Tag Archives: FDA

PMA Process Taking Longer and Longer

In the medical device arena, pre-market approval (PMA) submissions to the FDA keep taking longer and longer to process, according to Bob Rhatigan, senior vice president of facial aesthetics for Allergan Inc. 

“A decade ago we used to see a PMA approval time of 9-12 months,” Mr. Rhatigan told attendees of the Summit in Aesthetic Medicine 2012. “In the middle of the last decade, that increased to 16 months, and as recently as 2010, that time frame is over 2 years. It’s something that we are anxiously watching. We don’t see any signs of that abating.” 

The implications are gloomy for clinicians engaged in research of medical devices who wish to continue working in the United States. The current regulatory environment, Mr. Rhatigan said, “is working to push clinical research and studies outside of the U.S. market. It is not inconceivable, looking forward, to think about the bulk if not all of clinical research moving offshore as a result of companies like Allergan needing to get products approved more quickly. We are a bit pessimistic right now but [are] attempting to influence [legislators], as we want to make sure innovation in this industry continues to be ripe in the U.S. market.” 

— Doug Brunk (on Twitter@dougbrunk)

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FDA Takes the Measure of Nanotechnology

The  Food and Drug Administration is paying attention to the little things—the very little things. The FDA recently released guidelines for industry on the use of nanotechnology in food and cosmetics. The draft guidelines have been issued for public comment, according to the FDA website.

Courtesy Wikimedia Commons/KoS/Creative Commons License


The Nanodermatology Society issued a statement in response to the guidance for nanotechnology use in cosmetics—an issue that will continue to interest dermatologists as the technology evolves. The NDS stated its belief that the FDA has a responsibility to ensure the evaluation of nanomaterial use in cosmetics, including both over-the-counter and prescription products.

The guidelines must measure up to the science, however. “The NDS believes that the guidelines should not be based on controversial evidence, weak evidence, or pure conjecture,” according to the NDS statement. To that end, the NDS pointed out a few areas of the guidelines where scientific evidence could be more complete. For example, with respect to titanium dioxide, the NDS notes that “TiO2 can accumulate in tissues such as kidneys, but can also be eliminated, for example, in the liver in some animal models.” In addition, the NDS notes that a guideline proposing that penetration studies should be conducted on both intact and impaired skin might not be appropriate in cases where products are recommended for use on intact skin only.

In addition, the NDS recommended an expiration period for the final guidelines, due to the swift evolution of nanotechnology.

Check out the draft guidance on the use of nanotechnology in cosmetic products at the FDA’s website:

What’s your take? Should the FDA monitor nanomaterials in cosmetic products?

–Heidi Splete (@hsplete on twitter)

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The Trauma of Politics in Medicine

It’s been a quick reversal for the Susan G. Komen for the Cure Foundation, reinstating funding some 72 hours after cutting off Planned Parenthood because of new criteria barring grants to organizations under investigation, prompted in this case, by a Republican congressman.

“We will amend the criteria to make clear that disqualifying investigations must be criminal and conclusive in nature and not political,” Komen CEO and founder Nancy Brinker said in a statement issued Friday.

The uproar brought more than $3 million in donations to Planned Parenthood in just three days, but also highlights the volatile mixture of politics and medicine.

Dr. Richard Carmona recently observed that one of the most popular presentations he made during his tenure as the 17th Surgeon General of the United States did not address emerging infections, physical trauma, or national diasters, but rather the plague of politics in medicine.

“This traumatic plague of politics is more insidious and virulent than emerging infections; has potentially more morbidity and mortality than hemorrhagic shock or blunt or penetrating trauma; has virtually no diagnostic criteria; and is resistant to all therapy, especially voices of reason, substantive discussion or positions of compromise,” he said during a memorial lecture at the recent meeting of the Eastern Association for the Surgery of Trauma.

Dr. Richard Carmona Patrice Wendling/Elsevier Global Medical News

Dr. Carmona didn’t have far to look for examples to flesh out his diagnosis.

