Paying for Trial Participation: A Question of Incentive v. Influence

When it comes to offering to pay clinical trial subjects to participate, the line between compensation and coercion is difficult to draw but all too easy to cross.

 

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Reimbursing participants for expenses incurred — travel, lodging, childcare — is a standard practice and clearly approved by the FDA. But the agency’s stand on incentive payments is not as clear, aside from a cautionary note in its Payment and Reimbursement to Research Subjects information sheet that advises IRBs to consider whether “proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent.”

But one IRB expert says the consideration of influence as opposed to incentive should begin with the research team.

“Research teams have an obligation to implement an effective consent process, which includes ensuring that there are no undue inducements introduced into the process,” says David Borasky, vice president of IRB compliance for WIRB-Copernicus Group.

“When an IRB reviews a proposed study, it is only able to consider the population of potential subjects in the aggregate. The IRB cannot know how every potential participant might react to an incentive, and so it must approve research where the potential for an undue inducement has been minimized and rely on the research team to conduct an appropriate consent process.”

“I am not sure why it should be the IRB’s role to determine how individuals may want to use their time in order to receive a financial incentive, or why an IRB would believe it is in the best position to understand the impact at the level of the individual.”

Still, most IRBs are cautious about payments and may reject or reduce those that are “out of the norm.” The FDA advises IRBs to review both the amount of the incentive payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence. For instance, payment should not be contingent on a participant’s completion of the trial. “Any credit for payment should accrue as the study progresses and not be contingent upon the subject completing the entire study,” the agency says.

But too much IRB involvement in setting payment amounts can hinder a trial. “There is nothing wrong with mere influence and demonstrating respect for persons by allowing individuals to decide for themselves,” Borasky says. “In fact, one could argue that if an IRB chooses to require a lower incentive, it is then making it impossible for a segment of the population to participate, because participation for some is not feasible without the presence of a financial incentive.”

“I don’t think there’s any doubt that lower-income individuals may be more attracted by a financial incentive compared to someone from a higher income bracket, but that does not mean it is automatically an undue influence,” he continued.

Paying for participation can also level the field among such disparate groups, says Susan Groth, associate professor at the University of Rochester School of Nursing.

“Use of financial incentives can enhance enrollment without undue coercion of any particular population and can serve as a means to equalize study participation,” says Groth, who served as a co-investigator on an NIH-funded study that explored the use of electronic technology to promote healthy pregnancies among women.

But the question of “reasonable” financial incentive can be challenging. Thinking in terms of risk in addition to time and effort, she explains, helps illustrate the difference between payment for services and compensation for a personal contribution. It’s important to demonstrate respect for what participants give — or give up — to take part in a clinical trial.

Packaging Trends and the Future of the Generics Market in India

Around the world, the pharmaceutical market is rapidly evolving, driven by greater access to medicines, an increased focus on patient needs and the emergence of innovative therapies for chronic conditions such as diabetes, multiple sclerosis and rheumatoid arthritis.

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Industry analyst firm QuintilesIMS predicts that global medicine spending will grow 4-7% and reach nearly $1.5 trillion by 2021. India will play an important role in this phenomenon, especially as access to healthcare increases and global and domestic drug manufacturers expand their footprint in the country. As such, India is expected to be one of the top 10 pharmaceutical markets by 2021.1

Alongside this growth, there is increasing demand for high-quality packaging components across the pharmaceutical, biotechnology and generics markets as drug makers look to pair their injectable drugs with container/closure and delivery systems that can help ensure speed to market and competitive differentiation.

In India and globally there are a number of trends driving the need for innovation and quality in injectable drug packaging and delivery. These include:

Growth of Generics–The generics segment is experiencing dynamic growth in India and the Asia Pacific region. According to a 2016 study, the global generics market is expected to experience a 10.53 percent compounded annual growth rate (CAGR) from 2016-2020, with the value of drugs coming off expired patents equaling $150 billion by 2020. IMS Health foundthat more than 90 percent of dispensed medicine will be generic by 2020.

One of the biggest challenges faced by generics manufacturers is ensuring speed to market. Generics makers offer low-cost options for patients and provide needed medications when critical drugs are in short supply. But to lead in today’s generic drug environment, manufacturers need to file drug applications quickly, as well as respond to unforecasted market demand. Once a medicine is manufactured, it’s important to get it to market, and to patients, quickly without compromising quality or reliability. Pairing an injectable generic with quality packaging components that can be quickly and efficiently produced can aid in reducing the time to market and help enable generics manufacturers to stay competitive.

