Thinking about going to ACRP in 2012? A recap of ACRP 2011

Reflecting now on ACRP 2011 several months later, I wanted to share some of the valuable insights I gathered there. ACRP 2011 was an excellent conference, with more than 2100 attendees. Topics were wide-ranging, from business and finance to global challenges and ethics. As with many conferences, my major difficulty was choosing among the numerous offerings running concurrently. Here is a sampling from those I attended.

Carmen Gonzalez held a session as lively as she is, “La Sangre Latina: The New Force in Study Participation,” with many tips to helps you boost enrollment and retention of Latinos. Her surveys have shown that “Latino study participants are three times more likely to be unemployed, uninsured, or on Medicaid than U.S. averages for Latinos.” As a result, 82% of the participants, who are also more likely to be uninsured, did so just to access basic care for their chronic illnesses. Among other strategies, I learned that word of mouth from friends and Spanish language TV are particularly effective recruitment tools in Latino populations and that social media is less effective.

Given the economy, we’ll undoubtedly see more people volunteer for basic care, which presents troubling ethical issues. For example, some people may lie about their level of drinking, or past medical history, so as to meet inclusion-exclusion criteria. Others might take risks that they wouldn’t have under less trying conditions. As a Principle Investigator, I’ve always tried to be very attuned to my volunteer’s motives and understanding of risks, and even not to offer a study if I have concerns about it not being good for the volunteer.

Now that many trials are now being outsourced, I also attended several offerings on clinical trials in developing countries. Issues of ethics were again a significant focus, along with cultural sensitivities. There were good discussions of related questions: Are there different values? Who makes decisions? Are there benefits to the larger community? What is the impact of introducing new technologies or drugs that may not be available or affordable after a trial ends?

Fabio Thiers put a new twist on globalization. He had effective visual displays illustrating changing patterns in research activity globally, broken down by the type of indication. For example, CNS studies are increasing in the US, while cardiovascular and oncology trials and decreasing their US sites. The acceptability of placebo arms varies strikingly by countries and is generally the least accepted in France and Germany. All of these factors can help both sites and sponsors plan more effectively to remain competitive in the global market. The global industry trend is to have R&D be more visible and standardized, via registries, SOPs, and processes across sites.

Trials in India drew significant interest amongst attendees. While there are huge numbers of treatment-naïve patients, regulatory hurdles are major downsides; multiple agency approvals are required, and there can be difficulties over drug and supply imports as well. Getting a broker to navigate these supply problems and meet regulatory requirements is vital. The increased negative press attention over ethical issues and “slumdog trials” is shifting the placement of clinical studies away from India. So, too, are the ongoing fights between major multi-national pharmaceutical companies and small Indian generics manufacturers, centering around patent disputes. Immediately after the ACRP conference, I spent several weeks in India. While not directly involved in clinical studies there, the trip gave me the opportunity to meet with people and see first hand some of the logistical difficulties of conducting clinical trials in India.

According to Thiers, the EU is the big winner in the bid for attracting clinical trials. The EU is showing the most clinical research growth, projected to reach 46% of world market within a few years. India is not attractive for upcoming HIV trials, as they require the subjects to have been on other anti-retrovirals. On the other hand, Brazil is making a strong showing for HIV trials, given a baseline high level of care.

The globalization of trials can lead to confusion, as well as to added logistical hurdles in obtaining drugs, in the shipping of specimens, and of the reporting of labs in a timely and consistent fashion. For example, SAE reporting requirements are different under ICH than by the FDA; everything needs to be carefully spelled out so you are compliant with the regulations.

One welcome change in clinical trials is that studies of seniors are gaining in importance—for many of my trials, being older than 65 was an exclusion. This is, thankfully, changing. But you have to choose your words carefully here, so as not to offend by calling someone “old” or “elderly” when that doesn’t fit their self-perception. Retention can be a problem with senior subjects, as they may travel a great deal and be gone for extended periods. A very useful recruitment suggestion is to recruit by symptoms, rather than the disease name. Transportation may be a difficulty for these patients, as can very long, drawn out study visits, so plan accordingly.

