BLOGSCAN - More About Methodologic Flaws in Targeted Genetics Trial

We have posted a few times about an ill-fated trial of a gene therapy treatment. To summarize the case thus far, a young woman received a dose of an adeno-associated virus carrying a gene that was meant to have a local immune suppression effect, tgAAC94, made by Targeted Genetics, directly into her joint as part of a phase I study meant to assess the safety of the treatment. Soon after the treatment, she became ill, then very ill, and ultimately died in an intensive care unit. Although many flaws in the trial were identified in retrospect, and although there was no proof one way or the other whether the treatment was related to the patient's death, the trial was just allowed to resume (see most recent post here). This post by Dr Chris Evans on the Bioethics Forum identifies yet more methodologic problems with the trial, further challenging the wisdom of resuming it without substantial modifications.

Post Title → BLOGSCAN - More About Methodologic Flaws in Targeted Genetics Trial

No Questions Answered, but Targeted Genetics Gene-Therapy Trial to Resume

We previously discussed, most recently here, the unfortunate and unexplained death of young patient after an injection of an experimental gene-therapy agent. To summarize the case thus far, a young woman received a dose of an adeno-associated virus carrying a gene that was meant to have a local immune suppression effect, tgAAC94, made by Targeted Genetics, directly into her joint as part of a phase I study meant to assess the safety of the treatment. Soon after the treatment, she became ill, then very ill, and ultimately died in an intensive care unit.

Whether the treatment had anything to do with her illness and death were initially unclear. A hearing by the US National Institutes of Health (NIH) Recombinant DNA Advisory Committee did not reach any conclusions about what caused the patient's death. (See post and here.) The NIH panel "said it was too early to conclude that the gene therapy had not been a factor, perhaps by suppressing ... [the patient's] immune system," (per the International Herald Tribune.) I should also note that even apparently innocuous viruses sometimes are not. The US Center for Disease Control (CDC) recently warned of cases in which people have died after infection with a type of virus, a type 14 adenovirus, that usually just produces a mild upper respiratory infection.

Nonetheless, now the US Food and Drug Administration (FDA) is allowing Targeted Genetics to restart the trial. The company's CEO, H. Stewart Parker, is claiming "this is a vindication for the product, the company and the field of gene therapy," (per Bloomberg News. There is a similar quote in a Seattle Times article.)

The study will apparently resume with many of its previously identified problems unaddressed. Questions were raised about the conduct of the trial, including:

• whether the patient was lead to believe she might benefit from it, even though the study was meant only as an initial, Phase I, safety assessment;
• whether she was influenced to participate because her rheumatologist was an investigator, and he administered the informed consent form, without disclosing he was paid to participate in the trial;
• whether she found the consent form understandable;
• what institutional review board (IRB) reviewed the trial; and
• whether Targeted Genetics unduly delayed reporting the patient's condition to the US Food and Drug Administration (FDA)?
  

None of these questions have yet been answered, However, Per the Washington Post,

Kyle Hogarth, an intensive-care unit physician at the University of Chicago who cared for Mohr and was involved in the investigation, said yesterday that he feels reasonably certain that the treatment did not kill her. But he is still bothered by the study's design, he said, because it allows participants to keep taking prescription medications that cannot be distinguished from the immune-suppressing protein made by the treatment's gene-modified viruses.

That makes it impossible to fully sort out whether problems that arise during the experiment may be caused by the treatment or the drugs the subjects are taking, he said.

Although conventional arthritis medications can, on rare occasions, make patients especially susceptible to fungal infections, Hogarth and others have questioned whether the gene treatment left Mohr especially defenseless.

'I think they have a horrible design,' Hogarth said. 'It muddies the picture.'

Hogarth also echoed a concern raised by others in the course of the investigation: that Mohr was recruited into the study by her personal physician, who stood to profit from each new patient he enrolled. Medical ethicists have criticized such arrangements as posing a potential conflict of interest.

