Filling clinical trials and enrolling sufficiently diverse, representative groups of patients, has long been a challenge, partly due to stringent participation guidelines. In an effort to attain larger and more diverse trial groups, an international team of researchers and policymakers has written new recommendations on how to determine eligibility criteria for lung cancer clinical trials.
The group was led in part by David Gerber, MD, along with representatives from the Food and Drug Administration (FDA), National Cancer Institute, European Medicines Agency, pharmaceutical companies, and the LUNGevity Foundation.
The recommendations, published today in JAMA Oncology, offer the first publicly available outline of upcoming FDA draft guidance on lung cancer clinical trials that are expected to make it easier to include more patients.
“This paper is the public’s first look at the FDA’s proposed changes to how we determine who can participate in a lung cancer clinical trial,” said Professor Gerber in the Hematology/Oncology Division at UTSW. “If these changes are successful, they could make clinical trials for lung cancer as well as other cancers more powerful and more representative.”
Ensuring that people from diverse backgrounds join clinical trials is key to properly evaluating how a new treatment will work among patients of all races and ethnicities. But today, only about 5% of all cancer patients enrol in a clinical trial, and only 11% of cancer clinical trial participants identify as a racial or ethnic minority.
For patients with cancer, participation in clinical trials requires not just a decision to try an experimental treatment, but time and energy spent understanding the trial, enrolling in it, and often attending extra testing or clinic appointments. Many researchers agree that complicated, inconsistent, poorly explained, and overly strict eligibility requirements to join a cancer clinical trial exacerbate this problem and are a key reason for the low number of underrepresented minorities in clinical trials.
“So many clinical trials never finish enrollment, close prematurely, or don’t recruit a population that lets researchers generalise the results,” Dr. Gerber said. “I think there’s widespread recognition that eligibility criteria have become too stringent.”
Addressing this for one cancer subtype, advanced non-small cell lung cancer (NSCLC), – the LUNGevity Foundation convened a roundtable discussion with experts from academia, industry, and regulatory bodies. The team assembled a prioritised list of eligibility categories that should be included in the descriptions of all NSCLC clinical trials and recommended criteria for each category. Some suggestions were more lenient than what has typically been included in previous NSCLC trial eligibility criteria; for instance, the team recommended that most patients with prior or concurrent cancers, most patients with brain metastases, and most patients with mild liver impairment – all of whom would likely have been excluded in the past – still be included in trials.
The team also suggested that these categories be clearly laid out on public websites advertising clinical trials in an easily searchable format.
The FDA will be releasing draft guidance on NSCLC clinical trials in the near future and hold a public comment period before finalising them. Other interdisciplinary teams have already convened to standardise eligibility requirements for clinical trials of other cancer types.
If the new guidelines prove effective, Prof Gerber said that clinical trials will likely be easier to fill and provide more complete and timely data on new cancer interventions.
“If you can involve more patients in clinical trials, you’re more likely to complete those trials quickly. That’s going to lead to new treatments faster,” he said.
Following a highly critical independent report and accusations of inadequate and unsafe care, the UK will shut down the Tavistock gender identity clinic for children – the only one in the country. It will be replaced by a number of smaller facilities with closer links with mental health care.
The Tavistock and Portman NHS Foundation Trust clinic, named the Gender Identity Development Service (GIDS), had faced complaints of both long waiting lists for a burgeoning number of referrals, as well as rushing to assign puberty-blocking drugs and cross-sex hormones to children experiencing gender dysphoria.
Concerns had been voiced as early as 2005, when a nurse working at the clinic said that patients were being assessed too quickly and giving in to pressure from interest groups. Nevertheless, demand for its services skyrocketed in later years, from less than 100 per year in 2010 to nearly 2500 by 2018. In 2018, concerns were raised anew, with staff going on to make serious public accusations.
In July 2019, Dr Kirsy Entwhisle, a psychologist at GIDS Leeds hub, said that staff misled patients and made decisions about young people’s “bodies and lives” without “robust evidence”. Some of the children had suffered “very traumatic early experiences” which had not been addressed by the staff. The trust’s safeguarding lead, Sonia Appleby, won a claim from an employment tribunal after trust managers tried to stop her from carrying out her role when staff raised concerns.