More than a century ago, public health officials’ efforts to control the bubonic plague outbreak of 1900 in San Francisco were nearly derailed by politicians who claimed that quarantine procedures, including closing the city’s harbor to incoming ships, were an over-reaction that would impede commerce and tourism, and result in the collapse of San Francisco, and possibly California. The Surgeon General who intervened based on the scientific evidence was labeled a heretic and asked to resign.

In the 1980s, similar calls were made after former Surgeon General Dr. C. Everett Koop refused to back down from statements that HIV could be prevented. At the time, Dr. Carmona reminded the audience, senior elected officials were telling the American public that HIV was God’s way of punishing homosexuals.

In the 1990s, the tenure of Surgeon General Dr. Joycelyn Elders  was cut short after controversy erupted over a 1994 speech at the United Nations World AIDS Day that included remarks that masturbation was a normal part of sexuality and that abstinence-only education was “child abuse.”

During his own term under President George W. Bush, Dr. Carmona said, abstinence-only became the mantra of the administration, “based solely on ideological and theological concepts, and not science.

“Science had really demonstrated that abstinence alone was a failed proposition,” Dr. Carmona said. “Ironic, that an administration that was repeatedly caught up in the issue of abortion did not see the connection that comprehensive sex education was the best method to prevent STDs, unwanted pregnancies, and therefore abortions. As Surgeon General, this is a science-based position I have always held.”

Dr. Carmona, the only Surgeon General to be unanimously confirmed to the position in over 200 years, said the trauma of politics and its preventable deleterious outcomes are owned equally by politicians on both sides of the aisle.

He pointed out that over-the-counter sales of Plan B stalled under the Bush administration before gaining limited approval in December 2006, but fared no better seven years later under the more liberal Obama administration. In December 2011, HSS Secretary and Democrat Kathleen Sebelius overruled the FDA’s decision to make the emergency contraceptive available, without prescription, to girls of all childbearing ages. While Sebelius cited a lack of conclusive data, Dr. Carmona said it was the administration’s desire to avoid a political battle in the face of an upcoming election.

“The immunization for preventing the continued viralness of political trauma is transparency, full disclosure, accountability for elected officials, a citizenry that is informed and participatory, coupled with civil discourse of complex issues,” he said.

–Patrice Wendling

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Beauty Poisoning

Foreign-made skin-lightening creams, found to contain toxic levels of mercury, are poisoning users as well as the people they live with, according to a report from the Centers for Disease Control and Prevention.

The CDC identified a Mexican-made cream as the likely source of mercury exposure in 22 people in 5 households in California and Virginia. While previous cases have shows similar levels of mercury exposure from skin-lightening creams, this is the first instance where exposure has been measured in non-users, CDC said. The non-labeled creams contained  2%-5.7% mercury.

Skin lightening agents that are readily available for sale in Ghana/ ©2011 Elsevier Inc. All rights reserved.

Among the sample, 15 people ages 8 months to 67 years had elevated urinary mercury concentrations (9 users and 6 non-users). Non-users were exposed to the mercury through contact with cream users or with contaminated household items, the CDC said.  Younger children, compared to older children, had much higher concentrations.

While 15 people had elevated mercury levels, only 6 (all users) exhibited symptoms of mercury exposure. Users of the skin-lightening creams said they had used it as an acne treatment, for skin-lightening, and to fade freckles.

Although mercury-containing creams are banned by the Food and Drug Administration, high levels of mercury have been found in foreign-made skin-lightening creams across the country, including Chicago, New York, Minnesota, and Baltimore.

In 2010, an FDA spokesperson told the Chicago Tribune that with fewer than 500 inspectors dedicated to reviewing imports, banned items often get through anyway. The FDA could not comment before press time.

The CDC advises clinicians who recognize mercury toxicity to consider mercury-containing creams as a possible cause, even for children. Consult a medical toxicologist before beginning treatment, CDC advises.

