Christine Bahls

Your first holiday gift of the season has arrived: updated FDA guidances from the past year—and one key update from the European Medicines Agency (EMA). These final guidances reflect the breadth of pharmaceutical and technology-related submissions that FDA now contends with. The agency even asks for help with its administrative tasks, such as asking stakeholders to put in submission cover letters whether there is real-world evidence or real-world data in the application.

Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) ­— Small Entity Compliance Guide

This guidance replaces the 2007 version. It is written for businesses that FDA refers to as “small entity establishments,” stakeholders who create human cells, tissues, or tissue-based products. The guidance details the agency’s regulatory framework on the manufacturing of these products.

Human Gene Therapy for Neurodegenerative Diseases

This guidance addresses creation of human gene therapy products for adults and children with neurodegenerative disease. Recommendations span the products’ development to clinical trial design.

Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA

This guidance was written to help stakeholders already in possession of an approved application, be it for a new drug application (NDA), an abbreviated new drug application (ANDA), or for a biologics license application (BLA), with making a chemistry, manufacturing, and controls (CMC) change, post-approval, by using a comparability protocol. The protocol is a plan to assess the identity, potency, purity, quality, and strength of the changed product.

Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products

Sponsors who are submitting NDAs, investigational drug applications, and BLAs—and including real-world data and/or evidence in their supporting documents—are encouraged to identify uses of such evidence in their cover letters. The agency says such identifications will help with internal tracking.

Clinical Decision Support Software — Guidance for Industry and Food and Drug Administration Staff

This final guidance focuses on clarifying the types of functions included in clinical decision support (CDS) software that up until now were outside the definition of non-device CDS criteria. FDA’s existing policies on digital health products policies still apply to software functions that meet its definition of a device.

Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices

FDA is separating software and its purpose, determining which devices will be subject to oversight, and which will not. Software used to display data, images, and waveforms, are included in the latter.

Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment

This guidance discusses the agency’s views on development programs and clinical trial designs for drugs and biologics intended to treat acute myeloid leukemia. It covers individual treatment phases.

ICH Guideline E19 on a Selective Approach to Safety Data Collection in Specific Late-stage Pre-approval or Post-approval Clinical Trials

This “internationally harmonized” guidance details those factors stakeholders can use to justify their reasons for collecting less types of data in specific interventional clinical trials.

 is a freelance writer for medical, clinical trials, and pharma information.

Articles

Summarizing important FDA and EMA revisions issued this year.

Key Guidance Updates in 2022

Let’s discuss—no, parse—the impact of inflation on clinical trials. Will each type of stakeholder contract equally, or will one segment be affected more than the others? How much contraction has already taken place? The trial world has ongoing serious problems, such as finding enough qualified staff to run a trial and working within the approved schedule to complete it. Staff shortages and time delays already impact budgets without inflationary help.

A larger question is whether inflation will alter, as the pandemic did, the design and production of these studies. Hints that this could happen are popping up: trial designs considered more efficient and adaptive, for example, are showing up more frequently in ClinicalTrials.gov; data discussed at the recent DPharm conference in Boston showed a majority of sponsors were incorporating decentralized trial (DCT) components into their studies.

Another pivotal question is whether sponsors will pull back on running global trials. It won’t happen, believes David Fenske, principal, delivery and client advisory, Auxilius. Regulatory bodies want trials to run in their countries; the FDA wants diversity; and if it is a rare disease trial, “there are only so many patients in rare diseases,” he says. “You have to go where the patients are.”

However, inflation will affect the outlook, operations and possibly the existence of smaller biotech firms; money, used for a mortgage or biotech startup, is no longer cheap. Those with one, maybe two, promising therapies in their portfolios will be absorbed, bought, or left behind. From a societal point of view, being overlooked is okay if you make sneakers, but not if that product has the potential to cure amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, or some other condition with a death sentence.

As a whole, no one interviewed for this article said the clinical trials world has met its demise. What has emerged from conversations and document reviews, including Q2 earnings reports, are industry viewpoints seen from macro and micro levels: industry is resilient, yes, but the cost of packaging and mailing temperature-sensitive samples from overseas could reduce the number of countries or sites involved in a trial. Anything that changes the costs of goods, says Jane Myles, vice president of clinical trials innovation at Curebase, will affect one or more aspects of the trial.

“Clinical trials are logistical puzzles,” Myles tells 

 The importation and exportation of samples are huge costs. Pharmacokinetic (PK) samples are fragile and maintaining that fragility “costs a lot of money,” she adds.

As do startups. With investment capital flowing more slowly, “the risk [of shutting down] is magnified if you are smaller,” says Sharon Langan, vice president, channel and strategic partnerships, Auxilius.

Before a sponsor will jettison a project, it will focus on increasing opportunities to drive project efficiency and the decentralized better monitoring that grew out of the pandemic, according to Craig Lipset, founder of the Decentralized Trials & Research Alliance. “I haven’t seen sponsors deprioritize entire development programs” he says. But inflation will be real, he continues: “As inflation drives up everything on a global basis, as those costs increase…[sponsors] may have to reduce the number of trials for next year.”

