Krista Armstrong

	A recurring challenge in assessing and treating Post-Traumatic Stress Disorder or PTSD is the inherently complex, ill-defined, and sometimes downright puzzling nature of its symptoms.

	The condition has had many names over the years. Among them: shell shock, combat exhaustion, irritable heart, and even nostalgia. The affliction, now widely know as post-traumatic stress disorder, was so conceptually vague for so long that many in the medical community still regarded it skeptically after the American Psychiatric Association formally recognized PTSD in 1980.

	A lot has changed since then. U.S. troops have been fighting wars continuously for almost 17 years, and the Department of Veterans Affairs estimates that between 11% to 20% of the men and women engaged in these conflicts suffer from PTSD. More than 3 million cases-military and civilian-are diagnosed in the U.S. each year. It’s estimated that one in 11 Americans will experience the condition at some time in their lives.

	PTSD’s invisible wounds can dramatically affect mental health and diminish patients’ quality of life. The Sidran Institute, a nonprofit organization serving people who have experienced or witnessed traumatic events, says PTSD patients make extremely high use of medical and mental health services, incurring the perhaps the highest per-capita costs among all psychological conditions.

	As early as the 1600s, exposure to trauma was recognized as having potentially severe psychological effects on survivors. Swiss military physicians used the term “nostalgia” to define a condition marked by disturbed sleep, heart palpitations, and anxiety. Names like “irritable heart” and “shell shock” were later applied. During World War II, the U.S. Army distilled the condition into an official slogan: “Every man has his breaking point.”

	The first edition of the Diagnostic and Statistical Manual (DSM) of Mental Disorders, published in 1952, described patients as experiencing “gross stress reaction,” and the 1970s brought an awareness of “post-Vietnam syndrome.” PTSD was added to the DSM-III as an anxiety disorder, but it was not until 1999-nearly 20 years later-that sertraline, under the brand name Zoloft®, was approved to treat the condition.

	Paroxetine (trade name Paxil®) reached the market two years later, but in the 17 years since, no new medications have been approved. More than 350 clinical research studies in PTSD are currently underway, but with most of them occurring in government agencies and academia, the pharmaceutical industry still has limited knowledge on how to conduct clinical trials in this indication.

	In 2013, PTSD was reclassified as a trauma-and stressor-related disorder in the DSM-5 with several changes to its diagnostic criteria. Still, there has long been debate over how broad or narrow a definition should be applied in diagnosis. The “gold standard” for assessing the condition, according to many-including the U.S. Department of Veterans Affairs-is CAPS-5, the fifth iteration of the Clinician Administered PTSD Scale. This 30-item scale is used to make current diagnoses (based on events of the preceding month), make lifetime diagnoses, and assess patient symptoms over the preceding week.

	CAPS-5 assesses 20 symptom groups in four clusters, taking a broader approach than its predecessor, CAPS-4, which evaluated patients according to 17 symptoms in three clusters. This more inclusive approach is at odds with another popular set of measurement criteria, the World Health Organization’s ICD-11 (International Classification of Disease, 11

Edition). WHO views the CAPS-5 criteria as encompassing many symptoms that are not core to PTSD and limits its view to six specific symptoms to avoid overlap with other disorders.

	Reasonable people often disagree, so for purposes of this discussion, we’ll focus on CAPS-5, developed over three years to streamline administration and scoring of patient evaluations and render a system that is easier to learn, reduces variability among raters, and takes less time to administer and score than CAPS-4.

	A recurring challenge in assessing PTSD is the inherently complex, ill-defined, and sometimes downright puzzling nature of symptom criteria. Working with conceptually difficult symptoms like psychogenic amnesia and flashbacks, researchers really need to understand PTSD to assess it accurately. Patient self-rating is generally insufficient, as the symptomatic nuances and complexities are just too extreme and not well-understood even by trauma experts. Accurate assessments require highly structured interviews by a clinician who fully understands the conceptual basis of PTSD.

	Under ideal circumstances, CAPS-5 would be used only by qualified clinicians with:

	· Training in structured diagnostic interviews and differential diagnoses.

	· Thorough understanding of the conceptual basis of PTSD symptoms.

	· Detailed knowledge of the features and conventions of CAPS-5.