—Frances Correa (@FMCReporting on Twitter)

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Can Pill Color Prompt a “Nocebo” Response?

What’s the opposite of a placebo? An active drug, of course. But what’s the opposite of a placebo response? That would be a “nocebo” response, in which placebos produce adverse side effects.
 
“It’s somewhat hypothetical, but you can imagine that if somebody feels they will get better, they will get better, and if they feel that they’re taking something that’s not good for them, they might get worse,” according to Dr. Allan Krumholz, professor of neurology and director of the Maryland Epilepsy Center, Baltimore.

Image courtesy of Dr. Tricia Y. Ting

Pill color and appearance have been identified as a potential source of “nocebo” response, and differences in appearance between brand-name and generic drugs have been postulated to explain why some patients experience increased adverse events when they switch from brand-name to generics.

In response to this growing concern, in August 2010 the Food and Drug Administration solicited proposals for bioequivalence studies of the impact of switching from brand-name antiepileptic drug lamotrigine (Lamictal) to generic among patients with epilepsy in the outpatient setting.

This is a new way of conducting such trials. “Pharmacokinetics trials across all areas of medicine have traditionally been highly controlled single-dose studies in healthy volunteers dosed in the laboratory setting,” said lead investigator Dr. Tricia Y. Ting, a neurologist who works with Dr. Krumholz at the UMD epilepsy center.

Because the brand-name Lamictal and its generic counterparts look very different, the investigators decided to over-encapsulate the pills with identical coverings in order to “blind” the patients to which formulation they were taking.

But in order to do that, they first needed to determine whether the color of the pill would impact the patients’ perception of safety and efficacy. A group of 80 adult epilepsy patients were shown standard AA size capsules in five “global colors” (white, yellow, gray, caramel, maroon) and asked to select any color(s) considered “unacceptable” and to rank their preferences.

More patients deemed gray, caramel and maroon colors “unacceptable” (21%, 19%, and 20%, respectively) compared with the white and yellow (5% and 4%, respectively). There was a clear preference for white and yellow pills over the other, darker colors, without much difference between white and yellow.

But, there were patients who selected maroon as their “preferred” color. “Some people didn’t have any preference. Some had a very strong preference. One patient, an artist, liked the darker colors. It was different for different people,” noted Dr. Karen M. Aquino, a neurology fellow who worked on the nocebo study.

So what pill color will the bioequivalence study use? “To optimize drug adherence, white colored capsules will be used for over-encapsulation,” Dr. Ting wrote in her poster, which was presented at the American Epilepsy Society’s annual meeting in Baltimore. Dr. Krumholz and Dr. Aquino presented the pill color preference data in a separate poster at the meeting. The bioequivalence results are expected in 2013.

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Is Abstinence Contraception?

For many women, abstinence is a reliable way to prevent unwanted pregnancy. But is it a valid form of contraception for young women who are taking the powerful teratogenic drug isotretinoin?

Courtesy Wikimedia Commons user Diacritica

Advisers to the Food and Drug Administration danced around that topic at a meeting examining whether the risk management program for isotretinoin — called iPLEDGE — was effectively reducing the number of pregnancies in women of child-bearing age who take the drug.

Isotretinoin is indicated for a severe, scarring form of acne, but is used off-label for other types of acne, as well.

iPLEDGE began in 2006. As part of the program, young women who are capable of getting pregnant are required to have monthly pregnancy tests during their course of treatment, and to use two methods of birth control. But it’s left up to the women to decide what they will use. According to data submitted to the FDA by isotretinoin maker Mylan Pharmaceuticals, after birth control pills, abstinence was the top choice for all women as a primary method of birth control.

About 13% of women who became pregnant on the program were using abstinence as their primary method, with no back-up contraception. Twenty-five percent of women in the program who were not pregnant used abstinence and no back-up, and another 10% used abstinence as their primary method, with oral contraceptives as the secondary method.

