1. I will not complain when my travel plans are disrupted.
   Too loudly.
   To strangers.
   Except I will start complaining loudly to you, sir to my left, who is under the impression that he has purchased my seat as well as his own. 
2. I will not get frustrated when I don’t get an immediate reply to an e-mail.
   I realize that the study I have e-mailed for information about is only one of a dozen studies that the Research Coordinator is responsible for, in addition to her clinic hours, in her part-time position with the site. I realize that the in-house contact is fielding questions from fourteen sites and the Project Manager and Regulatory Affairs and Clinical Safety, and even still she usually manages to respond to me within the hour. I realize that the world does not revolve around the fact that I leave for the airport in fifteen minutes.
3. I will show my appreciation for the contributions made by the Research Coordinator.
   He has a million other things to do, and yet he clears off his desk so that I can have a comfortable place to work. He offers me coffee and shows me where the bathroom is and runs all the photocopies I request. He shows incredible grace and understanding when I enter query after query in his hard work. And after I deconstruct his hard work, he welcomes me back in two months for another visit. The least I can do is send an e-mail after our visit to thank him for his efforts.
4. I will be more productive during my travel time – but I will think twice before writing a report on the redeye back from the West Coast.
   I know from experience and way too much time spent on edits that sometimes it’s just not worth it. 
5. I will ask study staff at each site, How can I help make this better?
   Because no matter how overwhelmed a site is, because no matter how experienced and organized a coordinator is – there is something I can do to help make things run just a little more smoothly, and I’m genuinely happy to help in any way I can. Here’s to science and success in the New Year! 
   
    
    
    

Recently the FDA issued a draft guidance on the study and evaluation of gender differences in medical device clinical studies. The guidance is issued with hopes to increase the number of female subjects enrolled in clinical trials.

Why is the inclusion of women important in such cases? Certain medical devices could elicit different responses depending on gender, according to the federal watchdog agency. Basic differences such as genetics, hormones, body size, diet and socio-cultural issues may play a role in the efficacy of medical devices in patients, the FDA said. This was further elaborated on in a recent MassDevice article which states that “A 2009 study of cardiovascular med-tech premarket approval applications showed that only 1 in 3 patients enrolled in pivotal trials were women. A 2001 report by the U.S. Government Accountability Office found that nearly 40% of studies didn't report enrollment demographics.”

Studies have shown that women may be less likely to enroll in clinical studies. According to a 2008 FDA Workshop, some suspicions of why women are under represented in clinical studies include:

• Fear of fetal consequences if the woman becomes pregnant.
• Lack of understanding about differences in disease etiology and pathophysiology may lead to under-diagnosis and under-referral of women.
• Avoidance of female patients by investigators and sponsors due to the perception that it takes more time and money to recruit them.
• Inclusion/exclusion criteria that may not be necessary to define the study population may unintentionally exclude women.
• Family responsibilities which limit ability for time commitment to study follow-up.

The draft guidance also suggests approaches to enhance the enrollment of women by considering the following approaches:

• Target investigational sites where recruitment of women can be more easily facilitated (e.g., women’s clinics).
• If women are likely to benefit from your device but may not meet certain study enrollment criteria, consider parallel cohorts for collecting data on device use in women.
• Plan focused efforts to enroll women under a continued access study.
• Include provisions to ensure certain minimum enrollment for women (e.g., mainntain open enrollment for women until pre-specified proportion is reached).
• Consider flexibility in follow-up visit scheduling with provision of child care or elder care services during appointments.

It is critical that the group of patients enrolled in a study represent the population that may receive the device once it is on the market. How do you think the FDA’s new draft guidance, Evaluation of Sex Differences in Medical device Clinical Studies, will effect our industry? Please share your thoughts with us!

Dr. K. Kringle
Adjunct Professor of Child Psychology
Far Northern University

Dear Dr. K. Kringle:

At the regularly scheduled December 24 meeting, the IRB reviewed your protocol, “A Global Observational Study of Behavior in Children.” While we believe it has many good features, it could not be approved as submitted. If you choose to revise your study, please address the following concerns:

