The Lancet, UNSW and Khachigian’s cancer cure

Levon Khachigian is cardiovascular researcher, and an extremely overpaid institute head at the University of New South Wales (UNSW) in Sydney, Australia. He had 6 retractions, while his financially conflicted university whitewashed him every time while pushing his clinical trial with a phony cancer drug. Hence, Khachigian’s awards, his breakthrough cancer cure and his innocence of all suspicions of research misconduct is all we learn from his Wikipedia page, which is most obviously curated by his lawyers and reputation managers (as it is the case for all dishonest professors).

In 2004, Khachigian won the Australia Science Prize 2004, his UNSW almost burst with pride when announcing:

“[Khachigian lab’s] most recent discovery is of molecular (DNA) tools that block the growth of aggressive melanoma in mice. By suppressing the action of a gene, c-Jun, they prevented the formation of the new blood vessels that cancer cells require to survive and proliferate. When c-Jun is overactive, it can act as an oncogene that triggers the formation of a cancer. They published their graphic results this year in the Journal of the National Cancer Institute (USA) – without publicity until now.

Last year they discovered another tool that stopped the growth of breast cancers in mice. The “magic bullets” developed in Sydney are DNA-based “designer enzymes” (DNAzymes) that act as scissors to cleave the gene product, switching it off in the cells. The results are dramatically visible.

The effects on cancers build on Khachigian’s previous finding that another gene, Egr-1, is “master regulator” of vascular abnormalities that cause cardiovascular illness. These observations have demonstrated the versatility and promise of DNAzymes for precisely attacking cells whose rapid growth normally leads to disease. Following success in mice and pigs, human trials are required.”

Clinical trial nevertheless

A human clinical trial with the DNAzyme Dz13 did indeed happen, despite UNSW being fully aware the preclinical data was manipulated and the drug didn’t work, except of side effects. The men in charge had namely solid financial conflict-of-interests, so it was decided not to scare away the patients by basically denying them the right to a proper informed consent. The Lancet made clear once again that they don’t give a flying toss about informed consent or basic research ethics as long as the university does the same.

The UNSW now stands accused of corruption, after it repeatedly rigged the misconduct investigations and even apparently misinformed the investigators, all to get their star scientist Khachigian acquitted. That farce is described in the recent Australian ABC news report, where the lawyer Elizabeth Lacey is quoted with:

“Complainants in this matter have been trying to raise the flag over so many years, and each time they meet the hurdles of the university saying ‘we’ve investigated ourselves and we’re fine‘, […]

An independent body simply must be given the scope to investigate what’s occurred and ensure that they have full access to all of the relevant documentation [and] all of the relevant research.“

4 of the 6 Khachigian retractions appeared in the zero-tolerance Journal of Biological Chemistry, another two were retracted by Circulation Research and Biochemical and Biophysical Research Communications (BBRC). The bigger problem however, as ABC mentioned, is that Khachigian’s “discoveries”, retracted for data manipulations, now entered a clinical stage. A clinical study on the drug’s safety was published in The Lancet, nine patients were subjected to Khachigian’s skin cancer drug Dz13 between September 2010 and October 2011, all based on falsified preclinical data. A follow-up trial was registered, then suspended. It might resume again any time.

The research integrity activist David Vaux of the Walter and Eliza Hall Institute in Melbourne tried to get that Lancet paper retracted because the clinical trial endangered patients, based on a falsified preclinical data and lacked proper informed consent. The journal however told Vaux to get lost. Several times. If it reminds you of The Lancet‘s refusals to retract fraudulent papers by Andrew Wakefield, Suchitra Sumitran-Holgersson and Paolo Macchiarini: yes, there is a pattern. Ethics count nothing, patients are a renewable resource, but doctors’ careers and journal’s impact factor must be protected at all costs.