Among isotretinoin-using pre-teen and teenaged girls, abstinence was listed as the primary method. It was the second most popular contraceptive technique for 20- to 29-year-olds.

Mylan reported that there have been 836 pregnancies in the 5 years since iPLEDGE began. Four hundred women chose to end their pregnancies, possibly because of the risk of birth defects. The company does not know the outcomes in 282 of the pregnancies. There were 45 live births; of those there were 8 children born with congenital anomalies.

Pregnancies are declining, though, as reported in our news coverage of the meeting. But even Mylan said in its background materials that, “the most common reason for iPLEDGE pregnancy as reported by the prescriber and the patient, was failure to comply with the iPLEDGE contraceptive requirements (e.g., did not use two forms of birth control, did not use contraception on the date of conception, unsuccessful at abstinence).”

How many pregnancies could be avoided with more specific education for prescribers and for young women about which birth control methods are the most effective?

The FDA advisers heard from Dr. Eleanor B. Schwarz, a University of Pittsburgh ob.gyn., who pleaded for the iPLEDGE program to make a strong recommendation for young women to use IUDs or contraceptive implants.

Some members of the advisory committees agreed that perhaps it was time to provide a more comprehensive guide to the effectiveness of various contraceptive techniques.

FDA officials were largely silent on that matter. And it’s hard to imagine them — or the isotretinoin makers — weighing in on such a dicey topic as which birth control method young women should be using.

What do you think? Should the iPLEDGE program be giving young women more evidence-based information about contraceptives?

—Alicia Ault (@aliciaault on Twitter)

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Approved or not Approved? That is a Good Question.

In a move last month that apparently took at least two device manufacturers completely by surprise, one center of the Food and Drug Administration recommended against an intended use of their products, despite the products’ approval and licensure by another FDA center.

PharmaJet's Stratis is used to vaccinate a Cambodian child against measles. Photo courtesy of Heather Potters.

Recent jet injector models, including Bioject’s ZetaJet and Biojector 2000 and PharmaJet’s Stratis, were approved and licensed by the FDA’s Center for Devices and Radiological Health (CDRH) as needle-free alternatives for injecting vaccines and injectable medications. Both companies had been marketing their devices for influenza immunization in the current flu season.

On October 26th, the FDA’s Center for Biologics Evaluation and Research (CBER) issued a notice  advising healthcare professionals that inactivated influenza vaccines should be administered only with a sterile needle and syringe. The reason: “Safety and effectiveness information that would support labeling inactivated influenza vaccines for delivery by jet injector have not been submitted to FDA.” However, CBER said, individuals who have already received a flu vaccine with a jet injector do not need to be revaccinated.

Currently, only the measles-mumps-rubella vaccine is approved and specifically labeled for administration by jet injector.

So what’s the concern with influenza vaccine? “A jet injector subjects the vaccine to a different pressure than it would receive during administration by sterile needle and syringe and as a result the effectiveness and the safety profile of the injected vaccine may be altered,” according to the CBER document.

Evidently this information had not been previously communicated to the manufacturers. “We were provided no notice by FDA of any concerns about Jet Injectors or FDA’s statement. To our knowledge, no other needle-free injection manufacturer received notice or an opportunity to discuss this matter with FDA,” PharmaJet said in a statement.

Bioject’s President and CEO Ralph Makar was similarly taken aback by the FDA notice. “The FDA communication on the use of jet injectors with influenza vaccines was surprising given that Bioject’s Needle-Free Injection Devices…are both FDA 510(k) cleared with indications for use that describe their use in delivery of subcutaneous or intramuscular injections of vaccines and other injectable drugs,” he said in a statement.

In a public comment at the October meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, PharmaJet Inc’s chairman Heather Potters said, “Last year we scaled up to provide several hundred thousand syringes, and this season we were expecting to sell several million. Now, our domestic sales have virtually stopped, except for [investigational trials].”

