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.

New FDA Inspection Plans & Other Notable Headlines

I was tempted to name this post “Six Really Cool Health Science Headlines You May Have Missed” but I wanted to give my “new post announcement” email a fighting chance to get through our subscribers’ spam filters.

I’ve been exploring Twitter lately, learning about the opportunities it presents and about the conventions and etiquette of the micro-blogging community. My last blog post blew the dust off of a 7-year old TED talk about big data. This post is rooted firmly in the present, because, as I have found, nothing on Twitter is very old…except for some of us tweeters. To build a context for the Twitter topics I’m following, I’ve been clicking a lot of links, reading articles, blog posts, newsletters, and white papers about the advances of this amazing industry as they happen. Many of these advancements do not directly relate to the work we do at Polaris, but rather than read about them, marvel, and move on, I thought I’d share them with our readers in case, as I say, you missed them.

FDA Plans to Use Big Data to Help Identify Highest Risk Manufacturers
I like the symmetry here. PatientsLikeMe, GNS Healthcare, and others are using big data to predict what treatments would have the most benefit for a given patient. Now, big data may soon be used by FDA to determine the best way to ensure the safety of those treatments. FDA has issued an RFI (Request For Information), and is looking for a vendor to supply an off-the-shelf, risk-analysis system to identify high-risk manufacturers. The system would analyze inspection and REMS (Risk Evaluation and Mitigation Strategies) reports, bioequivalence data, pre and post approvals, and other sources to help decide who should be “next on the inspection list.” To read more: http://bit.ly/ZggT6R.

.PHARMACY Domain To Weed Out Non-compliant Online Pharmacies
Here’s another headline related to patient safety and drug efficacy. The National Association of Boards of Pharmacy (NABP) found that 97% of the 10,000 online pharmacies they analyzed were out of compliance with US pharmacy laws and practice standards. They have applied for a new domain name, .PHARMACY, which would be available only to legally operating online pharmacies. To read more: http://bit.ly/10gRm1z.

Edible Electronic Medical Devices Could Be Swallowed Like Regular Pills
This is a fun one. You may recall that in August of 2012, FDA granted approval to Proteus Digital for its edible sensor, the Ingestion Event Marker. Developed to ensure that medication is taken correctly and on time, the sensor is encased in a pill. Before it is digested, the sensor relays information to a skin patch, which sends it to a mobile app, to create an ingestion data log. Now, less than a year later, Carnegie Mellon researchers have developed a non-toxic edible battery that could be used to power biodegradable electronics. The result could be tiny electronic medical devices that, when swallowed, would provide non-invasive treatments, like drug delivery or tissue-stimulation. To read more: http://bit.ly/10IB1iH.

Protocol Development via CrowdsourcingTransparency Life Sciences (TLS) is designing clinical protocols using input provided by a diverse set of doctors, researchers, patients, and caregivers. Protocol Builder, a technology TLS developed for crowdsourcing its study designs, encourages open dialog among communities of interest and collects participant input. Believe it or not, you can view the crowdsourced protocol they are developing to study Lisinopril, an adjunct treatment for multiple sclerosis, at http://bit.ly/10JDqfY. They’re not kidding about the “transparency”thing.

GlaxoSmithKline Opens its Patient-level Clinical Data to Other Researchers
In keeping with the theme of transparency and collaboration, the homepage of GSK’s new data sharing platform reads, “Access to the underlying (patient level) data that are collected in clinical trials provides opportunities to conduct further research that can help advance medical science or improve patient care. This helps ensure the data provided by research participants are used to maximum effect in the creation of knowledge and understanding. Researchers can use this site to request access to anonymized patient level data from our clinical studies to conduct further research.”

Currently, the site includes all GSK global studies since 2007, with plans to include all the studies conducted since the company’s formation in 2000. You’re even free to view studies included on the site before creating an account at http://bit.ly/16FVsor.