1. You propose to study “children of all ages.” Please provide an exact lower and upper age limit, as well as the precise number of subjects. Provide a statistically valid power calculation to justify this large of a study.
2. Your only inclusion criterion is “belief in Santa Claus.” Please provide a copy of the screening questionnaire that determines such a belief. Provide a Waiver of Authorization under HIPAA in order to record these beliefs prior to enrollment in your study. The Board recommends that you obtain a Certificate of Confidentiality as beliefs are sensitive and personal information.
3. You propose to “know when they are sleeping and know when they are awake”. How will this be done? Will children undergo video monitoring in their beds? Will they have sleep EEGs? You list 100 elves as research assistants. Are any of them a sleep physiologist?
4. Your primary outcome measure is to “know when they’ve been bad or good.” What standard is being used to determine ‘goodness’? Do children have to be good all year or just most of the time? What if they have been really, really, good except for one time when they hit their little brother?
5. You propose to conduct your research by entering the subjects’ homes through the chimney. Have you considered the damage to the roof, carpeting, etc., that this will cause? Moreover, children are likely to be startled by your appearance late at night. Please revise your protocol to conduct your home visits between 9 am and 5 pm Monday through Friday with at least one parent being present.
6. You state that compensation for participation will be “sugarplums, candy, and toys” for the good little girls and boys. This may not be appropriate for the children with obesity, dental caries, and hyperactivity. Also, your proposal to leave a lump of coal in the stockings of the bad children will be unfairly stigmatizing to them individually and as a group. In general, the Board suggests a small token of appreciation for all participants. Perhaps a $5 Toys-R-Us gift card would be better.
7. The database of good and bad children will be kept “on a scroll at the North Pole.” Please describe the security provisions you have in place to protect the research data. Is the scroll kept in a locked cabinet in a locked room? Who has access to the scroll? Are there backup copies of the scroll and how often are they compared to the original?
8. You mention the participation of “eight tiny reindeer” in your protocol. Please provide the Board with documentation of Institutional Animal Care and Use Committee approval.
9. Please provide the Human Subjects Protection training dates for Mrs. Claus and the elves.
10. As this study involves prospective data collection and is more than minimal risk without prospect of direct benefit to the subjects, informed consent signed by both parents will be required. Please have the consent form translated into every language spoken by children.

Please submit 25 copies of your revised protocol to the lRB. The IRB will be on Holiday Season schedule for the next two weeks. If approved, you will be able to conduct your study sometime in January.

Sincerely,
E. Scrooge, MD – Chair, Institutional Review Board

Direct Source:
“Season’s Greeting from Your IRB.” Karp, David R. Journal of Clinical Research Best Practices, Vol. 4 No. 1, January 2008.

It is not unusual for a monitor to come across upwards of a dozen Notes-to-file at a monitoring visit. At some sites it can seem as though the art of the Note-to-file is perfected as a Magic Eraser with regard to explaining away regulatory discrepancies. The regulatory purist in me shudders at this practice; but at my last monitoring visit, I stepped out of my normal comfort zone and recommended that my site staff colleagues compose several Notes-to-file to document resolution efforts that would otherwise be doomed to follow-up item purgatory. A Note-to-file should not be the immediate solution to a nagging regulatory issue, but there are several instances that can elevate this documentation tactic to preferred status.

So, when is a Note-to-file appropriate?

• To document the location of sometimes-centralized essential documents, such as CVs, medical licenses, laboratory certificates, and clinical trial agreements/budget agreements; or to note the location of a log that might be updated and stored outside of the regulatory binder for the site’s convenience
• To document a specific site practice that is otherwise unusual or unclear
• As a way to document efforts to resolve a potential deviation or non-compliance that has become otherwise unresolvable

To elaborate on the final point, it can be conceded that there are times when certain situations can result in regulatory discrepancies that have no hope of resolution. For example, consider a situation where you are two years into a study and cannot locate training documentation for staff that performed study-related tasks and no longer work at the site. After doing some investigating, you determine that they cannot be located and, unfortunately, there is no copy on file with the sponsor. In this situation, a properly composed Note-to-file will not correct the fact that the documentation does not exist, but it may keep you or someone else from having to go down the same investigative path in the future. In this circumstance, what should be included in the Note-to-file?

For these more complicated regulatory issues, Notes-to-file should describe in brief:

• A summary of the problem or discrepancy
• The action that was taken to resolve the issue
• Why the actions failed to resolve the issue
• Any issue the site has taken to prevent a similar circumstance in the future
• Date and signature of the Research Coordinator and/or Primary Investigator (depending on the severity of the issue documented)

However, if there is a repetitive history or major regulatory non-compliance, it might be in the best interest of a site to complete a Corrective Action Plan and include the Note-to-file. The presence of a Note-to-file will not necessarily stave off a Warning Letter, should the non-compliances be severe enough. There is not a Note-to-file in existence that will take the place of proper staff training and solid SOPs, nor can it ever be considered a replacement for source documentation.

