Patients Are Eager for Trials But Aren’t Getting the Word, Survey Finds

Patients are eager to participate in clinical trials, but they’re having trouble finding the information they need — not just on social media, but from their own doctors, a new survey suggests.

Many respondents said they’d be interested in joining trials — nearly three-fifths said they would be willing to share genetic information or their health records as part of a trial — and one in five said they had proactively asked their doctors about trials, but only 15 percent had ever enrolled in one. Fewer than one in five said their doctor had suggested trials for them.

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The survey was conducted by Inspire, a healthcare-focused social media platform, which surveyed nearly 9,500 of its more than 1 million patient and caregiver members about a range of issues, including awareness of clinical trials.

There also seems to be something of a gender gap in patient readiness for trials. Nearly one-quarter of men said their doctor had suggested a trial for their diseases, but fewer than one-fifth of women received similar advice.

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This is the fourth year Inspire has surveyed patients and caregivers about their treatment. The ongoing lesson, Inspire Research Manger Hannah Watson Eccard says, is that people “are more than recipients of medical care. They are active partners who work with healthcare professionals to make medical decisions and find the best option for them.”

For some patient advocates, the Inspire survey is wake-up call to the trials industry.

“We need to do a better job of initiating conversations about new treatment options — especially clinical trials,” says Dana Dornsife, founder of the Lazarex Cancer Foundation, a California nonprofit that helps patients overcome obstacles to trial enrollment.

Dornsife says she and her colleagues “receive calls daily from cancer patients for whom standard care isn’t working and can’t find the information they need as they investigate clinical trial options.” The group is in the midst of a project it calls IMPACT, a three-year pilot program aimed at improving enrollment in trials.

“The system is fragmented and flawed and leaves many patients out,” she says. “And if a patient does find a clinical trial for which they’re eligible, they’re often blindsided, in many cases, by insurmountable travel costs just to get to the clinical trial. “

Keep Investigator’s Brochure Updates Clear, Concise and Timely, Experts Advise

Investigator’s brochures (IBs) are meant to be a living document, updated at least once a year to keep up with progress and developments in the trial.

But scheduling and drafting updates can prove challenging, says Tiffany Guckin, associate director of regulatory affairs for Invicro, an imaging services and software company.

 

IB means - Investigator's Brochure
IB means – Investigator’s Brochure

The FDA doesn’t stipulate when investigators and sponsors should submit updates to their IRBs and the agency, but it does require sponsors to submit an annual report to the agency within 60 days of the anniversary of the date an IND became active. Scheduling the two updates together in advance is an efficient way to keep reporting requirements on track, she says.

Most of the information in a clinical trial’s annual report is contained — often in greater detail — in the investigator’s brochure, so it makes sense to produce those documents in parallel, Guckin says. She notes, however, that an IB would need to be updated immediately if any crucial safety-related information came to light.

Beyond timing, Guckin says investigators often struggle with keeping IB updates clear and concise, balancing the need to provide all the relevant information with the need to produce a document that an IRB can quickly and easily digest. She suggests including with each IB revision a brief, easy-to-read summary of changes since the last iteration of the brochure. This summary can perform double-duty, she adds, as it can likely be copied and pasted directly into the annual report. She also suggests investigators track changes to make it abundantly clear what has been revised in the new version of the brochure.

Lindsay McNair, chief medical officer for WCG, agrees that transparency is key. “When an IB is revised,” she advises, “provide a clear notation of what data or sections have been changed or updated so the reader knows what to focus on, especially when assessing whether the risk profile has changed.”

As an investigative product moves through development, McNair says, it’s important to revise the sections of the IB containing clinical and non-clinical study results, rather than simply flooding those sections with more data. As the results of more studies become available, investigators can offer a brief summary of past results that have become comparatively less important. For instance, the results of single-dose animal toxicity studies can be minimized once data from chronic-dosing studies are available, she says.

McNair, who has served on a number of IRBs, says sponsors also could be clearer about which possible adverse events would be considered “expected” when drafting the original IB. The regulatory guidance says that serious adverse events will be considered unexpected — thus triggering the filing of an IND safety report to the FDA — if they’re not listed in the IB. “Which sounds straightforward,” she says, but can be “surprisingly hard to determine in practice.” Often, an IB will include safety data on the product related to other conditions, or in combination with other drugs, which may have different expected safety profiles.