One of the loudest critics of Tavistock Centre is Keira Bell, who at 16 was assigned puberty blockers, then cross-sex hormones at 17, and had a double mastectomy at 20 before later de-transitioning.
The former patient, who said she was suffering from anxiety and depression at the time she received treatment, said medics should have considered her mental health issues, “not just reaffirm my naïve hope that everything could be solved with hormones and surgery”.
Along with the unnamed parent of an autistic girl at the clinic, she won a ruling against the NHS assigning cross-sex hormones to children under 16 – but was overturned on appeal.
Helen, a parent of a patient at the clinic, welcomed its closure, but expressed concern for the future of her son’s treatments, according to LGBT site Pink News. While she said her son was treated quickly and received puberty blocking drugs, “From that point on, it felt like it was a little bit like they were winging it,” she said.
During therapy sessions at Tavistock, she said her son was asked a lot of questions and treated “almost like a little bit of an academic curiosity”. She criticised the fact that the same staff evaluated children for medical interventions and also offered therapy session, creating “a fear that they would stop access to medical support”. In contrast to the legal claims of Keira Bell’s and the unnamed patient, she said that GIDS refused to even discuss cross-sex hormones.
Dr David Bell (no relation to Keira Bell) welcomed the closure of Tavistock, telling the BBC: “Some children have got the double problem of living with the wrong treatment, and the original problems weren’t addressed – with complex problems like trauma, depression, large instances of autism.”
The fields of Alzheimer’s disease and cancer research have both been shaken by recent investigations which have revealed image falsification and plagiarism. These findings call into question specific avenues of research which have received considerable funding.
Neuroscientist Matthew Schrag, a junior professor studying Alzheimer’s, had already ruffled some feathers criticising the FDA approval of the Alzheimer’s drug Aduhelm when he was approached by an attorney to investigate Simufilam, another Alzheimer’s drug under development.
According to Science, he used funding given to him by the attorney to investigate the data behind the drug’s development. The research focuses on amyloid beta (Aβ) plaques, long thought to be the culprit behind Alzheimer’s.
Schrag identified apparently altered or duplicated images in dozens of journal articles, and sent them to the National Institutes of Health (NIH), which had funded tens of millions of dollars.
The investigation drew him towards a bedrock of modern Alzheimer’s research, a 2006 Nature study by Sylvain Lesné of the University of Minnesota in the laboratory of Karen Ashe, which identified an amyloid beta protein.
Schrag avoids describing the suspicious data as fraud, since that would require unfettered access to the original material. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he said. “The data should speak for itself.”
The work focused on ‘toxic oligomers’, subtypes of Aβ that dissolve in some bodily fluids, a potential Alzheimer’s cause that had gained traction in the early 2000s partly due to their discovery in autopsied Alzheimer’s patients.
Using transgenic mice, the UMN team discovered a previously unknown oligomer species, Aβ*56. They isolated Aβ*56 and injected it into young rats, causing a reduction in cognitive ability.
This discovery, the first to show a direct cause, resulted in an explosion in related research, with related studies receiving $287 million in National Institutes of Health funding in 2021, compared to no funding in 2006.
In concert with molecular biologist Elisabeth Bik, no less than 20 of Lesné’s papers were flagged, 10 of which related to Aβ*56. A finding which some Alzheimer’s experts say calls into question 16 years of amyloid beta research. Some had been suspicious and had failed to replicate the findings, but journals are reluctant to publish research which proves a negative or which contradicts a prominent researcher’s findings.
Cancer research has been dogged by its own crisis with fabricated data, according to an investigative report by Nature. For years, a prominent US cancer-research laboratory run by leading cancer geneticist Carlo Croce at the Ohio State University (OSU) had been dogged by allegations of plagiarism and falsified images. To date 11 papers he has co-authored have been retracted, and 21 have needed corrections.
In 2017, The New York Times first reported on allegations of research misconduct against Croce, when OSU opened inquiries into papers from Croce’s lab. These proceeded to formal investigations, Nature learnt, two of which found multiple instances of research misconduct, including data falsification and plagiarism, by scientists Michela Garofalo and Flavia Pichiorri, in papers they’d authored while in Croce’s laboratory.
Garofalo claimed she did not received proper image manipulation training and Pichiorri said she did not understand plagiarism at the time. They have since moved on from OSU.