	However, it is also possible to train people to conduct CAPS-5 assessments, and investing in a certification or validation process for raters can contribute to rater quality and inter-rater reliability.

	Each CAPS-5 item includes ratings of symptom frequency and intensity (see Figure 1). CAPS-5 provides comprehensive coverage of the DSM-5 criteria for PTSD and includes a feature for assessing Criterion A, the exposure to the traumatic event. As there is now a dissociative subtype of PTSD, CAPS-5 includes a couple of dissociation items. It also includes items to measure overall distress, functional impairment, response validity, and global severity. 

Figure 1. CAPS-5 Item 1-Intrusive Memories 

	These ratings are combined into a single zero-to-four severity rating using a scoring grid (see Figure 2). In previous versions of CAPS, a very low-intensity symptom could still be scored highly if it occurred at a high frequency. However, the updated rules in CAPS-5 require that a symptom first meet a minimum level of intensity, and the final severity rating is qualified by the frequency.

Figure 2. CAPS-5 Past Month Scoring Rules

	For the purpose of clinical trials, it is important to keep in mind that there are past-month and past-week versions of the CAPS-5. Typically, the past-month version is used at screening to establish eligibility for a study. Once a patient is enrolled in the trial, the past-week CAPS-5 is used to establish a baseline and then to track symptom severity throughout the study as the primary outcome measure. 

	The approach is heavily scripted to pose the right questions in the right sequence and to provide clear guidance for accurate scoring. It includes standard prompts and assessments of symptom frequency and intensity. It’s a testament to the protocol’s architects that just about any rater given enough experience with CAPS-5 can quickly become proficient in assessing PTSD-associated trauma.

	The conspicuous lack of progress in developing drugs to treat PTSD underscores the need for government and industry to conduct more research to address this large unmet need. The Department of Veterans Affairs, Department of Defense, and industry have been showing more interest in psychopharmacology research for PTSD than ever before. For sponsors considering a PTSD indication, understanding the complexities and nuances of this condition is critical for planning and executing successful clinical trials.

	Please register for a free on-demand webcast here 

https://premier-research.com/webinars/where-expertise-meets-nuance-conducting-ptsd-clinical-trials/

, VP & Head of Neuroscience, Premier Research

Articles

A recurring challenge in assessing and treating Post-Traumatic Stress Disorder or PTSD is the inherently complex, ill-defined, and sometimes downright puzzling nature of its symptoms.

Complex, Puzzling, Ill-Defined: Challenges in Assessing PTSD

	Dementia is a global epidemic, affecting nearly 50 million people worldwide.

 By 2050, it’s estimated that 115 million people will suffer from some form of dementia. Alzheimer’s disease (AD) is the most common type of dementia occurring late in life. AD is also the only condition among the leading causes of death that cannot currently be prevented, cured or even significantly slowed.

	Despite intensive research, we have seen no new Alzheimer’s medications since 2003, when memantine (marketed as Namenda®) was approved by the FDA. For those living with Alzheimer’s disease and their loved ones, there is a significant unmet need for progress in understanding and treating this most prevalent form of dementia. In 2010, Congress passed the National Alzheimer’s Project Act to create a national plan to address AD, and in 2012, that plan articulated the goal of preventing and effectively treating AD by 2025.

	For sponsors who are pursuing this ambitious goal, understanding the obstacles inherent in Alzheimer’s clinical trials can help in planning for, and overcoming, these challenges. 

	Treatments for Alzheimer’s disease can be classified according to two broad categories:

	Approved symptomatic therapies include the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantime, a glutamate-NMDA receptor modulator. Other cholinesterase inhibitors, nicotine receptor agonists, serotonin receptor modulators, h3 histamine receptor antagonists, and numerous other neurotransmitter system-targeting agents have been investigated without success. Currently, sigma1 and muscarinic receptor modulators, intranasal insulin, peroxisome proliferator-activated receptor gamma agonists, and glucagon-like peptide 1 agonists are under development and investigation.