Guckin emphasizes the need for coordination and interdepartmental cooperation when preparing annual reports and IB updates. “I suggest that if you have multiple IND applications, you send the due dates out to all the involved departments at the start of the year,” so they can be prepared for regulatory affairs to reach out to them for information.

And when an IB is updated, the newly revised document should be sent to all clinical site investigators involved in the trial.

CDER Drug Trials Report Shows Declining Enrolment

CDER released its fourth annual Drug Trials Snapshots report, which shows a significant drop in the number of participants in pivotal novel drug trials that led to agency approvals.

The overall number of participants dropped by more than half from approximately 106,000 in 2015 to 44,000 in 2018, according to the latest report.

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Mark Summers, president, patient engagement, WCG Clinical, noted that clinical studies — especially those for cancer drugs — don’t need as many people as they used to.

“In areas like oncology everything’s moving toward biomarkers. You don’t need as large a population. That could be a factor as well,” Summers said, cautioning that the report doesn’t speak for overall participation in clinical studies because it only covers the enrollment rate of pivotal studies for FDA approved drugs.

Another significant trend was a shift in the trial demographics toward inclusion of more female and black or African American participants. The overall percentage of women increased from 40 percent in 2015 to 56 percent in 2018, while black or African American participation doubled from 5 percent in 2015 to 10 percent in 2018. Hispanics were not recorded in the first two snapshot reports but accounted for 14 percent in 2017 and 2018.

“In recent years, the representation of certain subgroups, such as women and people of racial and ethnic minority groups, has become of greater interest to the general public,” CDER director Janet Woodcock said.

The trend for participants aged 65 and older was generally upwards, with a spike in 2017 to 32 percent, but dropping off last year to just 15 percent representation. The spike may have been the result of several trials that were focused toward geriatric patients, such as Portola Pharmaceuticals’ Bevyxxa (betrixaban) for prevention of thromboembolism.

CDER approved 59 novel drugs last year — either new molecular entities or biologics — ranging from oncology drugs to a preventive migraine drug to treatments for bacterial skin infections, smallpox disease and epilepsy, among others.

The report includes data on the ethnicities, age and sex of participants in each approved novel drug trial. Some trials differed significantly in terms of their demographics. For example, participants in the pivotal trial for Amicus Therapeutics’ Fabrys disease treatment Galafold (migalastat) were nearly all white (97 percent) and more than half were female (64 percent).

On the other hand, the key trial for Theratechnologies’ Trogarzo (ibalizumab-uiyk), an HIV-1 treatment, was more evenly distributed, with whites, black or African Americans, Asians and Hispanics accounting for 55 percent, 33 percent, 10 percent and 25 percent of the participants, respectively, with a 15 percent female makeup.

Read the report here: https://bit.ly/2DXLzHU.

Doing More With Less: The Road To Success For Clinical Trials

Conducting a clinical trial can be both a time consuming and costly affair for pharmaceutical companies. If one is to be successful, they must have their affairs in order, from navigating protocols and regulations to the basic budgeting.

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As the Vice President of Clinical Development Operations at Endo, Rosie Filling’s job is to do just that. Since taking the role in February 2018, she’s been responsible for protocol concepts through corporate social responsibility (CSR), and ultimately through any regulatory submission Endo may be compiling.

A biologist by training, Filling has more than 20 years of experience in the clinical trial industry, exposing her to all functional groups responsible for the execution of a clinical trial.

On behalf of Clinical Research News, Lee Yuan spoke with Filling about the challenges that come with outsourcing clinical trials, what innovations excite her, and what she’s looking forward to as the industry progresses.

Editor’s note: Lee Yuan, a Conference Producer at Cambridge Healthtech Institute, is planning a track dedicated to Managing Outsourced Clinical Trials at the upcoming Summit for Clinical Ops Executives, SCOPE, in Orlando, February 18-21. Filling will be giving a co-presentation at the program. Their conversation has been edited for length and clarity.

Clinical Research News: What do you feel are the biggest challenges in outsourcing clinical trials today, and why?

Rosie Filling: Currently I think the biggest challenge a lot of management is continuing to hear is knowing how to save costs while maintaining quality. It’s definitely that model of “do more with less.” I think as an industry we are constantly being challenged to evaluate cost saving measures, and that leads us to many different questions. Do we change our trial designs? Do we execute our clinical trials differently? Going through the evaluation process is best for the program as well as for your company. Trials are continuing to become more and more expensive. Some of that is certainly related to the requirements that are being enforced by certain regulatory bodies. But as our trials are becoming more and more complex, and when building budgets, it’s very easy for many of us to use previous estimates that we may have from our past experience, etc. Now, we really have to take a step back and look at the many different factors that are driving the additional costs and how those can be offset.

