I’m going to be providing this training internally at my company. I’m wondering if it is of interest externally as well….
The use of Electronic Clinical Outcome Assessments (eCOA) or Electronic Patient Reported Outcomes (ePRO) via mobile devices (smart phones, tablets, etc.) has been evolving and expanding in recent years. As an industry, we’ve conquered some of the early challenges experienced with the use of these devices in the clinic, usually on lower risk data and often with a paper backup process in place. However, as we move forward with increasingly complex devices and data collection schemas for higher risk efficacy/safety data the stakes have raised. Adding to this risk is the advent of adaptive trial design and increased time pressures in clinical research. New challenges have emerged that need to be considered and mitigated as we move forward with the promise these technologies hold in the improvement of trial design and data quality. This training is designed to enhance the understanding of professionals in all areas of clinical research (Clinical Operations, Monitoring, Clinical Scientists, Data Management, Biostats, Medical Writing, etc.) and the service organizations that support them (IT, Procurement, Contract Management, Quality, RA, Safety, etc.) including Senior Leadership who drive the initiatives to adopt best-in-class tools and design.
A Summary of the New MHRA ‘GXP’ Data Integrity Guidance and Definitions – March 2018
For over 20 years, there have been Health Authority regulations governing the use of Electronic Records and Electronic Signatures (eReS) for GxP purposes. These regulations (the US part 11, the EU Annex 11, and their ilk globally) are arguably among the most elegant, concise, and consistent across jurisdictions (with differences mostly limited to context and emphasis rather than substance).
That being said, there has been a considerable amount of confusion in interpreting and applying the eReS regulations as both the Regulators and those in Industry have evolved their understanding of these regulations as the various guidance documents have emerged, been rescinded, revised, re-issued, clarified, etc.
This latest guidance document (which can and should be read in its entirety here (21 pages): https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/687246/MHR), is very mature in its outlook and takes what has come before and builds upon it. The result adds a huge amount of clarity by specifically expounding on the general theme “This what we want, yes it means exactly that, and yes we understand the practical considerations and resource impact of what we want”.
Some key items in the guidance include:
Its application is intended across all GxP areas (Excepting Medical Devices – which I found interesting)
The principles of data integrity (which are separate from those of data quality) are meant to be adaptable, and are designed to evolve with Technology and promote a risk-based approach.
The non-technical aspects of data integrity are addressed, including the organizational responsibility to create a culture and environment (controls) that ensures that data is complete, consistent, and accurate in all forms (They focus on the oft neglected idea that PEOPLE are part of the process).
They revisit both ALOCA and ALCOA+ (Attributable, Legible, Contemporaneous, Original, and Accurate + Complete, Consistent, Enduring, and Available. They go on to clarify that these two acronyms are differing ways of explaining the same expectations.
Differing paper, electronic, hybrid scenarios are discussed as are the ideas around Risk, Risk mitigation, and documentation around both. Warnings are made about poor organizational controls and the over-reliance on a system’s validated state.
Challenges and considerations around designing data processes and controls are discussed in some detail.
Key definitions are explained in some detail for: Data, ALCOA, Raw = Source Data, Metadata, Data Integrity, Data Governance, Data Lifecycle, Recording & collection of data, Data transfer & migration, Data Processing, Data Exclusion, True Copy, Transactional data, Audit Trail, Reconstructability, Electronic Signatures, Data review and approval, Data Retention/Backup/Archival, System Access, the Admin Role, Validation, and IT Suppliers including Cloud providers).
May you live in interesting times… A colleague flagged this for me. I’ll be very interested in the particulars of how this all works going forward. #ItsAllAboutApps
New warning letters out! These are largely GMP-specific. Like no other agency, FDA is reknowned for updating regulations via warning letter (rather than the onerous process of getting an actual new or updated regulation approved)….so it is good to always keep an eye on these to be clear on “FDA’s current thinking”. YMMV. In any case, check out the full information at the link below!
~TJK
We’ve submitted this course proposal for the April SQA Quality College in Anaheim. Feedback has been good, but even if it isn’t picked up for this venue…it will eventually happen *somewhere*:
Instructors: Timothy J. Kuhn and Conrad Kawaguchi
Target Audience: Seasoned Auditors with little eData/CSV experience or CSV professionals with little auditing experience.
