Developing Standards for Clinical Research

This past fall, the nonprofit Alliance for Clinical Research Excellence and Safety (ACRES) and its partner the British Standards Institution (BSI) launched a Global Standards for Excellence (GSE) working party to develop standards for accreditation of high-performing clinical research sites around the world. The goals are to promote professionalism and excellence in clinical research; accelerate medicine development; and enhance the performance, safety, and quality of clinical trials.

Sara Monday (ACRES VP of site development and support) is the liaison between BSI and the ACRES working teams. “Our domain teams include research professionals from around the world, each working toward one common goal,” she says. “This effort will bring much-needed changes to our industry and lead to accreditation of research sites.”

Led by cochairs Arti Bajpai (president of Compliance and Quality Integration Consulting) and Amir Kalali (vice president of Quintiles), the working party encompasses 10 cross-functional teams creating standards that will provide a foundation for globally recognized accreditation of research sites. Standardization and accreditation would improve connectivity, interoperability, productivity, sustainability, and efficiency in conducting clinical trials while reducing times for start-up and study completion.

Domain team leaders are Anthony Rissling (CTMG, Inc.), Katie Porter (Hamilton Health Sciences), Mary Westrick (University of Wisconsin), Ivo Ivanov (AstraNova), Sara Monday (ACRES), Penny Jester (University of Alabama at Birmingham), Nadina Jose (Anidan Group), Larry Kennedy (Quality Management Institute), Nonna Stepanov (Mountain State Health Alliance), and Terry Stubbs (ActivMed Practices and Research, Inc.) Steven Hirschfeld of the US National Institutes of Health is serving as a liaison.

The three- to six-member ACRES teams are working with professional standards-writers from BSI to complete a set of draft standards by mid-2017. Those will be circulated worldwide for review and comment by research sites, sponsors, regulators, ethics committees, contract research organizations (CROs), information technology (IT) providers, investigators, and patients. After revision, the initial set of standards will be pilot tested. Based on proven high-performance models from other industries, this “Dynamic Accreditation” process will differ from many such schemes by using real-time information during normal work flows to immediately identify potential challenges and opportunities for improvement.

Greg Koski (ACRES cofounder and CEO) notes that “prominent industry leaders, such as Freda Lewis-Hall (Pfizer) and Briggs Morrison (Syndax Pharmaceuticals) have previously underscored the importance of high-performing sites in improving clinical trial performance. The standards and processes now being developed will provide an effective mechanism and incentives for sites to improve without imposing new bureaucratic and financial burdens.”

Cancer Immunotherapies Are Growing Fast

The world market size for cancer immunotherapies is expected to grow more than fourfold from US$16.9 billion in 2015 to $75.8 billion by 2022 — representing a rapid compound annual growth rate (CAGR) of 23.9% — according to business intelligence provider GBI Research. The company’s Global Cancer Immunotherapies Market to 2022 report counts 2,037 products in active development (representing 37% of the total oncology pipeline).

“Although the cancer immunotherapy pipeline is clearly strong, a significant proportion is made up of early stage products, namely those from discovery to phase 1,” says Yasser Mushtaq (senior GBI Research analyst). “This is indicative of the difficulty associated with progressing cancer immunotherapies from preclinical laboratory studies to clinical application in humans. The imbalance between early stage and late-stage product development is more pronounced than typically seen in the industry, and it may suggest greater difficulty than normal in developing cancer immunotherapies. However, these findings may also indicate a substantial drive to invest in early stage cancer immunotherapy development, which could eventually filter through to late-stage product development.”

Several late-stage pipeline drugs and already marketed drugs are expected to achieve blockbuster status by 2022, and a number of existing blockbuster therapies are forecast to experience strong revenue growth. Established immunotherapies — particularly Revlimid (lenalidomide), Opdivo (nivolumab), Keytruda (pembrolizumab), and Gazyva (obinutuzumab) — expect rapid sales growth throughout the forecast period, with the Keytruda and Opdivo brands seeing $7 billion and $9 billion rises, respectively. The Revlimid drug will experience similar levels of growth driven by label expansions covering multiple forms of leukemia and lymphoma.

Mushtaq adds, “A number of pipeline products are also forecast to be approved by 2022, some of which are expected to be commercial successes. AstraZeneca’s durvalumab and tremelimumab, in development as individual therapies and in combination, will be the most notable products.” Additional anticipated blockbusters by 2022 include cancer vaccines Novartis’s CTL-019 (tisagenlecleucel-T) and Kite Pharma’s KTE-C19 CAR.

Biopharmaceuticals on Demand?

Researchers at Harvard and the Massachusetts Institute of Technology have created tiny freeze-dried pellets that include the molecular machinery for translating DNA into proteins, which could form the basis for on-demand production of biologics. Containing dozens of enzymes and other molecules extracted from cells, these pellets can be stored at room temperature for extended periods. With added water and freeze-dried DNA, the pellets begin producing the encoded proteins. These pellets are a few millimeters in diameter, making them portable for soldiers, astronauts, and healthcare workers in remote areas.

