Key Points of FDA's Draft Guidance on Manufacturing Quality Agreements

At the end of May, FDA published its draft guidance, officially titled “Contract Manufacturing Arrangements for Drugs: Quality Agreements”.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In Europe, Sponsors (or, in the vernacular of the draft guidance, “Owners”) can outsource the final product release/rejection of finished goods for distribution.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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Examining the Slow Transition to Risk-based Monitoring

In August 2011, the FDA published its draft guidance to industry, Oversight of Clinical Investigations – A Risk-based Approach.  The EMA, MHRA, and European Commission have also published papers in support of risk-based or adaptive monitoring.  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.

The FDA guidance encourages organizations to forgo the former one-size-fits-all, gold standard of monitoring:  100% source data verification (SDV) and on-site visits every 4 to 6 weeks.  There are two distinct themes at play here.  First, information technology reduces, if not obviates, the need to review study data on-site.  That site visits might be less frequent as a result cannot be a wholly unexpected consequence.  A move towards remote data monitoring, and any associated decrease in on-site visits, does not necessarily represent a philosophical shift for FDA, so much as an acknowledgement of the inevitability of advancing technology.  Had the new guidance been titled Oversight of Clinical Investigations – A Remote Monitoring Approach, the industry might not have raised a collective eyebrow.

A far more philosophical departure is FDA’s position that traditional absolutes, such as100% SDV, are often overkill -- they don’t necessarily produce more reliable results or offer greater subject protection than less intensive approaches would.  Instead, FDA says that decisions about frequency, intensity, and type of monitoring should be made according to the risk that each study, and even each site, presents.  Variables to consider in these decisions are therapeutic area, protocol complexity, investigational product safety, population vulnerability, investigator experience, EDC capabilities, and study phase.

Verifying anything less than 100% of source data is easier, cheaper, and faster than verifying all of it.  Applying more resources to critical areas and fewer resources to less important, less risky areas sounds obvious.  So why haven’t sponsors and CROs scrambled to implement these process changes as fast as possible? 

Assessing risk is hard.  You can download all the risk assessment tools you want, but it doesn’t change the fact that striking a smart balance between risk and benefit is the result of careful analysis, long experience, and good judgment.  You’ll probably never know if you overestimate the risk you face.  You’ll just end up performing unnecessary monitoring procedures that offer little benefit, but only after you’ve spent a lot of time and money on a useless risk assessment effort.  If you underestimate the risk you face and fail to sufficiently monitor the study, you defeat the entire essential purpose of study oversight, jeopardizing the safety of your patients and the reliability of your results.

Another reason sponsors and CROs have moved slowly towards an adaptive monitoring approach rests with the study sites themselves.  Without 100% SDV, sites need to integrate quality management into their processes, rather than rely on monitors to identify questionable data.  Risk-based monitoring requires more vigilance from site staff than is necessary with the traditional monitoring approach, and may require additional site training. 

Despite these difficulties, some sources report that companies are nevertheless beginning to implement risk-based approaches to clinical oversight.  In January, the Applied Clinical Trials website published a trend analysis developed by Medidata Insights.  Among their client companies, Medidata reports that median SDV percentage rates have been dropping steadily since 2007. 

Still, the perception is that transition to risk-based monitoring is slow.  An Outsourcing-Pharma article recently quoted the CEO of Annex Clinical who says firms are still checking every piece of data associated with a clinical trial, including data not central to data integrity or subject protection.  That same publication summarized the opinions of many attendees and speakers at this year’s Partnerships for Clinical Trials conference.  They believe that the guidances on risk-based monitoring lack clarity, and are urging regulatory authorities to make more solid rules.  Even Big Pharma concedes it has to understand risk-based monitoring better.  In September, Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Pfizer, Roche’s Genentech division, and Sanofi formed the non-profit TransCelerate BioPharma, with the goal of improving the quality of clinical studies and accelerating the development of new medicines.  Among their stated objectives is the development of risk-based site monitoring approaches and standards.