Course Objectives
• Establish and differentiate between the eData Audit Function and the Operational CSV Quality Roles.
• List the considerations for the GxP eData Audit Program (Contributing to other GxP Audits, Independent Focused Data Integrity Audits, etc.)
• Explore the various roles that the eData Auditor may serve as part of an audit (SME, Co-Auditor, Audit Lead)
• Define and list the desired skill set for the eData Audit Team
• Break down the various types of audits and risk areas for each: GLP Labs, Central Clinical Labs, Central Readers (eCG, Imaging, etc.), ePRO (Electronic Patient Reported Outcomes – AKA Diaries), Acquisition Due Diligence, GMP Manufacturing Sites and Vendors, PV, eSystem Validation, Databases, IT Infrastructure, Cloud Providers, Software Providers, SaaS vendors, Pharma, Device, Combo Product, and others.
Course Description: Electronic Data (eData) is pervasive in the GxP world and auditors in that GxP eData space need to understand what is most important in these areas. This course will explore considerations in establishing an eData audit program, give auditors with little Technology/eData/Computer System Validation(CSV)/IT saavy the understanding needed to assess the eData/eSystems they encounter in the course of their existing GxP audits, and expand the understanding of eData auditors beyond the software vendor audit so as to know what is most important in GxP audits. The course will demonstrate “what to look for” for a variety of audits, both technology-focused and more conventional areas in which technology has “encroached”.
As 20 Americans and Brits flew to a Caribbean island for a controversial herpes vaccine trial, many of them knew there were risks.
The lead U.S. researcher, William Halford, openly acknowledged he was flouting Food and Drug Administration regulations in the consent forms they signed. He would be injecting them with a live, though weakened, herpes virus without U.S. safety oversight.
Still, many of them felt upbeat when they arrived on St. Kitts and Nevis in the spring of 2016. They had struggled for years with debilitating, painful herpes. Halford, the creator of the vaccine, sounded confident.
Maybe they could be cured.
“It felt like paradise,” one of the participants recalled. “Or therapy combined with vacation.”
A year later, their optimism has turned to uncertainty. Memories of kicking back in a Caribbean hotel during the trial have been overshadowed by the dread of side effects and renewed outbreaks.
They also can’t rely on his university, which shares in the vaccine’s patent but says it was unaware of the trial until after it was over. Because the FDA didn’t monitor the research, it can’t provide guidance. Indeed, there is little independent information about what was in the vaccine or even where it was manufactured, since Halford created it himself.
At a time when the Trump administration is pushing to speed drug development, the saga of the St. Kitts trial underscores the troubling risks of ambitious researchers making their own rules without conventional oversight.
“This is exactly the problem with the way the trial was conducted,” said Jonathan Zenilman, an expert on sexually transmitted diseases at Johns Hopkins Bayview Medical Center in Baltimore. “These people are supposed to have rights as human subjects, but now there’s nowhere for them to go. We may never know if this vaccine worked, didn’t work or, even worse, harmed anyone.”
Rational Vaccines, the U.S. company co-founded by Halford, still hopes to market the vaccine. It touted success online and to other researchers, prompting millions of dollars of recent investment, including from a company run by President Donald Trump backer Peter Thiel.
Thiel, a PayPal co-founder who has excoriated the FDA as too bureaucratic, declined to answer questions about his investment, which occurred after the trial had ended.
Kaiser Health News interviewed five of the 20 participants in the clinical trial and several associates of Halford.
The participants agreed to speak on condition of anonymity because they don’t want to be known as having herpes. Most also said they feared retaliation from Halford’s company but hoped by speaking out some of their concerns might be addressed.
Their accounts, along with documents, a video and emails obtained by KHN from the offshore trial, pointed to what experts said were serious irregularities:
Halford did not rely on an institutional review board, or an “IRB,” which monitors the safety of research trials.
The company has said it doesn’t know where Halford manufactured the vaccine, so it isn’t known whether he followed U.S. government guidelines when transporting it.
Halford offered booster shots of the unapproved vaccine inside the U.S. FDA regulations prohibit such injections.
“The FDA goes after these types of violations,” said Holly Fernandez Lynch, a lawyer and assistant professor who specializes in medical ethics at the University of Pennsylvania’s Perelman School of Medicine. “[Researchers] can be prosecuted.”