One final point regarding Notes-to-file: this Magic Eraser does not absolve the site of regulatory reporting requirements. If subject medical records were not reviewed for SAEs in a timely manner, a site cannot simply document the oversight in a Note-to-file and claim the issue resolved. Sponsor, IRB and FDA reporting requirements must still be adhered to.

How does your organization handle Notes-to-file?

Following an FDA inspection and exit interview, the FDA investigator will discuss the findings from an inspection and if deficiencies are found, a FDA 483 Inspectional Observations may be issued. The 483 describes any inspection findings that represent deviations from applicable agreements and regulations. The response to a FDA 483 is crucial. An article published in GxP Perspectives highlights sentence fragments from Warning Letters which seem to indicate a missed opportunity to avoid a Warning Letter following an FDA 483:

“The adequacy of the response cannot be determined because the response did not include…”
“We have reviewed your firm’s response and note that it lacks sufficient corrective actions regarding…”
“Your response does not address…”
“Your response is inadequate because…”

The article further points out that while a response to a 483 is not always mandatory; the FDA is more likely to view a quality response as adequate. What are some guidelines when preparing a response?

• Establish the true root cause of the observation from the 483 so it can be fixed properly and permanently.
• Provide specifics regarding any corrective actions taken or proposed.
• Provide supporting documentation for every claim to re-enforce commitment.
• Review recent FDA Warning Letters and note responses that were not adequate to ensure mistakes are not repeated.

Whether you are a sponsor, monitor, or site, everyone has a stake in the outcome of an inspection. Being aware of the most common FDA findings and trends is important for any study team member to help prevent repeating the same mistakes. IMARC has two whitepapers currently available under the Resources Tab which detail the Top Ten Warning Letter Findings from 2009 & 2010. Please take time to download our papers.  And, stay tuned for IMARC’s upcoming whitepaper for 2011 FDA Warning Letter Findings for Clinical Investigators.

The process of obtaining approval for new medical devices can be a long and windy road.  This complicated and sometimes confusing process may soon get a little easier, according to an Industry News press release.

LifeScience  Alley™ is a 650 member organization that prides itself on aiding, educating, and leading their members in their pursuits for success.  According to their website, LifeScience  Alley™ also “partners with organizations to educate and lobby legislators on issues critical to the success of our members.”  This strategic affiliation will now include a partnership between them, the FDA, and academic experts to take a new look at the procedures, practices, and science behind the approval of medical devices.  The goal is to bridge the gap between what some call a slow, confusing process and what others say is a somewhat lackadaisical review process before a device goes to market.

This idea of getting both regulators and manufacturers on the same page to streamline the process of getting a device to market, if successful, seems like a win-win for everyone involved.  Including the patient who just may be waiting for a miracle…

IMARC is a proud member of LifeScience Alley™ and looks forward to the partnership for the clinical research industry. 

How do you feel about this new partnership?

On November 10th, a FDA press release announced they issued a draft guidance aimed at fostering early-stage devices within the U.S.  The guidance contains new approaches toward early feasibility studies, which are conducted in a small number of patients early in device development, while providing appropriate human subject protection.  The FDA is seeking a small number of companies that could pilot the new approach, as the results of the pilot will help inform the final guidance.

The FDA also issued a guidance regarding clinical trials and medical devices. It outlines the FDA’s process for approving applications from companies that want to conduct medical device trials. Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health indicates “Today’s guidance documents give sponsors and FDA device reviewers more flexibility to start investigational studies sooner while maintaining appropriate human subject protection, and they propose efficient ways to support product or study design changes once the study begins.”

The draft guidance “FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations" clarifies the FDA’s process for approving clinical trial of medical devices and includes:

• When the FDA might allow patients to enroll in a study while issues are resolved, an approach called "approval with conditions." Appropriate issues might include data analysis methods that can be resolved prior to gathering the data or minor divergences from study endpoints or study design assumptions.
• When the FDA might allow studies to begin with a smaller group of subjects while companies gather additional data, prior to the larger general enrollment, an approach called "staged approval."

Do you feel these draft guidance documents will help facilitate investigational medical devices studies in humans? Share your thoughts with us.

Back in October, Reuters reported that the FDA is seeking public input on a plan to create a network of outside experts to help understand the new technology in medical devices. The goal of panel would be to help speed up device approvals.