Disease-Modifying Therapies and Therapies for Behavioral Disturbances

	To date, there are no approved disease-modifying treatments for AD. Potential disease-modifying compounds fall under two dominant approaches: anti-amyloid agents and tau-targeted therapies. The amyloid therapy hypothesis (searching for agents that decrease production, prevent aggregation, or increase removal of beta-amyloid and simultaneously improve cognitive functions) has been the primary target for disease modification therapies for more than 20 years. Unfortunately, the search for agents that decrease production, prevent aggregation, or increase removal of beta-amyloid has failed to yield an effective treatment that improves cognition. More recently, the focus of research has shifted to tau-targeted therapies: phosphorylated tau protein.

	Beyond the shift from anti-amyloid treatments to tau-targeted therapies, we are also seeing a shift in the stage of AD being studied in clinical trials. With advances in our understanding of the underlying anatomical and pathophysiologic changes that precede the onset of clinical symptoms, research and development has begun to focus on mild cognitive impairment (MCI) or prodromal AD. Of the 143 Alzheimer’s trials active as of July 2017, 51 are targeting healthy, healthy at-risk, or MCI to mild AD patients, including 21 studies focused on completely asymptomatic patients.

Maximizing the Likelihood of Clinical Trial Success

	Approximately 70% of compounds currently in Phase II or III trials aim to alter the underlying pathophysiology of AD, while the remaining 30 percent aim to treat the behavioral symptoms associated with the disease. In July 2018, a pipeline analysis presented at the Alzheimer’s Association International Conference showed 68 compounds in Phase II trials. According to this analysis, 31 drugs in Phase III clinical trials may launch in the next five years.

	The robust research activity in AD is promising, but to mitigate clinical trial risk, sponsors must learn from the failures of the past.

	In the U.S., approximately 85 to 90 percent of AD trials experience delayed recruitment. As a result, sponsors may want to consider adding countries outside the United States to accelerate enrollment. If the decision is made to include international sites, understanding the startup timelines and the competitive clinical trial landscape and local regulatory environment in each country under consideration is critical for successful enrollment. There are also special considerations and nuances that must be considered when planning a global AD trial, including:

 Level of education can vary significantly from country to country, and it is known that AD tends to progress more slowly in individuals with lower levels of education. 

Level of exercise is also country-dependent, and individuals with higher levels of exercise have lower levels of amyloid deposition in the brain. 

Factors influencing drug pharmacokinetics. 

For example, differences in body size may contribute to differences in brain exposure levels at the same dose of drug and may also affect drug metabolism and distribution.

Polymorphism may influence drug metabolism, central nervous system drug exposure, and drug response across ethnic groups. Genetic diversity also creates differences in the biology of AD. 

Use of clinical trial instruments and equipment. 

Nearly all widely used clinical instruments for AD were developed in North America and may need to be adjusted for cultural or ethnic differences. In addition, capabilities, access, and willingness to adopt new technology may vary widely among regions, requiring additional training. 

Raters with little or no experience may contribute to greater score variability and more difficulty demonstrating a drug-placebo difference. Providing standardized training for raters and implementing in-study rater surveillance programs can help in optimizing data quality.

	Most of the common protocol designs for AD clinical trials were created in the development programs for cholinesterase inhibitors and memantine. These programs consisted of double-blind, placebo-controlled, parallel group studies with a dual outcome including a cognitive measure, and a global impression or activities of daily living outcome. Participants were randomized to drug or placebo, and changes from baseline between groups were compared after a specified time. In most cases, the investigational agent was an add-on treatment to the standard of care.

	A typical challenge of clinical trials in AD is finding ways to differentiate between symptomatic effects and disease-modifying effects. A number of newer clinical trial designs that seek to adjust for symptomatic effects and allow clinical rating scales to be used as endpoints include:

In this type of study, disease modification is inferred from sustained divergence in outcome measures between groups over time. While this may be the best current trial design, these studies are time-consuming and expensive, and optimal study duration is still unclear. 

Often used in combination with other design strategies, a wash-in analysis compares the change in clinical outcome measures between groups over the initial weeks or months of a study. If a greater improvement is seen with the investigational agent, this might indicate an early symptomatic effect because it would be too early to see a true disease-modifying effect. 

Wash-out analysis/staggered withdrawal. 

In this analysis, treatment is withdrawn from both the active agent- and placebo-treated groups at the end of the study. The active agent is assumed to have disease-modifying effects if patients treated with the agent show slower disease progression throughout the double-blind treatment period and less severe deterioration after treatment withdrawal.

Randomized staggered start/delayed-start. 

