Strategic Partnerships in Big Pharma: Implications for Small and Mid-sized Sponsors

Traditionally, large biopharmaceutical companies have outsourced clinical study responsibilities to a wide variety of external vendors, distributing the work across many service providers.  For their part, large CROs have routinely provided services to both large and small biopharmaceutical companies to keep their top-notch resources utilized to capacity and add to their bottom line.

Over the past several years, large sponsors and CROs have been trading in these transactional, fee-for-service business relationships for longer-term, tightly-integrated strategic partnerships.  And the trend is only accelerating.

Risk-based Monitoring vs Traditional Monitoring: the ADAMON Project

Many clinical research professionals are RBM believers, convinced that a risk-based approach to monitoring represents an effective and more efficient alternative to the tradition of frequent on-site visits and 100% SDV.  Many others are cautiously open to the idea, and are waiting for news of successful RBM studies to start filling the industry journals and online forums.  From those same journals and forums, we know that RBM studies have been, and are currently being, conducted.  In collaboration with CluePoints, GSK Vaccines is piloting a central statistical monitoring approach.  Sanofi and Lilly are currently piloting the TransCelerate methodology published in May.  Bayer and other sponsors are using an analysis of EDC data and metadata to steer their on-site monitoring activities.  Many CROs are offering their sponsor clients alternative monitoring solutions; Quintiles has conducted upwards of 60 studies using a number of different RBM implementations, Health Decisions has had years of experience conducting trials using its adaptive monitoring approach, and ICON has just announced its ICONIK Monitoring service after several years of piloting it alongside the traditional approach.  Finally, almost every RBM webinar (RBM-inar?) I’ve attended has mentioned that government and academic clinical trials commonly employ a RBM strategy.

But it’s been quiet.  The big headlines necessary to assuage lingering doubts have not been forthcoming.  Even as we begin to hear about RBM successes, how will we know if RBM is as good as traditional techniques? 

Finding Clinical Trials During Government Shutdown

As a result of Congressional impasse, almost half of the approximately 15,000 FDA employees are subject to furlough.  In “15 Things to Know About FDA’s Operation During the Shutdown,”  Regulatory Focus editor Alexander Gaffney reports, “ClinicalTrials.gov, which is run by NIH, is being maintained by ‘minimal staffing,’ meaning that registering a trial may be difficult even if FDA does approve a trial to go forward.”

Over the past few months, I’ve been assembling a list of clinical trial finders for use in a future blog post.  I had planned to provide as complete a list of websites as I could, highlight benefits, draw comparisons, and include some details of operation.  I’m not close to that yet, but even though my research is incomplete, what I currently have may help someone now who is looking for very up-to-date clinical trial information.  So, without a passable transition sentence, here’s what I have.  I hope it turns out to be useful to someone.

(Note that some of these sites get their information, in part, from clintrials.gov, but they also use other sources that would hopefully be unaffected by the shutdown.)

What If You Needed SOPs to Run Your Household?

Last week I traveled to Phoenix to videotape a presentation for Natural Products INSIDER’s upcoming Digital Summit.  The 45-minute presentation, entitled “A Guide to SOPs and Compliance for Dietary Supplement Distributors,” goes into  much more detail than our February blog post on the same subject (which you can read here: http://bit.ly/YGTQWd).

Rosanne Sylvia-Heeter, Director of cGMP Compliance at Polaris, is always chanting the FDA compliance mantra, “If it’s not documented, it didn’t happen.”  As I worked on the blog post with her last winter, I was struck by the amount of documentation actually needed to comply with 21 CFR Part 111 distribution regulations.  As we worked on the Digital Summit presentation this summer, I was struck by something else.  In the course of simply maintaining a residence, members of my household actually perform a lot those Part 111 activities.  And so do yours.

The big difference is that we don’t have to write it all down.

Assessment of FDA’s Final Guidance on Risk-based Monitoring

Yesterday, FDA finalized its 2011 draft guidance on risk-based monitoring (RBM). Without preamble, here’s what has changed.

Compared with the draft version of the guidance, the final version:

• Reinforces, even strengthens, its support of RBM

• Suggests “more intensive monitoring” does not necessarily indicate on-site monitoring

• Provides specific examples of critical/non-critical data and tasks that could be accomplished remotely

• Emphasizes the importance of protocol and CRF design

• Notes that, under RBM, delegating monitoring obligations to a CRO requires more clarity, communication, and evaluation than traditional monitoring

Unraveling Risk-based Monitoring Terminology

“Judging by the sheer number of conference presentations, forum discussions, and webinars, not to mention all the new vendor offerings built to facilitate the process, risk-based monitoring might be one of the most frequently discussed topics in clinical research today.”

That sentence opened our December blog post on risk-based monitoring, and it’s as true today as it was then. (In fact, I’ll say it’s even truer today, if only to spark debate about truth being an absolute.)