If Big Pharma is still struggling to understand comprehensive risk-based monitoring, smaller biotech companies are even further from implementation.  Smaller companies are less likely to have the resources and experience necessary to conduct thorough risk assessments and then translate them into adapted monitoring plans.  Also, small biotechs are more likely to conduct significantly smaller studies, which may translate into smaller risk tolerance.

And then there’s this:  Big Pharma is notoriously risk averse when it comes to deciding what biotech firms to purchase or what new products to license.  A due diligence team needs to present an airtight case to its management, who, in turn, wants to make sure the company’s investment will be sound.  Smaller firms understand this.  They know that they may only have “one shot on goal” to either partner or sell, and are concerned that their Big Pharma suitors will be dissatisfied with anything less than 100% SDV and frequent on-site visits. 

So what happens from here?  Transition to a risk-based monitoring approach may continue to inch along at its current pace.  Organizations like TransCelerate may develop standards which set the stage for large-scale adoption.  Maybe a final version of the FDA guidance will offer clearer parameters for implementation.   Whatever happens in the industry at large, it’s likely that the need to reduce clinical development costs will motivate some companies to aggressively move toward risk-based approaches, with or without accepted industry standards or further regulatory guidance.  They’ll be the ones to watch.

By Laurie Meehan

Yes, SOPs Are Hard To Write…It’s Not Just You

Ask anyone who works in a regulated industry about the purpose of SOPs and you’ll be told it has to do with minimizing variation.  Consistency, they’ll say, promotes quality.  It follows, then, that SOPs must be straight-forward and unambiguous.  If procedures are too complex or can be interpreted in a number of ways, they will not produce consistent results, and quality of the end product, whatever it is, will be at risk.  Simple.  Obvious.  SOPs 101.

It’s too bad for us that tasks are not always simple or obvious.  Often, a worker can achieve a quality result only by correctly responding to a number of variables that could arise.  An SOP that outlines such procedures has to describe each situation the worker might encounter and then provide the appropriate corresponding response.  In complicated procedures, these situations can become nested.  (Is it A, B, or C?  If it’s C, is it X, Y, or Z?)  An otherwise simple, linear set of instructions can quickly become a complex decision tree.  Also, the distinction between situations that require different responses may not be clear cut, and may only be a matter of degree.  Unless decision criteria are thoroughly explained, each worker will devise his or her own, and consistency will be lost.  Naturally, the more complicated the instructions, the more subject to misinterpretation they are.  SOP writers are challenged to capture all this complexity in a clear, concise set of procedures.

We expect a lot from our SOPs.  In many companies, SOPs don’t just supplement training, they are training.  Once upon a time, new employees were mentored by seasoned workers who would teach them the rationales behind the procedures and share undocumented nuances that they’d learned over the years.  Now, with mentorship programs becoming an extravagance most companies can no longer afford, we increasingly rely on SOPs to communicate that accumulated wisdom.  We also use SOPs to demonstrate regulatory compliance.  Sometimes, we even expect to use our SOPs as a means of legal defense, should our conduct be called into question.  Is it any surprise that the more we try to cram into our SOPs, and the more masters we have them serve, the harder it is for us to write them in a concise, easy-to-follow manner?

Smaller companies, with minimal or non-existent training staff, may rely more heavily on SOPs than their larger counterparts do, yet maintaining SOPs requires a significant resource commitment of its own.  Subject matter experts are needed to research the latest regulations, determine their impact on existing procedures, and author updates.  It’s difficult for experts in small companies to move steadily through this process because SOP maintenance is necessarily put on the back burner when profit-generating work demands. 

So, if all along you’ve been wondering why writing and revising your set of SOPs seems so hard or takes so long, maybe you can take some comfort from the fact that it’s not just you!

By Laurie Meehan

If you think you might like some help writing or maintaining your SOPs, contact us at info@polarisconsultants.com and we’ll set up some time to talk.