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It is widely known and understood that the no. 1 cause of delays in clinical trials is inefficient patient enrolment. The problem has become widespread and does not show any signs of abating. According to a TUFTS analysis, 48% of investigative sites either under-enroll or fail to enroll subjects. This leads to prolongation of study timelines, delayed marketing authorizations for important drugs and very significant financial losses for pharmaceutical and biopharmaceutical companies.

To rectify the patient enrollment gap, much time and effort is spent on advertisement for participation in clinical trials. The use of traditional and social media in direct-to-patient advertising of clinical trials is well established and popular in areas such as the United States, but the problems regarding delays in enrollment are not ceasing. This clearly indicates that new strategies should be sought out and implemented.

Many sponsors and CROs have tried to increase patient enrolment rates by engaging external physicians. EC/IRB-approved principal investigator (PI) letters to colleagues and other physicians is a well-known example of such attempts. However, in reality, PIs typically lack both time and motivation to fully engage in building and managing a referral network. Even when external physicians respond to a PI’s letter and try to refer patients, without proper organization and support, many of these patients simply never reach the investigative sites.

Some useful data illustrating the current state of engagement of referring healthcare professionals comes from a 2017 Tufts CSDD survey of 2,000 nurses and physicians. It was revealed that 70% and 90% of them are comfortable with discussing clinical trials with their patients but less than 0.2% actually do so. The main reasons for this, according to the Tufts impact report, are that: Physicians and nurses have limited information about the relevant clinical trials, they do not have enough time, and poor communication and co-ordination between the parties involved in the referral process makes it inefficient.

This firmly suggests that supportive strategies should be developed, which will create a system of support for external physicians’ referrals and improve communication between referring physicians, sponsors and CROs, and study investigators.

A new, innovative strategy which targets these problems, is ePatientFinder’s Clinical Trial Exchange™ platform. On the platform, patients’ electronic health records (EHR) and information regarding ongoing trials (filtered by geography and specialty) are matched and brought to the attention of physicians who have suitable patient resources. The patients identified through the system, are invited by physicians for a discussion and personal pre-evaluation which makes sure that the patients who are eventually referred are highly qualified and willing to participate in clinical studies.

We here at Clinical Accelerator and ClinAccel.Net have always valued the role of external physicians in effective patient enrolment campaigns. Having worked in the patient enrolment support field for many years, we have developed an enhanced patient enrolment model involving a large, ever-growing network of referring physicians working in all major therapeutic areas and our PEMs (patient enrolment managers) who identify relevant external physicians, help them with patient identification and manage the whole referral process. They ensure streamlined and effective communication between the referring physicians and study investigators and take care of simple but important tasks such as patients’ transportation to clinical sites and remuneration for their spent time.

Rather than focusing on direct-to-patient advertising campaigns, our focus is on patient information campaigns delivered by our partner physicians who care medically for the patients we seek for enrolment into clinical trials. Our PEMs assist doctors in designing and delivering these patient-oriented campaigns and providing them with IRB-approved supporting materials which are typically used within healthcare institution environments.

The end result of taking full advantage of referring physicians’ untapped potential, is that qualified patients are identified, screened and referred in high numbers and at speed, leading to faster patient recruitment, more compact study timelines and reduced trial costs.

Anna Nikitina.

References: Poor physician and nurse engagement driving low patient recruitment. Tufts Center for the Study of Drug Development Impact Report.  Jan/Feb, 2017, Vol. 19 No. 1.

Over 6,800 rare diseases such as Haemophilia, Tay Sach’s disease and Gaucher disease are affecting more than 25 million Americans. Still yet, there is limited understanding or knowledge of these debilitating, life threatening and progressive diseases. The Orphan Drug Act defines rare diseases as disorders affecting less than 200,000 people in the United States. Such a small patient population is the exact cause of problems and challenges in patient enrolment.

One requirement for the study of human diseases is an appropriate trial design. Randomization and control are considered essential if efficacy is to be attained and bias to be reduced, but for this a large sample must be acquired. However, due to scattered patient populations, variations among disease sub types and simply by necessity, clinical trials in rare diseases enrol small samples and still yet with difficulty.

This is partly due to the fact that the majority of rare diseases affect children and reduce lifespan. This leads to families being less likely to enrol their child into a study in which they may receive a placebo. Ethical issues may arise too as children are considered a ‘vulnerable’ population. In addition, problems occur if several studies are being carried out simultaneously as enrolment of a patient in one study may cause illegibility in another. As a result of enrolment challenges, it’s calculated that approximately 30% of phase III trials in rare diseases fail.

Clearly, rare diseases require an approach that is tailored to the study goal and specific indications. Two solution that are arguably vital are: in-home Clinical Trial Support and Patient Registries.

In-home Clinical Trial Support

Traditionally, patients are faced with the inconveniency of traveling to sites numerous times during the study. This puts strain on the patients’ budget and induces drop-outs. In-home Clinical Trial Support however takes into account the patients preferences and difficulties. The nurses travel to the patients’ home instead to carry out the clinical tests, PK sampling, drug infusion administration etc. This saves the patients major costs in regards to accommodation and reduces the number of visits to the sites making the concept of enrolment more appealing.