Biologics and Biosimilars on the Rise–Over the past several years, the industry has seen a steady rise in new biologic drugs coming onto the market for the treatment of many chronic conditions. As these drugs come off patent, India has the potential to become a major player in biosimilars manufacturing. These therapies often have very specialized containment needs. They can be sensitive to certain materials used in injectable drug packaging and delivery systems, such as silicone oil or tungsten. Concerns around possible interactions between biologics and the materials used in container/closure systems are driving the need for packaging that minimizes the adverse impact on injectable drug

products. Many manufacturers are adopting packaging components produced from novel materials, such as cyclic olefin polymer containment and delivery systems, as high-performance offerings designed to help maintain drug safety, purity and efficacy.

Increasing Demand for At-Home Administration and Combination Products–Self-administration and biologics have increased the popularity of combination products, such as wearable auto-injector systems and self-injection systems used for the management of chronic diseases. These new developments in wearable drug delivery technology are helping to provide a safe, reliable and effective method for home-based drug administration, which more and more patients are desiring.

Patients have different reasons for wanting home-based drug administration. For some, it’s about convenience. Others do not want to inject themselves with medications, or their conditions make it difficult for them to do so. Additionally, for some injectable medicines with higher-volume doses, it can be hard to administer the drug consistently via a prefilled syringe. Furthermore, some drugs – including many new biologics –require large volumes of viscous solutions, making a single-dose option difficult or impossible.

While patient-controlled self-injections systems and wearable injectors both offer tremendous opportunity for advancing at-home administration, developing these new systems can pose a significant challenge for pharmaceutical manufacturers: how to design a wearable injector that patients not only can use, but also want to use. To meet this challenge the makers of injectable medicines must fully understand and incorporate the needs of end users when bringing a self-injected therapy to market. This requires giving careful thought to how a medication will be administered by patients in order to ensure optimal patient outcomes. As such, the design of an injectable medicine’s delivery system is fast becoming an essential aspect of the manufacturer’s go-to-market strategy for a drug.

Auto-injectors, wearables and other new systems will only increase the already budding demand for combination products in the coming years as companies in India and Asia Pacific create them for local use and for export to the rest of the world.

Regulatory Focus on Quality –Driven by concerns for patient safety, regulatory agencies are asking drug and packaging manufacturers to build quality into their products from the start to ensure consistent quality throughout a drug product’s lifecycle. Quality by Design (QbD) is,therefore, growing in importance in the pharmaceutical industry. A QbD approach to packaging design and manufacturing delivers an improved, data-driven output that can lead to a superior product. Utilizing a QbD approach can also help to minimize disruptions to the supply chain. By incorporating QbD principles into the development of packaging,drug manufacturers can be confident that the products they provide to patients are contained with packaging of the highest quality.

The regulatory requirements are increasing for generics as well. For example, as more Indian biopharmaceutical generic manufacturers are trying to market their drugs globally, they will need to comply with evolving regulations such as the U.S. FDA’s Generic Drug User Fee Amendments (GDUFA), which was updated in 2017.

Because of their smaller operating budgets, generics manufacturers are looking to leverage existing delivery system components and combination products. This can be challenging given that in many cases, the original combination product for an injectable biologic drug is custom-made and there may be exclusivity with a delivery system manufacturer.

Summary
There is continued focus across the pharmaceutical, biotechnology and generics industries on ensuring that drugs are brought to market and delivered to patients safely, efficiently and reliably. Pairing injectable drug products with innovative, high-quality packaging components and delivery systems is key to helping drug manufacturers address these trends and stand out in an increasingly crowded marketplace. Early collaboration between drug manufacturers and their packaging partners is critical to ensure optimal speed to market, effective drug delivery and, most important of all, enhanced outcomes for patients.

Novotech CRO strengthens South Korean Clinical Capabilities partnering with 2 Major Hospitals

Ulsan University Hospital (UHH) and Seoul National University Hospital (SNUH), Hepatology Division have joined the Novotech CRO partnership program

SYDNEY, Apr 18, 2019 – (ACN Newswire) – Novotech, the award-winning Asia-Pacific CRO with 23 years of experience in the region, has further strengthened its presence in South Korea with two major hospitals joining the Novotech partnership program – bringing more quality investigators, KOLs, and up to 4 million patients.

The 900 bed Ulsan University Hospital (UUH), and the Hepatology Division in Gastroenterology, Department of Internal Medicine at the 1,778 bed Seoul National University Hospital (SNUH), have joined the Novotech CRO partnership program, further strengthening Novotech’s clinical service capabilities in South Korea.

South Korea is a fast-growing destination for clinical studies with quality infrastructure, world-class medical and hospital facilities, and supportive rapid start-up regulations. South Korea was Asia’s most active country in clinical research after China last year, with over 400 sites opened by biopharma companies.

Novotech is well established in Asia with offices in 11 countries and more than 550 staff, while 19 leading hospitals and medical facilities across the region have now joined the Novotech CRO clinical partnership program.

Novotech CEO Dr John Moller said biotech clients were increasingly running Phase I studies in Australia, benefiting from the 41% R&D tax credit, then moving to Asia for subsequent trials. “Having the same company that understands the study as it transitions into Asia is always reassuring for clients. Novotech uses the latest Oracle and Medidata technology, so seamlessly connects with global clinical partners.”