OSU declined to charge Croce with misconduct as his involvement did not relate to direct plagiarism or image fabrication, but did note that these cases resulted out of his “poor mentorship and lack of oversight.”
Croce was removed from a number of his positions – for which he attempted to sue – but is still employed by OSU, and many of the papers identified by OSU have not been retracted by their journals.
The pandemic may have changed doctors’ end of life decision-making, making them more willing to not resuscitate very sick and/or frail patients and raising the ICU transfer threshold, suggest the results of a snapshot survey of UK doctors published in the Journal of Medical Ethics.
Views on euthanasia and physician-assisted dying remain unchanged however, with around a third of respondents still strongly opposed to these policies.
The COVID pandemic transformed many aspects of clinical medicine, including end-of-life care, prompted by thousands more patients than usual requiring it, the researchers said.
Because of this, they wanted to find out if the pandemic significantly changed the way in which doctors make end-of-life decisions, specifically in respect of ‘Do Not Attempt Cardio-Pulmonary Resuscitation’ (DNACPR) and treatment escalation to ICU.
These aspects of end-of-life care were chosen because of the controversy surrounding DNACPR decisions, in part prompted by an increase in cardiac arrests associated with COVID infections, and concerns about ICU capacity strained by the pandemic.
The researchers also wanted to know if the pandemic had changed doctors’ views on euthanasia and physician assisted suicide as surveys on these issues by the British Medical Association (BMA) and the Royal Colleges of Physicians and General Practitioners had been carried out before it started.
The online survey was open to doctors of all grades and specialties between May and August 2021, when hospital admissions for COVID in the UK were relatively low.
In all, 231 responses were received: 15 from foundation year 1 junior doctors (6.5%); 146 from senior junior doctors (SHOs) (63%); 42 from hospital specialty trainees or equivalent (18%); 24 from consultants or GPs (10.5%); and 4 others (2%).
In respect of DNACPR, which refers to the decision not to attempt to restart a patient’s heart when it or breathing stops, over half the respondents were more willing to do this than they had been previously.
When the responses were weighted to represent the different medical grades in the NHS national workforce, the results were: ‘significantly less’ 0%; ‘somewhat less’ 2%; ‘same or unsure’ 35%; ‘somewhat more’ 41.5%; ‘significantly more’ 13%; and ‘not applicable’ 8.5%.
When asked about the contributory factors, the most frequently cited were: ‘likely futility of CPR’ (88% pre-pandemic, 91% now): co-existing conditions (89% both pre-pandemic and now): and patient wishes (83.5% pre-pandemic, 80.5% now). Advance care plans and ‘quality of life’ after resuscitation also received large vote-share.
The number of respondents who stated that ‘patient age’ was a major factor informing their decision increased from 50.5% pre-pandemic to around 60%. And the proportion who cited a patient’s frailty rose by 15% from 58% pre-pandemic to 73%.
But the biggest change in vote-share was ‘resource limitation’, which increased by 20%, from 2.5% to 22.5%.
When asked whether the thresholds for escalating patients to intensive care or providing palliative care had changed, the largest vote-share was the ‘same or unsure’: 46% (weighted) for referral; 64.5% (weighted) for palliative care.
But a substantial minority said that now they had a higher threshold for referral to intensive care (22.5% weighted) and a lower threshold for palliation (18.5% weighted).
When it came to the legalisation of euthanasia and physician assisted suicide, the responses showed that the pandemic has led to marginal, but not statistically significant, changes of opinion.
Nearly half (48%) were strongly or somewhat opposed to the legalisation of euthanasia, 20% were neutral or unsure, and around a third were somewhat or strongly in favour before the pandemic. These proportions changed to 47%, 18%, and 35%, respectively.
But a substantial minority said that now they had a higher threshold for referral to intensive care (22.5% weighted) and a lower threshold for palliation (18.5% weighted).
When it came to the legalisation of euthanasia and physician-assisted suicide, there was no statistically significant change in opinion.
Nearly half (48%) were strongly or somewhat opposed to the legalisation of euthanasia, 20% were neutral or unsure, and around a third were somewhat or strongly in favour before the pandemic. These proportions changed to 47%, 18%, and 35%, respectively.