Patient Registries

With rare diseases it is often the case that sufficient data or information is unavailable. Patient registries help improve understanding and expand the knowledge base for companies developing treatments. Patient registries are global online data-repositories encompassing patients’ treatment-related health information which are created by several nations such as the U.S and Europe. They allow the development of communities which are able to share information regarding clinical trials which in turn increases the rate of patient recruitment, reduces enrolment delays, and allows better site planning as wider knowledge on the subject is made available.

The current status in regards to rare diseases is that we have a significant knowledge gap. In order to reduce this, continued collective efforts must be made to improve the clinical trial protocol design which will ultimately reduce time delays, hasten patient recruitment and most importantly, benefit those suffering from rare diseases.

References:

Augustine, Erika F., Heather R. Adams, and Jonathan W. Mink. “Clinical Trials in Rare Disease: Challenges and Opportunities.” Journal of child neurology28.9 (2013): 1142–1150. PMC. Web. 9 June 2017.

Khaleel, Samiya. “Rare Disease Patient Recruitment And Retention.” Clinical Leader. N.p., n.d. Web. 8 June 2017.

Leavy, Michelle, and Richard Gliklich. “Patient Registries and Rare Diseases.” Applied Clinical Trials. N.p., 2011. Web. 8 June 2017.

Stevenson, Danielle. “Clinical Trials for Rare Diseases – Finding and Keeping Patients.” BHD Foundation. N.p., n.d. Web. 8 June 2017.

Tirunagari, Sreedhar. “Rare Disease Clinical Trials‘Patient Recruitment Challenges.’” Global Health Trials. N.p., n.d. Web. 8 June 2017.

Anna Nikitina

What are the implications and consequences of the Brexit vote for the pharmaceutical and MedTech industries so close to the heart of most reading this piece? Many in these industries and in academic research establishments argued that a Brexit vote would be damaging for research and patient access and change the way drugs and medicines are tested and marketed; worryingly, two US companies intimated to the National Eczema Society that trials of new treatments would not take place in the UK in the event of Brexit.  Other campaigners, criticising ponderous bureaucratic nature the European Medicines Agency (EMA), have said that drugs could be made available more quickly if the UK votes to leave.

Whilst every EU member state has its own medical regulatory body (’Competent Authority’ – this being the MHRA in the UK) able to license new drugs, the European Medicines Agency (EMA) is currently a centralised body staffed and run by regulators from all EU member states providing marketing authorisation that is valid throughout all member states and countries in the European Economic Area (EEA i.e. EU plus Iceland, Liechtenstein and Norway).  Now, the EMA happens to be based in London, so the question is what happens given that the country with the EMA HQ is no longer to be a member?  It seems more than likely that the EMA will have to move its HQ out of London to an EU country. Apart from this obvious major upheaval, some in the pharmaceutical world argue that this will in itself reduce the importance of the UK in the eyes of the global drug companies.

If the UK decides to negotiate to stay in the EEA (a likely scenario?) there should not, in practice, be much difference to regulation. But if the UK stays out of the EEA, drug companies would need to go through a separate process with British regulators for new products without the benefit of a centralised European route.  However, UK drug and device companies will certainly want to market their products internationally, whatever happens to the infrastructure of the regulatory bodies and their internal procedures.  Thus it seems most logical that trials in the ‘independent’ UK must continue to run along the same guidelines as the rest of Europe. All procedures must still remain entirely compatible so that the EU could agree authorisation for marketing UK drugs and devices – one can argue that accepting this premise should mean no major changes in procedures and counter some expectations that not being an official part of EU-harmonisation might jeopardise the currently high degree of involvement in rare disease trials (the UK conducts around 40% such trials) as well as appeasing non-UK companies reluctant  to perform trials in the UK following Brexit.

There is also a move for even closer harmonisation within remaining EU states over the next few years to allow a single EU-central entry point for companies to apply for clinical trial authorisations (CTAs). Currently, of course each country still ‘competes’ to obtain their own CTA from Competent Authorities to local procedures.  Without care, this could distance the UK from EU regulations and trials conducted therein.

The Leave campaign argued that the existing EU Clinical Trials Directive has damaged medical research and innovation in the UK. For example, the UK Commons Science and Technology Committee said in a recent report: “Weaknesses in the 2001 Clinical Trials Directive significantly increased the administrative burden and cost of running academic clinical trials and saw a reduction in trials taking place in Europe.”  It did then acknowledge that the new regulations due to take effect in 2018 appeared to be an improvement [2].

There are legal aspects to consider: EU Directives governing medicinal products require the UK to implement relevant legislation into national law (done by reference to the European Communities Act of 1972 and through the implementation of the Human Medicines Regulation of 2012). The UK’s departure from the EU would mean these laws remain in place unless the UK government decided to change them.  Also, if the UK adopts national legislation that is significantly different to the new EU Regulation, this is likely to make the environment difficult for companies wanting to undertake trials in a number of countries that includes the UK.

Few would disagree that the result of the referendum vote is important for drug and MedTech companies and their products.  What of the reactions from some regulatory and official bodies?  Do these cast any light on future developments?  The MHRA, in their response, have said that they would work closely with the government to ‘consider the implications for the work of the Agency’ and to ‘continue to make a major contribution globally to improving public health through the effective regulation of medicines and medical devices, underpinned by science and research’ [3].   The statement from the Association of the British Pharmaceutical Industry (APBI) says that they ‘are committed to working closely with the government to agree what steps need to be taken to send a strong signal that the UK is open for business [4].