As for a possible recession, the clinical trial industry should be concerned, notes Justin Culbertson, life sciences senior analyst, RSM US LLP. The industry is experiencing capital funding slowdowns and extremely high labor demand—“which means [higher] wages, and it will cost more to bring a drug to market,” he says.

The No. 1 affected stakeholder, Culbertson believes, will be the consumer, should trials be axed. Deciding what nascent trial to eliminate will be difficult for the survival of a more mature one, adds Ken Getz, director of the Tufts Center for the Study of Drug Development (CSDD).

But reducing trial numbers, from the strict vantage point of the industry itself, may not be a bad thing, considering the record-number of studies ready to go and the lack of qualified staff to run them.

 quoted analysts saying the pharmaceutical index was gaining because pharma can “weather recessions relatively well.”

That doesn’t mean drug manufacturers won’t take a hit: in mid-October, the index’s year- over-year was 893.97 vs. 769.48.

In IQVIA’s second-quarter earnings call, Ari Bousbib, its chairman and CEO, said his company and the contract research organization (CRO) industry at large were, financially speaking, a hardy bunch.

 “During the recessionary times over the past two decades, annual S&P 500 revenue contracted by as much as 10%, while IQVIA’s clinical business and the CRO industry as a whole never experienced a year of revenue decline,” he said.

As of this writing, the US is facing—not in—a recession. A few figures to consider: The Bureau of Labor Statistics’ Producer Price Index

shows that, from September 2021 to September 2022 the costs to businesses of basic inorganic chemicals rose 28.8%; basic organic chemicals rose 7%. Paper boxes and containers were up 19%; plastic packaging, 12.9%; water transportation, 27.9%; warehousing, 7.9%; and traveler accommodation services, 17.7%.

As for stock performance, the year-over-year changes for six of the larger CROs are all southbound, some more significantly than others. One organization dropped to 173.9 from a high of 313; another to 48.19 from a high of 194.18. Many are buying back stock shares, presumably to bolster stockholder value.

GlobalData reported that pharma had a month-on-month dip of 2% from July into August, but job postings went up 10% during the month.

The Council for Insurance Agents and Brokers, generally speaking, said premiums for cybersecurity in Q1 2022 rose an average of 27.5%, slightly higher than during the same period last year.

As for salaries and staff turnovers, this publication discussed those issues earlier this year. It found that average turnover for clinical trial professionals, especially for the lower paid but critical position of coordinators, was 26%. As for salaries, the differences between manager and associate coordinators, as compared to site directors, ranges from a high of $75,000 for the former, and $250,000, for the latter.

According to RSM research, in 2016 a Phase III, biologics trial took 2.5 years to complete (based on 94 studies); a drug study, 2.6 years (608 studies). By 2021, excluding COVID-19 studies, a biologic study took 3.3 years (85 studies) and a drug study, close to 3.5 years to complete (435 studies).

“Only 46% of Phase III studies started over the past five years reported having met enrollment requirements,” the report said, attributing most of these lag times to significant labor shortages at investigative sites.

Q2 earnings reports showed pass-throughs are on the high side: 20% of revenue for one company, another was $46 million above the unmentioned guidance range midpoint. Interest rates, discussed in one report, were already $50 million above the initial figures given in the company’s January guidance. The adjusted figure for the year was $210 million.

As for global digital health funding, the drop is remarkable—36% in Q1, according to CB Insights.

Langan said Auxilius recently surveyed biotech organizations across the sector; she says 93% experienced site costs out of line with initial per-patient cost projections. The majority of respondents indicated they struggle with estimating clinical trial accrued expenses, in part due to variability in actual cost drivers.

Over the past five to seven years, Fenske says, investigator budgets “would go out 50%. Now I have seen that shift starting at the 75% percentile.” Sites are “being squeezed with staffing” and that is limiting the number of trials, he adds.

Tufts CSDD’s Getz started analyzing clinical trials in a scholarly way more than three decades ago. Since then, the US experienced at least four recessions. Getz notes that economic pressures constantly weigh down on sponsors, CROs, and vendors. So inflation, 

doesn’t stop a sponsor from continuing a clinical trial or reducing the number of patients.

Sponsors, says Getz, have a way of responding to these pressures. Full-time equivalents might be replaced with more outsourcing. They can downsize, consolidate, and can turn to digital tools, he points out.

“It’s not sort of a linear this, then, that,” Getz tells 

. The pressure, he believes, will be on the CROs to follow the trial model and streamline the costs—which can be very difficult, say, with an oncology trial being conducted in numerous countries. Along with difficulty in finding patients, “most of these trials require DNA samples,’’ adds Getz.

While these difficulties extend timelines, these factors are not the primary cause of the extensions. “Our research shows that it is too difficult to determine what the individual factor is extending cycle time,” says Getz. “All of our trials are taking longer. So [any] argument that inflation will delay treatments getting into the marketplace isn’t supported by hard evidence.”

But they won’t get to market if there is no trial. “The CROs were saying a year ago they didn’t have enough people,” says Culbertson, adding that he thought there were too many trials “because [CROs] don’t have enough people to work on them.”