About Novotech – https://novotech-cro.com/welcome
Headquartered in Sydney, Novotech is internationally recognized as the leading regional full-service contract research organization (CRO). With a focus on clinical monitoring, Novotech has been instrumental in the success of hundreds of Phase I – IV clinical trials across the Asia Pacific region.

Novotech provides clinical development services across all clinical trial phases and therapeutic areas including: feasibility assessments; ethics committee and regulatory submissions, data management, statistical analysis, medical monitoring, safety services, central lab services, report write-up to ICH requirements, project and vendor management.

Development of biologics: The market requires short development times and high productivity

Biologics offer new therapy options for numerous diseases: They are already used to treat cancer and autoimmune diseases such as rheumatoid arthritis as useful alternatives to standard therapies.

 

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The extent of their market potential is revealed by the fact that the number of patent applications has been on the rise for decades now. However, the route from the lab to mass production is much more complicated for biologics than for conventional drugs. The desired biomolecules (biologics) are manufactured using living systems, consequently a careful development and selection process of the cell line to be used, as well as thorough checks, are absolutely essential in order to ensure straightforward production later.

For this reason, contract developer UGA Biopharma GmbH has developed a high-speed cell line development workflow including analytics, purification and bioprocess development in bioreactors. Using an optimised expression vector means that highly productive clones can be generated. In this way, monoclonal and highly productive cell lines can be developed within just four months, and an optimised bioprocess within a further three.

Traditionally, drugs used in chemotherapy or antibiotics were produced using chemical synthesis. By contrast, biologics are manufactured using genetically modified, living cells in bioreactors. Many factors can significantly influence the quality of biologics manufactured in this way, including process conditions during manufacturing, such as temperature during fermentation, pH, dissolved oxygen concentration and nutrient supply and, of course, the cell line used. If the cell line is contaminated or the isolated monoclonal cell lines (clones) are unstable, the drug may end up being unusable – with correspondingly high financial losses for the manufacturer.

For this reason, UGA Biopharma GmbH pays particularly close attention to the productivity, stability and quality of the clones when developing new cell lines. As a result of its specially optimised processes and many years of experience, the company only requires seven months for the development of a cell line, including bioprocess development and the development of a purification process, in addition to providing of all necessary analytical data.

From concept to production cell line
UGA Biopharma’s work starts with a biomolecule: “If a biomolecule with a potential therapeutic effect is identified during the course of research at a university or a company, this may be an interesting discovery but it is still a long way from becoming a product. Often, research institutions and companies do not have the necessary expertise or capacities to quickly turn interesting discoveries into biotherapeutic products, or biologics,” explains Dr Lars Kober, Managing Director of UGA Biopharma GmbH. “This is where contract developers like us come in: We develop highly productive cell lines which are able to produce the desired biologics with high yields.” To do this, the molecule first needs to be characterised in order to determine the desired quality attributes and the gene of interest (GOI), which will then be transferred into the company’s own expression vector. “In recent years, we have optimised the expression vector and cell line generation work flow to such an extent that we are able to create highly productive stable production cell lines within a very short period of time, achieving product concentrations of up to 7 g/L,” Kober adds.

In recent years, a Chinese hamster ovary (CHO) cell has proven particularly well suited. During cell line development, the expression vector is introduced into this CHO cell, creating a mixture of cells with different characteristics. Using single-cell cloning, highly productive monoclonal cell lines (clones) can then be isolated, cultivated and used to create cell banks for long-term storage at 196°C.

Searching for a suitable clone
“Generally speaking, pharmaceutical companies have many requirements of the isolated cell lines, such as scalability, monoclonality and, of course, high productivity and clone stability,” Kober explains. “In addition, the biologics should neither trigger immunogenic reactions in patients nor should the production cell lines be contaminated with viruses or mycoplasma.” For this reason, the company acts in accordance with the requirements of the European Medicines Agency (EMA), which is responsible for the evaluation and monitoring of drugs. During the development process, the company also conducts glycan analyses in order to obtain useful information about the selection of promising clones early on in the process.

The isolated clones are then expanded in the next step: “Usually, therefore cells are cultivated at lab-scale in shake flasks. Many contract developers leave it at that.” However, in order to guarantee the scalability of the cell lines, the laboratory staff then carry out a process transfer into bioreactors and derive a suitable bioprocess from this.

“But even the ‘best’ cell line is of no use to the pharmaceutical company if it cannot be cultivated and the manufactured biological drug cannot be purified,” Kober notes. As a result, UGA Biopharma does not restrict itself to the optimisation of the manufacturing process in bioreactors. Furthermore, the right purification process is also developed and the potency of the purified biologics is tested via various binding assays and in different cell culture models. If necessary, an optimised cell culture medium can also be provided for the cell lines and the developed manufacturing process. Normally the company’s own culture medium, First CHOice, is used, which was developed by UGA Biopharma. With the aid of this medium and the relevant feeds, both the product concentration and thus the cost of goods achieved in the final manufacturing process, as well as the product quality of the manufactured biologics, can be influenced advantageously.