Similarly, just over half (51%) said they had strongly or somewhat opposed the legalisation of physician assisted suicide, 24% had been neutral or unsure, and 25% had been somewhat or strongly in favour. These proportions changed to 52%, 22%, and 26%, respectively.
The impetus to make more patients DNACPR, prompted by pressures of the pandemic, persisted among many clinicians even when COVID hospital cases returned to low levels, the researchers noted. The factors informing it were compatible with regulatory (GMC) ethical guidance, with the exception of limited resources.
“At the start of the pandemic, the BMA advised clinicians that in the event of NHS resources becoming unable to meet demand, resource allocation decisions should follow a utilitarian ethic.
“However, what is clear from our results is that for a significant proportion of clinicians, resource limitation continued to factor into clinical decision making even when pressures on NHS resources had returned to near-normal levels,” they wrote.
The survey results also suggest that the pandemic has helped clinicians gain a greater understanding of the risks, burdens, and limitations of intensive care and had further educated them in the early recognition of dying patients, and the value of early palliative care, they added.
“What is yet to be determined is whether these changes will now stay the same indefinitely, revert back to pre-pandemic practices, or evolve even further,” they conclude.
Industry-sponsored studies on a new drug or health technology are more likely to be found ‘cost-effective’ than independent studies, across a range of diseases, according to findings from a study published in The BMJ.
In a linked editorial, experts make a call for better reporting of results, more transparency, open-source cost-effectiveness models, and more independent studies, to reduce decision makers’ reliance on potentially biased cost-effectiveness analyses.
A cost-effectiveness analysis (CEA) provided the manufacturer is required by some countries to weigh up a product’s costs and effects.
This cost analysis evidence can be used to set the price for a drug or health technology or decide whether insurance policies will cover them. New drugs covered by insurance plans can be much more profitable than those not covered, which could lead to bias in CEAs funded by the drug and technology manufacturing industry.
While previous studies have consistently shown sponsorship bias in CEAs, most studies were limited to specific diseases, and are out of date. To fill in the gaps, Feng Xie and Ting Zhou from McMaster University, Canada, analysed data from all eligible CEAs published between 1976 and March 2021.
They selected CEAs that reported an incremental cost-effectiveness ratio (ICER) using quality-adjusted life years or QALYs – a ‘value for money’ metric of years lived in good health.
The authors used data from the Tufts Cost-Effectiveness Analysis Registry. In total, 8192 CEAs were included in the study, of which nearly 30% were sponsored by industry.
The study defined CEA industry sponsorship as an analysis funded by drug, medical device, or biotechnology companies, either wholly or in part.
The results show that the industry-sponsored CEAs were significantly more likely to conclude that the new medicine or health technology was cost-effective than those not sponsored by industry.
For example, industry-sponsored studies were more likely to report the intervention being studied as cost-effective below the commonly used threshold of $50 000 per QALY gained than non-industry sponsored studies.
Among 5877 CEAs that reported the intervention was more effective but more expensive than the comparator, the ICERs from industry sponsored studies were one third (33%) lower than those from non-industry sponsored studies.
While only having the registry information to work with was a limitation, the authors said their analysis provides a basis for comparison with previous investigations.
As such, they suggested that “sponsorship bias in CEAs is significant, systemic, and present across a range of diseases and study designs.”
In lower and middle-income countries, industry bias can increase drug prices, where fewer resources mean decision-makers often need to rely on published, rather than independent CEAs.
In a linked editorial, Adam Raymakers at Cancer Control Research, Canada, and Aaron Kesselheim at Brigham and Women’s Hospital, USA, argue that decision-makers “should exercise caution when using published cost-effectiveness analysis in coverage decisions.”
They say finding solutions to tackle bias is more important than ever, and make the case for open-source analysis models, increased transparency, and increased funding for independent analyses, to help minimise reliance on industry-sponsored cost analyses.
Taking the time to obtain proper informed consent is one of the most effective ways to avoid medico-legal challenges. Other than building the doctor-patient relationship, it ensures that patients do not encounter unpleasant surprises on their care journey which may result in unnecessary anger and blame.
Informed consent is a process where you provide information sufficient to enable the patient to make an informed decision relating to their healthcare. Although the signature of a consent form often constitutes completion of the consent process, a signature on a consent form without a balanced discussion does not constitute informed consent.
