Clinical Trials in India

I am thrilled to have a guest commentary this week on Carl Anderson's wonderful GXP Perspectives blog on recent changes in the clinical trials landscape in India.  New rules and guidances emerging in recent months are all pointing - I believe - to an even stronger clinical trials enterprise in a country whose credentials are already very good.   Please go on over to Carl's blog and take a look, make a comment.  I'd love to get your thoughts.

Thanks very much indeed to Carl for his support.

FDA's New Guidance on Clinical Monitoring Arrives

The FDA has released its long awaited update and replacement to the outdated 1988 guidance on clinical monitoring.  The draft guidance for industry on Oversight of Clinical Investigations - A Risk Based Approach to Monitoring is early evidence that the findings and recommendations of the Clinical Trials Transformation Initiative (CTTI), FDA's public-private partnership with Duke University among others, are beginning to take hold in practice in the clinical trials domain.

According to a CTTI survey, clinical trial sponsors are successfully employing a range of monitoring modalities, such as centralized monitoring by biostatistical and data management personnel, targeted on-site visits to higher risk sites as well as frequent on site visits to all sites by clinical monitoring personnel.  Yet historically, industry sponsors have rarely relied on any mechanism other than comprehensive all-site monitoring performing 100% source data verification, every four to six weeks.  It is a well-understood, costly and time consuming method of monitoring that the industry perceives is preferred by FDA.  Yet, given the vast changes in the clinical trial landscape in the decades since the FDA's previous 1988 guidance and the regulations covering sponsor obligations, including the increase in the number and complexity of clinical trials, investigator experience, changes in ethical oversight, treatment options, and geographical dispersion of clinical trial sites, the FDA now calls on the industry to employ new and more effective methods for monitoring clinical trials.  

This is big news.  As in the recent final rule on safety reporting, which requires sponsors to make judgments about whether a single case is instructive enough to warrant reporting to the authorities, FDA here is encouraging sponsors to reduce their reliance on a one-size-fits-all, on-site, 100% source data verification comprehensive monitoring approach in favor of a more diversified, horses-for-courses approach, building monitoring plans and employing monitoring modalities based on multiple factors such as:

·           type or study and endpoints (whether objectively or subjectively derived)

·           disease state of patient population

·           sponsor experience with investigator and investigator experience with research

·           complexity of protocol, such as adaptive designs, stratified designs, complex dose titrations, etc.

·           availability of EDC to facilitate centralized monitoring

Throughout the guidance, the FDA continually refers to the prevalence of electronic data capture (EDC) that allows for centralized and risk-based monitoring.  It appears that their expectation is that EDC usage is now or very soon will be the norm rather than the exception.  This is certainly one of the most important advancements in clinical trials technology that allows for alternatives to comprehensive on-site 100% monitoring and indicates that despite its earlier struggles for acceptance during the 1990s, remote data capture is here to stay at last.

While this is a draft guidance, the FDA is putting teeth into it by:

·           withdrawing the extremely outdated 1988 guidance

·           ensuring that BIMO guidance manuals are compatible with the recommendations

·           ensuring affected areas of FDA are aware of the goals of the guidance

·           will consider establishing processes within CDER for sponsors to voluntarily submit feedback on proposed monitoring plans.

It will be interesting to watch how sponsors and CROs implement this new guidance. Having traditionally supported comprehensive, frequent on-site monitoring methodology, CROs will have to develop new pricing models other than X monitors spending Y days onsite every Z weeks.  Sponsors by their turn will have to revise their SOPs and employ different kinds of training to use centralized electronic monitoring methods efficiently.

This post was published at the Clinical Leader site.  I am grateful to Rob Wright, Chief Editor of Life Science Leader magazine for his support.

Upcoming Clinical Research Conferences & Events

In about 10 days I will be in San Diego for the first Ethics in Clinical Trials conference.  

Current deals (I think these are still good - call 720-212-0440):

·         4 for 3: Send 4 delegates for the price of 3

·         10% off: Mention booking code leoE11

·         Free Pre-Conference Workshop: preE11  (Led by me, a discussion of emerging region clinical trial ethics) 

Call: 720-212-0440 or click www.ethicsintrials.com.

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Later in March I will be at Partnerships in Clinical Trials in Phoenix - March 30-April 1.  I am chairing a market insight round table discussion on Strategies for Indian Clinical Trials on Thursday Mar 31, at 11:00 AM.  Click here to register, or here for pricing.

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Finally, I will be in a panel discussion at MAGI's Clinical Research Conference in Philadelphia, May 22-25. 

I have attended and presented at the western edition of this conference a couple of years running; this will be the first time I travel east for MAGI. I am delighted to join again with Joan Chambers of CenterWatch, Nye Pelton of Eli Lilly and Marlene Llopiz of Venn Life Sciences to discuss the current state of globalization of clinical trials.

According to the conference organizers, two-thirds of attendees will have 5+ years of experience. About 48% of attendees will be from sites, 27% from sponsors, and 25% from CROs and other service providers.

The conference website is here.  A friend-of-speaker discount can save you $100 - code Q367.

Click here to register. Enter the above discount code when prompted. (Does not apply retroactively or to already-reduced group rates.)