Another major topic at ACRP was regulatory affairs. Once, again, there were many useful tips. Oversight was like a mantra. Sponsors must remember that they provide oversight of the CROs activities at the site level. CDER is focusing on the sponsor’s responsibilities—and again, there should be a SOP or delineation for everything. One recent trend is for the inspectors to do audits during a trial, rather than after it has ended, in the interest of patient safety. The choice of which study is audited now depends on the risks of the trial and vulnerability of the subject, and is no longer confined to top enrollers.

Balancing such serious sessions were social activities and opportunities for networking. The only slightly sour note in this well-arranged conference was the lack of internet capability—it is unfortunate that the exhibition center made the cost prohibitive.

ACRP was otherwise well-thought out and well-executed, with topics that spanned the gamut of topics likely to be of interest to the clinical trials professional. There truly was something for everyone. So, hope to see you next year at ACRP.

#ahcj11

This past week I attended my first conference of the Association of Health Care Journalists, aka #ahcj11. I was initially drawn to the meeting by seeing that some of my favorite bloggers—Maryn McKenna, Pharmalot, Scott Hensley—were moderating panels. The conference far exceeded my expectations. While neither my fingers nor my mind have the agility to live tweet, here were some of the highlights for me:

Workshop: Mapping and charting health in your area

Introduced me to neat mapping that can be done with Google’s Fusion Tables. I’m a visual person, so love the ability to display reams of data visually, such as global patterns in TB. Later, I was also impressed by esri’s GIS mapping capabilities.

Workshop: What are your criteria in reporting on health care research?

This session, on critically reviewing stories, was excellent. Th-e session and the accompanying book, “Covering Medical Research,” taught more about how to evaluate articles than I received throughout my medical training, sadly enough. Gary Schwitzer’s Health News Review uses this approach, and is a valuable resource. Schwitzer’s point about differentiating stenography from journalism is broadly applicable and well taken.

Later sessions included a briefing by Donald Berwick, an overview of nanotechnology in cancer, and Francis Collins’ perspective on NIH research. Given my own clinical research background, I found the talks on problems in drug development, detecting fraud in medical research, and James Wilson’s lessons from gene therapy trials (Jesse Gelsinger) gave valuable perspectives.

Overall, the knowledge of many of the speakers and of the journalist questioners was impressive, with many perceptive, pointed questions being addressed to the panelists.

I even felt comfortable enough with the group to raise questions of my own.

One of the most provocative sessions was that on food safety. I’ll have more on that in my next post.

Photo courtesy Pia Christensen, ahcj

Clinical Trials of Obese Patients Lacking

There are huge numbers of markedly obese patients in the US. While I have seen little literature on this topic, I am acutely aware of in my own practice is the lack of data on treating the morbidly obese.
For example, a weight >300 pounds is a common exclusion on many clinical trials. The result is that there is little evidence-based medicine, and considerable problem knowing how to dose patients with a variety of medications. Little pharmacokinetic or pharmacodynamic information is available, and much of that is limited to healthy volunteers. Accurate physical examination is near impossible at times. Many patients are too obese to have diagnostic imaging studies, especially CAT scans or MRI scans, reducing us, it seems, to veterinary medicine. There are various recipes for drug dosing in obese patients—some based on ideal body weight (IBW), some on actual body weight, or some based on witchcraft (somewhere in the middle between IBW plus a percentage of the excess weight). The concern about the lack of evidence is particularly timely now, given that serious illness and deaths from Influenza A H1N1 are disproportionately affecting the obese. Some studies are proposed, as Oseltamivir Pharmacokinetics in Morbid Obesity (OPTIMO), but are just getting started (November 2009). Given the unfortunate change in patient demographics in the US and the epidemic of obesity here, clinical trials focusing on this population would be timely and most welcome.

International Clinical Trials Day

Tomorrow, May 20, is International Clinical Trials Day.

This annual event was established by the European Clinical Research Infrastructures Network, a group formed to help interconnect national networks of clinical research centers across the European Union and to help streamline multi-national studies.