The more a topic is discussed, the more words people use to discuss it.  Of course, a few subject-specific, well-defined terms can facilitate conversation, but over time, meanings blur.  Industry-established definitions give way to corporate-centric, implementation-specific usage.  We’ve all seen this recipe for miscommunication before.  The German and the Frenchman know that they speak different languages and can take measures to assure accurate translation.  Two people who speak the same language and use the same words may not even realize they might not be saying the same thing.

This blog post looks at the terminology used in what are arguably the three most important and oft-quoted papers on Risk-based Monitoring in the industry:

·        FDA draft guidance Oversight of Clinical Investigations – A Risk-based Approach

·        EMA Reflection Paper on Risk-based Quality Management in Clinical Trials

·        TransCelerate BioPharma Position Paper on Risk-based Monitoring Methodology

I carefully reviewed these three documents looking for consistencies on which we can rely, and inconsistencies of which we need to be cautious.  For each set of terms below, I first present the conclusions I’ve drawn about usage consensus, or lack thereof, and then suggest some tips to avoid confusion in discussions you might have with colleagues and clients.  The sane among you will probably be interested in only my conclusions and suggestions; you linguists, skeptics, and masochists may be interested in the supporting details I added to the end of the post.

Sorting out terminology and definitions is a tricky business.   If you have different interpretations than I present here, or can add to this analysis, please post a comment and we can start a discussion.

Remote versus Off-Site Monitoring

Conclusion:

Sources agree that these terms are synonymous and used to describe traditional on-site monitoring activities that, thanks to technology, are now able to be conducted elsewhere.

Tip:

You can use these terms interchangeably, but continue reading to avoid confusion with the term “central”.

Remote/Off-Site versus Central Monitoring

Now that we’ve established that remote monitoring and off-site monitoring can be used interchangeably, let’s compare the pair to central monitoring.

Conclusion:

Sources agree that central monitoring includes remote/off-site monitoring activities, but includes other functions, as well, predominately statistical analysis. 

Tip:

Sometimes the literature uses “remote/off-site” and “central” interchangeably, but that’s risky.  Due to its statistical component, “central monitoring” has the widest range of interpretations of all the terminology in use, and some of the interpretations are very different from the comparatively straight-forward “remote/off-site monitoring” definition.  Read on.

(BTW, FDA uses “centralized”; TransCelerate uses “central”.  Tomato, tomahto.)

Central Monitoring and Statistical Analysis

Conclusion:

“Central monitoring” implies that data across study sites are collected centrally, and available for statistical analysis.  The type and extent of  statistical analysis that is performed to adapt a monitoring plan can vary significantly.   Sometimes analysis is limited to Key Risk Indicators or critical data points, and sometimes more rigorous statistical testing is performed on every data item, as any outlying element can be indicative of data quality.

Tip:

When using the term “central monitoring” outside a narrow culture, make sure to clarify whether you mean a slight superset of remote/off-site monitoring, statistical analysis of Key Risk Indicators, or something more.  Different computing platforms offer different features; if it’s appropriate, mentioning the IT platform that is being used could clarify the type of central monitoring being discussed.

Adapted versus Adaptive Monitoring

If you’ve stuck with this analysis thus far, you deserve some lighter commentary…

Conclusion:

Usage is too loose to be of much danger.

Tip:

Use interchangeably with giddy abandon.

Centralized versus Centralised Monitoring

Conclusion:

It depends on which side of the pond you are.

Tip:

Stick to verbal discourse and there is no difference.  (Tomato, tomayto.)

Closing Thought (before I lose you all)

My college French professor was the first to point out to me that irregular verbs, the verbs that refuse to follow regular conjugation patterns, are the most common verbs in every language – the verbs to be, to go, to do, to have, to see, etc. They’re used so often that they bend and blur and evolve on their own. I think the jumble of definitions that arises with an oft-discussed topic like risk-based monitoring is somehow analogous to the unstructured forms of irregular verbs. The more they get thrown around, the more they go their own way.

 

By Laurie Meehan

We at Polaris hope you find this information helpful. You can visit us at our website, www.polarisconsultants.com or you can contact us at info@polarisconsultants.com.
 

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Supporting Detail (as promised/threatened)

Remote versus Off-site Monitoring:

The FDA guidance does not formally define either of these two terms, but says, “source data verification and other activities traditionally performed by on-site monitoring can now often be accomplished remotely, as both trial data and source data typically become part of the central submission.”  The TransCelerate paper equates the two terms, and formally defines both as “monitoring activities as defined either within process documents or in the MP that occur away from the study site location (e.g. at a Monitor’s home or in a sponsor representative’s office.)”  The EMA paper uses neither term.

Remote/Off-site versus Central Monitoring:

The definition of central monitoring in the FDA guidance consists of 8 bullet items, only some of which are the technology-enabled remote/off-site version of traditional on-site monitoring.  The TransCelerate paper says, “Off-site Monitoring Activities are performed by Monitors and can be distinguished from Central Monitoring which could also be performed by Monitors or other roles within clinical operations or by other functions (e.g. Statistics, Data Management, Safety).”