This is the Lancet paper:

Eun-Ae Cho, Fergal J Moloney, Hong Cai, Annie Au-Yeung, Carlos China, Richard A Scolyer, Benafsha Yosufi, Mark J Raftery, Jason Z Deng, Stephen W Morton, Paula T Hammond, Hendrik-Tobias Arkenau, Diona L Damian, Douglas J Francis, Colin N Chesterman, Ross St C Barnetson, Gary M Halliday, Levon M Khachigian Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER) The Lancet (2013) doi: 10.1016/s0140-6736(12)62166-7

The study did not seek to cure skin cancer (everyone except the patients knew the drug didn’t work anyway), but it wanted to test drug tolerance, to justify further clinical trials and commercialisation. The Lancet paper reported seven adverse events, of which 5 were “mild”, 2 “moderate” and 3 “treatment related” (that, as reminder, is Khachigian’s own admission). As it turned out, the adverse effects were to be expected, and UNSW and the ethics review committee were warned about these. But not the patients.

A dud drug

The drug Dz13 is supposed to kill cancer cells specifically via the programmed cell death called apoptosis, at least this is what Khachigian and his UNSW colleagues claim. A study by Gozar et al Oligonucleotides 2008 however proved 5 years before the Lancet paper that the drug is just some non-specific poison without any involvement into apoptosis pathways. At the time when The Lancet paper was submitted for publication, Khachigian already had four retractions. JBC alone retracted 3 of his papers on 9 July 2010.

The retraction prompted Khachigian’s former postdoc Ying Morgan into action. She had the most extensive pre-clinical experience with Dz13 and discovered that it did not work in mice, and therefore was not suitable for clinical trials in humans, due to predictable absence of any benefit and possible adverse side effects. According to Morgan, Dz13 caused a “pneumonia lung” in mice, possibly as reaction to the phospholipid carrier substance used. In the end, same Dz13 carrier was used in the 9 human patients, while prepared under a regular tissue culture hood, and not under GMP conditions.

Morgan first alerted Khachigian about problems with Dz13 in 2007, predictably it did not stop him. She confronted Khachigian again in November 2009 and March 2010, where she requested that her name be taken off a manuscript submitted to Science Translational Medicine, because she had reason to believe the data therein was fabricated: 

“This matter is not only about this manuscript. Clinical trial is going to be start. Could you still recall, once you asked me “Ying, if you got BCC or SCC [basal or squamosal cell carcinoma, -LS], are you willing to go to Dz13 clinical trial?” and I answered to you very clearly “No”. If your relative were on this clinical trial, how would you feel?

Many people suffer and die from cancer. When people knocked my home door and rang my home asking for donation for cancer research, it seems knocking my heart and hitting my head. When I saw the news, people run Marathon for donation for cancer research, I felt my heart pumping fast.… I felt not peace and can’t sleep. Because, what I have seen is not right.

Because I believe this is very serious matter, should you bring this matter to the University and NSW Cancer Council to have totally independent review before the clinical trial?”

The paper was eventually published in 2012, as Cai et al Science Transl Med 2012, without Morgan, but with falsified data. It was titled: “DNAzyme Targeting c-jun Suppresses Skin Cancer Growth“, which basically served as preclinical proof-of-principle for The Lancet paper. But before that, Morgan brought the matter to the UNSW officials, up to the Deputy Vice-Chancellor (Research), Les Field, on 5 November 2009, and again with additional information in March 2010. Her accusations of data manipulation and cover-up were dismissed as baseless (see Field’s letter below), the clinical trial received its approval on 14 July 2010. In August 2010, Morgan contacted Field with additional evidence. There, she wrote:

“The DNZyme (Dz13) under the skin cancer clinical trial cannot be used in clinical therapy according to current patent status. I believe that it is not appropriate to precede the skin cancer clinical trial and I also believe that this is unethical. In addition, I have really concerns about the data and the results produced in the preclinical research”

Whistleblowers sidelined

In March 2010, another postdoc in Khachigian’s lab, Mary Liu, also submitted a formal written notification of research misconduct against Khachigian. Liu was coauthor on one of the retracted papers, Liu & Khachigian, JBC 2009, its retraction happened soon after, in September 2010. The former postdoc insists that UNSW never interviewed her and refused to say why her paper was retracted. Liu suspects that it happened after Khachigian submitted a falsified correction to the journal, behind her back.