So, what is the big hurry to resume this trial? We still don't know whether the trial intervention was responsible for the death of a patient who, although she had arthritis, appeared nowhere near chronically ill enough so that her death was expected. The treatment has no claim to be life saving, or likely to be so much better than old treatments that it is worth facing a risk of death to take it. The trial is already known to have multiple design defects. I fear that the hurry is generated, as we said before, by the belief held by many people involved with this trial that their new treatment was safe in the absence of much evidence one way or the other. Such a belief may have partly been influenced by their vested interests in their product's success. As Osagie K. Obasogie wrote, "It's also about how profit motives embedded in the clinical trial process can undermine patient safety."

Post Title → No Questions Answered, but Targeted Genetics Gene-Therapy Trial to Resume

The tgAAC94 Study Consent Form: Raising More Questions than it Answered

We previously posted, most recently here, about the unfortunate case of a young woman who died after participation in a Phase I safety study of a gene-therapy agent for inflammatory arthritis, tgAAC94, made by Targeted Genetics.

An astute comment on our last post directed me to the actual consent form for this study, available here, courtesy of Citizens for Responsible Care and Research. Review of the form, coupled with what is already available from the media about this case, (see discussion in previous post and links backward), raised even more questions about this benighted human experiment. These included questions about what was in the form, and what the form left out.

Did the Consent Form Exaggerate the Safety of the Treatment?

The consent form included various statements that seemingly were meant to persuade study subjects that the treatment was safe, even though the treatment's safety was unknown, and the ostensible purpose of the study was to test its safety.

First, it included statements in the "Study Agent" section that seemed to suggest that the adeno-associated virus (AAV) which would transfer the gene was innocuous:

AAV infects many people in everyday life, but does not cause disease in humans. Although tgAAC94 was modified from AAV, tgAAC94 cannot grow in your body because all the AAV genes, including those that it needs to grow, have been removed.

Then, the "Risks, Hazards, and Discomforts" section seems to contain multiple arguments why the treatment may be safe, which took more space than discussion of its possible hazards.

It noted that the AAV vector (without the gene for etanercept) could produce an "immune response," but this causes "no side effects" in previous studies.

Targeted Genetics Corporation has used AAV to introduce genes into 200 people. These included about 140 subjects with a genetic disorder called cystic fibrosis (CF) who received does of a similar AAV vector into the nose, maxillary sinus, and lung, and about 65 healthy volunteers who received an injection of a similar vector into the muscle in an HIV vaccine study. Some subjects administered the highest doses developed an immune response. This immune response consisted of elevated proteins that interact with AAV in the blood. No side effects related to the development of this immune response have been noted so far.

Later, it tried to minimize the relevance of reports that high doses of AAV could cause cancer in animals.

The U.S. Food and Drug Administration (FDA), which oversees clinical studies of investigational drugs in the United States, was made aware of an animal study where [sic] a number of newborn diseased mice injected with very high doses of an AAV vector developed liver tumors. This was a research study using an AAV vector that was not designed or produced for human use. The vector used for the mouse study did not contain the TNFR-Fc gene and it was not designed to treat inflammatory arthritis. Tumors have not been observed in other similar studies of different types of mice injected with higher doses of AAV vectors and watched for over a year. There have been no reports of tumors in the limited number of human subjects who have received an AAV vector. Tumors have not been reported in any other animal studies of AAV vectors, but the number of studies that have been done so far is small. It seems unlikely that the tumors are linked to the AAV vector, but we do not know for sure.

It reported that injection of tgAAC94 appeared safe in animal studies:

A single dose of tgAAC94 has been injected into the joints of both rats and monkeys without raising any safety concerns. A single dose of a different AAV vector, containing the rat version of TNFR-Fc, has also been injected into the joints of rats with arthritis without causing any problems.

It noted that tgAAC94 had been given to small numbers of people without ill effects.

A single injection of tgAAC94 has been given to the joint [sic] of approximately 10 humans in another study of tgAAC94 without raising any safety concerns.

It noted that repeat injections of tgAAC94 given to animals only produced mild side-effects.

Repeat injections of tgAAC94 into joint have been given to rats once a month for three months. After the second injection of tgAAC94, approximately 20% of the rats developed mild swelling to the joint [sic] that resolved after a few days.

Only at the very end were there these two sentences.