ECRIN launched the International Clinical Trials Day in 2005 to educate the public about clinical trials and to further discussion amongst various interested parties, including clinicians, industry sponsors, ethics committees, regulatory agencies, and patients.

May 20th was selected as the appropriate date for this celebration in honor of James Lind who in 1747 conducted a six-way comparison of cider, elixir of vitriol, vinegar, sea water, oranges and lemons, and a purgative mixture of spices, garlic and mustard seeds on sailors suffering from scurvy. Each treatment group had 2 men. Within 6 days, the two men receiving citrus fruits were well--such a dramatic improvement compared to the other groups that it made the statistical analysis unnecessary. His descriptive treatise was published in 1753 and makes for interesting reading.

When less than 5% of patients with cancer participate in clinical trials, it is clear that a bit more outreach still needs to be done, to educate physicians and patients—and insurance companies, who often have archaic rules that preclude participation. The Public Library of Science (PLOS) is trying to do its part and launched its open access clinical trials journal, also on May 20th.

Some other efforts are not quite as supportive. It probably doesn’t help when a mascot is proposed, “Clint,” the clinical trials guinea pig …nor when a celebration includes discussion of heart-warming topics like “inspections.”

What would you suggest as an enticing celebratory event? How do you encourage participation in, and support of clinical trials?

AccessCR-a Great Source of Infomation

A few months ago I discovered AccessCR, an Australian company with expertise in clinical research. Janelle Bowden, PhD, AccessCR's Managing Director, has a wealth of experience in clinical research and an obvious passion for making research accessible to and more accepted by the public. She also aims to improve communication and partnership between all involved in the clinical research process, from patient to researcher to government to industry. Her website and newsletter reflect that and are a terrific source of frequently updated information.

I’ve been following Dr. Bowden’s site avidly for several months and recently had the pleasure of speaking with her about some of the problems confronting clinical trials both in the US and abroad. I look forward to exploring this with her more in the future.

I highly recommend the AccessCR site and newsletter for interesting updates on clinical trials. Check it out here!

Nigerian Suit Against Pfizer Revived in U.S.

There is more to the Nigerian Trovan trial debate than has been mentioned in the Washington Post and similar articles. First, it is important to note that some illnesses are more common in developing countries—e.g., the “meningitis belt” in Africa, and thus studies need to be conducted in these settings, rather than in the U.S.

For example, in the 1996 meningococcal meningitis outbreak in Nigeria, ~12,000 children died over 6 months. (Three or four cases in a U.S. community would be considered an “outbreak.”) Pfizer’s study compared Ceftriaxone, given by intramuscular injections, to Trovafloxacin, given orally. Pfizer has been criticized regarding their informed consent documentation and IRB approval–not without justification, from the second-hand reports I’ve read, but…

What is rarely mentioned is that the survival rate was reportedly 94.4% Trovan vs. 93.8 Ceftriaxone. Nor is it widely known that Trovan was also being studied for meningitis in the US by well-respected pediatric infectious diseases specialists. The outcome in the US was clinical success in 79% of the Trovan patients vs. 81% in the Ceftriaxone group, and the longer-term sequelae showed no difference between the groups. (The Pediatric Infectious Disease Journal:Volume 21(1) January 2002, pp 14-22)

Nor is the value of developing oral treatments for infections generally discussed. Doctors Without Borders was treating other meningitis with intramuscular injections of Chloramphenicol—a wonderful drug that is now rarely used because it kills ~1/30,000 patients who receive it.

Multiple IM injections are painful, require sterile technique and more skilled health care workers than do oral medications. Supplies for injected drugs are more difficult and expensive to handle and administer, particularly in poorer, tropical countries.

Pfizer may not have not conducted this trial perfectly or with adequate informed consent—I don’t know, as I wasn’t there. But I do know the horror of watching young people die from meningococcal disease, and I do understand the rationale and goal of developing an oral drug for a devastating disease that episodically kills thousands of children. While I am often critical of this company, they deserve a fair trial.

Ouch! and a Clever Concept

I was reading the accounts of BioCryst's initial flu study failure with interest.