In this design, one group of patients is randomized to receive the investigational agent from the start, while the second group is randomized to receive placebo for an initial period before being given the investigational agent. If the agent has a purely symptomatic effect, the progression curves for the two groups should meet when the second group receives the drug. If the compound has a purely disease-modifying effect, the progression curves of the second group will never catch up with those of the first group.

In this design, the outcome of a single treated group is compared against a predetermined threshold value that reflects clinically meaningful change. The advantage of a futility design is that fewer patients are observed for a shorter period of time in Phase II to facilitate go/no-go decisions.

These designs can help minimize the overall sample size and duration of a study by stopping recruitment in response to strong signals of success or futility based on interim analysis. 

	The sponsor should keep in mind that none of these study designs is perfect, and each has limitations that may confound definitive conclusions about an agent’s disease-modifying properties. 

	Approximately 25 percent of AD trial participants fail to complete the double-blind treatment period. Consequently, study results may be confounded by missing data, which can unbalance treatment arms over time, introduce bias, and reduce the overall efficacy of the study. Methods for dealing with missing data include complete-case analysis, last observation carried forward, mixed modeling, and data imputation. 

	In addition, there are numerous instruments used to measure clinical endpoints in AD trials. Clinicians and may vary widely in their experience administering these instruments, leading to data variability. To overcome this challenge, many sponsors and CROs implement standardized training for raters, as well as robust and ongoing rater monitoring and quality assurance programs. 

	Increasingly, biomarkers are being used as surrogate outcome measures for disease modification. The most commonly assessed biomarkers in AD trials include:

, such as total tau (t-tau), phosphorylated tau (p-tau) 181 or 231, and the isoforms of amyloid beta. 

, using a variety of radioactive tracers including flouro-deoxyglucose (FDG), Pittsburgh compound B (PiB), florbetapir, and flortaucipir, which may not be available in every country. 

, ranging from amyloid beta precursors to C-reactive protein and insulin-like growth factor 1. 

To date, volumetric MRI measurement of different regions of the brain seems to be the most linked to cognitive decline.

	Unfortunately, to date, there is no single accepted surrogate outcome biomarker for AD.

	AD and other dementias may be among the biggest global health crises of the 21

century. As sponsors answer the call to action for developing new therapies, we expect to see a re-engineering of the overall approach to AD clinical trials that further optimizes study design to maximize the likelihood of success.

World Health Organization. Dementia – Fact Sheet, Updated December 2017. Available at http://www.who.int/mediacentre/factsheets/fs362/en/.

Yaari R, Hake A. Alzheimer’s disease clinical trials: past failures and future opportunities. Clin Invest 2015;5(3):297-309.

Us Against Alzheimer’s. Alzheimer’s Drugs in Development Pipeline, presented during AAIC 22-27July 2018. 

Cummings J, Reynders R, Zhong K. Globalization of Alzheimer’s disease clinical trials. Alzheimers Res Ther 2011;3(4):24.

McGhee DJM, et al. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease. BMC Neurol 2016;16:92.

For sponsors who are pursuing the goal of treating Alzheimer’s disease, understanding the obstacles inherent in Alzheimer’s clinical trials can help in planning for, and overcoming, these challenges.

Alzheimer’s Clinical Trials: Obstacles and Opportunities

	A clinical drug trial is nearing the start of enrollment when the sponsor gets a call from the CRO’s project manager. Notwithstanding the sponsor’s very aggressive start-up requirements, the PM recommends a protocol amendment that tightens the patient eligibility criteria-a change that would lengthen the enrollment process but yield a trial that’s more efficient and cost-effective in the long term.

	The drug under study is everything to the sponsor, a small biotech company, and to its small group of investors. And while it’s this young company’s first clinical trial, the CRO has performed four studies in the same indication in the past two years.

	Recognizing that there’s no substitute for experience, the sponsor wisely takes the PM’s advice.

	There are lots of reasons sponsors rely on contract research organizations to perform clinical trials. These projects can be extremely complicated, and just managing the data can be an overwhelming prospect, especially for a small company without the robust tools and processes a CRO can offer. But the most compelling reason may be the partnership that results when the sponsor-CRO relationship evolves to its fullest potential.

