Mark Packer, MD, FACS, CPI

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,” a blog series featuring contributions from members of the ophthalmic community. These blogs are an opportunity for ophthalmic bloggers to engage with readers with about a topic that is top of mind, whether it is practice management, experiences with patients, the industry, medicine in general, or healthcare reform. The series continues with this blog by Mark Packer, MD, FACS, CPI. The views expressed in these blogs are those of their respective contributors and do not represent the views of 

	In his latest blog, Mark Packer, MD, FACS, CPI, shares the rewards of becoming a principal investigator (PI) in clinical research, as well as the common mistakes to avoid. There are many reasons an ophthalmologist might want to be involved in clinical research as a PI: 

		Being on the cutting edge of innovation is exciting.

		Clinical research raises the profile of the practice and the PI. 

		Involvement in scientific advancements means contributing to the improvement of patient care and outcomes. 

		If managed correctly, clinical research can be a lucrative adjunct to clinical practice. 

		Your patients will receive the latest innovations long before they are available to the general public (while, of course, taking some additional risks).

	Over the course of many years’ involvement in clinical research as a PI, medical monitor and subject matter expert, I have observed some PIs who outperform their peers and others who create problems for their sponsors. I’d like to share a few of the practices that make a PI successful.

	1) Be scrupulously honest on the site selection questionnaire

	As a surgeon, one learns to “underpromise and overdeliver" with patients to avoid unrealistic expectations and the inevitable subsequent dissatisfaction. The same holds true for PIs and their communications with sponsors. I don’t recommend intentionally underestimating your site’s enrollment capability, but I do recommend avoiding overestimating. In the face of uncertainty, err conservatively. Almost nothing will stretch a sponsor’s patience thin like failing to meet enrollment goals. 

	If you are new to clinical research, it may be difficult to provide an accurate enrollment estimate.  However, one can analyze recent patient records to determine how many would meet the inclusion/exclusion (I/E) criteria.

	For example, in an IOL study, the sponsor is usually looking for subjects with healthy eyes other than cataract (i.e., no zonulopathy, no glaucoma, no macular degeneration, no retinopathy). It’s easy enough to look through last quarter’s cataract patients and find those without comorbidity.

	Of course, not every eligible patient will want to participate in a clinical trial. I would subtract all those who opted for presbyopia-correcting or toric IOLs, and then take 25% of the remainder as a conservative estimate. 

	2) Do not try to make yourself look good at the technology’s expense

	Some complications cannot be avoided. Every clinical trial has adverse events (AEs). We should not try to minimize their importance, but it is not a good idea to brag about them either. For example, I have seen PIs present their management of surgical complications related to investigational devices at conferences 

	Irrespective of whether that constitutes a breach of confidentiality (it does), I’m not sure what purpose it serves other than to increase the notoriety of the PI at the sponsor’s expense.

	If one wants to participate in future research projects, I would treat everything that occurs within the context of a clinical trial as confidential. In fact, the protocol will often contain a paragraph that constrains investigators from presenting or publishing data without the sponsor’s consent. 

	3). A case report form (CRF) is not a case report article

	In medical school, we learn to record all the positive findings and all the pertinent negative findings. The CRF is a list of only those history and examination fields determined relevant to the clinical trial, and only those findings that fit in each of the fields need to be recorded.

	However, there is almost always an area for additional comments. Some PIs want to add a lot of detail, much as they would for a case report in a medical journal. Not only is this unnecessary, it can lead to queries and questions from regulatory authorities that complicate the review process without adding any significant information. 

	For example, some subjects may have a lot to say about their visual perception following cataract or refractive surgery, and they may use a vocabulary all their own. These subjective impressions are best captured through a validated questionnaire, so that their significance can be evaluated consistently among subjects and across trials. It’s not helpful to write down every adjective a patient may use to describe a halo. 

	The clinical trial agreement (CTA) between the PI and the sponsor will spell out the compensation for conduct of the study, usually in terms of subjects and form completion. To effectively negotiate a fair agreement, the PI (or designee) must know what it will cost the site to run the trial per subject. An experienced site manager will know the cost for every test and procedure required by the protocol, as well as the costs associated with approval from an institutional review board (IRB), administration, surgery center services, and the PIs’ time. 