The study was a well-designed randomized, double-blind, placebo-controlled clinical trial designed to test whether peramivir, when administered intramuscularly during the acute infection, could reduce the duration of influenza symptoms.

Biocryst used elevated levels of a muscle enzyme, CPK, as a surrogate marker to show whether the patients had received intra-muscular injections, as was intended, as the levels of that enzyme rises with muscle injury. (Unfortunately, it can also rise if someone has severe fever or chills).

Analysis of the study results showed that while a single dose of peramivir did demonstrate improvement compared to placebo, the improvement was not statistically significant. On the other hand, for those patients who showed an elevation in CPK levels compared to their baseline, peramivir showed a dose-related improvement of 64.8 hours at the 300mg dose, and an improvement of 44.6 hours over placebo at the 150mg dose.

The most interesting discussion I read was "Size Does Matter" by Brian Orelli in the Motley Fool. I'm thinking that a 3" needle would be better for many of my patients...but that is another story. I'll be looking forward to seeing the results of further trials.

Court vs. Access to Experimental Drugs, Government vs. People

In follow up to the battle of patient rights vs. protectionism, MSNBC polled public opinion. Of more than 10,000 responses, 94% thought that the government should stop their paternalistic behaviour and allow patients—especially dying patients—to decide whether to take an experimental treatment.

Ethics Professor Udo Schuklenk gets the “Barb du Jour” award for noting,
“94% thought that we should enact legislation permitting dying patients to make such choices. This is much in line with other polls providing consistently overwhelming majorities in favor of the legalization of voluntary euthanasia. The bottom line we continue to send to our democratic representatives is that we want to maximise control of our lives when we are dying. Equally consistently legislators tend to ignore our wishes. That's liberal democracy Western style for you ...”

New NIAID Grants for Studying CA-MRSA

Recognizing the urgent need to develop antibiotics to address the explosion in community acquired MRSA (CA-MRSA) skin and soft tissue infections, NIAID announced two new grants to study the efficacy of older, off-patent agents in treating these infections. If inexpensive drugs such as Trimethoprim-Sulfamethoxazole or tetracyclines can be used, perhaps it will slow the use of expensive new drugs such as linezolid.

These older antibiotics are often used now by Infectious Diseases specialists, in an attempt to reserve new agents until absolutely necessary. Unfortunately, this trend goes against human nature. Many primary care physicians as well as some other specialists are anxious to use the new-fangled drugs. Some seem to need to boast that they are up to date by their use of the newest agents and scoff that use of inexpensive, older agents is behind the times.

The two new trials will be led by University of California, Los Angeles and the University of California, San Francisco. Each of the trials is designed to enroll up to 1,200 people. The associated contracts will total up to $19 million over five years.

While I am delighted to see the additional funding for this rapidly growing problem, the results of these studies will likely not be available for several years. In the interim, the excessive use of the new agents will continue, leading to further resistance. I sometimes wonder whether an urgent intervention, such as restricting the use of certain new drugs to specialists in the field, wouldn't be more rational, especially since there are almost no new antibiotics in the pipeline. I know this is heresy, but too much is at stake to squander our few resources in this battle. Perhaps we should be "unAmerican" and not allow business interests and free enterprise to win this battle but lose the global war.

Court Limits Access to Experimental Drugs for Terminally Ill

In a rather bizarre twist, a federal court has just ruled that there is no constitutional right to experimental drugs for those who are terminally ill and have no other options. "Terminally ill patients desperately need curative treatments," Judge Thomas B. Griffith wrote for the majority. But "their deaths can certainly be hastened by the use of a potentially toxic drug with no proven therapeutic benefit." [...] While I understand the conclusion that was reached, the rationale, if one can even call it that, is paternalistic, at best, and downright irrational on its face.

On the one hand, I can understand the demand for access to a novel compound when there is otherwise no hope. On the other, remember the House of God adage, “They can always hurt you more?” While drugs might prolong a person’s life, they might also make it far more miserable than it would have otherwise been. I have seen that far too many times.