The European Federation of Pharmaceutical Industries & Associations (EFPIA) has said that it ‘shares the common goal of ensuring rapid access to innovative medicines for patients across Europe, as well developing a regulatory and policy environment that fosters innovation and supports the research and development of new medicines to meet the needs of patients, healthcare systems and society.  As an industry, over the coming months, we are committed to engaging with stakeholders both in Europe and in the UK to support these objectives’ [5].

Clearly nothing is clear among ‘the powers that be’ about the effects of all this and what will happen at this stage! There is still much conjecture, and given that the EFPIA has also rightly said that ‘The process of the UK leaving the European Union is likely to be long and complex. The pharmaceutical industry stands ready to work closely with governments and EU institutions to minimise its impact on patients and secure the future of medical innovation across Europe’, there is much to discuss and plans are yet to be put in place.  Trials will go on in Europe and, of course, in other territories not embroiled in the EU and its regulations. As for EU developments, it really is a case, to put it in medical terms, of ‘watchful waiting’…….

Brian Cary

References

1. https://next.ft.com/content/1ce1a720-ce94-3c32-a689-8d2356388a1f
2. http://www.publications.parliament.uk/pa/cm201617/cmselect/cmsctech/158/15807.htm
3. https://www.gov.uk/government/news/medicines-and-healthcare-products-regulatory-agency-statement-on-the-outcome-of-the-eu-referendum
4. http://www.abpi.org.uk/media-centre/newsreleases/2016/Pages/UK-must-send-strong-signal-it-is-open-for-business.aspx
5. http://www.efpia.eu

Well, the people of Britain have now spoken – albeit not that clearly given a 51.9%:48.1% split in the referendum voting figures. Nevertheless, it’s a democratic decision and now the word on almost everyone’s lips is “Brexit”. Despite a protest march and some other attempts to try and overturn the result or re-run the event (constitutionally problematic?), previously ‘pro-remain’ politicians in Britain now appear to be fully accepting the decision and will actively participate in what is set to be the long process of extricating the countries of the UK from central EU control.  Hopefully this ‘divorce’ will be an amicable one, retaining the good will and well established personal and trading relations with EU citizens and companies.

Looking at the statistics of the vote for a moment, which give an interesting insight into some demographics of the voting electorate, it appears that the leave result was swung somewhat by the over 60’s with younger people voting quite convincingly to remain – but being fewer in number the overall impact was dampened (perhaps apathy or indecision among the young led them not to vote?)   Age, aside, other demographics from the 382 separate voting areas indicated that ‘Leavers’ tended to be more prevalent in low income areas and (paradoxically?) from areas most economically dependent on the EU; whilst ‘Remainers’ tended more to be degree-educated, in jobs requiring a degree or have not travelled abroad recently (non-passport holders) but of course there was no clear-cut divide as these were statistical trends and I know many in the more elderly spectrum voting to remain [1].

All sorts of financial and social consequences of a vote to leave were mooted and, indeed, the expected dismay and turmoil on world financial markets followed the largely unexpected result immediately and although nerves (financial markets, at least, at the time of writing) seemed to have calmed somewhat, people in different industries and professions will be wondering what the future operating landscape for their businesses will look like.

In the second of these two pieces we shall consider some of the arguments for and against ‘Brexit’ for the Pharma and MedTech industries and whether there is any indication of what happens next.

Brian Cary

References

1. https://next.ft.com/content/1ce1a720-ce94-3c32-a689-8d2356388a1f

According to Penn Medicine Researchers study’s, Twitter has the potential to promote patient recruitment into oncology clinical trials and increase the interest of patients [1].

Enrollment into clinical studies is crucial for the development of new treatment options for patients. It is also provides opportunities for those who are not responsive to the previous treatment or who cannot afford it. However, only about five percent of adult cancer patients participate in clinical studies, thus creating a problematic situation for the drug development environment.

According to statistics, approximately 15-20% of all trials never manage to enroll a single patient, 37% of all sites in a given trial fail to meet their enrolment targets. It is also worthy to keep in mind that nearly 30% of the time dedicated to clinical trials is spent on patient recruitment and enrolment [2]. To overcome this problem, companies are trying to reach their potential clinical trial participants via dedicated websites (Novartis), Facebook, Google, YouTube etc. [2].

Physicians from Abramson Cancer Center of the University of Pennsylvania analyzed a number of lung cancer tweets in the social media and found that a great number of posts were about clinical trials. Twitter users were particularly interested in immunotherapy. Surprisingly, only one tweet was used to help recruitment into a clinical study.

“Twitter provides a promising and novel avenue for exploring how cancer patients conceptualize and communicate about their health, and may have the potential to promote much-needed clinical trial recruitment.” said Mina S. Sedrak, MD, MS, a fellow member of the division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania and first author of the study published online 3 March 2016 as a research letter titled “Cancer Communication in the Social Media Age” in JAMA Oncology.

Nowadays, there are numerous cancer care organizations and centers that use social media, including Twitter, for promotional and educational purposes. Penn Scientists tried to find out to what extent the information about clinical trails for cancer patients present on Twitter are useful.

In the pilot study, Sedrak and his coworkers analyzed a randomly chosen sample of 1,516 tweets out of a total of 15,346 that contained the phrase “lung cancer” from January 5 – 21, 2015, and assessed who read them.