Open Government Data Exposes Hospital Billing and Healthcare Costs
I’ll bookend this blog post with another story about big data. On May 8, Alexander Howard wrote on E Pluribus Unum, “The Department of Health and Human Services (HHS) has released open data that compares the billing for the 100 most common treatments and procedures performed at more than 3000 hospital in the U.S. The Medicare provider charge data shows significant variation within communities and across the country for the same procedures. One hospital charged $8000, another $38,000 –for the same condition. This data is enabling newspapers like the Washington Post to show people the actual costs of health care and create interactive features that enable people to search for individual hospitals and see how they compare… According to Steven Brill, this end to hospital bill secrecy was prompted, at least in part, by his mammoth special report on healthcare pricing practices in the March 4 issue of TIME Magazine. If so, it’s one of the most important outcomes of a single feature of investigative journalism in this new century.” According to Brian Cook, an HHS public affairs director, the data release did, in fact, come in part as a response to Brill’s article. Now that’s noteworthy.

Thanks to my new Twitter community members for calling these stories to my attention, especially: @RebarInter , @Ivsin,@GCPWorks, @trialsonline, @eClincial_Jen, @Clin_Trials, @Medidata, @KGKSynergize, @Clinical_Tech, @AnnexClinical, @eclinical, @LaurieAHalloran, @Altus_Research, and @DrugSafetyNavig. You can follow them, too!

By Laurie Meehan

This blog discusses trends and issues in the pharmaceutical, medical device, and dietary supplement industries. Click the SIGN UP link to subscribe to notifications of new blog posts, or follow us on Twitter @ConsultPolaris.

Ignorance Isn't the Problem; Preconception Is

The dumbest thing you could do if you were trying to find the answer to a question is to ask someone who’s clueless, right?

Nope – it turns out you could do worse.  Hans Rosling of the Karolinska Institute in Sweden explains how.

Asked to teach a course on Global Health to Sweden’s top undergrads, Dr. Rosling administered a pre-test to see what the class already knew.  Five questions in the pre-test consisted of a pair of countries, and students were asked to select which of the two countries had a higher infant mortality rate.  To keep things sporting, he made sure that, in each pair, one country had at least double the infant mortality rate of the other. 

On average, the students scored 1.8 out of 5.  (In an amusing bit of self-deprecation, he confessed that this made him happy because now he had a job and his course had a place in the institute.)  The problem, he observed, wasn’t ignorance, it was preconception.  These top students knew statistically significantly less about world health than chimpanzees, who, he noted, would have scored a 2.5 answering randomly for banana bonuses.

Just so you don’t think this world-renowned researcher was picking on his students, he also performed what he called an “unethical” study on the professors at the Karolinska Institute.  These are the folks who hand out the Nobel Prize for medicine.  They scored on par with the chimpanzees with 2.4 correct answers.

Dr. Rosling told this story as an introduction to his TED talk, “Stats That Reshape Your Worldview”, which he delivered in 2006.  Yes, that’s right – 2006.  Why did I bother to blow the dust off of a 7 year-old presentation?  Because the chimp comparison is comic and the insight is brilliant.  As you read the news and watch world events unfold, you may begin to notice, as I have, how often false preconception, rather than ignorance, explains the ill-advised behavior that seems to be everywhere.

The other reason I chose to write about this TED talk is because current efforts to advance healthcare using big data reminded me of the kind of data wrangling I watched Dr. Rosling perform.  Out of the information mined from millions of patient EMRs, registries, and insurance claims, GNS Healthcare has created enormous datasets from an impressive list of collaborator companies and institutions.  The data is run through analysis algorithms that can then be used to predict whether a given treatment is likely to work for a given individual – one of a given gender, age, ethnicity, symptomatology, and genetic mutation.  PatientsLikeMe also performs data analysis to help patients assess likely outcomes of particular therapies.  The data they use come from subscribers of patientslikeme.com, a health data-sharing platform of 200,000 members suffering from over 1000 different diseases.  Both organizations are among a growing number in the industry that believe the way to less expensive, more effective healthcare can be found in data.  In fact, as members of Orion Bionetworks, a new alliance of private industry, non-profits, and research hospitals, they will be collaborating to develop predictive models for Multiple Sclerosis and other chronic diseases.