SIU, however, did little to discourage Halford. The university, which has a financial interest in the patent, said it learned of “the concerns” only after his death. In August, after KHN asked about the trial, the medical school’s IRB launched an investigation into whether Halford violated U.S. regulations or university rules.
In a statement to KHN, Rational Vaccines acknowledged that Halford “discussed a myriad of concerns … including the potential need for booster shots.”
“Unfortunately, Dr. Halford is no longer with us to address all the ways in which he may have investigated his concerns …,” stated the company. It added, “We nevertheless wholeheartedly intend to continue his line of investigation in a clinical setting to international good clinical practice standards.”
Racing Against Time
Halford first broke with scientific protocols in 2011, shortly after he was diagnosed with nasal cancer and treated with chemotherapy and radiation, according to an account he later posted on his blog.
By then, Halford was in his 40s and had worked almost a decade at SIU’s School of Medicine.
Halford, who did not have herpes, realized his cancer might not give him much time. If he submitted to the FDA’s oversight, it would take years, he reasoned in his account.
He decided to become his own research subject, injecting himself more than two dozen times with the vaccine.
“There is an ongoing herpes pandemic that demands the scientific community’s attention today, not tomorrow,” he wrote in his blog, which by his count received thousands of hits.
In 2015, Halford set his sights on launching an offshore clinical trial.
However, his unorthodox approach made some of his peers recoil.
“He sat in my kitchen and tried to convince me to join him,” said Terri Warren, a nurse practitioner in Oregon who was approached by Halford in 2016 to help with the trial. “He believed so firmly in his vaccine. He said, ‘Think of all of the herpes patients who are suffering.’”
Warren had previously worked with Halford on a different, IRB-approved trial studying a new blood test to diagnose herpes. This time, she said, she became concerned about his methods, including how he was selecting his participants.
“I told him absolutely not,” she recalled. “I didn’t want anything to do with it. I felt bad for him because he was dying, but I thought he had lost perspective.”
But Halford did find backers, including Hollywood filmmaker Agustín Fernández III, whose credits include action films and an award-winning documentary.
Fernández recently declined to respond to questions. But in an earlier interview this year with KHN, he said he initially contacted Halford to try to help someone he knew who was battling the disease. He said he didn’t have herpes, or a background in science.
Fernández, however, became such a believer in Halford, he said, he allowed Halford to inject him with the vaccine. In 2015, he co-founded Rational Vaccines with Halford and invested his own money into the company. That same year, the company licensed two patents related to the vaccine from the university.
“I felt like Bill had the answer, and we had to make sure he got a chance to prove it,” Fernández said.
‘Finally … Someone Who Cared’
As soon as news began spreading in the tight-knit herpes online community that Halford may have a cure, he began hearing from the most desperate who asked to be included in any future research.
For many, herpes is a mild disease that can be controlled by antiviral medicines. However, for some, it becomes a life-altering disease that destroys any hope of intimate relationships.
To several of the participants, Halford was an empathetic scientist who refused to give up on finding a cure.
“After dealing with doctors who had no answers, it felt like you were finally talking to someone who cared and could help,” said a participant in his 30s from the South who had described the trial as “paradise.”
There were other perks as well.
Rational Vaccines told some participants they would be reimbursed for their flight and hotel expenses. If they got through the entire trial, they would be given an extra $500.
As Halford organized two groups of 10 participants, he instructed them on drawing their own blood for the trial, according to a video filmed in a medical lab.
He proceeded with the trial from April to August 2016, giving participants three shots over three months.
Once in St. Kitts, many of them quickly bonded with one another and Halford. Even though they ranged in age from their 20s to 40s and came from different regions, they had the disease in common. They commiserated about how herpes had wreaked havoc on their lives.
“It was a relief to meet people who understood what we were talking about,” the Southerner said.
But other participants now say they noticed some troubling signs.
They received the injection in a house in St. Kitts, not a medical clinic.
Halford, whose gaunt frame made his cancer apparent by then, at times appeared disoriented.
Fernández, a constant presence, was introduced to them by name and made some of them uncomfortable when they socialized over drinks and dinner.
Some patients became anxious about their participation soon after receiving the vaccine.
One, a web developer in his 20s, felt ill after receiving just one dose.