There may be other not-yet-identified side effects that could occur during the time you participate in the study or years after receiving the study agent. Unknown side effects could be mild, serious, or life-treateneing, and could result in pain, discomfort, disability, or, in rare circumstances, death.

Thus, much of the ostensible discussion of possible adverse effects of the treatment consisted of arguments that the treatment was safe, again, made before any safety data had been collected. This seems particularly inappropriate for a study designed to assess the safety of treatment.

Did the Consent Form Imply that Patients Would Benefit from Study Participation?

The study was ostensibly only meant to test the treatment's safety, not its benefits. Whether the treatment has any benefits for humans has never been assessed.

However, the "Study Agent" Section included,

By injecting tgAAC94 directly into an affected joint in your body (called the target joint), we hope it will help the body make a protein that stops the inflammatory process and reduces the progressive joint destruction and resulting disabilities associated with inflammatory arthritis.

Furthermore, in the "Risks, Hazards, and Discomforts" section are statements that, rather than relating to the agent's possible risks, seem to draw parallels that argue for its effectiveness.

The gene that is transferred to the body codes for a protein that is the same as the approved medication called etanercept or Enbrel. Etanercept has been given by an injection under the skin to many people with inflammatory arthritis with remarkable improvement in their symptoms.

It also included a statement about use of a gene transfer therapy for rats,

The arthritis in these rats seemed to improve.

Thus, the consent form clearly contained arguments that the treatment could be beneficial, even though its benefits had never been assessed. Furthermore, some of these arguments were interspersed through a section of the consent form that was supposed to discuss possible adverse effects of the treatment, possibly distracting the reader.

Could A Research Subject Understand the Form?

The form contained numerous scientific terms and used technical jargon. It is not obvious that participants who were not familiar with biology or medicine could understand most of it.

The form also raised questions about what it did not include.

Who Actually Designed and Implemented the Study?

The form did identify the study's sponsor, i.e., the organization that paid for the study to be done, as Targeted Genetics Corporation.

The version of the form available on the CIRC web-site listed the study investigator as Robert G Trapp MD, with an address in Springfield, Illinois, and gave a 24 hour phone number for him. It identified the study site as the Arthritis Center, at the same address. Dr Trapp appeared to be one of the physicians enrolling patients, and the Arthritis Center appeared to be the name of his practice location. The form did not identify Dr Trapp as the Principal Investigator, i.e., the person in charge of the whole study. Apparently, his role would be that of "research doctor," a term used frequently later in the form. It is possible that different versions of the form used at other sites identified other "investigators."

However, the form was silent about who was in charge of the study, who designed the study, or who would implement the study. In general, clinical research studies have a Principal Investigator, or perhaps two Co-Principal Investigators, who take responsibility for the design, scientific conduct, analysis, and dissemination of the study. Furthermore, clinical research studies are generally carried out by study teams, or could be based at a medical school, research institute, teaching hospital, or contract research organization (CRO).

The form, in fact, did not identify anyone as the Principal Investigator, or anyone other than Dr Trapp as being involved with the study. It did not explain who had designed the study. It did not mention who would carry out the study, for example, by collecting data, ensuring that patients had appropriate follow-up, entering data, analyzing data, writing up results, etc.

The form did identify the Institutional Review Board (IRB) which reviewed the study and the consent form itself as the Western Institutional Review Board (WIRB), stating "WIRB is a group of people who perform independent review of research." This statement seems disingenuous, since WIRB is also a profit-making company (see Emanuel EJ, Lemmens T, Elliott C. Should society allow research ethics board to be run as for-profit enterprises. PLoS Med. 2006 July; 3(7): e309. DOI:10.1371/journal.pmed.0030309).

Thus, although the form identified the "investigator" who would be the study subject's first point of contact with the study, it failed to identify all the other people who were doubtless involved in designing, and carrying out the study, and failed to identify anybody who had ultimate authority for the design and implementation of the study.

Summary

It seems the more we learn about this case, the less we realize we know. There have been questions all along about the appropriateness of the consent form and how it was presented to potential study subjects: whether it de-emphasized possible risks, hinted at benefits that may not exist, and was written and administered in a way that was not conducive to somber consideration by potential research subjects.