The companies are expected to meet with the FDA in early January to work this out. According to Mr. Makar, “We are looking into the matter to better understand the situation and the FDA’s concerns. A number of Bioject’s Needle-Free Injection devices have been on the market for many years and we are committed to resolving this matter with the FDA in a timely manner.”

-Miriam E. Tucker (@MiriamETucker on Twitter)

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A Win For Big Tobacco

A federal judge has just handed the tobacco industry one of its more salient victories in recent years, having decided that the Food and Drug Administration’s plan to require graphic warnings on cigarette packs violated the manufacturers’ right to free speech.

Image of proposed warning courtesy the Food and Drug Adminstration

Richard J. Leon of the U.S. District Court for the District of Columbia issued an order that prohibits the FDA from moving ahead until at least 15 months after he has rendered a final decision.

It’s a firm rebuke to the agency, which had trumpeted the warnings as a crucial means of dissuading Americans from smoking.  In June, the FDA shared nine cigarette package prototypes and issued a final rule that ordered manufacturers to comply with the new packaging by Sept. 2012.

A few months later, R.J. Reynolds Tobacco Co., Lorillard Tobacco Co., Commonwealth Brands, Liggett Group, and Santa Fe Natural Tobacco Co. sued the agency. And it’s not just big tobacco that is fighting the regulation. Tobacco marketing is big business.

Not surprisingly, the Association of National Advertisers and the American Advertising Federation filed a friend of the court brief in September.  The brief excoriated the government for overreaching.  And, the advertising groups likened the effort to a thinly-veiled propaganda attempt.

“If the government can deputize tobacco companies through their product packaging and advertisements to deliver its message, there is no reason it could not do so for other things — and history shows it will not hesitate to do so,” said the brief.

Judge Leon was persuaded, at least in some way, to weigh these First Amendment arguments. According to the New York Times, in his 29-page opinion (which has not been made available online yet), he lambasted the government’s “obvious anti-smoking agenda!”

But activists and others who fought for many years to find a way to regulate tobacco expressed dismay over his stay.

Rep. Henry Waxman (D-Calif.) called the Judge’s ruling “extremely regrettable.” He says that Congress already worked out all the First Amendment issues “to ensure the FDA could act as it has proposed….”

Sen. Tom Harkin (D-Iowa), who in 1998 introduced the first bill to give FDA the power to regulate tobacco products, said that graphic warnings were necessary. “This decision must be appealed so that implementation of the warning label requirement can go forward without delay,” he said, in a statement.

In January, a U.S. District Court Judge in Kentucky upheld FDA’s authority to require warnings in a similar lawsuit. That case is now on appeal.

It may now be years before the legal wrangling is settled.

—Alicia Ault (on Twitter @aliciaault)

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A Few Pills a Day to Keep Wrinkles Away?

Unilever, the international conglomerate that makes Dove soap, Axe body spray, Lipton tea and Ben & Jerry’s ice cream, is poised to bring the world a nutraceutical that it says can activate genes that will essentially repair the damage that leads to wrinkles.

Courtesy Wikimedia Commons user Bastet78/Creative Commons

According to an extensive article in the NewScientist, the nutraceutical will be launched in October in 44 spas that Unilever co-owns in the United Kingdom, Spain, and Canada.  Unilever is not seeking regulatory approval because the capsules contain ingredients already in use, and the company will not make any health claims, according to the article.

If Unilever is hoping to ever introduce the pill in the United States — which we can safely assume it will — it will likely take the same approach. Dietary supplements don’t require formal approval from the Food and Drug Administration, unless they claim to treat or cure a condition. (For more on how FDA regulates functional foods and supplements, see its web page here.)

The vast majority of supplements push as close to the legal requirements as they can, and some skirt past them, in the hopes that the FDA won’t notice. But the agency has been noticing more often and cracking down on products that make health claims.

The Unilever pill apparently has some scientific evidence to support its mechanism of action.