More than half (56%) of the tweets were focused on psychological support and prevention topics. Nevertheless, clinical trials were the topic of almost 18% of analyzed tweets posted by patients, health professionals and other people, making these studies the second largest theme of social communication. Most of the clinical trial tweets (79%) were about immunotherapy studies, and 86% of them contained links directing readers to original websites and articles.

Authors were surprised to find that only one out of one and a half thousand analyzed tweets were linked to a patient enrollment website [1, 3]. According to them, although some more effort is needed to better assess social media involvement in cancer education, prevention and information, it is worthy to start using it as a tool for recruitment for the cancer clinical trials. On the other hand, social media patient enrollment will be the new challenge to institutional review boards with respect to non-coercive content and the assurance of patient’s privacy. New rules and policies may be needed in order to control the social media enrollment campaigns.

Sedrak sums up that “We need to learn more about the ecology of social media because it is clearly not consistently directing patients to the right places (…) social media may provide an infrastructure for cancer centers, researchers, and physicians to interact with the public in new and productive ways, including stimulating interest in new clinical trials with targeted messages that connect patients, caregivers, and families with trial enrollment websites. This potential remains largely untapped” [1].

References

1. http://www.uphs.upenn.edu/news/News_Releases/2016/03/sedrak/ – assessed 23.06.2016
2. http://pharmaphorum.com/views-and-analysis/using-social-media-for-clinical-trial-recruitment/ – assessed 23.06.2016
3. http://www.symplur.com/blog/twitter-future-clinical-trial-recruitment/ – assessed 23.06.2016

Risk-based monitoring (RBM) is a method that uses risk algorithms to assess the right level of clinical trials monitoring. Food and Drug Administration (FDA) and European Medicines Agency (EMA) currently encourage this approach.

RBM focuses on improving quality of the data and helps to reduce the time consumed and costly on-site 100% source data verification. At times, 25-30% of the whole clinical study budget could be spent on the costs of monitoring (personnel, travel, expenses etc.). Implementing RBM can help to reduce these costs.

There are many other reasons for developing RBM. One of the main reasons is that it could help remove problems that are created through the traditional way of monitoring such as: lack of broadly understood principles; methodology and approach as well as terminology; scope of tasks; deliverables; roles and responsibilities while planning; conducting analysis; reporting and assessment of clinical trials. Additionally, it’s thought that important decisions concerning risks are not based on well-defined and objective criteria but are actually made on the basis of individual or teamwork assessments and opinions. Some observations indicate that there is limited emphasis put on the foundation of RBM with it’s usage restricted to the review of data and ignoring other respects of the study e.g. design of the protocol. It is linked to the fact that often no integrated quality management strategy is implemented. Such strategy should be the foundation of the design of the study, site selection, study management and general oversight aspects. Another problem is lack of sharing risk assessments within and between sponsors. RBM is a risk-based approach developed to manage all these problems.

The application of RBM in clinical trials is growing, especially for Phase II studies. Results of the global survey conducted by the Metrics Champion Consortium  (MCC) in 2013, reveal that all respondents were using some sort of RBM tools. Majority of stake holders (85%) continued traditional on-site monitoring involving 100% source data verification (SDV) activities, while more than a half reported using in the same time some type of RBM program on a pilot basis, or across a full program.

The most popular RBM programs involve on site monitoring with reduced SDV, or remote monitoring with support of the central data analytics (CDA). The methods of remote monitoring include the usage of data analytics reports, remote source data verification and patient profiling, which means monitoring individual study subject reports.

The reasons for adopting RBM varied among different stakeholders. Contract Research Organizations (CROs) and academic research institutes chose to implement RBM to reduce monitoring costs, whereas pharmaceutical and biotech companies chose it to improve quality oversight.

Implementing RBM also has many other advantages. Effective risk management requires a structured approach for risk identification, analysis and control. The system of risk management should be repeatable, reproducible, sustainable and adaptable in meeting regulatory demands and achieving quality outcomes. It outlines a systematic approach for the assessment, communication, control and review of risks related to the respect of quality. Implementing RBM can also help to facilitate many other aspects of the clinical trial, like site selection, qualification, protocol design and subject enrollment.

It seems like implementing RBM strategies would only be possible for big companies and institutions, but the truth is that designing and implementing RBM does not depend on the size of a company. All of interested stakeholders face similar problems e.g. lack of resources, time pressure and growing regulatory requirements and can benefit from developing an effective risk-based approach.

Another myth about RBM is the conviction that it’s implementation can be successful only with the aid of highly sophisticated IT systems. Sometimes, the simplest spreadsheets would be sufficient, but with the growth of study complexity, scope, number of arms and comparators more complex tools that minimize the workload may be needed.  All in all, IT software is not an essential element of the RBM strategy. The basis should be the overall philosophy inclusive identification of risks, analysis of their impact, likelihood and detectability. For such assessments no specific IT systems are necessary.

There is also an opinion that implementing RBM may influence the way of writing protocols and setting up trials. Of course some changes may be needed to improve the overall quality of the study. Indicated fields of improvement are: reaching planned recruitment targets, ending the study on time and on planned budget, launching proper number of amendments, delays and additional costs due to compliance flaws.