Now, it seems that the identities of the people who actually designed, controlled, and implemented this study are mysterious as well. I do not understand how experimental research can be done on humans without telling the research subjects who is actually responsible for the experimentation to be done on them. Furthermore, these identities remain mysterious even after a well-publicized NIH hearing on the fatal outcome of this study. I also do not understand how an official government hearing on this project did not involve, nor reveal, who these people were.

Perhaps some investigative reporting will solve some of these mysteries.

Meanwhile, this troubling and now too mysterious case should cause patients, physicians, and policy makers alike to re-consider whether we should continue to allow experimental testing of drugs or devices on humans to be done by those with vested interests in the success of the drugs or devices being tested.

Post Title → The tgAAC94 Study Consent Form: Raising More Questions than it Answered

An NIH Hearing About the Death of a Patient in a Gene Therapy Trial

We previously discussed, most recently here, the unfortunate and unexplained death of young patient after an injection of an experimental gene-therapy agent. A US National Institutes of Health (NIH) committee, the Recombinant DNA Advisory Committee, just conducted a hearing about the case, which received considerable media coverage. The coverage did illuminate a few more important details, although much about the case remains mysterious.

To summarize the case thus far, a young woman received a dose of an adeno-associated virus carrying a gene that was meant to have a local immune suppression effect, tgAAC94, made by Targeted Genetics, directly into her joint as part of a phase I study meant to assess the safety of the treatment. Soon after the treatment, she became ill, then very ill, and ultimately died in an intensive care unit. Whether the treatment had anything to do with her illness and death were initially unclear. Questions were raised about the conduct of the trial, including

• whether the patient was lead to believe she might benefit from it, even though the study was meant only as an initial, Phase I, safety assessment;
• whether she was influenced to participate because her rheumatologist was an investigator, and he administered the informed consent form, without disclosing he was paid to participate in the trial;
• whether she found the consent form understandable;
• what institutional review board (IRB) reviewed the trial; and
• whether Targeted Genetics unduly delayed reporting the patient's condition to the US Food and Drug Administration (FDA)?

The key points from the hearing, as reported by the New York Times and Washington Post, were:

• The patient died apparently from a massive histoplasmosis (fungal) infection, possibly complicated by major internal bleeding
• The patient was also taking "Humira, a drug similar to Enbrel that has also been linked to infections, including histoplasmosis. She was also on two other immune-suppressing drugs." [Times]
• The genetically engineered AAV had spread to her liver and spleen, although the President of Targeted Genetics said the the levels of the virus were "tiny"
• The patient did not appear disabled or seriously ill from arthritis before entering the trial, her "husband, Rob, told the panel that his wife was only mildly affected by her arthritis and was not properly warned of the experiment's risks." [Post]
• The panel was concerned "about the way his wife was signed up for the study. They noted that, although no regulation prohibits the practice, it can be ethically problematic when a patient's personal physician recruits the patient.... Patients routinely overestimate the chance that an experimental treatment will help them, and this 'therapeutic misconception' is even more likely when the recruiter is the patient's personal doctor...." Also, her "physician also signed her up immediately, rather than having her take the materials home to consider.... And there was no mention in the informed consent document that her doctor was being paid by Targeted Genetics for every patient he enlisted." [Post]

In my humble opinion, the main achievement of this meeting was affording a potentially important case more publicity. To me, the major questions remain: what relationship, if any, was there between the experimental therapy and the patient's illness and death; would changes in the conduct of experiments like this, particularly involving informed consent, lower the probability of future tragedies?

The larger question is whether companies and other organizations should be sponsoring and controlling research on human beings when the companies and organizations have financial (or ideological) stakes in the outcome of the studies?

Targeted Genetics employees seemed to be taking a persistently optimistic view about the role of their treatment in this case. Note the comments above of the President minimizing the importance of admittedly preliminary data showing that the AAV had spread beyond the joint into which it was injected. Furthermore, in a Seattle Times report, a company spokesperson also asserted that the virus was "unlikely" to have been related to the patient's death, and that the data so far was "very positive." Of course, when one's job and company's financial future depend on a particular interpretation of the science, one is likely to support that interpretation.