Short development time is a prerequisite
In total, it only takes seven months until the developed cell line can be supplied: four months are required for the cell line development and three for the bioprocess development, the development of the purification process and for analyses to be carried out. “Short development times are essential in the pharmaceutical industry because patent protection for pharmaceuticals generally expires after 20 years,” Kober emphasises. “In this time, all phases of the technological development, various clinical trials including the marketing authorisation procedure has to be completed as quickly as possible because the profit margins for the drugs developed generally drop sharply once the patent protection has expired. Every month counts here because short development times facilitate early market entry and thus the profit is secured before the patent expires.”

Once development is complete, the company supports its customers where necessary with the process transfer to the manufacturing facility and is always on hand if there are any problems. “It is our aim for all biologics to be manufactured to the same level of quality at their designated destination as they are in our laboratory. This not only includes a stable monoclonal cell line but also the First CHOice cell culture medium and the manufacturing and purification process,” Kober confirms.

UGA Biopharma GmbH was founded in Henningsdorf near Berlin in 2009. The company’s core area of business is the contract development of biologics and biosimilars. This involves all the necessary steps from cell line development and bioprocess development to the development of purification processes and analytics. Furthermore, high-performance cell culture media and feeds are supplied under the trade name First CHOice in order to optimise the quality and product concentration of biologics and biosimilars. If necessary, the company can support its customers in transferring the manufacturing process to their production facility. UGA Biopharma’s unique selling feature is also that it offers its customers what are known as ready-to-use biosimilar cell lines. The company supplies its customers in Germany and abroad from its headquarters in Henningsdorf and already has several users with UGA products in clinical trials or who have already received a market approval.

Pharm-Olam Wins 2019 CRO Leadership Awards

Pharm-Olam, a global, midsized CRO offering full-service clinical development solutions for oncology, infectious diseases and vaccines, and rare and orphan diseases, has been named a winner in Life Science Leader magazine’s 2019 CRO Leadership Awards.

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Pharm-Olam was rated highly by small pharma survey respondents, as well as all survey respondents combined, for delivering excellent clinical research services in Compatibility, Quality, and Reliability core award categories.

“Our team works very hard to earn our reputation for quality performance and nimble, expert service,” said David L. Grange, CEO, Pharm-Olam. “Not only do we hold ourselves accountable for study conduct, but also for study site and vendor performance. Sponsors have come to rely on us for the extra attention to detail that leads to successful trials.”

Life Science Leader’s annual CRO Leadership Awards are based on actual customer feedback. They are intended to help clinical researchers decide which outsource partners to work with. “We share our clients’ commitment to creating a healthier world through research,” said Grange. “And as these awards show, customers appreciate our high standards, particularly in the context of challenging international trials.”

This year, the magazine again worked with Industry Standard Research to perform the CRO Quality Benchmarking Survey. Sixty CROs were assessed on more than 20 performance metrics. Survey participants were decision-makers recruited from pharma and biopharma companies of all sizes. Respondents only evaluated companies they’d worked on an outsourced project with in the past 18 months.

CROs may win these awards in up to three groups of outsourcing respondents — big pharma, small pharma, and overall (big and small pharma combined). Core award categories include Capabilities, Compatibility, Expertise, Phase IV, Quality, and Reliability.

For more information on Pharm-Olam’s full-service global support for Phase I-IV clinical trials, visit Pharm-Olam.com

About Pharm-Olam
Pharm-Olam is Helping Create a Healthier World as a global, midsized CRO that offers flexible, innovative and highly personalized clinical solutions to pharmaceutical, biotechnology and life science companies. Our team is well-known for producing quality results with reduced risk, costs and timelines in challenging international trials. Learn more about our full-service solutions, data protection services and expertise in oncology, infectious diseases and vaccines, rare and orphan diseases, pediatrics and general medicine at pharm-olam.com.

Top Academic Centers Flouting Trial Reporting Requirements, Report Shows

Top U.S. academic centers are routinely ignoring federal rules requiring them to report clinical trial data, a new analysis by a pair of nonprofit advocacy groups finds.

Nearly one-third of the 450 university-based trials surveyed by Universities Allied for Essential Medicines (UAEM) and TranspariMED failed to report trial results within the 12-month window federal law allows.

“Only 15 out of the 40 universities assessed are in full compliance with U.S. trial disclosure law, while 25 universities are in violation of the law,” the groups say in a report issued last week.