	Service providers of all kinds like to talk about how they are more to their customers than mere vendors, casting themselves instead as full-fledged partners. And there may be no better example of that distinction than the complex interplay between sponsor and CRO. Clinical trials are hardly commodity products, after all. The work is highly collaborative, in contrast to the transactional exchanges that typically characterize contractor relationships. 

	Small biotechs and specialty pharma companies in particular need help with planning, protocol writing, budgeting, capitalization, regulatory filings, and numerous other aspects of the drug development process. Such strategic partnerships are rooted in constant and candid dialogue, the type of intense interaction that enables the CRO to:

The CRO must really get to know the sponsor’s team: who needs lots of backup, who just wants the facts, and who is the strongest influencer. This insight leads to more precisely tailored and targeted service.

Suppose the sponsor assumes, incorrectly, that the CRO knows about a site contract it signed in Germany and one it declined in South Korea-and meanwhile, the CRO doesn’t know about a startup issue related to the central laboratory that may affect when enrollment can start. These things happen and are generally unforeseen and unavoidable. Regular contact between the CRO and sponsor can minimize the impact of such occurrences, which can be embarrassing at best and devastating at worst.

CROs must staff to meet their margins and may have alternate plans for a project team when the current assignment ends. To ensure that the team is available for a large planned project, the CRO needs to understand the sponsor’s roadmap.

The CRO project manager must be comfortable with phrases like, “I’d approach that differently” and, “Have you considered …?” The sponsor is paying for expertise and collaboration, not live in an echo chamber of agreement when the team can provide advantageous alternatives.

	You’re going to spend a lot of time with your CRO, so it really helps to work with people you feel comfortable with. And you need professionals who will handle your compound as if your livelihood depended on it. So here are some questions you should ask potential teammates:

	· What is your expertise in my therapeutic area and disease indication?

	· Have you worked in the countries where the trial may be conducted? What is your experience with those countries’ regulatory guidelines, ethical standards, and import-export regulations? 

	· Do you have experience with the nuances of rare and complex indications?

	· Have you dealt with sites that have never participated in industry-sponsored research? Have you successfully conducted training at such sites?

	· Do you have the background and self-assurance to work with key opinion leaders, investigators, and large academic institutions without feeling intimidated?

	· Have the people who would staff your trial worked together before? Do they augment your internal team’s potential deficiencies?

	Attitude is just as important as qualifications. The CRO and the individual team members need to understand that the project is not just about data management or writing queries or monitoring outcomes, but about the success of the sponsor’s organization, about people’s jobs, and about whether a potential treatment moves to the next phase of development.

	An effective partnership also involves risk-sharing. When sponsor and CRO pursue common goals, following a timeline and plan that was developed mutually, risk-sharing can be highly beneficial. If the CRO isn’t hitting its targets, the sponsor isn’t paying for failure-but if the CRO delivers ahead of schedule, the sponsor may be able to submit its dossier earlier, financially benefitting both parties.

	Risk-sharing agreements between sponsors and CROs are becoming increasingly common, and it’s a constructive trend in an industry ruled by project deadlines and rising costs. These arrangements focus both parties early on the elements most important to ensuring a successful trial and motivate the CRO team to perform-drawing, again, on the spirit of partnership.

	Having participated in a lot of these, we like to avoid the term “risk” in describing what are more accurately 

-sharing arrangements. Risk implies penalty, but in truth, the last thing sponsors would want is to exact fines when their research partners fail. These agreements instead should emphasize incentives for compliant or superior performance-payments the sponsors make gratefully as their projects proceed on or ahead of schedule.

	The best sponsor-CRO relationship is a fully functioning partnership, not a transactional vendor or employer-employee affiliation. Every aspect and every interaction should be designed with that goal in mind, and the arrangement will thrive on the strength of continuous and candid dialogue. Such an enterprise produces superior results without disruptive and costly surprises, helping advance the development of life-changing therapeutic advances.

, Senior VP, Clinical Development Services & Global Head of Neuroscience, Premier Research

Krista Armstrong explains the CRO's evolving role within clinical trials.

Krista Armstrong

Articles

Complex, Puzzling, Ill-Defined: Challenges in Assessing PTSD

Alzheimer’s Clinical Trials: Obstacles and Opportunities

Vendor? Strategic Partner? The CRO’s Evolving Role in Clinical Trials