Dr. Rosling would be proud.  His TED talk has over 5,000,000 views, so maybe you saw it.  If not, here’s the link:  bit.ly/ZEyZhU . It’s excellent, and as far from a boring PowerPoint presentation as you can get. 

Jamie Heywood, the founder of PatientsLikeMe, also delivered a TED talk in 2009:  bit.ly/17Mgtf8 .  An MIT grad, Jamie talks about the sophisticated algorithms used by the investment industry, and asks, “Wouldn’t it be great if the technology we use to take care of ourselves was as good as the technology we use to make money?”

Yes, yes it would.

by Laurie Meehan

Who's Looking Out for the Investigator Sites?

Almost universally, it is the sponsor or CRO that arranges and pays for independent audits of their investigator sites.  It’s no surprise, then, that these audits are designed primarily to benefit the sponsor or CRO, not the site.  As a clinical investigator, wouldn’t it be a comforting change of pace if the auditor assessing your facilities, reviewing your documents, and evaluating your quality systems were looking out for your interests – organizing audit results and tailoring recommendations to help your business?  Many types of organizations do routinely hire independent 3^rd party consultants to be conduct audits of their own facilities, for their benefit.  Contract pharmaceutical manufacturers have been doing it for decades.  Might not clinical investigators benefit from the same practice?

How would Investigator Sites benefit from hiring their own Auditors?

Any GCP site auditor that a sponsor hires can assess the site’s compliance with regulations and with the protocol. Any instances of noncompliance that are encountered will be documented and the findings will be reported back to the sponsor.  Auditors you hire yourself are, by definition, on your side, and will do more than identify compliance problems; they will help you determine and implement the optimal solutions.  Unlike most site staff, professional auditors have seen how dozens, if not hundreds, of sites have remediated deficiencies similar to yours and have prevented them from reoccurring – or from occurring in the first place.  They can share best practices and recommend which ones would work best in your particular environment.  They can advise you against bad practices and prevent you from becoming the subject of cautionary tales they may have witnessed at other sites.  They can help you identify inefficiencies in site operations and optimize resources and procedures.

It’s not unusual for an investigator site to hire a consultant when a sponsor threatens to drop them from a study, but periodic 3^rd party audits could avoid that crisis altogether.  A proactive auditing program would also prepare an investigator site for sponsor site evaluation visits, even those that occur on short notice.  Favorable audit results demonstrate regulatory compliance and overall study fitness to prospective sponsors, giving the study site a competitive edge over others.  Some sites derive a substantial part of their revenue from conducting clinical research; the impressions they create and the reputation they have in the industry are particularly important to their businesses.  The very existence of an audit program would demonstrate a site’s willingness to invest both time and money in ensuring the quality, safety, and integrity of the research they conduct.

Why relying on Monitoring may not be sufficient

Of course, part of the study monitor’s job is to look for areas of noncompliance, so why couldn’t a site simply rely on that?  As a matter of fact, most investigator sites do, but there are several advantages to retaining a 3^rd party auditor.  A study monitor who finds a compliance issue may recommend a set of corrective and preventive actions for the site to take.  Are these remedies the only ones that could be pursued by the site, or are they the ones that this sponsor is most familiar with?  Would other remediation actions correct the deficiency equally well, and fit more seamlessly into the site’s operations?  That’s not really the sponsor or CRO’s primary concern.

Many sites conduct research for more than one sponsor or CRO.  The manner in which each sponsor or CRO plans to meet regulations may differ; the philosophies they follow may not entirely align, and the guidance they offer the site may conflict.  An independent auditor who has worked with numerous sites, sponsors, and CROs, and on a variety of studies, can help the site staff to reconcile any disparate input it receives.