The organization, which is interested in developing the Risk-Based Monitoring programs rose as RBM Consortium. It associates quality risk management industry experts, risk-based technology firms, data analysts and biopharmaceutical business strategists. RBM Consortium is a transnational alliance to improve awareness of RBM in clinical trials and give advice to interested stakeholders on the area of quality risk management and methodologies in RBM.

Due to its many advantages and overall interest in ensuring best quality data, RBM seems to be gaining more and more followers and may become the gold standard of risk-monitoring activities in the area of clinical trials.

Source:

Risk-Based Monitoring in Clinical Trials, Applied Clinical Trials, May 2015

In Part 1 we looked at the guidelines [1] for the requirement in India to make AV-recordings of the investigator(s) and patients (and any necessary witnesses/representatives) during the consent process and potential implications [2]. So how, in practice, has this new requirement affected the conduct of clinical trials in India and are there implications for the regulatory environment in other parts of the world?

It seems that results and reactions have been somewhat mixed.   Having to record the procedure on camera will surely have encouraged those investigators agreeing participation in a trial to consent patients fully and properly. There must be little doubt that where there is successful videorecording to the required procedures this is achieving the desired aim of ensuring a clear, transparent and honest record of the process to regulatory ethical standards. But this has come at a cost – the challenges referred to earlier did result in a reduction in numbers of trials and recruitment rate.

For instance, The India Times reported in January 2014 that videorecording was driving away subjects, citing one reason as unwillingness of patients to discuss their condition, especially terminal or embarrassing illness, on camera.  At a Supreme Court hearing statistics presented indicated withdrawal or early termination of 25% (40/157) of cases of Global trials [3].

In April last year the India’s Economic Times again reported that volunteers were being put off clinical trials. Investigators were reporting, for example, that telling burqa clad women to unveil for videographing consent for trials (guidelines insist, understandably, that all participants are identifiable facially) was proving to be some task. The challenge was extreme in a place where people follow strict social and religious prescriptions, it was said. This reflects earlier reservations mentioned that culture and preferences of patients as well as discomfort could affect recruitment.  Suspicion by naive patients of what the recording might also be used for was also mentioned – even the fear that the video might be sold to the media for nefarious purposes was said to put patients off as well as make the investigator feel somewhat awkward! [4]

Lack of infrastructure at the sites (major government hospitals as well as smaller institutions) was, as anticipated, also cited as a reason for reduced involvement in trials, but this is something that institutions and sponsors can remedy to some extent over time.  Some sites have declined to participate in trials since the mandate was introduced for other reasons – this is not necessarily a reflection of the sites ability to undertake the work ethically but the fear of being a scapegoat as part of a possible future witch hunt, it is believed [5].

Other sources, from the sponsors’ monitoring perspective, report that the introduction of videoconsenting has been a good success – at least that is where the capability and willingness to run trials with the mandated process exists.  The impact on recruitment rate was said to have fallen by only around 10% at participating sites (presumably for reasons mentioned above of patient discomfort or wariness) but monitoring the process was not considered problematic [5].

It has to be said that despite recent tightening of affairs, particularly in the improvement of proper consent, there are, apparently, still some shortcomings being found at audit in the quality of trials. For instance the World Health Organization has reported quite recently that for one Indian CRO “Critical” lapses were found in a trial of HIV drugs, including the fact that two-thirds of patients’ ECGs turned out to be identical duplicates with changes in names, dates etc. to make them appear as if they were from different subjects; the standard of record-keeping was also criticised resulting in a ‘notice of concern’ issued by the WHO inspectors in June this year [6].

Nevertheless it is encouraging from the pharmaceutical industry perspective to see the Indian regulatory agencies taking measures to try and ensure quality of trials in their country.  Indeed, the Economic Times of India recently reported (August 12th this year) that India’s Cabinet Committee on Economic Affairs had just approved a proposal for strengthening and upgrading the drug regulatory system at Central and state level at a total cost of Rs 1750 ($270 million) [7]. This has to be done, of course, to protect a potentially great source of income from the conduct of trials.

What of the implications for other world territories involved in trials?  Are we to see this somewhat burdensome requirement of videorecording consent being rolled out elsewhere?  There’s obviously a natural opposition for this in many quarters – especially where strict audits or ‘whistleblowing’ have not revealed malpractice – but for some it will be seen as a further safeguard for patients.

The FDA already publish guidelines on the use of electronic systems and processes that may employ multiple electronic media (e.g., text, graphics, audio, video, podcasts and interactive Websites, biological recognition devices, and card readers) to convey information related to the study and to obtain and document informed consent [8]. Although the use of electronic processes to obtain informed consent (e.g. an interactive interface) is not quite the same thing as documenting the process by filming, it is a relatively short step away from having a video record of the IC process as proof that it was performed appropriately with and by the investigator and participants specified on a written document.

However, perhaps most tellingly, the FDA already recommends video records as a valid way of vouchsafing the process of consent in case of illiterate participants who can understand and comprehend spoken English but are physically unable to talk or write [9].

We shall just have to ‘watch this space’ to see how this matter develops. In the meantime, in most areas of the world, we shall be allowed to conduct the consent process – naturally, in diligent and professional fashion – away from the glare and any perceived intrusion of the cameras.