What innovations in the trial space have you most excited, and why?

I think there’s a lot going on out there. One thing in particular, I think, that’s exciting and has been certainly creating some noise over the past several years, is patient engagement. I still think we have come a long way over the past five to seven years in terms of both patient engagement and eCOA [Electronic Clinical Outcome Assessment], but I still think we have a lot of growth potential in that area. I’m excited to see where that goes.

Another one is the oversight of our CROs [Contract Research Organizations] and, in particular, our CRAs [Clinical Research Associates]. Having efficient processes to ensure that we have appropriate oversight, that we’re giving appropriate oversight, and not causing more complexity or harm to the clinical trials is crucial.

In general, what are you excited about in the industry?

Right now I think there needs to be a lot of focus on true partnerships. I think if you ask any CRO or any vendor out there, and even some pharma companies, are you really executing in a true partnership model? I think you’d be surprised with the responses that you would get. I think it’s important, and I like to speak about investing the time and effort in building relationships. Don’t give up too soon. Stick it out with your vendors; try to make it work. I have been fortunate to set up different models at many different pharmaceutical companies, and while my function is to ensure that we execute our portfolio with the greatest quality at the best cost, I have also instilled a culture in these places to ensure that our suppliers are set up to succeed and deliver for our teams as well.

Genentech Pulls Plug on Two Alzheimer’s Trials

Genentech has closed two large Phase III trials for its once-hyped anti-Alzheimer’s drug crenezumab after an independent data monitoring committee warned the company that crenezumab wasn’t likely to hit its primary endpoint.

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The CREAD 1 and CREAD 2 trials had enrolled 1,500 patients worldwide, all of them in the early stages of Alzheimer’s disease, and offered patients doses four times higher than in the Phase II trials that had showed promise in helping patients.

But Genentech, a subsidiary of Roche, an­nounced last week that its IDM committee told them the drug didn’t seem to be improving patients’ scores on individual cognitive tests.

Genentech officials acknowledged the “disappointing” results but said that they’re still studying crenezumab in an ongoing trial of clinically healthy patients in Colombia who carry the genetic mutation associated with heritable Alzheimer’s

Particle Sciences partners with Encube Ethicals to Develop Novel Vaginal Rings

Contract development and manufacturing organization (CDMO), Particle Sciences, a Lubrizol LifeSciences company, has announced its partnership with leading Indian contract manufacturing organization (CMO), Encube Ethicals.

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Under the partnership the two companies will develop innovative intravaginal rings with the intent to out-license to biopharmaceutical marketing partners.  The partnership will focus on rings for the administration of existing approved drugs, improving drug effectiveness and patient compliance. The use of drug-eluting devices to provide sustained-release dosage forms has seen continued growth due to the ability to provide constant, localized, site-specific drug delivery.  The market continues to be of interest as these devices can improve patient compliance, one of the greatest challenges in healthcare today.

Both parties will leverage each other’s drug development and manufacturing strengths: Particle Sciences has a proven track record and extensive expertise in the development and manufacturing of intravaginal ring devices and complex formulations, while Encube Ethicals has strong capabilities in developing complex topical and transdermal delivery systems, with two decades of experience in commercial manufacturing of Topical products for a variety of markets, including women’s health for multiple countries.

The project is Particle Sciences’ latest in the complex generics space using the 505(b)(2) US Food and Drug Administration (FDA) regulatory pathway to develop new drugs that better meet the requirements of patients and physicians.  Dr. Barbara Morgan, general manager of Particle Sciences said: “Our collaboration with Encube Ethicals is an important step in our work on complex pharmaceuticals and particularly toward our efforts to accelerate improved therapeutics through the use of the 505(b)(2) pathway.”

Mr. Mehul Shah, founder and managing director of Encube Ethicals said: “We are deeply invested in finding innovative ways to deliver drugs that make the patient’s experience significantly better and safer. We hope to leverage Encube’s experience in Topical products development and manufacturing to bring impactful breakthrough innovations to the market. We are delighted to partner with Particle Sciences’ extremely talented team and excited to see the possibilities the effort creates.”