	If a sponsor’s proposal doesn’t net a profit, one may still decide to participate in a study if the value of participation includes important intangibles-at least one will know why one is participating. 

	On the other hand, one may wish to participate in a lucrative, but not particularly exciting trial to enhance the site’s bottom line. In either case, these decisions cannot be made in the absence of knowledge. 

	5). Understand the regulatory environment

	It’s impossible to do a good job as a PI without a thorough understanding of the regulatory process and its requirements. Every site initiation visit (SIV) includes a review of good clinical practice (GCP) and the protection of human subjects. However, the PI’s understanding should go beyond these basics. 

	What are the relevant regulatory time lines related to starting the study, obtaining review and achieving approval? What is involved in a site inspection? What have been the challenges encountered by the sponsor during previous investigations of similar devices or drugs? The greater your understanding, the better job you can do in helping the sponsor reach the goal. 

	This list of pearls and pitfalls is not exhaustive by any means. But it is a start, whether you are just getting involved in clinical research or seeking to improve your performance as a PI.      

Articles

Interested in becoming a principal researcher? Read this first.

Pearls and pitfalls for principal investigators

	Take-home message: Rho kinase inhibitors are intriguing in that they work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.

 in use today primarily targets the pathogenic cause of increased IOP: impaired function of the conventional trabecular outflow pathway.

It may be time to change your views of amblyopia

	As Kopczynski and Epstein noted in an editorial last year: “The trabecular outflow pathway is the primary draining tissue for the aqueous humor in the eye. It consists of 3 structures, the trabecular meshwork, juxtacanalicular tissue, and Schlemm’s canal. In a healthy eye, IOP is maintained within a narrow range through dynamic regulation of trabecular outflow resistance. In a glaucomatous eye, elevated IOP is due to an abnormally high resistance to outflow in the trabecular outflow pathway. The causes of increased outflow resistance are not fully understood, but it has been hypothesized to involve an increase in the contractile tone and stiffness of the trabecular meshwork and changes in extracellular matrix composition and/or a change in the conductance of Schlemm’s canal.”

	The most commonly prescribed class of ocular hypotensive drugs-the prostaglandin analogues-reduces IOP by increasing uveoscleral outflow. While this pharmacologic activity remains relatively consistent over time, IOP still tends to increase, and patients tend to require additional adjunctive medications, because the outflow resistance of the trabecular meshwork continues to increase as the disease progresses.

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	Similarly, drugs that decrease aqueous production-such as carbonic anhydrase inhibitors, alpha agonists, and beta-blockers-may actually serve to reduce trabecular outflow in a counterproductive fashion by increasing trabecular resistance indirectly through feedback mechanisms that attempt to regulate IOP.

	In fact, the addition of second and third medications to the regimen of patients with glaucoma yields progressively less satisfactory results in terms of IOP reduction.

	However, in a recent fortunate development, a novel class of glaucoma medications, the rho kinase inhibitors, have been found to actually increase trabecular outflow by acting directly on the contractile tone of the trabecular meshwork.

	Rho kinase is a serine/threonine kinase whose activity increases actomyosin contraction in smooth muscle cells, including the smooth muscle-like cells of the trabecular meshwork. Bacharach et al. have recently published results of a phase II clinical trial of AR-13324 (Rhopressa, Aerie Pharmaceuticals), the first of a new class of ocular hypotensive compounds that inhibits both rho kinase and the norepinephrine transporter.

	The authors note: “Consistent with its inhibition of rho kinase, AR-13324 seems to reduce IOP in part by increasing outflow facility. In addition, AR-13324 seems to lower IOP by decreasing the production of aqueous humor. This latter activity may be related to the inhibition of norepinephrine transporter, although this relationship has not been directly demonstrated.”

	Perhaps most interesting of their results, Bacharach et al. demonstrated that AR-13324 effects a more consistent reduction in IOP irrespective of baseline. This result is in contradistinction to the effect of prostaglandin analogues, which tend to demonstrate a smaller reduction in IOP in subjects with lower baseline IOPs. For the prostaglandin analogues, patients with mild to moderately elevated IOP generally realize a smaller absolute reduction in pressure. Not so for rho kinase inhibitors.