There is gray area in the federal rules that require some, but not all, clinical trials to post results to the database ClinicalTrials.gov within a year of wrapping a trial. But the WHO has said that prompt reporting is a best practice. Failure to do so “is not a victimless crime,” UAEM and TranspariMED say in their report. “It has substantial negative consequences for patients, public health and access to medicines.”

In the UK, similar findings about unreported clinical trial data has led to parliamentary inquiries and even threats to drag university leaders before legislators to account for themselves. In addition to the U.S. and UK, European Union guidelines require drugmakers to post clinical trial data for any products registered with the EU.

The report’s naughty list includes some of the world’s most prestigious U.S. academic research institutions — MD Anderson Cancer Center left 23 percent of its trials unreported in 2017, the Mayo Clinic owed data on 58 percent of its trials, the University of California-San Francisco owed data on 63 percent of its trials and Columbia University owed 83 percent of its data, the report states.cww2313_Univer-1024x1024

Those four academic centers, plus the University of Chicago, accounted for half of the unreported trial results, Essential Medicines and TranspariMED say.

Adil Bharucha, director of Mayo’s clinical trials, said the clinic is “currently reviewing” its case files “and will do whatever is necessary to close the loop.”

“Mayo Clinic makes every effort to be compliant with FDA clinical trial transparency requirements. We recognize the importance of sharing results with our patients and public and take this seriously,” Bharucha said.

The report also makes note of universities that have “put significant effort” into catching up with their reporting obligations, including Indiana University, University of North Carolina-Chapel Hill, University of Rochester, University of Pittsburgh and Yale, which all have cleared more than 85 percent of their backlogs as of February 2019.

To keep track of their data tracking responsibilities in the future, UAEM and TranspariMED recommend universities accept and implement the WHO standards for data transparency and commit to posting results within 12 months of trial completion for all trials, not just those required by U.S. law.

Read the group’s report here: https://bit.ly/2U33KWh.

Innovation in Investigator Site Contracting

In the perpetual pursuit of a more efficient clinical research process, biopharmaceutical sponsors and contract research organizations (CROs) have traditionally focused their resources on the more costly and time-consuming aspects of study start-up such as protocol development, regulatory and ethical review, and data management and analysis. Investigator site contracting and management of site payments are often overlooked as opportunities to accelerate study start-up and to reduce the expense and complications of managing study site contractual relationships. However, by targeting this smaller, yet still significant, aspect of study start-up, sponsors and CROs can expedite the process of contract negotiation, reducing both the cycle time and burden on the legal infrastructure.

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Historically, it has been common practice for sponsors and CROs to adopt a standard Clinical Trial Agreement (CTA) and budget template to use during negotiations with clinical trial sites. While a standardized template might seemingly appear to streamline the negotiation process, many sponsors are finding that they are wrought with inefficiencies of their own.

As the legal landscape has evolved, the CTAs themselves have become longer and more complex in an effort to address the increasing intricacy of clinical trials and the changing legal landscape in which they reside. This has led to a more embattled negotiation process, lengthier review times, and undue scrutiny on the negotiation process itself.

In order for sponsors to truly remove these barriers and delays from the contract negotiation process,
they need a partner that specializes in this area. At the most basic level, a well drafted contract provides the sponsor with the essential retention of its proprietary rights and intellectual property, as well as the unambiguous authority to fully realize the information generated by each study site for the development of the drug.

When choosing a partner to assist with the negotiation process, sponsors and CROs should look for partners who will ensure that the sponsor’s rights and interests are adequately protected and the burden on the sponsor’s legal department is minimized. An ideal partner will:

  • Establish the proper framework for negotiations from the outset of the study – aligning competent resources with legal and budget experience.
  • Have trained negotiators who understand the specific laws and institutional policies of each country in which a sponsor is conducting trials, and can utilize their local knowledge of language, site personnel, regulatory scheme, legal nuances, customs, and country budget.
  • Embrace a strategy of marrying the budget development, negotiation, and payment processes to one another.
  • Work with the sponsor to prioritize each facet of contract language.
    For example, some sponsors might place a higher value on the protection of intellectual property, while others might prioritize strict indemnification and insurance requirements.
  • Handle a large enough volume of contracts yearly to establish professional relationships with sites, greatly increasing their ability to negotiate each
    contract with an understanding of each site’s requirements and negotiation styles.
  • Offer strategies for global investigator site payments and reporting that reduce operational burden on the sponsor, and ensure compliance with each country’s laws and regulations.
  • By enlisting the support of an experienced partner who specializes in contract negotiations, sponsors are able to decrease negotiation cycle timelines and avoid additional unproductive steps in the negotiation process.

    Contract negotiation is more than a function; it is an outcome-driven art. A successful negotiator should be a subject matter expert who brings best practices to the table and is allowed the freedom and flexibility to offer proactive solutions that address the other party’s concerns while advancing the sponsor’s position. Flexible solutions inevitably cut down on unnecessary negotiation and escalation, minimizing execution times and allowing the trial to begin and produce results.