1. http://www.cdsco.nic.in/writereaddata/Guidance_for_AV Recording_09.January.14.pdf
2. http://www.cdsco.nic.in/writereaddata/Office Order dated 19.11.2013.pdf
3. http://timesofindia.indiatimes.com/india/Video-recording-of-consent-for-clinical-trials-driving-away-subjects-SC-told/articleshow/29626348.cms
4. http://articles.economictimes.indiatimes.com/2014-04-22/news/49318820_1_trials-cervical-cancer-consent-process
5. Personal Communications via ‘Freelance Clinical Researchers’ Yahoo Group
6. http://apps.who.int/prequal/info_applicants/NOC/NoticeConcern-Quest_July2015.pdf
7. http://articles.economictimes.indiatimes.com/2015-08-12/news/65490088_1_ccea-drug-regulatory-system-proposal
8. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM436811.pdf
9. http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm

Lights, camera, action!  Starring Investigator and trial participants….

Back in November 2013, following a number of scandals in India involving revelations that vulnerable patients were being recruited into unethical clinical trials without proper informed consent, a supreme court order demanded that mechanisms be put in place to address these worrying ethical issues. This resulted in the CDSCO (Central Drugs Standard Control Organization) issuing a direction requiring an interesting and some would say challenging, new procedure in the recruitment and consent process.

The direction from the Drugs Controller India [1], which is aimed at all sponsors, investigators, institutes/organizations and other stakeholders involved in clinical trials went (in part) as follows: “In all clinical trials, in addition to obtaining written informed consent, audio-visual recording of the informed consent process of each trial subject, including the procedure of providing information to the subject & his/her understanding on such consent is required to be done while adhering to the principles of confidentiality”. This was to apply to all local and global clinical trials.

This move was understandably greeted with some consternation and scepticism about the practicality of this potentially burdensome additional requirement.  However, as the immediate consequence of the Supreme Court’s reaction to the scandals was that the number of new clinical trials dropped dramatically (data from the Indian Government show that the number of trial applications/approved studies fell from 480/253 in 2012 to 207/73 in 2013) strong regulatory intervention was necessary to try and restore some confidence in the ethics and integrity of Indian clinical trials as far as sponsors and regulatory agencies, non-governmental organizations and the public were concerned.

Some initial guidance on the requirements was provided for clarification and, indeed, to achieve a degree of standardization to deliver quality suitable for audit.

The strict guidance outlined key aspects of required procedures: Basic requirements for the AV recording (equipment, surroundings etc); documentation and approval requirements; the process of A-V recording consent (with initial consent being required for the recording as well as covering, and ensuring understanding of, all the required points – including foreseeable risks or discomforts that might have been missing from poorly obtained consent with overstated benefits); points to consider (such as testing the equipment, reaffirming consent to recording, clear facial identification of participants, ensuring no interruptions etc.); storage of recordings (pen drive, CD/DVD, security, archiving etc.).  Guidance also states that it is the Investigator’s responsibility to adhere to the principles of confidentiality; AV recording should be treated as written medical records in terms of confidentiality, removal from the site and access by patients as mentioned in ICMR (Indian Council of Medical Research) & Indian GCP.  With digital recording, safeguards regarding electronic transmission are as important as the safeguarding of the physical location of the recording, they point out.   Other guidance topics include access to A-V records (e.g. controlling this and maintaining confidentiality); video re-consenting as necessary during the trial; requirements for special populations (video recording of the usual consent from independent witnesses or legally acceptable representatives).  Roles & Responsibilities are covered – with the PI also having overall responsibility for identifying and training the site staff and AV recording of consent process etc. [2]

If fully and successfully applied, adopting these procedures should clearly improve the reliability, transparency and quality of conducting the informed consent process to internationally recognized standards and be welcomed at an ethical level but at the same time its introduction will surely have placed extra challenges on sponsors and investigators to apply them as required.  These challenges, at best, put pressure on potential recruitment numbers at sites and at worst prevent some potential investigators taking part in trials at all.

Firstly, there is the infrastructure at study sites to consider in making AV recording at the sites possible – suitable rooms for the recordings in a quiet environment and the equipment itself – and this will incur some additional consent costs to the budget, especially as the recordings (and storage/archiving) applies to all patients being consented, including screen failures.  A little extra time is also need to set up and conduct each process.

There is also the question of culture and preferences of potential participants, which may prevent proper recording according to necessary guidelines; feelings of intrusion or any discomfort at being ‘on camera’ may simply result in refusal to participate – with an obvious negative impact upon recruitment. One also has to remember that consent is a ‘process’ not a simple ‘event’ and recording this can produce more work at the site.  A potential language barrier may also exist, particularly for external monitors, meaning a careful more restrictive choice of personnel for this task is necessary.

Note that for consent of ‘special populations’ of patients (e.g. illiterate patients, those not able to consent for themselves) any necessary witnesses, representatives or guardians are also involved as participants in the recordings and so their willingness (and consent) to the process must also be established.

Any ‘re-consenting’ required after amendments also creates extra work and potential dilemma – for example, what to do if a participant refuses further video recording yet  wishes to continue in the trial?

Further, there is an extra, but obviously important, dimension to video consent – that of interpretation of ‘body language’, both of the patient/representatives and of the investigator / study staff.  Although assessing degree of willingness on behalf of the patient or possible coercion on behalf of the investigator is the principal benefit not apparent with a simple signature, it puts the extra onus on monitors and auditors to understand and interpret the scenario and, in some cases, perhaps even feeling confident to question the purported freely given nature of the consent.  Training of these personnel in this and other aspects of video-consent is also an important consideration requiring extra time and expertise.