	In their randomized, double-masked, 28-day trial, the authors compared two concentrations of AR-13324, 0.01% and 0.02%, with latanoprost in subjects with ocular hypertension or open-angle glaucoma (pseudoexfoliation and pigmentary glaucoma were excluded).

	The primary effectiveness endpoint was the mean diurnal IOP at day 28. A pre-specified analysis of the endpoint stratified by baseline IOP ≤ 26 mm Hg or > 26 mm Hg was performed because of the suggestion from an earlier study that the hypotensive effect of AR-13324 may not vary with baseline IOP, which, in fact, is what the study showed.

	Two hundred thirteen subjects (95.1%) completed the trial. Mean unmedicated baseline diurnal IOP was 25.8, 25.6, and 25.5 mm Hg in the AR-13324 0.01%, AR-13324 0.02%, and latanoprost groups, respectively (

	On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mm Hg, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mm Hg. Latanoprost and AR-13324 0.02% were similarly effective at all time points in the subset of patients with baseline IOPs ≤ 26 mm Hg, producing decreases in mean diurnal IOP of 6.0 and 5.7 mm Hg.

	The authors reported: “Although AR-13324 0.02% was less effective in ocular hypotensive efficacy than latanoprost by 1 mm Hg in the (intent-to-treat) population, it showed similar efficacy to latanoprost in a pre-specified patient subgroup that excluded patients with baseline IOPs of 

	The improved relative efficacy of AR-13324 0.02% in the subset of patients with baseline IOP ≤ 26 mm Hg was due to the decline in absolute IOP reduction with latanoprost (from 6.8 mm Hg in the intent-to-treat population to 6.0 mm Hg in the subset with baseline IOP ≤ 26 mm Hg), compared with the more consistent absolute IOP reduction with AR-13324 0.02% (5.7 mm Hg in the intent-to-treat population and 5.7 mm Hg in the subset with baseline IOP ≤ 26 mm Hg).

	The most common adverse event experience by subjects was conjunctival hyperemia. However, the redness was generally transient (i.e., less noticeable in the morning than immediately after the evening dose) and gradually diminished during the course of the study.

	“By the first morning visit on day 28, the incidences of mild to moderate conjunctival hyperemia were 18% and 24% in the AR-13324 0.01% and 0.02% treatment groups, respectively, compared with 11% in the latanoprost group.”4

	Despite these promising results, phase III registration trial (Rocket 1) results for Rhopressa announced in April 2015, did not meet the primary efficacy endpoint of demonstrating non-inferiority of IOP lowering for once-daily Rhopressa compared with twice-daily timolol.

	However, in a pre-specified secondary analysis for patients in the study with baseline IOPs below 24 mm Hg, Rhopressa did demonstrate statistical non-inferiority to timolol at all nine measured time points and numerical superiority over timolol at the majority of measured time points. Results from a second phase III trial are expected in the third quarter of this year.

	In a compelling study of mechanism of action, Pattabiraman et al. treated human trabecular meshwork cells with AR-13324 alone or in combination with fibrinogenic mediators TGFβ2 and CTGF to test induced expression of fibrogenic and myofibroblast specific markers.

	They found that AR-13324 induces cell shape changes, loss of actin stress fibers, and loss of focal adhesions in human trabecular meshwork cells, and that AR-13324 significantly suppresses TGFβ2- and CTGF-induced levels of α-SMA, collagen1A, and FSP1in HTM cells. These cell-based observations revealed anti-fibrogenic activity of AR-13324 in cultured human trabecular meshwork cells.

	In further elucidation of the mechanism of action and consistent absolute IOP reduction with AR-13324, Kiel and Kopczynski have shown that this compound reduces episcleral venous pressure (EVP) in an animal model (Figure 1).

	The trabecular outflow pathway drains into downstream episcleral veins in the eye, and pressure in the veins contributes significantly to IOP. Using Dutch Belted Rabbits, the protocol involved once-per-day topical application of AR-13324 0.04% for 2 days. On the morning of the third day, the animals were anesthetized and surgically prepared, and then measurements were obtained before and for 3 hours after dosing with AR-13324 or vehicle (3 to 5 days of dosing were determined to be necessary to measure peak effectiveness).