ADDENDUM (20 September, 2007) - The consent form for this study is apparently available on the web here. See first comment below. It appears to raise more questions than it answers. Stay tuned.

Post Title → An NIH Hearing About the Death of a Patient in a Gene Therapy Trial

More Details and Concerns About the Death of a Gene-Therapy Patient

Details continue to come out about the death of a woman who was participating in a gene-therapy trial of an agent made by Targeted Genetics meant to treat joint symptoms of rheumatoid arthritis. We posted about the case here and here.

Almost two weeks ago, the Seattle Times reported on the company's response to initial news stories about the case.

Chief Executive H. Stewart Parker said in an interview that the company has always applied 'the highest rigor in clinical trials' and that it behaved properly.

The company said it reported the incident to the FDA 'within 24 hours' of determining that the patient's illness was possibly related to the drug. A chronology released by the company shows that occurred 18 days after the patient was injected, in the wake of her admission to a hospital.

Staff at the hospital where Mohr was being treated was the first to alert the FDA, Parker confirmed in the interview.

Targeted Genetics said the patient received a second dose of the arthritis therapy on July 2. On July 10, the company learned that she and another patient suffered nausea, fever and vomiting. The other patient recovered, but Mohr was hospitalized on July 13. The clinical investigator thought it unlikely that the symptoms of both patients were related to the drug, the company said in a statement.

On July 17, the investigator told the company that Mohr's condition 'was deteriorating,' but that it was unrelated to the therapy. The next day, Targeted Genetics notified the chairman of the independent data safety-monitoring board that supervised the study, and on July 19 determined that the incident was possibly related to the therapy.

On July 20, the company informed the FDA.

Last week, the Washington Post reported more details about the demise of the patient.

The 36-year-old Illinois woman who died last month after being treated with an experimental gene therapy was infected with a fungus that usually causes only a mild illness. But the infection spun out of control and ravaged her organs, suggesting that her immune system was seriously impaired, said a doctor who is part of the medical investigation.

The woman's body was also teeming with a cold-sore virus that the body normally keeps in check, another indication of a faltering immune system. And because of a tear inside her abdomen -- perhaps caused by infection, perhaps by injury -- she had an internal blood clot the size of a watermelon.

The picture will be complicated, however, because Mohr was also taking conventional immune-suppressing drugs for her arthritis. One of those in particular, adalimumab, whose brand name is Humira, is known to make patients susceptible to histoplasmosis, the kind of fungal infection that Mohr had. Inexplicably, Mohr suddenly became ill in July even though she had been taking that drug for years and the fungus that causes histoplasmosis is ubiquitous in the area where she lived.

Meanwhile, a columnist in the Seattle Post-Intelligencer wondered about the implications of the case.

Those tragedies reflect one of the more troubling regulatory failures in the U.S. health care system: the inability to develop sensible and enforceable rules to oversee a growing biotech industry that is using humans to test what it hopes will become the next big moneymaker -- all without having much of a clue as to gene therapy's long- or short-term impacts.

When a federal committee charged with reviewing gene therapy trials evaluated Targeted Genetics' arthritis study in 2003, members openly questioned its justification, as it involved patients who were not very ill and evidence from animal studies didn't seem all that promising. They also worried it could trigger dangerous immune responses and questioned the informed consent documents' clarity. But as they have no binding authority or enforcement powers, Targeted Genetics was free to continue as it saw fit.

But this isn't simply about regulatory failure. It's also about how profit motives embedded in the clinical trial process can undermine patient safety. Pharmaceuticals had the fifth-most profitable return on revenues of any industry in 2006; the top five drug companies took home close to $30 billion in profits. Such companies as Targeted Genetics hope gene therapy and other biotech products will help them tap into and expand those markets. To be sure, Targeted Genetics CEO H. Stewart Parker told the P-I in 2005 that arthritis treatment could be 'a $7 billion market ... by 2011' and that the gene therapy used in the clinical trial that may have led to Mohr's death might help the company capture '15 percent to 40 percent of that opportunity.'