Extra care would be necessary to protect the confidentiality and integrity of the additional personal information and identity of patients on behalf of the investigator (camera, pen drives, SD cards etc.) and particularly the sponsor’s personnel who have access to, and review, the videos.  Tampering with the video record – inappropriate editing down, for instance – is something sponsors and regulators should also be on their guard about, although one trusts that this would be a rare occurrence.

In part two on this topic we shall consider how this requirement has been received and how, in practice, it may have affected the conduct of clinical trials in India.

1. http://www.cdsco.nic.in/writereaddata/Office Order dated 19.11.2013.pdf
2. http://www.cdsco.nic.in/writereaddata/Guidance_for_AV Recording_09.January.14.pdf

New draft guidance has just been issued by the US Food and Drug Administration (FDA), which aims to make it easier for medical device companies to rely on data obtained from clinical studies conducted outside the United States (conveniently termed ‘OUS’ studies by the FDA).  Naturally, this is provided that those studies are conducted to appropriate federal standards.

The draft guidance document (1) is closely related to a rule proposed by FDA back in February 2013 (2), which proposed a requirement that all clinical studies conducted outside the US in support of a device application comply with US regulations on good clinical practice (GCP).

The goal, regulators explained, was to promote consistency in the trials whilst assuring that human subjects participating in the trials were given adequate protection. The FDA now accepts data from foreign-conducted clinical studies meeting requirements of code of Federal Regulations 21 CFR 812-14.  This states that the data must be scientifically valid and must have been collected in accordance with the ethical guidelines of the Declaration of Helsinki or local laws (whichever offers stronger protection to research subjects).

These data are most commonly used in support of an application that includes data from the US, but the FDA encourages sponsors to discuss plans with them if the application will be “based solely on foreign clinical data”. Those requirements are less stringent than required for clinical trials conducted within the US, which are held to various US-specific regulations (e.g. 21 CFR 56 for IRBs and 21 CFR 50 for informed consent).

In this newest draft FDA guidance, the change regulators need to account for is that medical device trials are becoming increasingly global.  They say that the number of IDE applications and submissions for marketing authorization supported by ‘OUS clinical trials’ has increased in recent years and it is likely to continue increasing in the future.  They also say that this increasing globalization of clinical trials presents challenges to both US and foreign regulators. Among the challenges are constraints in resources that have an impact the number of foreign clinical site inspections and unnecessary duplication of clinical studies and administrative burdens.

Another proposed change acknowledges Section 1123 the FDA Safety and Innovation Act (FDASIA) of 2012,  Here, the FDA was required to accept data from clinical investigations conducted outside the US as long as the data were collected according to acceptable good clinical practice. While the FDA said it had a “longstanding” approach to accepting these types of data, FDASIA served to codify the practice into law and called on the FDA to clarify the processes by which the data could be accepted.

Thus an Either/Or Approach is indicated in its guidance document. Either a company’s clinical trials conducted outside the US meet federal human subject protection requirements exactly, or they meet local standards, which a company must show are either equal to or greater than US requirements for human protection under the Declaration of Helsinki (1983 version). In addition, the FDA’s guidance addressed what it calls “valid scientific evidence” – this is evidence from what the FDA defines as “well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts and reports of significant human experience with a marketed device.” Should the FDA determine that the OUS data constitute valid scientific evidence, under its code 21 CFR 860.7, then the OUS data can be used to support clearance or approval of the application, say the FDA. Sponsors intending to initiate or rely on an already-conducted OUS data should “seek input from the relevant Center for Devices and Radiological Health (CDRH) or Center for Biologics Evaluation and Research (CBER) review division at the earliest stage possible using the Pre-Submission process,” it adds.

Given all this, one might ask what factors sponsors should take into account when assessing whether they can rely on data obtained from studies conducted in countries other than the US. The FDA says that there are three main considerations:

• Are there differences in clinical conditions which might affect the standard of care afforded to a patient?
• Are there differences in the populations being studied, which might preclude the data from being extrapolated to US patients?
• Are there differences in regulatory requirements which might cause the study to fail to meet US requirements?

If readers require further insight into these considerations, seven examples are given in the 15 page draft document (1) of issues that can arise when using clinical data from device studies collected OUS to support FDA regulatory decisions. How the FDA and sponsors may seek to resolve such issues and the likely review outcomes are also mentioned.

Clearly from all this, medical device companies or other researchers aiming to conduct important or pivotal studies in countries other than (or in addition to) the US wanting FDA-standard data – and, in certain areas of the globe, there are considerable advantages in ease of set up, speed of recruitment as well as significant cost benefits without any sacrifice in data quality – should use a reputable Clinical Research Organisation well versed in all regulatory issues with well GCP-trained sites to ensure that all appropriate study standards meet or exceed those of the FDA and other regulatory bodies.

These new guidelines are currently published as a draft for the time being, with the FDA accepting comments until 20 July this year.

1. ‘Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States’ http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/UCM443133.pdf?source=govdelivery&utm_medium= email&utm _ source = govdelivery
2. ‘Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices’
   https://www.federalregister.gov/articles/2013/02/25/2013-04201/human-subject-protection-acceptance-of-data-from-clinical-studies-for-medical-devices

It is well known in the clinical trial industry that the start-up phase of clinical studies can be very challenging. It is at this stage of development that clinical trials must lay the groundwork for success, and good intelligence gathering must be integrated into every aspect of strategy, from site identification to patient enrollment.