To put the industry’s labor shortage in perspective, Culbertson notes that the life sciences labor market returned to its pre-pandemic level one year ahead of the rest of the country, which took two years. But demand and inflation are driving up wages. RSM research shows that the unemployment rate would have to reach a minimum of 4.6% to start getting inflation under control, he says, so either reduce demand for research or increase available workers —but something has to give, Culbertson adds.

The demand for research, at least in oncology, isn’t shrinking. Recent data show grant applications to NIH’s National Cancer Institute (NCI) are up more than 50% as compared to about 5% for the agency’s other institutes.

Small biotechnology companies, and even more established ones, are facing a contracting capital market that is holding back investment dollars. “That capital will not stretch” to cover all trials out there, says Lipset. Will they sell to large pharma, will they make deals with smaller firms?

The big organizations will be scooping up those “biotechs that are hurting,” and the firms with just one product in their pipeline aren’t likely to start any trials, adds Fenske.

According to Culbertson, biopharma is already reacting to market forces. “We are seeing hesitancy picking next products, seeing more desire to negotiate prices,” he says. But he also noted that even though clinical trials are costing more money, if a trial is still running once the market reopens, that sponsor could secure more funding and finish the study.

Getz strikes an optimistic note, explaining that when a developer has a great molecule, one would be surprised how it can find merger opportunities. His research, he points out, hasn’t shown evidence of a mass exodus of biotech firms. “They find other ways to adapt,” says Getz.

Fenske was asked if there is wiggle room within trial phases to see what could be cut. In Phase I, there is not a lot of give and take in a negotiation, with the volunteers from healthy populations. The CROs have it down to lunch for $8 and dinner for $12. There is no place to cut dinner. But some agreement terms can be adjusted. Fenske had one sponsor client who objected to paying the CRO 100% upfront for a six-month Phase I trial. However, the sponsor CEO said give the CRO 10%—with 30 days to pay; they eventually compromised to 25%.

The CRO wasn’t being unreasonable and the sponsor prevailed. But now, in current master services agreements, the payment window is much shorter and the upfront money is paid in 10 days.

Phase II is more flexible, says Fenske. And while there isn’t “a lot of slush” in there, if this part of the trial has 75 patients and eight sites, for instance, Fenske suggests reduce the number of sites and increase the number of patients per site. Another place to cut would be to reduce the number of face-to-face meetings with the sponsor. A meeting every six months on an 18-month trial isn’t necessary, says Fenske. Another possible time saver is to adapt the monitoring plan from a former trial. Fenske notes he regularly reviews costs from previous studies.

CROs do not regularly review prior study costs, he adds, as such a review depends on how much time the sponsor gives the CRO to put together the proposal. “Sponsors are shooting themselves in the foot, when they say ‘we need it in 10 days,’ says Fenske. “They are not giving the CROs enough time” to build the budget more efficiently. But CROs have run thousands of studies, the sponsor likely just a few. Ideally, the sponsor should say to the CRO, “‘Here are the endpoints I want, you go design the study, we will agree on the price and the risk is on you,” explains Fenske.

A Tufts CSDD study found that in the long run, DCT components used in Phases II and III can save time—perhaps three months each—and money, with a seven-fold ROI. The study found reductions in screen failure rates and in the number of protocol amendments when decentralized components are in use.

That time-savings, says Curebase’s Myles, is vital. If the DCT model can save six months between the last patient out and data becoming accessible, “that is huge,” she notes.

But, cautions Myles, planning a DCT can be complicated. The trial team, she says, has to consider how the components are distributed: Some patients may want to visit a brick and mortar site, others like being at home, and those visiting nurses are earning more these days. Not everything happens in the cloud, reminds Myles. Another consideration is the investigator grant—it won’t extend to at-home visitation. “The doctor isn’t paid for what happens in the home,” says Myles. Investigators will be paid for oversight and data review of patients. “It is more a distribution of costs over a broader network,” she adds.

In the long run, according to Getz, these new solutions and tools indicate opportunity in the research enterprise, pointing to artificial intelligence, augmented and risk-based analytics, and new protocol designs. ClinicalTrials.gov listed 32 active interventional adaptive design studies, and 79 enrolling as of Oct. 11. “All of these things are new innovations that can improve on and address economic pressures,” he says.

, Freelance Writer for Medical, Clinical Trials, and Pharma Information

David Wainer. Pharma Is Place to Hide During Recession. 

https://www.wsj.com/articles/pharma-is-place-to-hide-during-recession-11657749897

IQVIA Holdings, Inc. (IQV) Q2 2022 Earnings Call Transcript | 

Bureau of Labor Statistics. September 2022. 

https://www.bls.gov/news.release/pdf/ppi.pdf

World Economy News. GlobalData finds continuous layoffs amid sizable decline in active, posted, closed jobs | Hellenic Shipping News Worldwide. Sept. 9, 2022.

Commercial Lines Market Trends Report–Q1 2022 | Property & Casualty. 

https://www.cbiz.com/insights/articles/article-details/commercial-lines-market-trends-reportq1-2022-property-casualty

Commercial Property/Casualty Market Index. Q2/2021. Q2 P/C Market Survey 2021.