Informed consent is both a legal and ethical requirement. The National Health Act gives patients the right to be informed of the various treatment options available, and the benefits, risks and costs of each treatment option. It also gives patients the right to participate in decisions regarding their treatment and the right to consent before any treatment is given unless it is an emergency and they aren’t able to consent. From an ethical perspective, informed consent has two main objectives, firstly to respect and promote patients’ autonomy and secondly, to protect patients from potential harm. Medical intervention with a patient’s body is potentially an infringement of the constitutional right to bodily integrity and is legally wrongful unless there is a ground of justification. One such ground of justification is patient consent.
Knowing your patient will help focus the discussion during the informed consent process. Enquire about your patient’s personal circumstances, expectations and fears, and assess their understanding of medical concepts and ability to make decisions.
Use simple language and avoid technical terminology when discussing medical facts.
Ensure your patient understands their medical condition and its natural history before discussing treatment options. This lets them know what to expect without treatment.
List the range of diagnostic procedures and treatment options generally available. For each, highlight potential benefits and risks, including recognised complications and any potential follow-up treatment.
Explain the possible need for emergency management of unforeseen conditions that may emerge.
Discuss cost implications and payment responsibility. This considers medical aid coverage, any out-of-pocket costs, the cost of the different procedures, as well as any complications.
Allow an opportunity for questions and answers. Encourage your patient to ask questions. Test your patient’s understanding. Let patients contact you prior to the planned procedure, if they have more questions or concerns.
If a patient has specified that they would rather a procedure didn’t go ahead in the event of certain clinical findings, the patient’s decision must be recorded and respected.
If the patient decides to consent to an intervention, obtain their signed written consent. The patient’s details, health status, the treatment options discussed and the procedure to be performed must be entered into your consent form.
Document complications that have a reasonable likelihood of occurring and/or which are likely to be of importance to your patient, considering personal circumstances.
For example, an abnormal sense of touch after carpal tunnel syndrome surgery may affect a practising dentist more significantly than a retired librarian.
Ensure that your consent form documents that no guarantees or promises have been made regarding the outcomes of the procedure and the patient has a right to refuse the procedure.
Your consent form must include any discussions relating to financial consent, the use of anaesthesia and blood products and the need for emergency management in the event of unforeseen complications.
Check that the patient initials the document and signs with the correct date. Countersign and date the consent form. Attach any relevant patient information sheet to the informed consent form and allow the patient to take a copy and keep one for the practice.
Consent remains valid until it is withdrawn by the patient or until their circumstances change in a meaningful way. However, if significant time has passed since the original consent was obtained, you may need to update and document your discussion with the patient. Additions or corrections to the consent form must be dated, timed and signed by both parties.
Trust EthiQal to provide you with local legal advice and professional support when you need it most.
EthiQal is a division of Constantia Insurance Company Limited, a licenced non-life insurer and an authorised Financial Services Provider (FSP 31111).
With the US Supreme Court’s overturning the Roe v Wade decision, abortion rights are now up to individual US states. However, while there are no legal implications for the rest of the world, it will undoubtedly have a huge influence on other countries’ abortion campaigning and lawmaking decisions. Future anti-abortion efforts in the US may also impact the country’s funding of reproductive services in regions such as Africa.
Without access to legal, safe abortion, many pregnant people will turn to unsafe methods. According to the World Health Organization, 97% of all unsafe abortions happen in developing countries. Some 4.7–13.2% of maternal deaths are attributable to unsafe abortion.
Although Roe v Wade does not have a legal effect in Africa, it was frequently invoked in abortion. Tunisia liberalised its abortion law just nine months after the Roe v Wade ruling – allowing women to access the service on demand. Additionally, in 1986, Cape Verde allowed for abortion on request prior to 12 weeks gestation which aligns with Roe v Wade holding of the same.
In South Africa, the right to abortion is not directly enshrined in the Constitution, but the 1996 Choice in Termination of Pregnancy Act greatly widened accessibility to safe, legal abortions, causing a 90% drop in abortion mortality from 1994 to 2001. The previous apartheid-era laws and their enforcement were predictably stained by racism: abortion was limited to encourage white population growth while contraceptives were promoted to control the population growth of black and coloured people. Wealthy whites could fly to England for an abortion there if they could not arrange one. The 1996 Act was met with significant opposition on religious grounds, and it is speculated that had the ANC done this with an open vote, it would not have passed with such a wide margin.
