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Practical Problems and Limitations of Hair Survival Studies

Shapiro Ron, PerezTextbook Hair Transplantation 5th Edition 2010

INTRODUCTION
Clinical research in hair restoration can be incredibly exciting and intellectually satisfying; however, it is also one of the most challenging and demanding experiences that one may ever encounter. Research requires qualified and dedicated professionals to ensure that the goal of high-quality investigation is achieved. We recognize the value of the ISHRS Research Grants for stimulating research studies done by the ISHRS members also for the past fifteen years the Orlando Live Surgery Workshop has been the place to initiate important research studies related to surgical techniques, new devices, storage solutions, and other equally important components to the treatment of hair loss.

In the past decade or so, hair restoration techniques have evolved as well as the introduction of numerous instruments that have been designed and developed to attain the best possible results following hair transplant surgery. Sometimes these new instruments are declared to be the best possible approach to hair restoration by their inventors or proponents. It is important that these new techniques and devices have validity. Unfortunately, scientific studies or statistical evidence is not generally presented and without trusty information or data and examination of the postoperative results, there is a great confusion among hair restoration surgeons and patients. It is of critical importance to observe objective results among the different techniques and instruments. Each study should have comparable techniques or instruments to be evaluated on the same patient and should apply to the modern follicular unit and follicular unit extraction techniques where smaller and smaller hair grafts are harvested, dissected and placed according to the surgical plan.

A number of factors make it intrinsically difficult to objectively compare different techniques in hair restoration surgery. We believe an awareness of these factors is important and may help both surgeons and patients be more open minded when attempting to evaluate and compare various techniques related to hair growth and hair survival. Before mentioning those factors, we would need to address several important aspects of clinical research that applies and should be well known in hair growth and hair survival studies.

Conference of harmonization (ICH)

Comment [M1] Can this section be made more brief? It’s useful background information, but I think we could get away with fewer specifics (for exmaple the description of key research participants).

Due to the growing globalization of clinical research, it became apparent that international guidelines on the conduct of clinical research were necessary. In 1990, the ICH process was initiated. The International Conference on Harmonization Guidelines were developed to provide a unified standard for the European Union (EU), Japan, and the United States that would facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. The guidelines were developed with consideration of the then current Good Clinical Practices (GCP) of the European Union, Japan, and the United States as well as those of Australia, Canada, the Nordic countries, and the World Health Organization.
The ICH guidelines are an international ethical and scientific standard for clinical research. The ICH topics are divided into the following four major categories, each consisting of several guidelines:

  1. Quality (Q)- Guidelines on chemical and pharmaceutical Quality Assurance.

  2. Safety (S)- Guidelines on in vitro and in vivo pre-clinical studies.

  3. Efficacy (E)- Guidelines on clinical studies in human subjects.

  4. Multidisciplinary (M)- Guidelines on topics that do not fit uniquely into any of the other categories.

Key Participants in Clinical Research
The principles of ICH GCP are supported by a system of checks and balances in which all those participating in clinical research, including the subjects, have specific responsibilities. Table 1 highlights the roles and responsibilities of the key participants defined below.

  • Institutional Review Board (IRB)/Independent Ethics Committee (IEC). The IRB/IEC is an independent body composed of medical, scientific, and non-scientific members whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial.
  • Sponsor. The sponsor is the individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.
  • Investigator. The investigator is the person responsible for the conduct of the clinical trial or study at the trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.
  • Subject. A subject is an individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as control

To conduct quality clinical studies, it is critically important that all participants understand their roles and carry out their responsibilities conscientiously.

Well designed clinical studies have several common elements, including:

Comment [M2]Hi David, the center for evidence-based practice at the University of Toronto (www.cebm.utoronto.ca) offers a great paradigm for evaluating studies. I thought I would share it with you. They evaluate studies by asking two questions: 1) Is the study valid; and 2) Is it important. The validity is assessed based on randomization, length of follow-up, intention-to-treat analysis, blinding, equal treatment, and group similarity. The importance of the study is broken down into the magnitude and precision of the effect. Finally generalizability of study results is considered. Just something to think about…
  • Study objectives; the study objective can also be viewed as a hypothesis which is tested in the clinical study.
  • Description of the study populations (i.e., inclusion/exclusion criteria);
  • Types of study comparisons
  • Endpoint measures; the primary endpoint is the main point of the entire clinical trial. The selection of the primary efficacy endpoint is one of the most critical and challenging of all study design decisions. Secondary endpoints are other measures that are of interest in the trial but are not the primary focus of the trial.
  • Control for bias. In order to maximize credibility for the conclusions, the trials should be designed to minimize bias. Bias in clinical studies refers to the systematic tendency of any aspect of a clinical study—design, conduct, analysis, and interpretation of the results—that leads to an estimate of a treatment effect that is deviate from its true value. Perhaps one of the most pervasive sources of bias is the expectations of investigators and subjects. Randomization and blinding are two techniques used to control bias.
  • Treatments groups (experimental and control)

Single center and Multi-Center Studies

Statistical Concepts

Comment [M3] I feel that a lot of this information, and the surrounding sub-sections is quite basic. I don’t think it should be included.