But guess what? The Vice-Rector Field dismissed also Liu’s allegations, in a letter from 11 April 2011, and refused to appoint an investigative panel. However, he did reply to Morgan on 12 October 2010 (20 days after the first patient was injected with the drug, and 6 months after receiving her allegations), that in his view, there was a prima facie case for research misconduct, that, if proven would “have a serious consequence in that they have resulted in false information on the public record, and are underpinning a Phase 1 Clinical Trial”.

Field’s letter is labelled “confidential”, this is why I publish it in full below:

Conflicted investigation

As announced, Field involved the Dean of Medicine Peter Smith and the Deputy Vice-Chancellor (Academic) Richard Henry, the latter was tasked with establishing an independent external research integrity investigation against Khachigian and another suspect, Hong Cai, the first author of Cai et al Science Transl Med 2012. Which then proceeded to whitewash both Cai and Khachigian. Actually, the investigative panel led by Bob Williamson did find 7 instances of research misconduct, but the investigators were not allowed to call it as such. Instead, UNSW reclassified their findings as “academic misconduct”, and subsequently publicly reported in 2013 that no “research misconduct” was found in Khachigian’s work.

Now, it should be reminded that as a chemist without any medical qualifications, Field is not supposed to decide about clinical trial safety, even if he likes to do so. What helped him to green-light the trial despite misconduct evidence, was his chairmanship of NewSouth Innovations, the UNSW spin-off which owns the drug Dz13. This enormous financial conflict of interests also presumably prevented Fields from notifying the Human Research Integrity Committee (HREC) of Sydney Local Health District, which approved and oversaw the clinical trial. Field only did so in March 2011 (i.e. a year after Morgan’s second set of allegations, and when the trial was long since ongoing). Even then, Field did not directly inform the Chair of the HREC, Rob Loblay, no.

You know what Field did instead? He asked Khachigian to meet Loblay and to summarise the allegations which these nasty women postdocs raised against himself. To be fair, Loblay was perfectly eager to be bullshitted by Khachigian. Neither he nor his HREC ever challenged Khachigian’s version or undertook any efforts to interview the whistleblowers or to screen any evidence. Loblay also decided not to wait for the results of the misconduct investigation, exactly because its findings would scare away the trial participants. As Loblay himself explained in May 2016 (full letter here):

“it was not necessary for information regarding the allegation to be provided to the study participants. […] In this case, the HREC did not consider the allegation to be of sufficient substance to outweigh the risk of causing unwarranted anxiety, and no change to the information and consent documents was recommended.”

Misinformed patients

Now, nobody ever questioned that Khachigian’s preclinical data was problematic, what with the reused images and other falsifications. The big men all just assumed that none of that preclinical data fakery bore any relevance to the clinical trial, because they mate Khachigian explained it to them. After all, it is just some nameless cancer patients being injected with what two hysterical Chinese females say is an ineffective and potentially toxic drug. The business-minded gentlemen of UNSW however saw the financial potential of Dz13, and decided to hide the information from the patients. The Dean of Medicine Smith (who is apparently into Christianity, but not the compassion bit) explained in 2013:

“We felt the potential for DZ13 to help patients outweighed the risk and as I said, it was a phase 1 study starting at low dose, escalating the dose to see how well it was tolerated.”

Here you have yet another doctor saying the patient’s informed consent as defined by the Declaration of Helsinki and Australian National Statement on Ethical Conduct in Human Research, is for losers. Money and peer loyalty counts. Sod these cancer patients, they would soon die anyway and there are many more where these came from. As aside: a similar thing once happened in Germany, where a terminally ill cancer patient was misinformed and recruited to suffer miserably for a bizarre experimental tracheal transplant, and purely coincidentally, bled to death just weeks later. The scientists Heike and Thorsten Walles continued with experimentation and went on to have grants, professorships and books written in their honour.