The program is part of the agency’s efforts to reform the 510(k) approval process. There has been much controversy surrounding the 510(k) process.  The Institute of Medicine  (IOM) recently reported that the process did not adequately protect patients and calls for an overhaul of the process.

Currently, the FDA’s devices center already has a staff of scientist, engineers and clinicians, but they often reach out for external expertise in reviewing products. The experts in the pilot program will not provide policy advice, but will be asked to help the staff form their own conclusions.

Do you feel this panel approach will add any value to the 510(k) review process? If not, please explain why.

The Leahy-Smith America Invents Patent Reform Act that went into effect in late September could help some medical device companies. According to an article in MedCity News, the legislation recently passed by Congress represents the biggest changes to patent law in the United States since 1952.

The Leahy-Smith Acts has established the filing fee for the new prioritized examination at $4,800 for large entities and $2,400 for small entities. For small companies that are seeking prioritized examination, this will shorten the regulatory process, which ultimately could be a benefit.

Not everyone agrees on the impact of the act. Senator Maria Cantwell (D-WA) that “this is a big corporate patent giveaway that tramples on the rights of small inventors.”

If you are part of a medical device startup, share your thoughts.

It’s holiday time already! When thinking about how to prepare to resist the delicious holiday temptations that will cross my path over the next two months, I came across two Yahoo news articles. According to Global Industry Analysts, Inc., the U.S. bariatric surgical device market will reach $2.6 billion and the drug market will reach $10.3 billion over the next five short years.

Why so much? The world health organization statistics state that being overweight and obese is the fifth leading risk for death totaling 2.8 million adults each year and the problem continues to worsen. Several physicians in an article published in Cardiology Today May 2011 contend that little options are available right now to help their patients manage their weight. Compounding the issue are the rising costs for treating the co-morbidities that contribute to 44% of diabetes cases and 23% of ischemic heart disease cases in the world.

Current weight-loss options are not completely favorable. A study conducted in Belgium this past April highlights that the success of the Gastric Lab-Band device has a poor long-term outcome. Nearly 1 out of 3 patients experienced band erosion, and nearly 50% of the patients required removal of their bands, contributing to a reoperation rate of 60%. These reports compounded by the fact that three obesity drugs that were met with some tough regulatory decisions and denied market approval last year left bariatric leaders mystified. Now, the FDA is beginning to reconsider those decisions. Early this year, The National Institute of Health published a “new strategic plan for NIH obesity research [that] seeks to curb epidemic.” The primary goal is to “use technology to advance and increase the scope of obesity research.” Still, with apprehension about the US Food & Drug Administration (FDA) review process and its impact on advancement in the obesity solutions, academia and industry will work together to identify best practices for clinical trials to standardize the clinical investigation and review process at a meeting schedule last month. According to the FDA, their challenge will be to strengthen their premarket review programs improve the quality, consistency, and predictability of their regulatory decisions.

Still, it’s a tricky landscape for bariatric device manufacturers. One problem exists with clinical trial design for obesity studies. Meaningful outcome metrics, such as reduction in comorbidities like heart attacks, are often not factored into the trial design. Therefore, relying solely on simple weight loss outcomes leads to less meaningful endpoints explains Dr. Wolfe, past president for the American Society of Metabolic and Bariatric Surgery. Additionally, methods for “identifying appropriate candidates for devices versus drugs are underdeveloped,” resulting in lower patient enrollment in pivotal studies.

A new way of thinking about weight loss options has begun. During the last decade, the device industry has focused on restricting food intake or caloric absorption. But these surgical options have been relatively invasive, by restructuring or physically attaching a device to the stomach. The recent trend is to get “back to basics” by identifying weight loss solutions that are less invasive, reversible, and focused on the physiological triggers behind obesity.

On the horizon are over 20 new device trials currently underway, as well as the huge opportunity for more obesity treatments to be brought to market. Among the top 60 of 2011’s best medical innovators by the Cleveland Clinic, is Satiety, INC. in Pal Alto, CA. Satiety’s TOGA System is an incisionless restrictive device, which creates a smaller passageway for food within the stomach using a stapling instrument. The movement of food through the stomach is slowed, giving patients a feeling of fullness with a smaller amount of food. The procedure is performed without any surgical cuts, and no implant is left behind, just staples. The TOGA procedure has treated more than 450 patients worldwide in a multi-center, randomized, sham-controlled study, the outcomes of which will be used to seek FDA approval to market the system in the U.S.

Not sure, but perhaps someday, we can eat our holiday cookies and have our cake, too?