“I experienced tiredness and ringing in my ears,” said the web developer, who reported the feelings along with “disequilibrium and slurred speech” continue to this day.
He said he decided not to return to St. Kitts for follow-up shots after Halford dismissed his symptoms as arising from a common cold.
Another participant, a Colorado woman in her 40s, said she told Halford she experienced flu-like aches and pains and tingling and numbness soon after the second shot. The symptoms were followed by an “excruciating” 30-day outbreak of herpes.
“I have new symptoms every day,” that woman later wrote Halford in an email exchange provided to KHN. “This is terrifying.”
Halford initially dismissed her symptoms, speculating they were caused by a mosquito-borne virus, she said.
She returned for the third shot but had her doubts. Halford and Fernández met her at a café to talk about her concerns, she recalled.
“[Fernández] kept saying, ‘You signed the consent form. You knew the risks,’” said the Colorado woman, who said Halford then removed her from the trial.
Another participant, a Californian in his 30s, said he went through with all three shots despite feeling a “terrible pain in my stomach.”
Halford then told him he had noticed in his research of mice that another version of the virus entered the gut of the mice and killed them, the participant said.
“I then thought maybe this is dangerous,” said the Californian, whose pain went away but his outbreaks did not.
Warren, the nurse practitioner in Oregon, said two participants tracked her down as a herpes expert. She said that they described possible side effects from the vaccine.
Halford had told participants he would follow up on their reactions to the vaccine for a year, according to the consent form. But he stopped sending questionnaires to the two participants who said they had been dropped from the trial.
Warren said that even when researchers stop administering a vaccine because of possible side effects, known as adverse events, they have a duty to track the subjects’ reactions.
“There is no doubt that these were adverse events that should have been reported,” Warren said.
Rational Vaccines did not respond to questions about the complaints. In previous public statements, it acknowledged that one of the 20 participants was concerned about possible side effects.
Some participants also wonder where Halford made the vaccine and how he transported it to St. Kitts.
Halford told his business partner he had made it outside of the United States, without disclosing where.
After the trial ended, some participants began complaining that the vaccine hadn’t worked. Halford and Fernández offered booster shots, according to four participants.
One participant, a man in his 40s who was also from California, declined to get the booster. He said he decided to go back to antiviral drugs when his outbreaks returned.
The Southerner said he agreed to allow Halford to give him booster shots at an office in Springfield, Ill., where Halford worked.
“It was between me and him,” said the participant. “He was doing me a favor.”
“I don’t know if it was a different strain or what, but he gave me a set of double boosters at the same time, one in each leg,” recalled the Southerner, who said he didn’t have records of the injections. He said he received them as Halford continued to collect data for the trial.
Months later, he said, he returned a second time for another set of boosters.
Courting Support Without Results
Halford, meanwhile, tried to persuade a U.S. scientific journal to publish a lengthy manuscript detailing the results of both his experiments on himself and his offshore trial. Halford put the cover letter on SIU letterhead.
In December 2016, only months after the trial had ended, Halford’s paper was rejected by the journal.
“This manuscript is partly a vision, partly science, and partly wishful thinking …,” said one reviewer for the journal. “Neither safety nor efficacy has been demonstrated by the data presented.”
Halford asked his former doctoral adviser, Daniel Carr, to attend a Rational Vaccines advisory board meeting. Carr, a University of Oklahoma Health Services Center professor, said he and other invitees heard glowing reports about the trial.
Carr agreed in May to present the trial data at a conference of herpes experts in Colorado.
A published summary of the event listed Carr as a lead author, though he said he wasn’t involved in the research.
“I just did it to help him out,” said Carr, who asked for his university’s permission to be on Rational Vaccines’ advisory board and is waiting for word on federal funding to study another version of Halford’s vaccine. “I also presented it because I thought that the scientific community would find it interesting.”
Despite its patent agreement reached in 2015, SIU said it was in the dark about Halford’s offshore activities until October 2016 — months after the trial had ended.
Halford, meanwhile, promoted his work at events attended by university officials.
Then, in April 2017, Halford and Rational Vaccines held a press conference to trumpet an investment pledge by Thiel’s company, according to materials handed out at the event. University officials, including SIU’s medical school dean, were invited speakers.