The Williamson investigation into the manipulated preclinical data began in May 2011. As ABC reported, the two whistleblowers Morgan and Liu were largely sidelined:

“Two of the whistleblowers, who first raised the allegations, have told the ABC they felt they were not able to give a full and detailed account. […]

“I haven’t been interviewed and I was not able to put all my evidence about what happened to the panel,” Dr Morgan said ”

None of the three panel members had medical qualifications, after all, these people were supposed to investigate data manipulations in laboratory research, and not advise on clinical trials. There was the development biologist Williamson, the second panel member was a lawyer, and the only connection the third member had to relevant clinical research, was the fact that Brandon Wainwright was Associate Investigator on the $3mn Cancer Institute NSW grant which funded that same Dz13 clinical trial, with Khachigian as Chief Investigator. No, of course this is not a conflict of interest.

No wonder the UNSW declared:

“As part of their investigation, the independent experts were specifically asked to advise whether the matters being investigated gave rise to any concerns about the clinical trial that was underway. The Panel advised the University that the matters under investigation were not relevant to the clinical trial.”

'What is science for: societal gain or personal credit? Sabine Kleinert, @skleinert1 senior executive editor, @TheLancet an excellent critique of research integrity in the current research climate @UniofNewcastle pic.twitter.com/kzFl0qAJ3W

— Clare Butler (@clarebutler123) October 22, 2019

No research misconduct

The information was shared live with HREC, who were according to this letter continuously informed that UNSW wants the clinical trial to continue and does not expect any research misconduct findings to happen. In October 2011, the recruitment of patients for the clinical trial was competed. The participants signed an mis-informed consent, where they were denied information that the trial’s Chief Investigator was under research misconduct investigation, accused of having falsified the preclinical results for the very same drug they were about to receive.

The investigators were forbidden from finding any research misconduct, as Williamson told ABC. Hence, on 7 February 2012, Deputy Vice-Chancellor Henry who issued these orders, proudly announced:

“The Panel made the following findings:
1. There was no research misconduct on the part of Professor Khachigian.
2. There was no research misconduct on the part of Dr Cai
3. There was nothing to question the integrity of the data underpinning the
clinical trial.”

Henry’s letter is marked as “Strictly confidential”, and this is why I publish it here:

However, in August 2013 ABC reported that further clinical trials with Dz13 were suspended. UNSW top males went berserk, unable to deny that their dream of getting rich by abusing patients went tits up. With foam at their mouths, UNSW issued this statement:

“The next stage of the clinical trial, which was due to test the effectiveness of DZ13, was suspended by UNSW in July 2013 due to concerns regarding aspects of the science underpinning DZ13. The trial had yet to commence patient recruitment.

Patient safety is the University’s top priority. The decision was made to err on the side of caution until concerns regarding some of the science underpinning DZ13 have been resolved. It should be stressed that these concerns do not relate to either the conduct of the trial or to the safety of the DZ13 compound.”

3 in a row for Lowy! Prof Levon Khachigian #genius just won the award for excellence in translational cancer research! Well done Levon!

— Childrens Cancer Institute (@KidsCancerInst) May 21, 2010

Khachigian has been suspended for over two years, on full pay of course. Also temporarily suspended were his grants, worth $8mn, as ABC reported. On 15 May 2015, university’s suspension against Khachigian was lifted, and the grant money started to flow again. Maybe UNSW assumed that the affair is forgotten and the suspended clinical trials with Dz13 can resume. They already smelled the money, hence UNSW reminded everyone:

“No finding of research misconduct was made in relation to Professor Khachigian.The investigations found that there had been breaches by Professor Khachigian of the UNSW Research Code but that these breaches were the result of genuine error or honest oversight, not deliberate or intentional conduct. The experts also found that the scientific conclusions in relevant published material were unaffected by the errors which were minor. The panels noted that Professor Khachigian did not fail in his supervisory responsibility and had mechanisms in place to ensure the accurate recording and reporting of original data and had procedures in place to avoid error.”

