.

Personal and Financial Stakes High

The arguments are mired in the technicalities of biostatistics and genetics, making them difficult for many clinicians to follow. And researchers on both sides of the debate have personal — and potentially financial — stakes in the argument.

Dr Awh owns shares in ArcticDx, a fledgling company that markets genetic tests for age-related macular degeneration. One of his coauthors, Brent Zanke, MD, PhD, is chair and chief scientific officer at ArcticDx. Other coauthors are consultants for the company.

The National Institutes of Health (NIH), parent to the NEI, receives royalties as an institution for a patent on the AREDS formula. And Frederick Ferris III, MD, leader of AREDS and an NEI employee, receives royalties as an individual. Emily Chew, MD, the lead author of several AREDS studies, is a deputy director at the NEI.

These disclosures raise questions about the way medical research is funded and who, if anyone, can provide an unbiased analysis.

None of the researchers involved disputes that genes and nutrition play a role in determining who will develop age-related macular degeneration, and how fast. Where they disagree is how these two factors interact with each other.

The argument goes back to the first publication of AREDS, which was funded by the NEI.

Conflicting Findings

The 3640 AREDS participants were randomized into one of four groups: an antioxidant regimen of vitamin C 500 mg, vitamin E 400 IU, and beta carotene 15 mg; a zinc regimen of zinc oxide 80 mg and cupric oxide 2 mg; an antioxidant plus zinc regimen; and placebo.

Over an average of 6.3 years, people with at least intermediate macular degeneration were 28% less likely to progress to the advanced form of the disease if they were in the antioxidant plus zinc group.

A subsequent study showed that some genotypes benefit more than others from the supplements, but AREDS researcher Michael Klein, MD, from Oregon Health & Science University in Portland, and his team concluded that their results do not "justify routine genetic testing at this time" (Ophthalmology. 2008;115:1019-1025).

On the basis of results from AREDS 2, the NEI recommended, for people in the intermediate stages of disease, a formula of vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg, and copper 2 mg (JAMA. 2013;309:2005-2015). Supplements providing the recommended formulation have sold widely.

But when Dr Awh and his colleagues conducted a new analysis of AREDS data, they found that some genotypes actually did not benefit from the recommended formulation (Ophthalmology. 2013;120:2317-2323).

The next year, the AREDS researchers and Dr Chew attempted to duplicate the finding of Dr Awh's team using a different dataset from the original study, but they could not (Ophthalmology. 2014;121:2173-2180).

Then, in 2015, Dr Awh's team reported that some genotypes might actually be harmed by the AREDS supplements (Ophthalmology. 2015;122:162-169).

Dr Chew and her colleagues disputed this finding as well (Ophthalmology. 2015;122:212-215).

The two parties appeared to be at an impasse, so everyone involved took notice earlier this year when Johanna Seddon, MD, from Tufts University in Boston, and colleagues leapt into the fray with another genetic study (Br J Ophthalmol. Published online July 28, 2016).

Her team, looking at the AREDS data in a new way, concluded that some genotypes do not benefit from the treatment, and although they identified a subgroup that might be harmed, the finding was not statistically significant.

Carving up the Data

How can researchers looking at the same data reach opposite conclusions?

The answer lies in a fundamental challenge of biostatistics: patients in any population can be grouped in different ways.

All the researchers used the finding that some genotypes are at greater risk for macular degeneration than others as their point of departure. The two genes related to risk for age-related macular degeneration are complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2).

Different people have different forms of these genes, or alleles. A person can have zero, one, or two of these risk alleles for each gene; the more alleles, the greater the risk for macular degeneration. But the researchers have used these alleles to group patients differently.

Table. Allele Groupings Used by the Different Research Teams

  CFH  ARMS2
Groups used by Dr Chew's team
   1. 0 0
   2. 1 0
   3. 2 0
   4. 0 1
   5. 1 1
   6. 2 1
   7. 0 2
   8. 1 2
   9. 2 2
Initial groups used by Dr Awh's team
   1. 0 or 1 0
   2. 2 0
   3. 0 or 1 1 or 2
   4. 2 1 or 2
Groups used by Dr Seddon's team
   1. 0 0
   2. 0 1 or 2
   3. 1 or 2 0
   4. 1 or 2 1 or 2

 

And in the study Dr Awh presented at the meeting, his team looked at the total number of CFH or ARMS2 alleles: zero; one; two; and three or four.