    About the Author:

    Steven Jones, JD is the General Counsel and Corporate Secretary for Clintrax Global, Inc.

    A seasoned corporate attorney with over 17 years of experience in legal and financial negotiation, Mr. Jones has worked inside both large pharmaceutical companies and CROs, globally implementing new legal and business engagements through effective, timeline sensitive negotiation while limiting the exposure to constantly changing regulatory and financial risks. Prior to Clintrax, Mr. Jones directed contracting and financial processes for a large, global pharmaceutical company, ushering $100+ million in outsourced, time-sensitive Phase I/II and large-scale Phase III studies from initiation to closure.

Clinical Trials Are About Hope and Possibilities, Author and Trial Veteran Says

In 2011, Mary Elizabeth Williams was diagnosed with metastatic melanoma, a finding that usually means a patient has six to seven months to live. Knowing melanoma doesn’t respond well to traditional cancer treatments, she decided to take a chance on a phase I immunotherapy trial of a new drug. Williams wrote about her experience in her book, A Series of Catastrophes and Miracles: A True Story of Love, Science and Cancer. It was a journey, she says, from last resort to hope and possibilities.

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Lindsay McNair, chief medical officer of WCG, spoke with Williams in a webinar last week, discussing the patient perspective on clinical trials, what they do right and how to change what they do wrong.

Q: Given your options — treatment that didn’t offer a good success rate, death or participating in a clinical trial — do you feel that you were well informed on your options and what participation in a clinical trial entailed?

A: At the time, Yervoy (ipilumumab) was a very new drug on the market and had a 30 percent success rate. It’s scary embarking on a course of treatment for which there is very little precedent. There were not a lot of human subjects who had come before me, and I knew that the risks could be great. There was a risk, not only of it not working, but of dying from the treatment, which did happen to some people on this trial. I had great conversations with the immuno-oncology team and they were very clear about why I would be right for this trial. It was a choice that was made, not just based on the drug and the cancer, but very much on the patient. And that was a turning point for me — that I was being listened to and that I was going to be collaborating with a group of people who believed in me as a patient.

Q: When you were approached about the trial — the informed consent process — what was the hardest thing for you to understand as people started to talk to you about what the trial entailed, etc.?

A: My understanding of clinical trials was limited, and my understanding of immunotherapy was nil. I had a lot of questions and concerns and there was a lot for me to process. My oncologist did the best she could in terms of explaining treatment. My initial conversation with the immunotherapy team at Memorial Sloane Kettering was the first time that I really felt that maybe I wasn’t going to die. That maybe treatment in a clinical trial would work, but with the understanding that maybe it wouldn’t. I was in a state of desperate, deep panic. I had a conversation with someone who said that maybe participating in a clinical trial didn’t have to be a last resort for me. Maybe it could be my first resort. And that really changed the game for me.

Q: How much of your information and your understanding about what the study would entail for you came from the process, this conversation you had with study team members as opposed to literally reading the paper document that you were handed?

A: I had an initial meeting with a nurse. I was handed the document, and we sat down together and the expectation was that I would sign it on the spot. Even though we went through the document thoroughly, I remember feeling that I would have to sign the document whether I fully understood it or not. I also recognize that there were a lot of things that just couldn’t have been understood at that time because it was such a process and a new form of treatment, but I am really struck with how vulnerable I was, how much I didn’t know and that there was such an expectation of me. And I don’t know, in retrospect, if there was a lot of understanding by the study team that I was not fully competent. I wasn’t. I was a complete mess — physically, mentally, emotionally. These decisions often need to be made under very difficult circumstances, quickly, and you do the best you can with the timeframe that you have. But I recognize now how hobbled I really was. And I don’t think that is unusual.

Q: How do you believe that the informed consent form and process in a phase I trial should talk about the possibility of benefits? How should we express the truth about the odds of success in a very early study, which are low, but still leave people with hope? How can we balance that?

A: That’s a very difficult question especially because in phase I trials, there is not a whole lot of expectation of success. My consent form was pretty clear about that. I felt that I had an understanding that there was a hope of success. But at that point, we were not talking about the word cure. There was no evidence of possibility that I would have all of my disease eradicated. It was really just about efficacy and potential tumor reduction. That is what was communicated to me. And the bar was set low. And my expectations were reasonable.

I’m grateful that the way it was communicated to me was, “We are going to try.” It was about time rather than about the disease. That is a smart way to approach it. Maybe this is about, “We can extend your life.” Because, ultimately, that’s really what we want. I would be happy to live with tumors if it meant I would live longer. That’s what I think most people approaching cancer now are really looking at management. So, I think that’s fine to communicate it that way.

For the rest of the interview, please go to WCG’s website: https://bit.ly/2U9qzqu.