All of that was actually a lie, especially the bit about accurate recording of original data. While UNSW was busy with washing Khachigian’s feet as if he was Jesus, the journal Circulation Research retracted in January 2016 his paper Tan et al 2009 for data manipulation, with this notice:

“UNSW was unable to locate any electronic record of the original images and was unable to locate any records of the images in original lab books.”

Money has an intoxicating effect, maybe this made UNSW’s men of power fantasise about all that original data which obviously never existed. JBC retraction notice from December 2018 for Ni et al 2010 confirmed again that UNSW lied to everyone:

“the Journal raised questions regarding Figs. 1A and 5B, which the authors were not able to address as the raw data were no longer available.”

Research integrity—have we made progress? This week's editorial: https://t.co/QK78paFjig #WCRI2017 pic.twitter.com/6W6IH8Rtab

— The Lancet (@TheLancet) May 5, 2017

Lancet is angry!

Faced with such attitude from UNSW, Vaux alerted The Lancet in August 2015. But The Lancet did not want to be alerted. Senior Executive Editor Stuart Spencer asked Vaux on 5 September 2015 to please go away:

“The editors have discussed this a number of times. After due consideration we do not feel that there is sufficient doubt over the ethics to warrant a retraction of the paper. Our recommendation, at this time, is that you ask the University of New South Wales to consider their position on this new issue. We do not have sufficient knowledge of specific timings, processes, ethics committee discussions and consent forms. These are more readily available to the University and it more appropriate that they deal with adjudicaton. If the University approaches us with a decision that this was unethical we can look at the issue again.”

Spencer however announced that The Lancet will discuss it with the Committee on Publication Ethics (COPE), the Editor-in-Chief Richard Horton is namely the founding member of that council. On 12 April 2016 Spencer, signing with “The Lancet”, warned Vaux not to bother them ever again:

“The advice of Council was quite clear; you should continue to take up the matter with the University authorities. Unless further evidence comes to light which causes the University to change its position and inform The Lancet of this, we consider the matter closed and will not enter into further correspondence.“

Doesn’t this remind you how COPE advised Horton to stay strong and not to believe all that slander about Paolo Macchiarini? Vaux contacted in October 2017 Lancet‘s Ombudsman, Malcolm Molyneux, Emeritus Professor at the University of Liverpool. On 9 April 2018, Molyneux asked Vaux again to stop pestering important people with his boring concerns about some obscure patients and silly ideas of informed consent:

“I have examined the comprehensive series of documents you have helpfully provided about Prof Khachigian.  In particular I have considered your request for retraction of the above publication in The Lancet of 2013. I have noted the lengthy series of panels and investigations into many aspects of Prof Khachigian’s work, and the retractions of several other papers.  These are important when considering the particular issue of the Lancet publication referred to above.
My conclusion is that, while much else remains to be resolved in this ongoing investigation, the issues relating to the Lancet publication, while recognised and understood, do not amount to grounds for retraction of the paper.
I am grateful for your extensive work in providing documents and discussion, but  please consider this correspondence now closed.“

The whole story is very reminiscent to the trachea transplant affair at UCL, in London. Also there, all requests to retract a fraudulent Lancet paper authored by Macchiarini and his UCL colleague Martin Birchall were rejected, by the journal and by the university, despite proven data manipulations and absence of proper informed consent. Also at UCL, investigations into manipulations of preclinical data found honest errors only, because the university wanted the clinical trials had to continue. Only that UCL’s failed technology is not just useless, it actually kills, as both UCL and The Lancet know perfectly well, and do not mind.

Maybe this is why Khachigian’s case barely raises an eyebrow?

Paolo Macchiarini is not guilty of scientific misconduct | Editorial http://t.co/ZQV2jR8sWK pic.twitter.com/pNNAJIeKJL

— The Lancet (@TheLancet) September 4, 2015

---