The patients were already separated into four treatment groups: an antioxidant regimen, a zinc regimen, an antioxidant plus zinc regimen, and a placebo regimen. But, to complicate matters, the researchers used slightly different datasets from the original trials. And Dr Seddon's team looked at individual eyes, rather than individual patients.

Naturally, the researchers don't agree on the merits of their approaches. Dr Awh argues that the groups in the 2014 study by Dr Chew's team were too small, so they did not have enough statistical power to show a correlation between genotype and the effects of the supplements.

Dr Chew argues that Dr Awh's team cherry-picked the groupings to show the best results. If you keep carving up the groups in different ways, you will eventually find the results you want, she said. To illustrate her point, her group produced an analysis showing that, using the same dataset and methods Dr Awh's team used, people born under the Aries and Cancer astrological signs are "harmed" by zinc.

And Dr Seddon argues that using eyes instead of patients is most definitive because it increases statistical power.

The arguments have gotten unusually personal and Dr Chew has said that she does not trust the statisticians involved in the studies by Dr Awh's team. And Dr Zanke has accused Dr Chew and Dr Ferris of not disclosing their conflicts of interest.

Financial Disclosures

Ophthalmologists are accustomed to considering the investments — both financial and emotional — that their colleagues have in various devices and medications. But it might come as a surprise to some that the bank accounts of individual researchers at the NIH can be affected by the studies they publish.

The practice has gone on since 1980, when an Act of Congress allowed government scientists to patent their inventions. The idea was to provide clear ownership of the intellectual property, so that private companies would transform these inventions into products of use to the public, Mark Rohrbaugh, PhD, JD, a special advisor for technology transfer at the NIH, told Medscape Medical News.

"Very few companies will develop a product that involves great risk, cost, and time — like a drug — if they think someone can copy it and sell it cheaper," he said. "Congress wants us to get a reasonable return on the licensing and a return back to the public."

The NIH has not released the amount of money it is earning from the patent for the AREDS supplements, which it has licensed to Bausch + Lomb. The law allows individuals to receive up to $150,000 per year.

But in response to a Freedom of Information Act request from ArcticDx, the agency provided a document entitled "Recipient: Ferris, Frederick III," with the figure $150,000 repeated on 12 lines. The agency declined to provide an interpretation of the document to Medscape Medical News, but Dr Zanke said the NIH told him that it means that Dr Ferris has so far received $1.8 million for his work on the supplements.

Dr Zanke and Dr Awh both freely admit that they could make more money if the NEI and professional organizations were to recommend genetic testing for age-related macular degeneration, and they don't fault Dr Ferris or the NIH for receiving royalties on the patent for the supplements.

But Dr Zanke does criticize Dr Ferris and Dr Chew for not consistently disclosing this relationship. "Their record of disclosure over the last 10 years is horrendous," he told Medscape Medical News.

Although some of the AREDS publications have disclosed the royalties paid to Dr Ferris and the NIH, others have not.

For example, a report on the risk for age-related macular degeneration after cataract surgery using data from AREDS 2 lists both Dr Chew and Dr Ferris as authors, but states: "The authors have no proprietary or commercial interest in any materials discussed in this article" (Ophthalmology. 2009;116:297-303).

The same is true for a report on the association between supplements contained in the AREDS formula and cataracts (Ophthalmology. 2015;122:1471-1479).

The disclosure statement is the same in a report on the long-term effects of the supplements on age-related macular degeneration, in which Dr Chew is listed as an author and Dr Ferris is listed as member of the AREDS research group (Ophthalmology. 2013;120:1604-1611.e4).

In a conversation with Medscape Medical News, Dr Chew at first said she has no conflicts of interest to disclose. "I don't get any remuneration for this; absolutely no money," she explained.

The amount of money the NIH receives for the patent is trivial compared with the agency's overall budget, she added. And she said she is not influenced by the money paid to Dr Ferris. "There is concern that my boss gets it, but I work independent of him. I'm working for the American people," she explained.