Again, according to the NewScientist, it will contain soy isoflavones, vitamin E, vitamin C, lycopene, and omega-3 polyunsaturated fatty acids extracted from fish oil. The omega-3s reportedly activate a PPAR gene (peroxisome proliferator-activated receptor). PPARs are involved in cellular differentiation, development, metabolism, and tumorigenesis.

The company could spend the money and time to seek formal FDA approval for wrinkle improvement — following in the footsteps of say, a Quaker Oats getting a cholesterol-lowering claim for its oatmeal. Competitors have basically ridden on Quaker’s coattails — if one oatmeal lowers cholesterol, they probably all do.

But I can’t see Allergan (which makes Botox) or Medicis (which makes Restylane) sitting idly by while Unilever mass markets an over-the-counter dietary supplement with a claim to erase wrinkles. A pill could be seen as an attractive alternative to the currently available injections, fillers, and surgical options.

And everyone’s always looking for the next best anti-aging product.

The NewScientist story caused an eruption in the blogosphere, with citations appearing everywhere from the beauty site Jezebel to the Yahoo health and beauty page, Shine. A quick Google search shows that it even ran on the Ecuador Times, which bills itself as a bilingual site for all things Ecuadorian.

The world is waiting, Unilever.

—Alicia Ault (on Twitter @aliciaault)

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Is Your Phone Smart Enough to Cure Acne?

The Federal Trade Commission (FTC) says no, definitely not.  On Sept. 8, the agency announced that it had reached settlements with two companies that were claiming that their apps could cure acne. It is the first time the FTC has pursued any company making a health claim for an app.

“AcneApp” and “Acne Pwner” both claimed to be able to treat acne with colored lights that come out of the phone when the app is activated. Purchasers were told to hold the screen next to the affected area of skin for few minutes daily.

The agency was having none of it. “Smartphones make our lives easier in countless ways, but unfortunately when it comes to curing acne, there’s no app for that,” said FTC Chairman Jon Leibowitz, in a statement.

Acne Clear app. Photo by Alicia Ault

According to the FTC, there were 3,300 downloads of AcnePwner, for sale in the Android Marketplace for 99 cents. AcneApp was downloaded 11,600 times from the iTunes store at a cost of $1.99 each. 

The AcneApp makers claimed that the app was developed by a dermatologist and that its technology was backed up by a study in the British Journal of Dermatology. Nope, not true, said the FTC.

The settlements bar the app makers from making acne-treatment claims and they were ordered to pay nominal fines. Koby Brown and Gregory W. Pearson, doing business as DermApps, have to pay $14,294, and Andrew N. Finkle, doing business as Acne Pwner, was ordered to pay $1,700.

The trade journal mobihealthnews reported that both apps had been removed from retail earlier this year or late last year.  Mobihealthnews also noted that the New York Times gave the AcneApp some press in late 2009. Gregory Pearson is identified in that story as a Houston-area dermatologist.

Apps that claim to offer curative powers were the subject of a two-day workshop that the Food and Drug Administration just wrapped up.  The agency has been mulling over how and when to regulate mobile apps.  It looks like the FTC may have beaten it to the punch.

But there are likely to be plenty more apps to scrutinize in the future.

A quick check of the Android marketplace today from my smartphone found, “Acne Clear,” from United Holdings Group, being sold at 99 cents.  It supposedly “uses a specific sound frequency and a blue color wavelength from the Lapis Lazuli gemstone to help clear and detox the skin.”  United also markets a “Skin Cleanser” app that supposedly uses a sound frequency and “a yellow color wavelength from the Imperial Topaz gemstone to help clean the skin of dark spots, sun spots, and acne scars.”  It’s 99 cents.

There’s also “SkinApp” from M&R Selected, which is free. and advises that it allows you to do “color light therapy on the go.” It is listed as having 10,000 to 50,000 downloads. The reviews are full of testimonials that it works, but also that it is just plain “bad.”

What kind of review would you give these apps? Should patients download them, or are they better off keeping their 99 cents?

— Alicia Ault (on Twitter @aliciaault)

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