Time is money; in the rush to get products to market, patient safety can inadvertently take a backseat. And the fact that Targeted Genetics doesn't currently have any products on the market suggests that it has a significant financial incentive to stop hemorrhaging cash -- financial reports indicate it has lost $8 million this year alone -- and do everything possible to quickly get its products out of the clinical trial phase.

Time will tell whether gene-therapy caused this death. It very well may not have.

However, in my humble opinion, the most troubling aspect of this case so far is how people involved with this trial seem to have believed that their new treatment was safe in the absence of much evidence one way or the other. In particular, they seemed to persist in their disbelief that the new treatment could have had anything to do with the patient's unexplained rapidly deteriorating condition. Why were they so confident that their new treatment could not have been responsible?

This treatment was not merely new, it was a new variant on a broad class of new treatments, genes delivered by viruses, which are not yet in clinical use because no treatment in this class has been proven safe and effective. Furthermore, a few previous attempts at gene-therapy have produced very bad results, most notably in the unfortunate case of Jesse Gelsinger. Thus, one would expect that people setting up a new trial of gene-therapy would be properly cautious, and concerned that the new treatment might have unanticipated kinds of risks.

In my humble opinion, it is all too possible, as suggested by the op-ed above, that financial concerns have pushed manufacturers, researchers, and physicians into believing that the new treatments they are developing just have to be safe and effective.

This is another argument that clinical research, that is, experiments on humans to evaluate new tests or treatments should not be designed, implemented, or reported by people who have a financial stake in the success of the product bying evaluated.

Post Title → More Details and Concerns About the Death of a Gene-Therapy Patient

More Unfortunate Details About Targeted Genetics' Fatal tgAAC94 Trial

Rick Weiss in the Washington Post just published a follow-up report on the death of a study participant in an early phase trial of gene therapy for (apparently inflammatory, probably rheumatoid) arthritis. We had first posted about this here.

In summary, the trial was of tgAAC94, a transgene encoding the receptor for tumor necrosis factor (TNF)-alpha, a cytokine that causes joint swelling in arthritis patients, made by Targeted Genetics. The trial used a viral vector injected directly into an arthritic joint. An NIH review panel that first considered the trial was worried that the new treatment was to be given to not very sick patients, and that the virus could escape from the joint into which it was injected and cause systemic problems.

Oddly enough, Targeted Genetics had bought out Genovo, the company whose gene therapy was associated with the death of a patient in Pennsylvania in 1999.

The new Washington Post report revealed some detail about the death in the tgAAC94 trial.

[The patient] had been feeling fine just a few weeks earlier, save for occasional stiffness from her arthritis.

[The] first shot, administered on Feb. 26, had no noticeable effect, and she wondered whether she got the placebo. But she was excited that the next one would be the real thing....

That happened on July 2, a Monday. She was tired and out of sorts after a weekend of boating with her husband and daughter....

[Her physician] recorded her temperature at 99.6, then gave her the shot.

'The next day she woke up and didn't feel good at all. By afternoon she started vomiting,' [her husband] ... recalled. 'By evening her temperature had shot up to 101.'

She spent July Fourth feverish and vomiting. Her family physician told her it was probably just a virus.

When her symptoms worsened and her temperature hit 104.1 on Saturday, she went to the emergency room. Tests indicated a possible infection and signs of liver damage, but she was sent home for more care from her family doctor....

But [she] ... only got worse, and on Thursday she was admitted to the hospital.

Things went downhill fast, with [her] ... body showing signs of being ravaged by an infection. But tests for standard bacteria and viruses came up negative. With breathing problems and the possibility she might need a liver transplant, she was transferred to the University of Chicago hospital.

[Soon she] was breathing with the help of a ventilator in a Chicago intensive care unit -- her body bloated from internal bleeding, her liver failing -- and no one could figure out what was wrong with her.

Three weeks after ... the injection that she had hoped would cure her, she was unconscious and beyond hope of recovery. With family and friends gathered around, her life support was removed.

Furthermore, the Washington Post article documented a series of problems with how the trial of tgAAC94 was done.

1) The study was presented to the patient as if it possibly could help her clinical condition, even though it was only a Phase I study designed to assess toxicity.