In response to a request for an interview with Dr Ferris about his disclosures, an NEI spokesperson acknowledged that the NIH guidelines call on its scientists to disclose "all relevant financial interests" to journal editors.

However, "in the cases you shared, there is no conflict because the papers were not specific to supplements and AMD," the spokesperson said to Medscape Medical News in an email. "Allegations of conflict of interest, whether real or in appearance, are taken seriously at NIH/NEI."

The spokesman quoted Dr Ferris as saying, "I believe I have a duty to report all conflicts and I believe I always do."

In a separate email, Dr Ferris noted that two of the studies concerned cataracts rather than macular degeneration, apparently implying that the patent on the formula for the supplements is so specific to age-related macular degeneration that its potential use by people with cataracts is irrelevant.

Dr Zanke pointed out that this seems to be in conflict with the disclosure policy at Ophthalmology. The journal uses a disclosure form provided by the International Committee of Medical Journal Editors, which asks authors to list "financial relationships with entities in the bio-medical arena that could be perceived to influence, or that give the appearance of potentially influencing, what you wrote in the submitted work. You should disclose interactions with any entity that could be considered broadly relevant to the work."

The form also asks, "Do you have any patents, whether planned, pending, or issued, broadly relevant to the work?"

After receiving a complaint from ArcticDx spokesperson Gerry Belgraver, George Bartley, MD, editor-in-chief of Ophthalmology, said the journal would print a correction for the disclosure on the study entitled Long-term Effects of Vitamins C and E, ß-Carotene, and Zinc on Age-related Macular Degeneration (Ophthalmology. 2013;120:1604-1611.e4).

The AAO Position

When conflicting results and allegations of bias muddy the waters, clinicians typically turn to their professional organizations to sort through the data. The AAO and the ASRS have both taken on that mission.

An ASRS spokesperson said its task force is working on the question and will issue guidance in January.

For its part, the AAO issued a guideline in 2015 stating that "the routine use of genetic testing is not supported by the existing literature and is not recommended at this time."

The studies published since then don't provide enough evidence to change that position, said Rahul Khurana, MD, clinical assistant professor of ophthalmology at the University of California, San Francisco, who currently serves as the editor-in-chief of the Ophthalmic News and Education (ONE) Network.

In the first place, Dr Khurana told Medscape Medical News, the AREDS studies were not primarily designed to answer questions about genotypes. An analysis of the data to look at this after the fact is susceptible to bias.

In addition, the finding by Dr Awh's team — that there might be a genotype at increased risk — has not been duplicated. And the finding that patients who do not have age-related macular degeneration could benefit from the supplements has not been published in a peer-reviewed journal, he pointed out.

"It's interesting, and I think we should try to replicate this in further prospective studies," said Dr Khurana.

For the time being, the prospects of such a study seem distant. The original AREDS cost about $35 million, and the NEI is not about to lay out that much for a similar trial, said Dr Chew. "We don't feel that there's a clinical question to ask," she said. "If we felt we were harming patients, yes, we definitely would. But we don't believe that's the case."

Typically, the company with the most to gain from research will foot the bill for a clinical trial. But ArcticDx does not have that kind of money on hand, Dr Zanke said. The Centers for Medicare and Medicaid Services has stopped reimbursing for the ArcticDx test, but the company is trying to persuade it to resume coverage. In addition, the US Patent and Trademark Office has made it much harder for the company to claim that it has an original invention.

"It's become exceptionally difficult to make money," Dr Zanke said. "We're lucky, in that we've got a lot of retina specialists who are investors in the company. They believe in the technology and they want to make it available to their patients."

For the time being, though, they'll have to do so in opposition to official recommendations.

The AREDS studies were funded by the National Eye Institute, which receives royalties for a patent on the AREDS supplements. Dr Awh holds equity and patents in ArcticDx. Dr Zanke is an employee and holds patents in ArcticDx. Some of Dr Awh's coauthors have been consultants for ArcticDx. Dr Ferris is an employee of the NEI and receives royalties for a patent on the AREDS supplements. Dr Chew is an employee of the NEI. A coauthor of Dr Seddon's study has received a consulting fee from ArcticDx. Dr Khurana is a consultant for Genentech, Regeneron Pharmaceutical, and Allergan.

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