The university’s IRB is continuing its investigation, which includes scrutinizing whether Halford used university resources.
“If there are areas of concern, SIU will report those findings promptly to Department of Health and Human Services,” said SIU spokeswoman Karen Carlson. “We will also communicate our findings with the scientific community and the public.”
FDA spokeswoman Lauren Smith Dyer declined to comment on the trial except to say the FDA does not have jurisdiction over offshore trials that don’t seek agency approval.
Dyer, however, added that the export from the United States of an unapproved vaccine for research use and the injection of it on U.S. soil would be within the agency’s jurisdiction.
Even so, some participants don’t regret taking part in the trial.
“When you feel like a disease has ruined your life, you become desperate,” said the Southerner, who believes the boosters have lessened his outbreaks. “Some people contemplate suicide. You’re willing to do almost anything.”
Other participants still hope for some sort of accountability.
“I feel like without a doubt that my symptoms were vaccine-related,” said the Colorado woman. “I feel like it triggered something that I’ll have for the rest of my life.”
No matter what, experts said, the university has a responsibility to conduct an in-depth investigation. So far, the university has not reached out to participants who spoke to KHN.
“This researcher went rogue,” said Fernandez Lynch, the lawyer who specializes in medical ethics. “It’s true that universities can’t stand behind their researchers watching their every move. But when one of their own goes rogue, a university should launch an aggressive investigation, interview the participants and make sure it never happens again.”
Healthy Volunteers needed for an investigational flu vaccine study.
According to the Centers for Disease Control and Prevention (CDC), an estimated 310,000 people in the United States were hospitalized for flu-related illness during the 2015-2016 flu season.
Researchers at the National Institutes of Health (NIH) Clinical Center are testing investigational vaccines to determine if they are safe and effective at preventing influenza.
During the study you will:
Complete a health screening including medical history, physical exam and blood tests
Receive either 1 or 2 investigational flu vaccines
Have 8-10 outpatient visits that may last up to 40 weeks
Receive compensation for your participation
You may be eligible if you:
Are healthy and between the ages of 18 and 70 (excludes those born from 1966 to 1969)
Do not have any medical conditions such as diabetes, hypertension, heart disease or psychiatric condition
Are not pregnant, breastfeeding, or planning to become pregnant
This study is being conducted at the NIH Clinical Center, America’s research hospital is located on the Metro red line (Medical Center stop) in Bethesda, Maryland.
For more information, call: 1- 866-444-1132 TTY: 1-866-411-1010 Se habla español Online: https://go.usa.gov/xNH7U
As a break from writing, I finished the first electronic version of my CSV Audit Mindmap. The intent is for it to be a mental tickler during an audit. Rather than 10-20 pages of checklists, this would be a visual layout of related topics that fit on 1 or 2 pages (or more if you like). Click the link to look at a pdf version…and be sure to let me what you think.
I was sad (though not surprised) to hear of JnJ’s pending layoffs. I have friends who work there. However, the thing that really caught my attention in this article is that the cost to develop a new drug has moved from US $800 Million to US $1.3-1.5 Billion in just a few years. I don’t have a lot of time to expound on this, but thought it worth flagging.
As all of the discussion on Healthcare reform comes to a head, I think it warrants some comments from me regarding “The Greed of Pharma”. Let me start by saying that Pharma is a for-profit business like any other.
I think it is important to note that neither pharma (nor the insurance industry for that matter) has particularly high profitability (ROE %’s). The following industries have a higher ROE % (Return on Equity rating) than Pharma (21 of them, and in the order listed). Cigarettes has nearly triple Pharma’s profitibility (and the US Gov is a de facto share holder); Aerospace has double. So why would Pharma be expected to foot the healthcare bill (and squeal like a pig -to paraphrase Congressman Marion Berry of Arkansas) when there are so many other more deserving candidates?
May you live in interesting times… A colleague flagged this for me. I’ll be very interested in the particulars of how this all works going forward. #ItsAllAboutApps
New warning letters out! These are largely GMP-specific. Like no other agency, FDA is reknowned for updating regulations via warning letter (rather than the onerous process of getting an actual new or updated regulation approved)….so it is good to always keep an eye on these to be clear on “FDA’s current thinking”. YMMV. In any case, check out the full information at the link below!
T. J. Kuhn | GxP Zone 