About Particle Sciences
Particle Sciences, a Lubrizol LifeSciences company, is an integrated provider of drug development services. Particle Sciences focuses on BCS II/III/IV molecules, biologics and highly potent compounds through a variety of technologies including emulsions, gels, micro and nano-particulates, drug/device combination products, solid solutions and others. Particle Sciences is FDA registered and DEA licensed. Through a full range of formulation, analytic and manufacturing services, Particle Sciences provides pharmaceutical companies with a complete and seamless development solution that minimizes the time and risk between discovery and the clinic. The company was founded in 1991 and is headquartered in Bethlehem, Pennsylvania.

About Encube Ethicals
Encube is an integrated pharmaceutical organization focusing on Topical, Transdermal and Complex delivery solutions that impact millions of lives around the world. Founded in 1998 by Mr. Mehul Shah, Encube has business verticals in contract services (CDMO), generic ANDA development and commercialization, and an innovative 505(b)(2) pipeline for the US market. Encube operates one of the largest manufacturing facilities for Topical prescription products in the world with 350 million units of capacity located at Goa and a large 120+ scientist R&D center in Mumbai.

About Lubrizol LifeSciences
Lubrizol LifeSciences is a preferred Contract Development and Manufacturing Organization (CDMO) partner for complex pharmaceuticals and high-end medical devices providing differentiated polymers and excipients, along with state-of-the-art design, development and manufacturing services to the healthcare industry.

Investigators Most Likely to Be Cited for Failing to Follow Protocols, FDA Records Show

Principal investigators continue to have trouble following their own trial plans, an analysis of FDA inspection records shows.

The FDA’s Bioresearch Monitoring Program (BIMO) cited 400 separate failures in fiscal 2018, of which nearly 30 percent — 118 instances — were for failing to follow the investigational plan.

The percentage of protocol violation has been remarkably consistent for several years, data analyzed by CenterWatch show. In fiscal 2017, protocol violations made up nearly 29 percent of all inspection observations. There were more than 25 percent of violations in fiscal 2015 and 2016, respectively.

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For Lindsay McNair, chief medical officer for WCG Clinical, the data reinforces three important points. The first is that researchers should remember that there’s no such thing as a protocol waiver.

“There is no mechanism through which prospective planned deviations from the protocol can be granted; these will still be considered failure to follow the investigational plan even if done intentionally,” she says.

The second lesson is that principal investigators must assume total control of those working under them — because they’re certainly going to be given total responsibility for any missteps, McNair says.

Finally, investigators should remember that if an IRB adds new requirements to the study as a condition of approval, then those new conditions are part of the protocol, too, she says.

The second most common citation was for failure to adequately maintain case records — at least 69 separate instances. This, too, seems to have been a consistent problem over time: failure to maintain case records were the second most common problem in fiscal 2015 (92 occurrences), fiscal 2016 (70 times) and fiscal 2017 (76 times).

Other frequent citations include failure to maintain IRB records (14 instances) and failure to maintain proper records of drug doses (13 cases).

BIMO cited five investigators in fiscal year 2018 for conflicts of interest, four for failing to obtain proper informed consent, three for failing to dispose of unused drugs properly, and one for using a site that wasn’t suitably built.

The CenterWatch analysis was based on BIMO’s annual inspection metrics reports from fiscal years 2015 to 2018.

UK Regulators Back Away from Trials Location Requirement as Brexit Looms

UK regulators have backed away from a proposed post-Brexit requirement that drug sponsors have a point of contact in the UK to conduct clinical trials.

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The MHRA had floated a requirement that anyone sponsoring a trial in Britain or Northern Ireland had to have an office in the UK. But “stakeholder feedback” convinced officials to reverse course. The new rules would allow sponsors to run trials in the UK as long as they have an office in one of several approved countries, which — for now — will include EU countries.

Without some kind of agreement, the UK will leave the European Union on March 29. The Brexit vote has already disrupted the clinical trials industry in Britain and Northern Ireland. Last year, an analysis by Fitch found that new trials in the UK had declined 25 percent since voters approved a referendum to leave the EU. The European Medicines Agency already is moving its headquarters from London to Amsterdam.

FDA Guidance: Start with Kids in Atopic Dermatitis Trials

Sponsors of atopic dermatitis drugs for children don’t have to wait to test a drug’s safety or efficacy on adults before beginning pediatric trials, the FDA says.

The new guidance, released last week, reverses longstanding FDA recommendations that drugs trying to treat a disease by affecting the entire body start with adult trials.