Lisa Henderson. Salary Survey: The Age of COVID. 

https://www.appliedclinicaltrialsonline.com/view/salary-survey-the-age-of-covid

Justin Culbertson. Life sciences services trends and outlook: Fall 2022. 

https://rsmus.com/insights/industries/life-sciences/clinical-trials-trends.html

Research Report. State of Digital Health Q1’22 report. 

https://www.cbinsights.com/research/report/digital-health-trends-q1-2022

Experts gauge threat level for global trials amid staffing and funding issues.

The Implications of Inflation for Drug Development

Cell and gene therapy (CGT)—its risks and promises—are succinctly summarized in this description of clinical trial number NCT01129544, a Phase I/II study in children born with X-linked severe combined immunodeficiency (SCID-X1), an inherited, rare, and life-threatening disease. The eight-person trial, which began in May 2010, continues today. The following paragraph has been edited.

Gene transfer is still research for two reasons. One, not enough children have been studied to tell if the procedure is consistently successful…. [And] we are still learning about its side effects and doing gene transfer safely. In previous trials, five children developed gene transfer-related leukemia; four are in remission; one died.

If the above information has stifled the research community’s scientific curiosity about CGT, it is not evident. Evidence from numerous sources—ClinicalTrials.gov, the Alliance for Regenerative Medicine (ARM), FDA—are chock-a-block with studies, trials, and figures showing these therapies’ popularity. In the second quarter of 2022, 3,633 such treatments were in development, up from 1,745 in May 2021. The vast majority are in the preclinical stage.

Most indicate that academics now have a remarkable presence in the CGT development space, including sponsorship. Last year, for the first time, ARM included sponsorship figures in its twice-annual industry report.

 Academic- and government-sponsored trials far exceeded industry for sponsored trials in CGT. Stephen Majors, senior director for public affairs, ARM, says the alliance knew of academia’s presence for the past few years, but only was able to get data this year from its partner, Global Data.

Less reliable, but still noteworthy, are data from ClinicalTrials.gov: for active Phase I trials, industry has 89; “others,” which covers academia and government, have 50. Industry enrollment for Phase I is 172; others, 116. Phase III is one for others, eight for industry.

A little disruption in pharma’s corner of the world? It seems that way. While basic bench to preclinical to clinical trial has long been the traditional route to FDA approval—and no one interviewed for this article suggested a reroute—what it does imply is that pharma members have some competition from the spin-offs and academic biotechs that historically they have absorbed.

“There are suspected trends that we are watching,” says Majors. As to whether academia’s presence in this spot can be called a trend depends on one’s definition of what a trend is. The Centers for Disease Control and Prevention (CDC) considers changes over a number years to determine a trend; financial investment firms typically evaluate over a two-year period. Considering that CGT companies raised $23.1 billion in 2021, 16% more than 2020,

 the answer to the above question could be, maybe.

The CGT space is still immature, according to Mike Rea, founder of Protodigm, a self-described exploratory research organization that partners with biopharma clients on alternative development and commercial solutions. Physicians need time to be comfortable with these therapies, notes Rea, so they may not be used on a regular basis.

For example, physicians have to understand how to deliver the gene, agrees cardiologist Arthur M. Feldman, MD, PhD, whose lab worked on a heart failure-related mutation in BAG3 for decades.

Last month, the company he founded, Renovacor, agreed to be acquired by Rocket Pharmaceuticals.

 “We are asking physicians to do something they never did before and to understand a very different set of information, including risk/benefit discussions that they didn’t learn about in medical school,” he says. Feldman is a Laura H. Carnell Professor of Medicine, Division of Cardiology, and a member of the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine at Temple University.

Chris Learn, Parexel’s vice president of cell and gene therapy, is unequivocal regarding academia’s increased presence in the drug development space focused around these treatments. He cites MD Anderson and Moffitt Cancer Center as two institutions that are sponsoring their own trials. “The lines are really blurring here,” he tells

The following is a look at how academia is showing up in various reports.

, ARM separated sponsorship, type of therapy—gene, cell-based, and tissue engineering—and trial phase. What these data show are industry far exceeding academic and government sponsored trials for gene therapy, while for cell therapy alone, the reverse is true: 656 cell therapy trials for academic and government, and 424 for industry. For gene therapy, there are 84 for the academics and government, and 222 for industry. In a later report, ARM found non-industry trials dropped.

Pharma Intelligence’s Pharma R&D Annual Review does not break down trials by their sponsors. It does, however, break down what’s in the pipeline in various categories, including by the number of therapies per company, and by disease type.

 In numbers captured prior to March 2020, the analysis reported 1,849 companies with a single drug in its pipeline, up from 1,633 in 2019, comprising more than half of all drug companies. As for types of therapies, gene therapy was in third place, the same spot it occupied in 2019. (Cancer-related therapies occupy the top spots.) Overall, biotech therapies in the pipeline increased by 13.2% in 2020 over 2019—6,135 vs. 5,422. Cellular therapy, the field in which academia is dominating, rose to 14th place, up from 33.