In this post I will discuss the some of the approaches to streamlining study start-up, and the new technologies that are being utilized, in order to achieve the greatest possible efficiency at this challenging phase of clinical trials design.

Workflow management

One aspect of the start-up phase that has evolved over recent years is the use of workflow management systems. This approach, involving the use of techniques such as CPM and Lean Six Sigma methodologies, allows study teams to improve their ability to manage key start-up steps, and to move away from an overreliance on simple data tracking. The aim of these systems is to create global visibility and promote better communication to create more seamless transitions between the different stages of study start-up.

Today, companies are building databases which enable CROs and sponsors better anticipate the future based on past project experience. In using this information, new protocols and products can be evaluated according to their overall design and composition. This more easily enables the prediction and therefore avoidance of risks that may occur along the same path.

However, the use of broad comparisons with past trials, even of a similar type and at the same phase, to predict a project timeline, is inadequate. For aspects of study start-up with high levels of complexity, it is vital that intelligence databases allow study teams to enter multiple unique parameters to generate the designs that are most likely to result in predictability around timelines.

Fundamental to the appropriate management of timelines is the ability to measure against baseline performances, and in order to establish realistic start-to-finish goal at the beginning of a project, key deliverables must be tracked against a baseline plan. While inevitable changes in circumstances, that alter a timeline, can be incorporated into a new projection, the initial baseline should always remain. This ensures that the appropriate data is available, and when delays occur and allows information gathering that will lead to swifter mitigation strategies, leading to greater timeline predictability.

Site selection

The identification of high performing sites and investigators is crucial for positive research outcomes. Choosing an appropriate site correlates with faster patient recruitment, and therefore success in reaching overall enrollment goals, superior data quality, fewer queries, and better patient retention.

However, the selection of poor clinical trials sites continues to be a problem, and it leads to an increase in the cost of clinical trials. Inappropriate site selection is principally due to lack of knowledge of relevant clinical investigators, and many sponsors predominantly rely on established connections with previously used sites, to find suitable investigators.

When recruiting sites, sponsors and CROs typically first identify regions in which the targeted patient population is more commonly located, and then determine whether the protocol is suitable. These initial assessments must be combined with information from regulatory intelligence databases to determine country and site feasibility. This should form the foundation when exploring locations to conduct trials.

Study start-up efficiency can also be improved by the use of enrollment modeling. This technology allows enrollment data, as well as intelligence regarding specific protocols, countries, and sites to be viewed in parallel. This enables study teams to predict the speed at which enrollment targets can be met using a set number of sites, and provides a means of measuring recruitment as the study progresses.

Technology

Over the past decade, there have been considerable advancements in global reporting systems and technologies for use in clinical development. This has gone some way to shift study teams’ workloads from the onerous tasks of compiling Excel spreadsheets, towards approaches that incorporate more real-time data and reporting. This has muerous advantages, such as enabling queries from regulators and ethical committees to sites in several countries to be shared worldwide, in real-time.

While digital methods of communication between investigators are becoming increasingly common, site implementation of web-based tools for the exchange of clinical document, remains slow. In 2011 a global survey found that traditional methods of communication, such as e-mail, fax, and courier, were the principal tools being used for the exchange of clinical trial documents in 73% of sites. [2] This is despite the fact that most investigators have access to tablets and smartphones.

It is the responsibility of CROs and sponsors to utilize these tools. Application of these technologies could be used, for example, to electronically distribute questionnaires, or predictable, pre-populated documents, to investigators. They could then be completed on a handheld device and signed with an electronic signature, helping to speed up the overall start-up process and reduce timelines.

Another area in which technology is affecting a more streamlined approach to study start-up, is through the use of online clinical document exchange portals. These can be used to simplify the task of tracking study start-up activities for several sites. Online portals enable the generation of reports, increasing the transparency of the status of a site’s progress. They also provide the capability to streamline communication, making for a clearer, user-friendly, and regulatory-compliant method for sites and sponsors to track and collaborate on operational data. Finally, these smart workflow technologies also make it easier for study teams to deliver real-time status updates to management, enabling the identification of bottlenecks and optimization of resources.

It is important to acknowledge that, as with the adoption of any new technology, the implementation of digital portal systems can be a challenge, requiring the creation of new SOPs, additional staff training, often at site already burdened with a heavy workload. However, it is vital that the clinical trial environment keeps pace with improving technologies, to manage competing demands, and to remain competitive and continue to increase efficiency.

Conclusion

New strategies and technologies, to streamline onerous and time-consuming start-up procedures, show potential. However, while the implementation of integrated data systems and digital document management remain uneven, challenges in estimating start-up timelines and identifying potential bottlenecks will continue. It is therefore essential that companies continue the process of collecting and compiling data, together with the use of appropriate systems to share that intelligence, in order to achieve ever-greater predictability in study start-up.

References:

1. Schimanski, M. Kieronski, “Streamline and improve study start-up,” Applied Clinical Trials, Vol. 22, Number 9, September 2013.
2. Bio-IT World, “IntraLinks Survey Highlights Need for e-Clinical Document Exchange Tools,” (2011), http://www.bio-itworld.com/news/06/14/2011/IntraLinks-survey-need-clinical-document-exchange.html.