	The authors concluded: “Consistent with the study hypothesis, AR-13324 lowered the EVP significantly. At baseline, half of the measured IOP in the AR-13324 treated group (34 mm Hg) was attributable to EVP (17 mm Hg), assuming the 1:1 correspondence between IOP and EVP in the Goldmann equation. At 3 hours post-dosing, the reduction in EVP caused by AR-13324 treatment accounted for 42% of the measured reduction in IOP. The remaining reduction in IOP achieved by AR-13324 is presumed to occur through 1 or more additional mechanisms of action, most likely increased outflow facility and decreased aqueous production, as occurred in a previous primate study.”

	Three distinct likely mechanisms of action characterize Rhopressa:

		relaxation of trabecular outflow tissue,

		suppression of aqueous secretion by norepinephrine transport inhibition, and

		reduction of episcleral venous pressure.

	A new combination product (Roclatan, Aerie Pharmaceuticals) links these mechanisms with the proven enhancement of uveoscleral outflow associated with latanoprost. In phase IIb trial results released in June 2014, Roclatan achieved its primary efficacy endpoint of statistically significant superiority over each of its components (Rhopressa and latanoprost) on day 29.

	The phase IIb 28-day clinical trial included 297 patients. The baseline IOPs tested in the study ranged from 22 to 36 mm Hg. Roclatan lowered mean diurnal IOP on day 29 from 25.1 mm Hg at baseline to 16.5 mm Hg, a 34% decrease in IOP. Roclatan mean diurnal IOP reduction on day 29 was about 2 mm Hg greater than latanoprost. Roclatan efficacy exceeded that of latanoprost by 1.6 to 3.2 mm Hg across each time point evaluated during the study (8 a.m., 10 a.m., 4 p.m. on days 8, 15 and 29).

	These results were statistically significant at all time points with 

 values less than 0.05. The most common adverse event was hyperemia, which was reported in 40% of patients and was scored as mild for the large majority.

	The emerging picture of the clinical efficacy, safety, and mechanisms of action of these agents suggest that new, powerful therapeutic tools will soon be available for reduction of IOP in patients with ocular hypertension and glaucoma. Most intriguing is the fact that these agents work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.

	In addition, the consistent absolute reduction of IOP regardless of baseline suggests increased effectiveness among the vast majority of patients who have mild to moderately elevated IOP. The impact of these therapies on patients with normal tension glaucoma will be an important topic for future investigation.

	Mark Packer, MD, FACS, CPI, is in private practice in Boulder, CO. Dr. Packer is a consultant to Aerie Pharmaceuticals.

	1. Kopczynski CC, Epstein DL. Emerging trabecular outflow drugs. 

2014;30:85-87. doi: 10.1089/jop.2013.0197. Epub 2013 Dec 4.

	2. Jampel HD, Chon BH, Stamper R, Packer M, Han Y, Nguyen QH, Ianchulev T. Effectiveness of intraocular pressure-lowering medication determined by washout. (2014) 

. Jan 30. doi: 10.1001/jamaophthalmol.2013.7677. [Epub ahead of print]

	3. Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. 

 2012;23:135-143. doi: 10.1097/ICU.0b013e32834ff23e.

	4. Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD; AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. 

 2015;122:302-307. doi: 10.1016/j.ophtha.2014.08.022. Epub 2014 Sep 27.

	5. Aerie Pharmaceuticals Reports Initial Rhopressa Phase 3 Efficacy Results. 

http://investors.aeriepharma.com/releases.cfm

	6. Pattabiraman PP. Effects of Rho kinase inhibitor AR-13324 on the actin cytoskeleton and on TGFβ2- and CTGF-induced fibrogenic activity in Human Trabecular Meshwork Cells. AOPT 2015. Poster 43.

	7. Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. ARVO 2014. Abstract 2900

	8. Aerie Pharmaceuticals Reports Roclatan Phase 2b Results Achieve All Clinical Endpoints. 

http://investors.aeriepharma.com/releases.cfm?Year=&ReleasesType=&PageNum=2

Rho kinase inhibitors are intriguing in that they work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.

Mark Packer, MD, FACS, CPI

Articles

Pearls and pitfalls for principal investigators

Directly targeting pathology: A novel approach to treating glaucoma