In 1982, Feldman was a resident in the cardiac care unit at the Johns Hopkins Hospital in Baltimore when he took care of a 22-year-old woman, a native Pennsylvanian, who was dying of heart failure. “Sadly, we didn’t have drugs with which to treat her,” he recalls. Feldman’s involvement with the case and the woman’s family led to his career as a cardiologist, he says. Twenty years later in Philadelphia, he was asked to see a heart-failure patient in consult, who turned out to be the aunt of the younger woman. It would take almost another 10 years until the technology became available to identify the genomic anomaly in this family. Here, a genetic variant that is produced by one of two alleles causes the protein product to be unstable. The result: the cell removes it, so the person with the variant has just half the amount of required protein.

BAG3 is an interesting protein that is found in the heart, the skeletal muscles, and the nervous system, including the brain. Its function is to help remove degraded and misfolded proteins, stop apoptosis or programmed cell death, and maintain the structure of the skeletal muscles. A missing allele isn’t the only genetic cause for heart failure, Feldman said. Other patients, while having the correct amount of DNA, have a point mutation–a single amino acid–in half of the produced DNA. That single letter is the wrong amino acid in the specific site in the protein.

Around this time, Kamel Khalili, PhD, Laura H. Carnell Professor, and chair of the department of microbiology, immunology, and inflammation; director of the Center for Neurovirology and Gene Editing; and director of the Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine, Temple University, had created a method by which he could excise the HIV virus from patients using the new technique of CRISPR-Cas9.

Khalili believes that BAG3 may be involved in the pathogenesis of HIV-1 in brain diseases and protein quality control caused by viral infection as well as several other disorders, including Alzheimer’s disease and dementia. BAG3 changes the homeostasis of the cell, he says. “The only solution is to fix the cell.” Khalili has used CRISPR technology to excise the viral genome in both small and large investigational animals and has recently started a Phase I trial to test the safety of the new gene-editing treatment. Khalili, too, started a company, but Temple holds the license. In the case of Renovacor, it was granted the license by Temple.

“As a scientist, when you are doing something in biomed research, [the] goal is to translate bench work to the clinic for [the] wellness of people. We are doing long hours and long days because we want to help. We are trying to see if discovery can help people,” says Khalili. “I know my limit, I stop at business aspects. My interest is to discover research which can help populations.”

Was Feldman happy with his business experience? “As a company gets bigger, others join the team who fulfill other roles, like acquiring funding or developing the actual product,” he says. “Releasing the control reins are difficult.” But if it speeds up the timeline to get an approved product into the clinic, “then it’s all worth it,” he adds.

Researchers such as Feldman and Khalili, says Kaspar Mossman, PhD, director of communications and marketing at QB3, a University of California biotech accelerator, are normally not deeply interested in business. He notes the new flagship space in UC Berkeley called Bakar Lab. So far, it has 25 companies, one-third from university labs. “They collaborate, they share equipment, [at times] they merge,” Mossman tells 

And, he adds, “Academics tend to be very smart individuals. The more time they spend in business, they learn stuff and become serial founders,” says Mossman. “They are honest about not wanting to be a CEO.”

In terms of business, the academics’ employers are also pretty smart. The huge bugaboo with CGT commercialization is the manufacturing process—the need for an apheresis unit, ultra-cold storage, and regulated cell processing facilities.

Some institutions are building their own manufacturing facilities to more easily meet the increasingly complicated standards pertaining to regenerative medicine production. Harvard, MD Anderson, Moffitt, the University of Pennsylvania, and the University Hospital of Liege in Belgium8 all have or are planning to build their own facilities.

As for how academia’s presence impacts the traditional pharma space, those interviewed cited pros and cons. More research is better, more companies vying for venture capital funding is not. But more trials mean more competition among similar therapies, which, says Majors, is a good thing.

“We need experimentation,” adds Rea. If left to pharma, he says, the research wouldn’t happen. “Smaller biotechs are taking the risk.” Over the last 10 years, Rea believes pharma has been slow in the risk-taking department. Once upon a time, pharma didn’t have many competitors. Now, with many numerous smaller companies with viable assets, willing to accept a smaller net profit, the competition is creating some angst. “Pharma can’t project everyone’s movement,” says Rea. “The gene/cell therapy landscape [for products] is huge.”

Likely adding to the angst: Those smaller biotechs are getting financial help. Between April 4, 2021, and June 24, 2021, of 23 start-up financing deals, 19 involved academics.

Learn’s viewpoint is different. He says there are too many players out there, and while large pharma may be averse to risk, “I really do believe what we are witnessing are simply market forces that have played into this.” There is so much cash coming in, he continues, that “people can be blinded by the pitfalls.” The CGT area, he adds, is “bloated” and he says the industry needs an overall strategy.

Learn doesn’t think that academia’s presence in the CGT space is a flash in the proverbial pan. The enthusiasm to find cures is real, and some research institutions have the endowments to see the trials through. “I think it is just the beginning,” says Learn. “Academia will put their futures in front of them. Why put all your sweat equity into it … and not have any fiduciary benefit of the approved product?”