There are also problems from the pharmaceutical’s perspective in allowing such expanded access, beyond the obvious liability issues. For example, it may drain very limited supplies of the investigational drug. Also, particularly for very small biotech companies, staffing is often quite limited. There are heavy regulatory submission requirements when an investigational agent is used outside of a protocol; the limited staff might not be able to meet these requirements as well as their other obligations to the drug development or ongoing clinical trials.

What happened to the concept of an individual’s autonomy? For example, I support Oregon’s right to die, or Death with Dignity Act. If there were unlimited supplies of these drugs, I would leave it to the individual, after presentation of an “informed consent,” to reach his or her decision regarding the desirability of taking an investigational medication. But there aren’t unlimited resources. Thus, ideally, perhaps this decision should be left to the patients and the individual sponsors to negotiate based on the availability of different resources.

What do you think?

For other reading, try:

The Right to a Trial by Jerome Groopman, one of my favorite authors! [New Yorker]

Court Rules Out Terminally Ill for Tests [Associated Press]

Should Dying Patients Have A Right To Use Experimental Drugs? [Justice Talking]

Death in Gene Therapy Trial

"Death Points to Risks in Research" touts the Washington Post story.

I would like to comment on Rick Weiss’ article, from the perspective of a clinical researcher. The death of Mrs. Mohr, subsequent to her participation in the Targeted Genetics gene therapy trial, is a tragedy, and worse, was perhaps an avoidable tragedy. There does appear to be a need to re-evaluate the safety mechanisms that are employed to protect patients who are candidates for trial participation, and to re-examine the propriety of the exclusion of public participation in the trial review and approval process that was initiated in 2000.

From the description, it appears that there were serious lapses in Mrs. Mohr’s care. However, there are also several errors in this report which do a disservice to the public, who need to be educated about trials and how to assess whether to participate, rather than be needlessly scared away by inaccurate reports.

For example, a “serious adverse event” requires prompt reporting to the FDA, whether or not it is felt to be related to the drug. The definition of a serious adverse event is one that causes death or is life-threatening, is permanently disabling, results in a congenital anomaly/birth defect, or one that results in new or prolonged hospitalization. Most sponsors require reporting from the investigator within 24 hours. The FDA should have been notified within days after Mrs. Mohr’s admission to the hospital (CFR 312.32).

There are two significant factual errors in the claim that “Two fundamental rules of clinical research were violated that day.” First, there is no FDA requirement that a patient take a consent form home and review it. That is also an impossibility on many trials dealing with acutely ill patients, for example. Nor is there any requirement that the investigator not present the consent form to the volunteer. In fact, some times there is no one else capable of explaining the trial in detail and answering the volunteers questions. To avoid this type of question regarding the adequacy of consent, I try to have family members present when I review the consent, so I can address their concerns as well, and also try to include an impartial witness.

It sounds as though the consent form for this trial was inappropriately technical. Consents are generally pitched at an 8^th grade level. Obviously, this is harder to do with a sophisticated gene therapy trial, but should be the goal.

It is disturbing and unusual to have an early phase trial include patients who are on multiple medications likely to cause serious side effects. The decision to allow this is now shielded from public review; there must be transparency, public review and accountability of the approval process.

I hope that there will be a thorough, thoughtful and very public review of this and other gene therapy trials, in particular.

However, articles in the popular press, such as the one in the Washington Post, often seem to dwell on the costs of clinical trials, and to ignore the benefits those trials have brought. Before the development of antibiotics, for example, an infection was often a death sentence, most cancers were considered incurable, and there was no way to control the disastrous effects of diabetes, heart arrhythmias, and many other common illnesses. While clinical trials are not perfect, and do sometimes injure those they are supposed to help, we have come a long way in the past 50 years, in terms of our abilities to develop useful interventions while providing reasonable protection to study participants. Every medicine goes through this sort of trial process. We need new medicines for serious diseases, such as infections, urgently.

Protections need to be in place, but they should not incapacitate research nor scare volunteers unnecessarily. Since many of the issues here revolve around potential conflicts of interest, the first step would be greater transparency, public discussion, and debate.