Atopic dermatitis is the dry, itchy rash caused by eczema that affects nearly 18 million Americans, most of them children. It often clusters with asthma and hay fever.

 

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The agency says its U-turn was prompted by recommendations from a 2015 meeting of its Dermatologic and Ophthalmic Drug Advisory Committee.

The FDA acknowledges that “some major safety questions” may be left open before trials can begin.

But it says it’s “not generally necessary to have an extensive safety database in adults before initiating pediatric studies” as long as the disease isn’t potentially fatal to pediatric populations and there’s a risk doctors may be prescribing therapies off-label before trials wrap up.

Trials will have to consider a drug’s effect on children of all ages, including toddlers and infants, the guidance adds.

Sponsors may have to start with older children first if specific data from an older subpopulation can help inform the study, if there’s an “age-related technical issue” or if there is some reason to worry about a drug’s safety in younger children.

Read the final guidance here: www.fdanews.com/10-02-18-AtopicDermatitis.pdf.

Re-Trials for Pediatrics Pay Off
The FDA’s pediatric exclusivity rules allowed drugmakers to reap a 680 percent return on their investments, a new analysis finds.

The Best Pharmaceuticals for Children Act of 2002 offered drugmakers six months of market exclusivity in return for running drugs already approved for adults through clinical trials again to test their safety and efficacy for children.

Congress passed the measure because it was concerned that doctors were pre­scribing adult meds to kids off-label and the pharmaceutical industry argued that limited exclusivity provided proper incentive to invest in fresh trials.

The incentive has proved lucratice, according to the analysis published in JAMA Internal Medicine.

Study author Michael S. Sinha and his colleagues at Boston’s Brigham and Women’s Hospital examined 54 drugs given exclusivity between 2007 and 2012.

They estimate pharma companies spent an average of $36.4 million to re-test their drugs in clinical trials and the median net return was $176 million—a ratio of about 680 percent.

“Meaningful knowledge of pediatric uses of pharmaceuticals has come from the pediatric exclusivity program, but at a high cost” in hefty drug prices passed along to consumers, Sinha said, noting that “other approaches … such as direct funding” for pediatric trials “may be more economically efficient.”

 

FDA Addresses Rare Disease Trial Challenges in Revised Draft Guidance

A new draft guidance on rare disease trials may help sponsors ease the tensions between the need for robust, scientifically sound data and the small patient populations that they’re hoping to treat.

The guidance offers sponsors advice on filling the gap by using such tools as natural histories, surrogate biomarkers, external controls and early randomization but perhaps most importantly, offers a new section on safety.

 

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Lindsay McNair, chief medical officer of WCG Clinical, says the guidance “synthesizes and updates information for the sponsors and researchers working in these therapeutic areas and addresses some of the issues that are frequently challenging.”

“I would say that the challenge in developing new therapies for rare diseases is that it often involves a lot of groundbreaking with little regulatory precedent and challenges in the study design, such as determining what the appropriate endpoints will be,” McNair says.

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In the new section on drug safety, the guidance encourages sponsors to come up with their own ideas for rare disease safety data, but also offers some suggestions on common approaches.

Drug sponsors should consider natural histories, trial eligibility, dose selection, computer arms or auxiliary safety cohorts as means to ensure that they’re giving regulators the best — and most — possible safety data for rare disease treatments, the draft says.

Canvassing possible approaches to expanded safety data, the agency says of each:

  • Natural histories can “help distinguish drug-related adverse effects from underlying disease manifestations;”
  • Trial eligibility: sponsors should “consider enrichment strategies to decrease heterogeneity and to enhance the ability of the clinical trial to demonstrate a potential treatment effect;”
  • Attention to dose selection is important to make sure that patients don’t stop taking medicines because their doses are too low or high; and
  • Auxiliary cohorts can include a trial protocol with a parallel safety cohort (alongside an efficacy trial), a trial that gives patients drugs under expanded access or gathers relevant data from other sources, such as trials using the drug for another purpose or studies of similar drugs.

When considering a rare disease drug’s feasibility — which also can be tough, given the small populations involved — sponsors should include all the disease’s permutations through different life stages of its patients.

“Sponsors also should determine prevalence estimates for all countries in which trial sites are being considered,” the document states. “Sponsors should provide the individual sources of current published prevalence estimates, rather than calculated averages, because published prevalence estimates can vary widely depending on study details … country or region, and advances in diagnostics and treatment over time.”

You can read the FDA’s new draft guidance here: https://bit.ly/2FAUUr6.

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