In Pharma Intelligence’s 2020 Pharma R&D Review, its author questioned the wisdom of so many drugs, overall, in the pipeline—4,001 added in 2018 and 4,730 added in 2019, for a total of 17,737 drug candidates. “[A]re the industry’s eyes getting too big for its belly? Unless it can continue to provide [approved therapies] then a certain degree of control in the pipeline might be advisable,” the report stated.

And now to costs. While no one doubts these cures change lives, the question of access persists. FDA’s approval of Bluebird Bio’s second therapy this year, branded as Skysona, for early but active cerebral adrenoleukodystrophy, is expected to cost $3 million. Learn doubts that payers are jumping up and down to get Skysona on their formularies.

It’s still a “fairly dicey business proposition” for companies to invest in this field, Steven Pearson, MD, president of the Institute for Clinical and Economic Review (ICER), said recently.

 There’s “still a risk” that next-generation therapies will not flourish “even in developed countries’ health systems,” he added.

One positive development in the US, however, occurred late last month when Congress reauthorized the Prescription Drug User Fee Act (PDUFA) for the next five years, 2023-2027. The action maintained FDA’s authority to collect fees from manufacturers and keep and recruit agency staff to review the increased number of CGT applications. Majors says most of FDA’s review of CGT products involves scalability and consistent reproducibility in the manufacturing process, which, of course, means traveling.

, FDA is seeking to hire at least 320 new staff members. In a statement, Pharmaceutical Research and Manufacturers of America (PhRMA) said a “modern regulatory framework supported by PDUFA helps ensure patients have timely access to lifesaving medicines.”

PDUFA reauthorization aside, there is little argument that the field of CGT, from research and drug discovery through commercialization, is advancing rapidly. In turn, so are the unique operational and manufacturing challenges that these therapies present. This reality may thin the currently crowded playing field in CGT going forward, with those sponsors and partners best prepared to deliver on the numerous touchpoints required separating from the pack.

Clinicaltrials.gov Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector. 

https://clinicaltrials.gov/ct2/show/NCT01129544?term=gene+therapy&recrs=d&type=Intr&phase=0&fund=3&draw=2&rank=4

ASGT. Gene, Cell, & RNA Therapy Landscape. Q2 2021 Quarterly Data Report. 

https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-july-20.aspx

ASGCT/Pharma Intelligence Quarterly Report: Q2 2022. 

https://pharmaintelligence.informa.com/asgct-report?gclid=Cj0KCQjw7KqZBhCBARIsAI-fTKLZMdW80GEkZY8VEkb6hMpJ4838NveiOXpauuas4OdNW_Tfyxw7CXwaAoHcEALw_wcB

Cell & Gene State of the Industry Briefing. 

https://alliancerm.org/arm-event/sotibriefing/

https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-acquire-renovacor-extending-leadership

PharmaIntelligence. Informa. Pharma R&D Annual Review 2020. 

https://pharmaintelligence.informa.com/resources/product-content/pharma-rd-annual-review-2020-whitepape

Lechanteur C, Briquet A, Bettonville V, Baudoux E, Beguin Y. MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process. 

. 2021 May 26;10(6):1320. doi: 10.3390/cells10061320. PMID: 34073206; PMCID: PMC8227789.

Eric Sagonowsky, Fierce Pharma. Fierce Next Gen: As gene therapies proliferate, pharma and payers look to avoid ‘cost shocks.’ Published online June 30, 2022.

Burr on FDA User Fee Agreements: Innovation is Key, When FDA Does Not Live Up to Commitments, Patients Suffer. 

https://www.help.senate.gov/ranking/newsroom/press/burr-on-fda-user-fee-agreements-innovation-is-key-when-fda-does-not-live-up-to-commitments-patients-suffer

As activity in this space grows, so do the hurdles in moving these products forward.

The Risk-Reward Proposition for CGT Clinical Trials

 Industry recognition for the clinical research as a care option, or CRAACO, movement goes to The Conference Forum, which has hosted the conference of the same name, for seven years. This year’s CRAACO event was held Sept. 12 and Applied Clinical Trials, at the time of this writing, is looking forward to attending and learning more from many of the speakers featured in this article.

At the Icahn School of Medicine at Mount Sinai, researchers are laying the groundwork for future massive genotype-based studies. Within three to six years, the database is expected to hold the sequenced DNA samples of one million people—all patients of the Mount Sinai Hospital System.

In Oregon and California, researchers wanted to see if people who were overdue for a colon cancer screening test would take one if they were mailed a FIT test. It took one year to identify 41,193 people in 26 federally qualified health clinics.

And in the Northwell Health System, researchers culled their electronic health record (EHR) system for patients with specific COVID-19 symptoms to help them determine whether the use of famotidine would shorten the number of days a COVID patient contended with symptoms. They found 55 fitting the bill within six weeks.

At the University of California, San Francisco, and across the country at Temple University Hospital, oncologist researcher Laura Esserman, MD, MBA, and pulmonologist Gerard Criner, MD, respectively, have been using their EHR systems for years to run pragmatic trials and to find eligible clinical trial patients in their respective clinics.