“The cell-free extracts consist of a few dozen enzymes, DNA, and RNA, as well as ribosomes and other molecular machines leading to transcription and translation,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s department of biological engineering and Institute for Medical Engineering and Science (IMES). “It’s a modular system that can be programmed to make what you need on the spot. You could have hundreds of different DNA pellets you can add in the field.”

Collins is senior author of a paper describing this strategy in the September 22 online edition of Cell along with Keith Pardee (assistant professor at the University of Toronto and former research scientist at Harvard University’s Wyss Institute for Biologically Inspired Engineering), Shimyn Slomovic (an IMES postdoctoral researcher), Jeong Wook Lee (a Wyss Institute research scientist), and Peter Nguyen (a Wyss Institute Technology Fellow).

This approach could be useful for generating a broad range of products, from drugs to molecules for diagnosing illness. In their study, the researchers produced a diphtheria vaccine and antimicrobial peptides. They also programmed pellets to generate enzymes that form a multistep metabolic pathway to synthesize the anticancer/antibiotic violacein, which is normally produced by bacteria. For diagnostic applications, the researchers used pellets to make several different types of antibodies, including one that can detect Clostridium difficile.

Collins anticipates that this type of technology should be useful in a range of settings: “It could be used in a very simple carry kit for healthcare workers in developing regions. We think it could be very useful for the military and for hikers and athletes on long hauls. You could even have it in the back of your car as an expanded first-aid kit.”

The pellets also could be incorporated into educational tools for “the biotech equivalent of a chemistry kit,” Collins says. “You could envision students conducting synthetic biology experiments at home or in middle and high schools.” Another application Collins plans to pursue is integrating the pellets into “smart bandages” that would detect an infection and then begin producing the appropriate antimicrobial peptide to treat it.

Toward a Recombinant Diptheria Antitoxin

The PETA International Science Consortium is funding German research that could spare thousands of horses who are currently used to produce antitoxins for diphtheria. The Consortium works to fund and accelerate the development, validation, and global implementation of alternatives to testing on animals.

In addition to addressing the ethical concerns of producing antitoxins in horses, development of this and other recombinant human antitoxins could prevent serum sickness that horse-derived antitoxins can cause in some human patients — and mitigate a global shortage of diphtheria antitoxin. This research could produce cell-culture–based recombinant human antibodies that block diphtheria toxin. The Consortium is providing €134,000 to the Institute of Biochemistry, Biotechnology, and Bioinformatics at the Technische Universität Braunschweig in Germany based on lead researcher Michael Hust’s expertise in the development of human antitoxins.

Each year, thousands of horses are used to produce antitoxins, which are isolated from their blood after the animals are repeatedly injected with toxins. Many of these horses live on farms in India, where recent inspections have uncovered negligence and inadequate veterinary care. Animals have showed signs of lameness, anemia, diseased hooves, eye abnormalities, and poor nutrition. Seriously ill and elderly horses were kept in close contact with other animals and left to die without euthanasia. Antitoxins from the blood of these horses are exported worldwide.

“This project is a much-needed step toward replacing the use of animals with nonanimal technologies that can produce safer and more effective human medicines,” said molecular biologist and consortium associate director Amy Clippinger.

Stefan Dübel (head of the university’s biotechnology department) added, “We are not only happy that we can help to tackle a serious health problem, but also that our long-standing commitment to develop a method that makes animal experiments obsolete for antibody generation is now rewarded by international recognition.”

Strategic Formulation Alliance

In February, Rentschler Biotechnologie GmbH and Leukocare AG announced a strategic alliance under which the latter will become a specialized technology partner and exclusive formulation developer for the former’s biopharmaceuticals business. Rentschler in return becomes the first and only contract development and manufacturing organization (CDMO) with access to Leukocare´s patented Stabilizing and Protecting Solutions (SPS) formulation technologies. The company’s ongoing and future business activities with pharmaceutical and biotechnology companies beyond the CDMO business will not be affected by this alliance, however. Rentschler is acquiring a 10% stake in Leukocare, and its CEO, Frank Mathias, will join the company’s board of directors.

SPS technology improves stability of, for example, liquid-dose formulations of therapeutic proteins, making them stable at relatively high temperatures over relatively long shelf lives. The platform is characterized by specific and innovative combinations of regulatory-established excipients that are in common use.

This alliance will incorporate formulation development strategically at every step throughout biopharmaceutical development and manufacturing. Working closely with clients, the partners will ensure that every drug product will have a best-in-class formulation and administration mode from the start. This approach offers competitive advantages, enabling clients to exploit the full potential of their products and markets.

“Our alliance brings to the forefront the importance of drug formulation as a key success factor in the development process. We believe our enhanced ability to improve formulations will result in value creation for our clients and ultimately also help doctors and patients,” said Mathias.

“This alliance will enable us to fully exploit the possibilities and advantages of SPS formulation technologies,” said Michael Scholl, CEO of Leukocare. “With a strong partner like Rentschler, we can offer our innovative formulation expertise to a broad range of clients and elevate the role of formulation strategy on the biopharmaceutical industry’s agenda.”