Intentional or Accidental, Bad Data Can Kill Trials and Careers

Two kinds of data integrity problems cast shade on research results and erode trust in scientific inquiry: questionable research practices and flat-out misconduct, a data integrity expert says. And while intentional misdeeds can result in regulatory, or even criminal, action, both categories can cause irreparable damage to clinical trials, companies and individuals.

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Most data integrity problems in research fall into the questionable practices category and are not due to intentional acts, said Donna Kessler, research integrity officer at Duke University, during a recent CenterWatch webinar. They result from professionals who take shortcuts, rush research or just make bad decisions.

Questionable research practices (QRP) are generally understood across the research community and include failure to properly cite sources and methods, sloppy or incomplete documentation of results or, most commonly, failure to retain data and results.

Intentional misconduct, however, is defined by regulators. Researchers who fabricate data, falsify existing data or plagiarize the work of others can be subject to legal penalties and or debarment from participating in government-funded research.

Misconduct and questionable practices across the spectrum are more prevalent than some think, Kessler said, citing research that found 2 percent to 3 percent of researchers admit to fabricating or falsifying data, 14 percent have observed a colleague falsifying or fabricating data, and 33.7 percent admit to using QRPs. More than 70 percent observed others committing QRPs, Kessler added.

Research misconduct can be a result of bad judgment, lack of training or poor oversight, she said. In other cases, misconduct stems from competition for funding and recognition, or a sense of entitlement.

Researcher Eric T. Poehlman, for example, served a year in prison and was barred from getting any additional federal grants after he falsified data in 17 NIH grant applications and 10 of his papers. He later said he was motivated by his desire to advance as a respected scientist. He felt his area of study was important enough to warrant what he considered “minor” misconduct.

The repercussions of QRPs and misconduct are many, Kessler said. They can not only skew results and erode public trust, they can do serious clinical harm, as well.

In one of the most notorious and harmful cases of research misconduct, British surgeon and medical researcher Andrew Wakefield in 1999 published a paper claiming a link between childhood vaccines and autism. Not only did he falsify his data, his sample size was only 12 children, and he did not have ethics board approval for the study.

Wakefield was ultimately barred from practicing medicine and the study was retracted, but the ripple effects and the debate over childhood vaccines continues. Vaccination rates dropped globally thanks in part to intense press coverage of the Wakefield study. Further studies have shown there is no link between vaccines and autism.

Both the Wakefield and Poehlman cases and others show the potential long-term effects of misconduct on public health and the harm it can do to the credibility of researchers and scientific knowledge, Kessler stressed.

Not all data integrity issues are covered in federal regulations, and Kessler stressed that researchers and institutions must go further to protect the reliability and validity of research results. “The regulations are really the floor; they’re the starting point. To have integrity in research, you have to go beyond the regulations,” she said.

You can’t really prevent wrongdoing if a researcher is bent on misconduct, Kessler said. But researchers and institutions can step in when problems are caused by lack of training, sloppy methods or bad judgment, especially if the problems are caught early in the research process.

You also can prevent intentional misconduct by providing integrity education and training, reviewing and improving research and data practices, and encouraging reporting and investigation of possible misconduct.

To encourage integrity review, Kessler said, make reporting easy, with anonymous or online reporting options, stand firm against retaliation and take credible allegations seriously. Organizations also can implement tools for mentors and trainees, such as plagiarism detection software.

“Raising awareness of these types of wrongdoing is helpful, but you have to have some more active programs and changes in order to create a culture and a climate where integrity is at the forefront,” Kessler said.

To listen to the webinar, go here: https://bit.ly/2V2m8uR.

Avoid Enrollment Pitfalls: Find Your Best-fit Clinical Trial Sites

Selecting the right site is the single most crucial decision you’ll make about your next clinical trial. And perhaps the single most important consideration in selecting a site is whether it can make its enrollment. Many don’t; in fact, 20-25 percent of all clinical studies close because they fail to meet enrollment targets.

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The startup process is often more complicated than either sponsors or sites anticipate. Research2 from March 2018 finds that:

  • Average time from site identification to study start-up completion is 31.4 weeks; that’s a month longer than 10 years ago.
  • On average, 11 percent of investigative sites initiated were never activated; what’s more, that figure hasn’t changed in 20 years.For decades, CROs and sponsors have found their “best fit” sites and returned for future studies. But in the era of precision medicine and adaptive trial designs, that may not always be the best course of action. It is becoming increasingly necessary to turn to untapped resources to find potential enrollees. As research increasingly focuses on rare diseases with highly targeted patient sub-populations, the percentage of new sites is expected to increase.

    According to Tufts research released in March 2018, sponsors and CROs report that 28 percent of their sites are new relationships with no prior history or familiarity. Those relationships can be tricky. The overall site initiation cycle time is nearly 10 weeks longer for new sites compared to repeat or familiar ones.4Moreover, sites with insufficient experience are more likely to violate protocols or have low-quality data, which leads to more on-site visits and more request for clarification—even additional training. And all of that takes time and money.5

    Finding Your Best Fit

    ——————————————————

    In this environment, how do sponsors determine the best-fit sites for their studies? Much of what constitutes “best fit” is specific to the study, the patient population and similar factors, but we’ve identified five characteristics that apply more broadly.