 Once found, the medical teams embed the trial into patient care.

If you are wondering if this article concerns EHRs and compatibility, you’d be correct. If you are thinking it concerns ways in which clinical trials can be run with less money and fewer data points, you’d also be accurate. And if you think it’s about improving patient care where they receive care—all while advancing research—you are spot on.

What these researchers are doing bears little resemblance to the classic, rigidly run, interventional clinical trial. Trial phases blend into one another. In some cases, molecules under inspection that aren’t working are eliminated as early as possible from the trial; molecules that do work are tested under more scrutiny. With clinical trials, time means money.

A key point: All enrolled patients were found after serious mining into the provider’s EHR. So yes, point of care works in large healthcare establishments, with fluid EHR systems. So yes again, point of care is not a routine approach in most trials. A serious problem, says Amy Cramer, steering committee board co-chair for the HL7 FHIR Accelerator Vulcan, is that most trials are still conducted using paper processes. Researchers need the data before the trial is started, she adds.

It is all about the technology, Christina Brennan, MD, vice president, clinical research at Northwell Health, tells 

 “We wouldn’t have been able to do [the famotidine trial] without” the EHR system, she says. Everything Northwell could determine about its potential recruitment prospects came from its system, as did all inputted data that led to results. “We screened thousands of patients for eligibility.”

At Temple University Hospital, running trials and treating patients have gone hand in hand for a few years. “Our clinical research program is not separate from our clinical care or our academic mission,” said Criner, also chair and professor, Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University; and director, Temple Lung Center, in a published interview

, who also reviewed this included information for accuracy. “If you embed it into your care program and your care program has to address what the needs of the patient community you treat are, you can’t help but make everything better—your research, clinical care, and training.”

As to what this clinical trial approach is called, there is no universal name. Brennan says she didn’t think point of care was applicable, and preferred clinical research as a care option, or precision/personalized medicine.

According to FDA—which, by the way, is a big supporter of embedding clinical research at the point of care–“Point of care trials take place in a clinical practice environment and make use of clinical infrastructure and personnel for trial-related activities.” A successful trial, an agency spokesperson continued, “may shorten the time needed to obtain safety and efficacy data for medical products.”

But do not think these trials are allowed to confuse real-world data (RWD) with real-world evidence (RWE). FDA, in its 2018 framework document,

 defined RWD as the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, and RWE is the clinical evidence regarding a medical product’s use and potential benefits or risks derived from analysis of RWD.

Says researcher Rachele Hendricks-Sturrup, DHSc, research director for real-world evidence at the Margolis Health Center at Duke University: "Healthcare data is not real-world evidence until it is analyzed and assessed alongside other sources of real-world data.”

Taking the 30,000-foot view, Jodyn Platt, PhD, MPH, an assistant professor of learning health sciences at the University of Michigan, says health care should be viewed as a point of learning. “There’s a fine line between quality improvement and research” in order to learn from that data to give better care.

But it could be worth it, Platt says. If researchers have the opportunity to use a system that allows them to see what is done correctly or not, “we have the potential for making the [healthcare system] better for everyone,” she says. “If we can think strategically, we can make the process better.”

Esserman, who built her approach to breast cancer trials in the early 2010s, described how the process works at the UCSF Breast Cancer Center. All registration data are collected and cleaned within 24 hours.

Each patient’s information regarding response to the therapy is used to build on to the next patient. This is all about finding early indicators of response and eliminating data detritus, which, says Esserman, clouds results.

The idea, she adds, is to have real-time data collection. “All data sets must be complete before randomization,” Platt says. “We are trying to focus on the data that inform the primary endpoints, so that we are less burdened with data of ancillary interest.”

She elaborates that most data, 90%, collected in trials is irrelevant because it is never used or “not germane to the primary endpoint.” And since all data collection requires time and money, more thoughtful decisions about what to collect matters.

It is a model other are adopting or participating in, including FDA and the National Cancer Institute.

In Northwell’s double-blind, placebo-controlled study on famotidine, researchers collected 1,358 data points from 55 patients with COVID; one arm got the famotidine, the other, placebo. Those in the control arm improved three days more quickly. All samples and all treatment were administered in the patients’ homes. The cost of the trial was less than $1.5 million.

 The success of the study and its cheaper cost have convinced Northwell that the model is worth incorporating into their trial formats. Along with this more patient-centric approach, Brennan says that hybrid trials are being requested more by sponsors.

Between 2014 through 2016, Mount Sinai used EHRs to find 2,050 patients of West-African ancestry with hypertension, no chronic kidney disease, and genotyped them for the 

 risk variant, which could be deadly for those subgroups.

 Once patients were found through the EHRs, study coordinators mailed invitations and then followed up with phone calls of those who declined, “and intercepted potentially eligible patients at clinics when they were hard to reach,” according to the study. The point of the trial was to quickly return genetic results to a randomized group to see how patient outcomes would be affected.

The intervention group reduced their blood pressure and adopted more healthy behaviors. The high-risk patients dropped their systolic blood pressure by 3.6%; the controls dropped by 1.3%.