Even today, research shows that abortion remains highly stigmatised among South Africans, with 75.4% of people surveyed indicating that it was “always wrong” in case of family poverty, and 52.5% indicating the same for either foetal abnormality or family poverty. Provincial splits are apparent, with Gauteng and Limpopo having a > 1 odds ratio of being against abortion.
The 2003 Maputo Protocol adopted by the African Union requires countries to authorise medical abortions in cases of sexual assault, rape, incest, or where the health of the mother is endangered. This specific provision draws from the 1979 United Nations Convention on the Elimination of All Forms of Discrimination Against Women (CEDAW), whose clause on access to safe abortion was based on on Roe v Wade. However, 12 AU members have not ratified the protocol, and many of those who did have not fully brought their laws into line. South Africa is only one of six African nations that effectively allow elective abortions. Of these, Mozambique and Benin only fully changed their laws in 2020 and 2021.
Abortion opponents led by the Catholic Church and its affiliates enjoy widespread political and social support in many African countries. In 2020, Bhekisisa investigated African pregnancy crisis centres funded by US anti-abortion groups. These centres actively discourage abortion, exerting pressure on girls and women and are rife with misinformation, such as grossly exaggerating the size and development of the foetus in early stages of pregnancy. One NGO offered training to say that abortion would “turn” women’s partners gay if they got an abortion.
Thus, while the legal outcome of Roe v Wade being overturned will have no bearing on South Africa, it will conceivably embolden anti-abortion groups both domestically and abroad and likely to increase the influence they already exert in the country.
The Constitutional Court has declined to confirm the constitutional invalidity of sections of the Births and Deaths Registration Act. This comes after the Pretoria High Court found that the Act denied parents the right to bury the remains of a foetus less than 26-weeks.
The application was brought by The Voice of the Unborn Baby NPC and the Catholic Archdiocese of Durban against the ministers of Home Affairs and Health.
The applicants argued that the Act was “insensitive, hurtful and disrespectful” as it only allows for a death certificate to be issued in “stillborn” cases when the foetus is more than 26-weeks.
High Court Judge Nomonde Mngqibisa-Thusi agreed and ruled that sections of the Act are unconstitutional on the basis it “deemed a foetus less than 26-weeks to be medical waste that must be incinerated”.
However, the Constitutional Court, in a unanimous judgment, said the judge was wrong. Acting Judge Pula Tlaletsi said the applicants had submitted that the provisions of the Act had the effect that no burial order could be issued for foetuses lost through miscarriage before the 26-week mark, and that the regulations only made provision for the burial of corpses and human remains, but not foetal remains.
“While it may be true, as the applicants argued, that throughout the years the practice has been to deny parents this right in the apparent belief that this is what the law provides, matters not. The Act contains no such prohibition,” Judge Tlaletsi said.
“The relevant sections cannot be declared inconsistent with the Constitution because of such omission … the Act does not stand in the way of that burial,” he said, noting that the Act only regulated the burial of “dead human bodies or still-born children”.
The Judge said that the court was not in a position to grant the relief.
The question as to what medical staff at public hospitals must do if parents expressed the wish to bury or cremate pre-viable foetal remains was not clear, he said.
“Such a burial or cremation would no doubt require the cooperation of healthcare professionals and public hospitals would be expected to allocate the necessary resources.
“Because of the way the case was pleaded, we do not have the necessary evidence to evaluate considerations relating to how hospitals would manage this … There may be other restrictions, for example, limitations imposed by municipal regulations (regarding cemeteries and crematoriums).”
The Catholic Church, arguing that its members held “sincere religious beliefs” that they become parents from the moment of conception, said the burial right should also extend to lost pregnancies “due to human intervention”, including termination of pregnancies.
But two amici in the case — the Women’s Legal Centre Trust and the Sexual and Reproductive Justice Coalition — said this would have a profound impact on the termination of pregnancy services offered to women, and the attached confidentiality.
This burden, they said, would lead to a decrease in facilities offering termination and a diminution of sexual and reproductive rights.