It can be difficult for a site to determine whether it is receiving an appropriate level of monitoring, especially with the introduction of risk-based techniques.  How much source data is being verified?  Are monitoring visits frequent enough?  Are the remote monitoring techniques being used effective?  These are concerns with which sponsors themselves wrestle.  DIA offers a training course entitled, “Who’s Monitoring the Monitor?”  A key learning objective of the course, “identify common errors and warning signs of problems in site monitoring,” suggests that this very human activity is far from flawless.  Not all monitoring plans are adequate, not all monitors are effective.  An investigator site that relies too heavily on its sponsor or CRO for compliance assurance could be putting itself at risk come regulatory inspection time.  An independent pre-inspection auditor would identify violations before an FDA inspector could encounter them, and prepare site staff for the types of questions and documentation requests the inspector is likely to have.

A clinical investigator site who recently hired us to perform a pre-inspection audit was the inspiration for this blog post.  Site audit requests from sponsors and CROs are quite common; requests from the sites themselves are far less typical.  Curious, I asked one of our senior auditors, a DIA instructor herself, if this might be a new trend in the industry.  “Not in my experience,” she replied, “but it should be.”

If you are one of the small number of investigator sites that hire your own auditors, we’d love to hear how that’s working out.  If you’re not, it might be something to consider.

by Laurie Meehan

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Part II: What SOPs Does A Dietary Supplement Distributor Need?

Last summer, we received a lot of feedback on our post entitled “What SOPs Do I Need As A Dietary Supplement Distributor?”   To respond to your questions and comments about 21 CFR Part 111, we’re posting an expanded version of the original article.

If you look at the cGMP regulations for dietary supplements, you’ll notice that only 1 subpart includes the words “holding” or “distributing” in its title.  With only 10 or so individual requirements, the aptly-named Subpart M, “Holding and Distributing,” is shorter than most.  If you’re thinking this means there’s a much lighter regulatory burden placed on companies that simply hold or distribute dietary supplements than on companies that manufacture them, you’d be right.  At the same time, you’d be incorrect to assume that regulations for holding and distributing dietary supplements are restricted to this single subpart.  At least 8 of the 16 subparts that comprise 21 CFR Part 111 are applicable to holders and distributors, and all the activities outlined in these subparts require SOPs.

Subpart B, “Personnel” requires that your employees be qualified for the positions they hold and be trained in hygienic practices and warehouse operations.  Naturally, this training needs to be documented.  SOPs are needed to describe the procedures you have in place to comply with these staffing requirements.  That’s important, because as you read on, you’ll see the warehouse staff has a lot of responsibilities.

Subpart C, “Physical Plant and Grounds” dictates that your warehouse be clean and pest-free.  Dirt, insects, lubricants, or other agents could compromise the packaging or prevent labels from adhering.  Your facility also needs proper drainage, adequate space, and work lighting.  (Do cramped or dark conditions increase the likelihood of dangerous product mix-ups?  Is any of your product sitting directly on the floor rather than on pallets?)  You must also make sure that the product you hold is not exposed to more heat, cold, humidity, or light than the manufacturer recommends.  (Is the heat tunnel you use for sealing shrink wrap too hot?  Do you have backup refrigeration?  Is there sufficient ventilation?)

Any homeowner knows that conditions in a building are not uniform; buildings have hotspots, cold spots, and damp spots.  Just as the pharmaceutical industry has done, some dietary supplement holders are using a technique called “warehouse mapping” to help ensure safe product storage.  In warehouse mapping, the 3-dimensional warehouse space is logically divided into many smaller blocks, a sort of Rubik’s Cube.  Sensors that monitor temperature and humidity are placed in all 8 corners, the areas of the “cube” that are most subject to variations in environmental conditions.  Monitoring is performed at least seasonally, as temperature and moisture will fluctuate throughout the year in most locations.  Sensor data can help warehouse staff pinpoint specific areas of the facility that have inadequate ventilation or excess heat or moisture.  Additional fans, air conditioners, or dehumidifiers can then be deployed to remediate any adverse environmental conditions.