“These results may support an approach of broad implementation of genetic medicine in primary care for certain use cases,” concluded Girish N. Nadkarni, MD, MPH, Irene and Dr. Arthur M. Fishberg professor of Medicine, Icahn School of Medicine at Mount Sinai, et al., in the study.

As to the question of just how common point of care trial research actually is, everyone interviewed had the same answer—it isn’t.

“There is a lot of activity in this space. But it is fragmented, as is our healthcare system,” says Platt. Her specialty is studying trust in the US healthcare system. Developing measures of trust to monitor how trial enrollees are faring is in the works, she she adds. “It is a huge issue because of digital care in the home.” What happens to the data if third parties are involved, or if a startup company that was monitoring patient progress dissolves? “How does your data live with this?” asks Platt.

She and her staff are starting research in artificial intelligence and how patients trust the technology in their healthcare systems. “That is a key research question—it’s a new form of technology that has little oversight, from institutions and government. We need to understand what the public feels like when they have a stake in the field.”

In May, the Duke University Margolis Center for Health Policy published a white paper on point of care-incorporated trials.

 It defined one aspect of the point-of-care scenario as: Using an EHR for enrollment, data collection, and randomization; running the trial where patient care occurs; and combining research and clinical care delivery workflows. “The focus is on the trial participants,” says Hendricks-Sturrup, a co-author. “We want to achieve better screening, consent, randomization, and data collection, then incorporating those finds into routine care.”

The difference between other trial designs and those that use point of care, says Hendricks-Sturrup, is that point of care is designed “to know if the therapy is efficacious across all populations.”

Margolis is working to resolve issues that could impede point-of-care progress, such as who runs the trial, who should pay for it, and how can data be collected and handled in an easy fashion across different systems? A major point is not adding burden to providers. “We are working to tackle policy,” says Trevan Locke, PhD, assistant research director for Margolis.

As for the blip, researchers for the colon cancer screening trial learned that buy-in from staff involved in the trial is essential. Staff at the various federally qualified health clinics didn’t all do as the researchers asked, like installing a piece of software into their EHRs to find and track possible participants. Researchers stated: “For most of the participating health centers, [this trial] represented the first time EHR tools were used to deliver cancer screening services outside the clinic. Implementation might have increased
with experience.”

Alexander Charney, MD, PhD, associate professor, departments of psychiatry and genetics and genomic sciences, and co-director of the Mount Sinai Million Health Discoveries Program, says that as it acquires patient samples, it is gaining approvals for future trials. No studies are established yet, he says.

“But let’s fast-forward five years,” Charney continues. A sponsor wants to run a trial comparing therapy X to therapy Y, when half of the patients have a certain genetic variant. “If a researcher wants to do that trial, five years from now, patients will already have consented,” he adds. “We have laid the groundwork.”

All 17 hospitals and clinics in the Mount Sinai Health System will be recruiting for this project, which is being underwritten by Regeneron. The volume of patients and unification of Mount Sinai’s operations make the enrollment goal possible, says Charney. His fellow co-director, Nadkarni, says enrollment is going slowly for a purpose.

“We want to make sure systems are good to go,” he tells 

 and that safeguards are working, like ensuring patients are not duplicated in the system. The platform, he notes, meets all NIH and Department of Defense security standards.

Partnering with Regeneron, says Charney, was key to getting the project off the ground. “There is no other way to sequence the genome of one million people,” he adds. Regeneron, notes Nadkarni, will sequence the DNA samples, and then return the patient data.

At Northwell, Brennan said that as each trial request comes in, the team is looking at whether an embedded study can work. Of the 2,000 trials in motion, 5% to 8% are designed as a hybrid approach. Despite all the talk about embedded, i.e., point of care, few are being run that way.

But, she adds, “We don’t want to go back to the former ways and traditional methods of running a trial. When we saw how to pivot in COVID, we were able to [be flexible].”

Coronado GD, Petrik AF, Vollmer WM, et al. Effectiveness of a Mailed Colorectal Cancer Screening Outreach Program in Community Health Clinics: The STOP CRC Cluster Randomized Clinical Trial. 

Brennan CM, Nadella S, Zhao X, et al. Oral famotidine versus placebo in non-hospitalized patients with COVID-19: a randomized, double-blind, data-intense, phase II clinical trial. 

. May 2022;71(5):879-888. doi: 10.1136/gutjnl-2022-326952. Epub 2022 Feb 10. PMID: 35144974; PMCID: PMC8844971.

https://theconferenceforum.org/wp-content/uploads//2020/09/CRAACO_Q3-1.pdf

Interview with Laura Esserman. The I-SPY Approach to Drug Development. 

Clinical Advances in Hematology & Oncology

Experts discuss solving the EHR-compatibility puzzle in point-of-care trials.

Christine Bahls

Articles

Key Guidance Updates in 2022

The Implications of Inflation for Drug Development

The Risk-Reward Proposition for CGT Clinical Trials

‘Record’ Gains in Bringing Research Closer to the Patient

The Evolution of Site Selection

The Post-Pandemic CRO Landscape