A Swedish court has convicted Paolo Macchiarini, a formerly lauded trachea surgeon, of causing bodily harm to a patient through negligence during a highly experimental stem-cell trachea transplant. For this, the court handed down a two-year probational sentence. He was acquitted of assault charges on two other patients; all three died in the months and years after the surgeries.
In 2010, Macchiarini was hired by the Karolinska Institute (KI) and the Karolinska University Hospital to support Sweden’s regenerative medicine innovation. His specialty was replacing damaged tracheae with artificial ones that combined stem cells with polymer scaffolds or decellularised donor tracheae. Starting in 2011, he began operating on patients as an experimental life-saving measure but his work at at KI was suspended in 2013 after the second of his three patients died. However, he continued performing surgeries in Russia.
Yet there were already hints that something was amiss even before the first surgeries. In 2011, another academic, Pierre Delaere of UZ Leuven in Belgium accused Macchiarini of misrepresenting research findings in published articles. In 2012, Macchiarini was arrested in Italy and charged with fraud and attempted extortion.
By 2014, after the death of his first patient, three separate allegations were raised of scientific misconduct in reporting the cases. He would later be cleared of these, but in 2016 a TV documentary called ‘The Experiment’ described the suffering and deaths patients of failed artificial tracheas transplants, and raised many issues concerning care and research ethics. The severe public backlash caused KI to launch another investigation into Macchiarini, amid an upheaval which saw a string of resignations and an overhaul of hiring and ethics. He was found to have falsified his CV, and published papers with false or misleading data that were subsequently retracted. By March, he had been fired and criminal charges filed against him.
BBC News reported that at least seven people had died following the surgeries. In 2018, KI found seven researchers guilty of academic misconduct. Swedish authorities decided to reopen investigations into the three deaths.
Matthias Corbascio, a cardiac surgeon at KI who testified in the trial, told SVT Nyheter that he doesn’t believe justice has been done. “My reaction is that it is very meager. It is a terrible scandal and terrible for the patients’ families that he could get away so easily,” he said.
Chief judge Bjoern Skaensberg said the court had agreed with prosecutors that the surgery had not been consistent with “science and proven experience”. However, he told public broadcaster SVT that it had concluded that “two of the interventions were justifiable, but not the third”.
The court had found that all three patients had suffered serious bodily injury, Judge Skaensberg said. But Macchiarini was cleared of assault as no intent to harm had been proven.
Macchiarini had always denied any wrongdoing, arguing that the transplants were aimed at saving the patients’ lives.
However, whistleblower Dr Matthias Corbascio told SVT that the verdict was a scandal and there had never been any chance of the operations succeeding.
The suspended sentence means he will be on probation for the next two years.
A new research paper has signalled a crisis in medical research: “over 60% of trials are so methodologically flawed we cannot believe their results”. Researchers estimate that 88% of trial spending is wasted.
Dodgy research design and bad statistical methodology mean that most randomised trials are a waste of time, money and effort, and of no or dubious scientific value, say Stefania Pirosca, Frances Shiely, Mike Clarke and Shaun Treweek, in a new paper published in the journal Trials in early June.
Their paper examined 1659 randomised trials, involving 400,000 participants, that took place between May 2020 and April 2021 in 84 countries as well as 193 multinational trials.
The majority of trials (62%) showed a high risk of bias. More than half of trial participants were in these high risk of bias trials. Trials where the risk of bias was unclear accounted for 30% of those reviewed, while trials with a low risk of bias – those that can be trusted – accounted for just 8% of the total.
Bad trials – ones where we have little confidence in the results – are not just common, they represent the majority of trials in all countries and across most clinical areas. For instance, all trials looking at drugs and alcohol exhibited a high risk of bias. The most reliable field was anaesthesia, with 60% of trials exhibiting a low risk of bias.
The research team drew trial data from 96 reviews from 49 of the 53 clinical Cochrane Review Groups. Cochrane is an international organisation that helps to gather and propagate the results of medical research to better guide medical decision-making. This is done by experts compiling and evaluating research trials and results in “standardised, high-quality systematic reviews”.
Bad science was common everywhere. “No patient or member of the public should be in a bad trial and ethical committees, like funders, have a duty to stop this happening,” the paper’s authors write.