Subpart D, “Equipment and Utensils” discusses the care and feeding of all machines used to control environmental conditions, and to move, store, repack, or otherwise handle product.  SOPs describe proper cleaning procedures, permissible cleaning agents, and cleaning frequency.  (Could this cleaning solution cause labeling ink to fade?)  They describe inspection and maintenance requirements.  (According to the manufacturer, how often should this thermostat be calibrated?  How often is electronic inventory control data backed up?)  They outline installation and operational qualification procedures.  (Has your industrial scale been installed on a flat surface?  Is your packing peanut dispenser blowing so forcefully that it could damage labeling or product container-closure systems?)  Finally, SOPs describe all of the associated records that must be kept and the internal QA procedures to ensure it’s all being done. 

Because you cannot ensure the quality of the product you distribute without verifying the quality of the product you receive, holders and distributors must implement some of the measures identified in Subparts E and F which cover Process and Quality Controls.  The contents of incoming shipments must be confirmed against invoices and other paperwork, and applicable certificates of analysis must be verified.  Product should be visually inspected.  (Has any product reached or neared its expiry date?  Is any product damaged?)  SOPs which describe these activities, as well as the procedures for handling damaged/expired product must be documented and followed.

Since Subparts G through L apply only to manufacturers, packagers, and labelers, alphabetically we’re now up to Subpart M, “Holding and Distributing.”  Not surprisingly, this section requires that product be held in a manner that prevents its contamination and deterioration, and preserves its purity, strength, and composition. As we’ve seen, Subparts B through F outline many of the detailed regulations you need to follow in order to protect your products…but not all of them.  Temperature, ventilation, and moisture content are not just warehouse attributes; they apply to shipping environments, as well.  To ensure that product receives the same protection in transit as it received in the warehouse, distributors must conduct shipping tests at various times of year and over a variety of shipping routes. (Will our product survive the stretch of Interstate 10 between Phoenix and Tucson in the middle of August?)  Lastly, Subpart M requires that samples of each batch of product be retained for a specified period of time.  Holders and distributors should document and follow procedures for periodically reviewing the condition of the samples and for investigating the cause of any deviations discovered.  (Are the product labels legible?  Is the packaging holding up? What should you do if the the appearance of the product has changed during its shelf life?) 

Even after your product has been delivered, your regulatory obligations have not been fully discharged.  Subpart N, “Returned Dietary Supplements” outlines quarantine and disposal requirements you must follow and quality control responsibilities you must carry out when product is returned to you.  (Under what circumstances can we redistribute product?   What if the return is simply the result of excess retailer inventory?)

Subpart O, “Product Complaints” outlines your responsibilities surrounding any product complaints you may receive.  Remember those samples you’ve been storing according to Subpart M?  Get them out, because that’s where your investigation will begin.  Some of the activities here resemble those of a traditional CAPA program:  determine the root cause of the problem and take corrective and preventive action.  (What if the problem is not mine – what is the protocol for dealing with manufacturing, packaging, or labeling issues? What are my obligations if we receive an email from someone who claims that the product has made him sick?)    

Finally, as a distributor, you would likely play a key role in any product recall.
Subpart P, “Record and Record Keeping” enumerates the data you must keep in order to respond appropriately to a recall order (as well as demonstrate Part 111 compliance in general).  Conducting periodic mock recalls to test your recall SOPs will help ensure that inventory and distribution records provide the information necessary to successfully recall all targeted product.

Perhaps to those involved in pharmaceutical manufacturing or clinical research, the regulatory burden placed on holders and distributors of dietary supplements may seem light.  In fairness, comparatively, it is light.   But that doesn’t mean complying with all the necessary Part 111 provisions is easy or straight forward.  It takes even the veterans time, effort, and expertise to develop the procedures necessary to achieve compliance, and it takes vigilance to follow and maintain them.

If you’d like some assistance navigating your way through 21 CFR Part 111 compliance, please visit us at www.polarisconsultants.com.

by Laurie Meehan 

with Special Thanks to Rosanne Sylvia-Heeter, Director of GMP Compliance

This article appears in “Quality Lifeline”, a MasterControl publication.  http://www.mastercontrol.com/dietary_supplements/sops-dietary-supplement-distributor.html?source=n3w5quality|70130000000XEpx

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