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The FDA has released its long awaited update and replacement to the outdated 1988 guidance on clinical monitoring.  The draft guidance for industry on Oversight of Clinical Investigations - A Risk Based Approach to Monitoring is early evidence that the findings and recommendations of the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.

Conducting Clinical Research

Time to play catch up with the blogging as the year begins to wind down.  The fall term at UC Santa Cruz will finish next week and I have no more conferences booked till January. 

A couple of weeks ago I attended and presented at MAGI West Conference on Clinical Research in San Francisco.  The event was neatly sandwiched in between the end of baseball pennant series' and the World Series, in which my beloved San Francisco Giants prevailed for the first time in, well, my whole life.  San Francisco was a very orange place to be during these days, and as a lifelong baseball fan left heartbroken by my team twice before in my adult life, it was a glorious time to be in the city. 

But this blog is not about baseball.  The MAGI conference was well attended by over 500 people, many more than had attended the same event last year in San Diego (on the last day of the baseball 2009 regular season, in case anyone is keeping track).  MAGI (Model Agreements and Guidelines International) so far is offered on either coast - in the east in spring and the west in the fall - and I think it is rapidly becoming one of the must-attend meetings on the yearly calendar for clinical research professionals, especially as the scope of the conference gradually expands from its origins in contracts and agreements to its current goal of "establishing best practices for clinical research operations, business and regulatory compliance".  The quality of speakers that I heard was uniformly quite high with little variation, although a couple stood out in both directions.  As the conference becomes larger it is also becoming an important networking opportunity and my LinkedIn connections have expanded significantly as a result of the acquaintances I made and renewed during the two days I attended.

One of the people I reconnected with in San Francisco is Dr Judy Stone of Maryland, the author of "Conducting Clinical Research", a newly revised quite complete how-to guide primarily written for investigators and would-be investigators to help them understand their role in the clinical research enterprise, particularly as relates to pharmaceutical industry-sponsored research, which is ultimately for profit.  Dr Stone has done her homework and produced an excellent reference that, while geared toward investigators, also offers new insights to the sponsor and CRO sides of the industry for those who might have a look.  It is always a good idea to remember to see things from the investigator's perspective, and Dr Stone has done this very well.  I plan to recommend this volume to my GCP students as adjunct reading material starting in the next term.

At the conference I was fortunate to participate on a panel entitled "Are Sponsors Re-evaluating Globalization of Clinical Sites?", moderated by Joan Chambers of Centerwatch.  In my next post I will review some of the key points of the discussion with the panel and audience. 

I close this post with the acknowledgement that our world became a great deal poorer last week when our friend Kate Allen died of gastric cancer.  She was 44.  She was a good teammate, colleague and friend, and she left many friends and loved ones behind who will miss her for the rest for our lives.

Questions

A former GCP student sent me this question today:  "Can you tell me if it is OK for a principal investigator to have his signature Xeroxed onto the ICF for the subject to sign?  This doesn’t seem appropriate to me, but I am having trouble finding anything that says otherwise.  Also, can they sign the ICF in advance of the subject signature, or should it always be after the subject consents to be in the study."

Every class term starts with my passionate admonishment that GCP is more than just knowing the rules, in fact knowing the rules is only a small part of the task.  To understand the rules, we have to think through why those rules exist.  Reading this students' question gave me an unsettling feeling that I am not being very effective at getting this point across.

Whether there is or is not a regulation about pre-signing informed consent forms, whether in ink or by photocopying, stamping, or smoke signals, is entirely beside the point.  The point is not the signature at all.   The point is what the signature represents.  (*Extra credit: is the investigator's signature even required under US regulations?)  My students have all been taught that the signature represents that the investigator's obligations to the patient with respect to the nature of the study, risks and discomforts, alternative treatments, right to withdraw and all the other elements of consent have been met.  Therefore, of course it is unacceptable to pre-sign the form, Xerox a signature onto the form or whatever else this investigator has thought up.



*Answer: No, only the patient's (21CFR 50.27(a)). Under ICH guidelines the consent should be signed by the patient and by the person who conducted the informed consent discussion (ICH E6 4.8.8).