Central Monitoring and Statistical Analysis:

The TransCelerate paper focuses on analyzing Key Risk Indicators to determine and adapt a monitoring strategy.  The appendices are ripe with examples that show how thresholds can be used to dictate actions and trigger on-site visits.  The paper doesn’t preclude analyzing all study data (both critical and non-critical) for outliers, but doesn’t discuss much about the role that this type of statistical analysis might play or provide details on its use.  The definition of “central monitoring” in the FDA guidance is more general.  “Conduct aggregate statistical analyses of study data to identify sites that are outliers relative to others” might refer to Key Risk Indicators.  It might also refer to the “analysis-of-every-data-element” approach that some platform vendors have implemented to detect outlying, hence higher risk, sites.  The EMA paper speaks only of the potential to develop central monitoring systems that use statistical methodology, and leaves it to future papers to delve into more detail.

Adapted versus Adaptive Monitoring
Of the three sources, the EMA reflection paper uses the term “adapted” the most, but never formally defines it.  “Adapted,” as it relates to monitoring, can refer to the practice of tailoring monitoring procedures for each protocol.  (“Safety monitoring procedure adapted to each trial”)  It can also refer to mid-study changes to the monitoring procedures that were set out at the beginning of the study.  (“[Priorities] should be carefully set out so that risk analysis is carried out and control measures are designed in a way that is continuously adapted to them.”)  The TransCelerate paper uses the term “adaptive,” almost as generically, when it defines risk-based monitoring to be an adaptive approach.

Centralized versus Centralised Monitoring:

No factual foundation whatsoever; I went out on a limb.

Key Points of FDA's Draft Guidance on Manufacturing Quality Agreements

At the end of May, FDA published its draft guidance, officially titled “Contract Manufacturing Arrangements for Drugs: Quality Agreements”.  Here are some of the highlights.

First, a Quality Agreement between a Sponsor and Contract Manufacturer has never been, nor is it now, explicitly required by FDA regulations. However, responsibilities and procedures of each company’s respective Quality Units are required to be documented, so a Quality Agreement that outlines the responsibilities of each company is a logical next step.

Note that “Contract Manufacturer” refers to any Contracted Facility that provides some or all manufacturing services, including processing, packing, labeling, holding, or testing.

In Europe, Sponsors (or, in the vernacular of the draft guidance, “Owners”) can outsource the final product release/rejection of finished goods for distribution. In the US, sponsors always assume this responsibility and cannot delegate or outsource it.

Because Contracted Facilities often provide services to multiple Sponsors, FDA advises that special consideration be given to reporting information about objectionable conditions.  Sponsors may wish to require that their Contracted Facilities make them aware of manufacturing deficiencies that may impact their products, even if the deficiencies were observed during an inspection of another Sponsor’s product.  (Note, our consultants also suggest that the Quality Agreement require that a Contracted Facility notify its Sponsor whenever the FDA inspects the facility.  The name of the inspected product and its Sponsor would be kept confidential, but this reporting of inspections tells a Sponsor how often FDA visits the site.)

FDA acknowledges that processes can change at both Sponsor and Contracted Facility companies for a variety of legitimate reasons, so communicating changes between the two companies should be discussed in the Quality Agreement. Examples include additional products brought into the line/facility, changes to key personnel and suppliers, and changes resulting from stability studies, process improvement projects, investigations into manufacturing deviations, out-of-specification results, customer complaints, recalls, or adverse event reports.

Finally, a Quality Agreement does not exempt Contracted Facilities from CGMP compliance. Regardless of the allocation of responsibilities in the Quality Agreement, the Contracted Facility cannot essentially agree to manufacture under non-CGMP conditions. Both companies could be held responsible – the Contract Manufacturer for the non-compliance, and the Sponsor for lack of oversight. FDA provided a few examples:

• The Contracted Facility receives a Warning Letter for deficient maintenance of facilities and equipment. The Quality Agreement specifies the Sponsor is responsible for this, yet the Owner has failed to provide the requisite resources or carry out the necessary upgrades and maintenance, and the Contracted Facility has continued to operate under non-CGMP conditions. (Possible course of action: the Contracted Facility could bear the costs of modifying operations in order to maintain CGMP compliance, and then seek redress from the Sponsor later.)

• Batch records do not match the manufacturing process of adding reclaimed powder, but the Contracted Facility claims that this is just as the Sponsor specified. (Possible course of action: the Contracted Facility could refuse to carry out the additional manufacturing step without including it in the batch record).

The draft guidance concludes by noting that “Owners and Contracted Facilities can draw on quality management principles to carry out the complicated process of contract drug manufacturing by defining, establishing, and documenting the responsibilities of all parties involved in drug manufacturing, testing, or other support operations.”

by Laurie Meehan

We at Polaris hope you find this information helpful. Contact us at info@polarisconsultants.com with a question or post a comment.