    A Best-fit Site Has a Strong Record of Success——————————————————

    Unlike what they say about securities, past performance does predict future results. A site that regularly hits its enrollment goals will likely hit them for your study. But how much do you really know about past performance of the site or the investigator?

    Most sponsors rely on site-reported data. So Clinicaltrials.gov and Citeline can give you insights into whether a site has participated in studies for, say RA or Alzheimer’s, but other than that it doesn’t give you much to go on. Not only is the data self-reported, it’s often not current.

    Without the right partner, it becomes difficult to assess past performance. With the right partner, however, you have access to verified data to help you make an informed decision. For instance, WCG has been able to partner with our clients and give them the data they need. Because we have five IRB companies in our portfolio, we have access to 95 percent of all protocols, allowing us to provide FDA-verified intelligence to support the site-selection process.

    A Best-fit Site Has a Strong Community Presence——————————————————

    No matter how diligently they scour their records and recruit their own patients, no site is going to fully enroll a study from its own patient population.
    A site that’s active in the community and has built community relationships is more likely to be successful at enrollment.

    Among the signs of a practice engaged in its community:

    • Participation in programs such as “lunch and learn,” which demonstrate presence in and commitment to the community.
    • Relationships with patient-support and condition-specific groups, which engender trust and can provide potential pools of trial participants.
    • Established referral pathways: Ideally, physicians are tapping colleagues in other practices as a source of participants.
    • A social media presence can, at the very least, keep patients alert to research opportunities and build connections with patient advocacy groups. What’s probably more useful is participating on sites such as www.inspire.com/, a social network for patients and caregivers that provides peer support and connects patients to clinical trials.

      A Best-fit Site Takes an Integrated Approach

      ——————————————————

      The best-fit sites embrace clinical research as another offering of care to the patient. It’s fully integrated into their practice, and they promote clinical research in much the same way they’d promote a fitness class or a smoking-cessation program.

      These practices are proactive. The approaches may use include:

      • Showing a list of opportunities on a monitor in the waiting room.
      • Talking to patients who may be eligible to participate in trials.
      • Engaging their colleagues in the practice —including nurses, NPs, PAs, etc.—to help them spread the word.These percentages are higher in practices that are clinical trial sites, but you’d be surprised at how many of even those fail to successfully promote their studies to patients.

        It comes down to a failure to see clinical research as an integrated part of the medical practice. Not only does that suggest that the practice devotes inadequate resources to the research, but it also suggests a lack of passion. As we’ve helped clients look for best-fit sites, we’ve learned that passion counts for a lot. Successful sites have a passion for research. Being a clinical trial site is an added responsibility for someone—and very few people want extra responsibility. A commitment to research is driven by passion more than revenue.

        But passion alone isn’t enough: The practice has to dedicate the resources.

        A Best-fit Site Has a Plan and a Dedicated Clinical Research Team to Execute It

        ——————————————————

        A clinical trial site can’t just do a study or two on the side. They need a plan and the right people to execute it. Enrollment is always top of mind for best-fit sites. The coordinator needs to be able to explain how they will identify and connect with potential research participants. Given that 68 percent of sites fail to meet their projected enrollment targets,8 you’ll want your coordinator to be able to explain how it will make up any potential shortfall.

        Still, a plan isn’t enough, either. Can the team execute? You can get a sense of this before or during the pre-selection visit. Here are some common red flags.

        • They are managing too many protocols with too few staff.

        • They don’t return questionnaires or other material in a timely fashion.

        • They can’t explain their recruitment strategy to you.

        • They seem harried and overworked.

        There’s one other element that may not be a red flag today, but it will be tomorrow: The site lacks some of the technology tools sophisticated sites use, such as e-consent and a clinical trial management system. In our experience, the more open to technology a site is, the better their enrollment.

        A Best-fit Site is Open to Innovation

        ——————————————————

        Small and emerging biopharma companies will always have unique challenges—but there’s help available. Small companies are in a great position to adopt new technologies, take advantage of the services that partners can provide, and to leave behind the “that’s the way we’ve always done it” mindset that has prevented the clinical trials operations field from moving forward at the same speed as medical advances.

        Finding Your Best Fit

        ——————————————————

        Everything rests on site selection: Pick the wrong
        site, and your trial could end up in rescue—or worse. Everyone understands that, yet roughly a third of sponsors and CROs say they are unsatisfied with their site initiation processes.9

        By working with sites that meet the aforementioned criteria, and by availing yourself of the data and other resources available, you can dramatically improve the likelihood that your next clinical trial will succeed.

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