South Africa was bad, but Spain and Germany may be worse
In the seven trials reviewed that took place in South Africa, four had a high risk of bias, two had an unclear bias risk, and one trial was “good science”. This share of bad science is roughly similar to those found in the clinical trials done in the UK and USA. The most reliable health research science was done in multinational trials – with these, 23% of trials were a low risk of bias. (The authors didn’t identify the trials.)
The least reliable science, in countries that conducted 20 or more RCTs, was done in Spain and Germany, with 86% and 83% of the trials exhibiting a high risk of bias.
While results from just one year were interrogated, the paper’s authors found that their results map to similar studies, and that bad science can be expected to be the norm, over time.
This amounts to a massive waste of money and effort.
Statisticians and research method experts have been sounding the alarm on biased research for years, since Doug Altman’s 1994 paper in the British Medical Journal, “The scandal of poor medical research”.
Doctors want to know if they can rely on a particular treatment to produce a desired outcome, and need research that confers a degree of confidence. One way to do that – the most popular – is randomised control trials.
Randomised trials are great – but you need statisticians
Randomised control trials, also known as randomised trials, or RCTs, are for many (though not all), the gold standard for achieving scientific knowledge about a medical intervention – whether a drug or another type of therapy. The way that RCTs are conducted is crucial, as it is adherence to the method that gives people relying on the research confidence that the results produce scientific knowledge. See this explainer video for more: How do we know vaccines work?
But, if there is a high risk that the results were biased by errors in how they were conducted and how results were achieved, they should not be relied on. Pirosca and colleagues did not examine the type (or domain) of bias in the studies, arguing that having a high risk in one type of bias is sufficient to undermine the trial’s results.
In short, for Pirosca and colleagues, health research in randomised trials is bad when there is an identifiable risk of bias in the way that the results were obtained.
The large number of high risk of bias trials appears to be due to “a lack of input from methodologists and statisticians at the trial planning stage combined with insufficient knowledge of research methods among the trial teams”. You would not, they say by analogy, think it appropriate that a statistician conduct surgery, just because they are doing work in a surgical domain.
Bad science during COVID
Recent medical scandals in the headlines have highlighted the risks of bad science in medicine. The Covid pandemic has brought a boom in medical research, and popular attention to the results of medical research. This environment has produced some remarkable science, but it has also created scientific fiascos, like the one that surrounded ivermectin.
As GroundUp has previously reported, a review of studies investigating ivermectin as a possible therapy for Covid initially suggested that the deworming drug led to better outcomes in those that used it. On the face of it, the small studies that supported this conclusion seemed to provide promise for a low-cost, life-saving Covid intervention. But once the methodology and statistics were looked at closely, many of these papers were deemed unscientific – for instance, patients were excluded from analysis for no good reason. And once these trials were excluded from the review, the drug’s promise as a Covid treatment vanished.
Medical research watchdog Retraction Watch currently lists 12 papers purporting to investigate ivermectin that were subsequently withdrawn or for which concerns have been expressed. According to their records, 235 Covid papers have been withdrawn to date.
But the crisis is not insurmountable. Pirosca and colleagues say that relatively simple fixes would dramatically reduce the amount of untrustworthy health research – by ensuring that methodological principles that underlie RCTs are not compromised.
More expenditure on statistical expertise will save money
A 2015 review examined 142 trials that exhibited a high risk of bias. The authors found that in half of the high risk trials, the methodological adjustments required to reduce the risk of bias would have been low or zero cost. Easy adjustments at the design stage would have made important improvements to 42% of trials that exhibited high risk of bias.
Pirosca and colleagues propose that no medical RCT should be funded or given ethical approval if it cannot prove that the team conducting the trial has a member that has methodological and statistical expertise. Every RCT should, in its design, use risk of bias tools to make sure that results are not compromised.
The expertise that could restore the worth to medical research is in short supply.
More methodologists and statisticians are needed, and money should be invested in training people with this expertise, and investing in applied methodology research and supporting infrastructure. The authors call for 10% of a funder’s budget.
This might seem like a lot of money, but, argue Pirosca and co, it would be a fraction of the cost of the wasted research in the year under review – estimated to be billions of rands.
The task is urgent: “Randomised trials have the potential to improve health and wellbeing, change lives for the better and support economies through healthier populations … Society will only see the potential benefits of randomised trials if these studies are good, and, at the moment, most are not.”