Informed Consent May Be Compromised & Medical Device reform

In a study published today in IRB: Ethics and Human Research (free abstract, $ subscription for full article), concluded that unrealistic optimism is prevalent among some clinical study subjects  and that it "has the potential to compromise informed consent".  Seventy-two early phase cancer study subjects completed questionnaires designed to assess their level of understanding of the study's purpose as well as to detect signs of unrealistic optimism.  Unrealistic optimism is defined as "specific to a situation and consider (sic) a form of bias...and is distinct from "dispositional optimism, which is a general outlook on life and is neither realistic nor unrealistic".  Questions to reveal unrealistic optimism revolved around the likelihood of particular individual outcomes as compared with other study participants, or the participant's tendency to give greater weight to possible benefits than possible risks.  According to the study's findings, 72 percent of the subjects accurately understood the objectives of the cancer trial in terms of potential benefits to future cancer patients rather than directly to themselves, which means that 28% of respondents did not clearly separate those facts.  The researchers' concluded that we need to improve the informed consent process by "paying more attention to how patients apply the consent information to themselves".  Reporting on the trial is found online at Medical News Today.  


In other news, last week the FDA announced proposed changes to improve the agency's 510(k) program for approving medical devices for sale.  Some of the recommendations include:

• consolidate the terms “indication for use” and “intended use” into a single term, “intended use”; 
• expand its statutory authority to consider off-label use when determining the intended use of a device; 
•  issue guidance on when a device should no longer be available for use as a  predicate;  
•  issue a regulation on its rescission authority;  
•  issue guidance to create a “Class IIb”; and  
•  seek greater authorities to require postmarket surveillance studies as a condition of clearance for certain devices.

The full report is here (PDF).  FierceMedicalDevices reported generally favorable reception of this news by the industry.  We have a long way to go until any of the report's recommendations become regulation, but now at least we have some ideas of which way the agency's thinking is going.  At the same time, the Wall Street Journal carried an op-ed by President Obama discussing the balance between regulator and free market. It all makes for very interesting reading.

Patient Participation in Clinical Trials: Is There a Country Difference?

In the December 2010 issue of PLoS One, a diverse group of authors from Brazil, Singapore, India and the US published a paper entitled:  So Different, yet So Similar: Meta-Analysis and Policy Modeling of Willingness to Participate in Clinical Trials among Brazilians and Indians.  Their objective was to conduct a systematic review and meta analysis (SRMA) of the literature to determine a model for predicting willingness of Brazilian patients to participate in clinical trials,and then compare the findings regarding Indian patients' willingness to participate in clinical trials.  The results if validated could be useful for sponsors and CROs planning studies to avoid wasting time and money in the wrong country and to better design protections for vulnerable patients.

The findings are based on a rather small sample of only five papers, narrowed down via various factors from 28119 (that's the systematic review part), and the authors grouped their results into two broad groups: factors favoring participation in clinical trials and factors presenting a barrier to that same end.  Interestingly, and again based on a relatively small sample, the researchers found that the most commonly cited reason for participating in clinical trials among Brazilian patients was altruism, at 55%.  Personal health benefits (30%), convenience (11%), and monetary reimbursement (6%) completed the list of favoring factors.  The barrier factors amongst Brazilian patients were: fear of adverse events (12%), mistrust (6%),  lack of knowledge (4%) and inconvenience (2%). 

By modeling this information to a previous systematic review of literature pertaining to Indian patients, the authors discovered a significant difference in Indian patients' motivations to participate in clinical trials.  The leading factors for Indian patients were: personal health benefits (48%), altruism (43%), monetary reimbursement (31%), and trust in their physician (8%).  Convenience did not factor at all for  Indian patients according to these findings.  The factors representing barriers to participation for Indian patients were:  fear of side effects (27%), mistrust of drug companies or researchers (26%), dependency issues (19%), loss of confidentiality (17%), and inconvenience (11%).

The authors also conclude from their research that Brazilian patients are more likely to participate in clinical trials than their Indian counterparts.  I think we can also draw from this the inherent vulnerability of clinical trial participants, especially in the developing and emerging regions,and use the factors favoring and inhibiting participation to help protect and reassure patients as they come into trials.

Focuses for the Upcoming Term

This tide marsh is located behind the building I where I work Monday through Thursday, on the east side of the San Francisco bay. It is close enough to walk to, and it has long flat dirt paths to run on when I feel energetic. On a clear day, such as we had this week, you can identify individual buildings in the downtown San Francisco skyline. Most days there is a haze on the water that precludes even seeing the mountains of the peninsula on the other side. I like to go out there during the day to clear my head or to think. Sometimes if I don't have early morning calls I stop by the marsh before heading into the office to watch the great white herons, snowy egrets, mallard ducks and other shorebirds make their living. I find the movement of the tides calming. The water of the bay has a different personality every day; sometimes calm, flat and glassy, sometimes grey and choppy. But the water in the marsh, seen here at high tide, is always smooth and tranquil.

The focus of this week has been building my network of experts in the field of clinical trials in emerging markets. I'm starting to do some research into the area of informed consent in emerging markets: what does signing a form mean to the patient, why are we shoving 15+ page consents down people's throats, and why do the ethics committees let us? I will be contacting my Indian, Eastern European and other connections in the developing world (although they don't know it yet) in the coming weeks to get their perspectives for the next iteration of the emerging markets course, to be offered in the spring term.

The winter term at UC Santa Cruz starts for me next week. It's been about an 8 week break since the fall term ended. Good Clinical Practices, my flagship class, begins Wednesday evening Jan 21 from 6-9pm, and runs for 10 weeks. I've improved (I hope) the curriculum for this term, updating some older information and including references to recent events in the NY Times, NPR, and other sources.