'It was presented to her like this is going to make her knee better,' said [her husband.]

Further in [the study's consent form], after long descriptions of how the product may help, a single sentence states: 'We do not expect you to receive any direct medical benefits from participation in this study.'

2) The patient was persuaded to enter the study by her rheumatologist, Robert Trapp, who was paid by Targeted Genetics to recruit patients, and who administered the consent form to her without giving her an opportunity to take it home and think it over.

Her rheumatologist, [was] Robert Trapp, whose Springfield clinic got payments from Targeted Genetics for each subject he recruited....

Trapp, one of 20 U.S. doctors testing tgAAC94, invited her to join the study on Feb. 12.

There would be two injections, months apart, he explained. The first might be real, or it might be a placebo, but the second would definitely be the test product. She signed up immediately, and Trapp drew several tubes of blood to get the study going.

Two fundamental rules of clinical research were violated that day, experts said. First, consent forms are to be taken home and considered, not signed on first sight. Second, when a patient's own doctor is a principal investigator in a study, someone else is supposed to make the proposal.

3) A lay-person would have found the consent form difficult to understand.

Jonathan Moreno, an expert in the ethics of medical experiments at the University of Pennsylvania, said the consent form used by Targeted Genetics to outline the drug's potential dangers was thick with technical descriptions and thin on explaining 'what's really going to happen.'

'Even a smart person would have a very hard time figuring out what they're talking about,' said Moreno, who examined the form at the request of The Washington Post.

4) The consent form and apparently the whole trial were approved by a not yet identified for-profit institutional review board.

The form was approved by one of the growing number of for-hire review boards that contract with biotechnology companies to ensure studies meet patient-protection standards. Targeted Genetics noted that the review firm it used is accredited and accepted by the FDA. But the use of private boards, as opposed to those run by universities or government agencies, has raised alarms among some medical ethicists since a for-profit review board risks losing repeat business if it is too tough on its clients.

Note that it is not yet clear whether Targeted Genetics directly administered the trial, or whether it was run by an academic institution, or a contract research organization.

5) Targeted Genetics delayed reporting of the patient's illness to the US Food and Drug Administration (FDA).

But Targeted Genetics and Trapp had at first classified the problems as not serious, and later classified them as serious but unrelated to the treatment. So no FDA report was made, and the study went on, with other volunteers unaware of the problems.

Finally, on July 20, a day after Mohr's emergency transport to Chicago and four days before she died, the company sent a serious adverse event' report to the FDA and suspended the study, conceding that her life-threatening symptoms were "possibly" due to the treatment.

In summary, it is too soon to tell if the patient died as a direct result of the gene therapy. It is also not clear whether any of the problems with how the research was designed and conducted were at all related to her death.

However, this tragic case does once again illustrate that commercially funded research is often not designed and carried out as well as it should be.

Furthermore, problems in research design and operation tend to favor the vested interests of the research sponsor. For example, regarding Targeted Genetics delayed reporting of a research participant's serious illness,

That reflects a widespread problem in clinical trials, said Adil Shamoo, a professor at the University of Maryland School of Medicine and editor in chief of the journal Accountability in Research.

'There are no uniform standards for 'adverse events' reporting,' Shamoo said. 'And there is no motivation to report them. . . . No one wants to show their dirty linen.'

Dirty linen can drag down a company's bottom line, and Targeted Genetics, like all companies, puts a lot of work into keeping that line afloat. An interim report on tgAAC94, for example, spoke in June of 'very encouraging results' and evidence of 'clinical benefit,' although, by one measure the company considered key, patients who got high, medium or low doses of the drug did the same as those who got placebos.

'The company was talking about lucrative markets and a promising product much too soon,' said Marcy Darnovsky, associate executive director of the Center for Genetics and Society, an Oakland, Calif.-based public interest group that focuses on genetic technologies.

This is another vivid and very unfortunate case that raises questions whether commercial firms should sponsor, run, or even just influence clinical research designed to test their own products.

Hat tip to the WSJ Health Blog.

Post Title → More Unfortunate Details About Targeted Genetics' Fatal tgAAC94 Trial