The statistical analysis section of the protocol identifies how the data from the study are to be analyzed. After all the data has been gathered from all the subjects, the data is tabulated, graphed, averaged, and analyzed. The data may seem to point to a clear conclusion. How strong is the conclusion from the data gathered? The strength of the conclusion drawn from the data obtained during the study depends to a large extent on the quality of the scientific approach and principles used.

P-Value
Statistical testing is used to determine whether the observed differences between treatment groups are explainable by chance alone. The p-value has been defined as the probability of obtaining, by chance, a difference between the treatment groups that is large as or larger than one observed in the experiment. If the p-value is sufficient small, usually equal to or less than 0.05, the researcher can reasonably conclude that the observed difference is due to real treatment effects, and not to chance alone.

Generally accepted guidelines for p-value are shown in Box 1 as follows
P> 0.05 is not statistically significant

Surgery Team Levels and Skills

Comment [M4]All the subsequent chapters should comprise the majority of the chapter. This is the meat and potatoes, and in my view the most interesting and useful part of this topic.

As mentioned previously, the hair restoration surgeon or principal investigator is fully responsible and should be qualified by education, training, and experience and assume liability for the proper conduct of the hair study. The investigators should be familiar with Guidelines of Good Clinical Practice (to protect human subjects in the trial), the Declaration of Helsinki (1964) and the Belmont Report (1979). The surgeon should be familiar with appropriate use of surgical techniques, devices or medical treatment, as describe in the protocol. He/she also should be knowledgeable in all the aspects of the hair transplant surgery including cutting and placing grafts. Surgical assistants are very important members of the surgery team but their skills vary at preparing and placing grafts. For this reason the hair surgeon should supervise each aspect of the research study.

Long Learning Curve
It may take twelve or more months to see the final result of a single hair transplant procedure and this also includes when multiple procedures are needed. This is unlike other cosmetic surgery procedures where results are often seen in a matter of weeks. This leads to a longer learning curve due to the greater length of time needed to see a sufficient number of results and to make the required adjustments in technique. The patient and investigator should be patient to evaluate the final results of the study. In the past we have seen several graft survival studies that have seen evaluated and concluded in six months or less and the final results would be different if the investigator had waited the right period of time.

Limited Patient Follow-up
Before starting the study, during the patient recruitment period it is critical to discuss with the patient all related specifications of the study – from the patient consent form, inclusion and exclusion criteria, risks, benefits, possible adverse events and incentive payment (if applicable). It is critical to explain in detail the research protocol, about before and after pictures, any macrophotos with tattoo in the center of the target area, # of visits including the time per visit and how many visits total. It is difficult to have every patient return for follow-up but this is critical for the success of the study. The decision each subject makes whether or not to participate in a study is not an easy one. A potential subjects should not make a decision that is based purely on emotions such as a fear and hope. Many times we don’t know how many of our patients with less than optimum results simply don’t return. If it is double-blinded study investigators and patients don’t know which group (placebo or active) the subjects belong to, we as investigators should reinforce that information as necessary. We should have a constant communication with the patient and encourage them to come back for the follow-ups. However, even with this effort, a large number of patients simply don’t return and are lost to follow-up. This limited follow-up adds to the difficulty in objectively evaluating our results, especially when added to the long learning curve.

Patient Selection and Hair Characteristics
Patient selection for hair studies is very important. We see a great variety of patients at different ages and with different patterns and degrees of baldness. In addition, patients possess different combinations of scalp (color) and hair characteristics (color, curl, and caliber). First timers or patients with multiple previous procedures are also important. All these variables impact results, and this creates a rich multi-factorial environment that is difficult to objectively evaluate. Two patients may undergo identical procedures with the exact same number of grafts but look totally different after the grafts grow due to differences in their characteristics. This variability in characteristics has to be factored during the inclusion/exclusion criteria and when evaluating the results. When hair growth and research studies are done it is vital to include healthy patients only, especially those without any type of prescription medication commitment. We do know that some diseases (HBP, diabetes) or medications (example, for high cholesterol) may impact the hair growth and survival.

Unpredictable and Variable Degrees of Hair Loss Progression.
Hair loss is progressive and unpredictable. The degree and rate of progression affects the ultimate look of a procedure and the need for future work. This means the visual results of identical procedures in two separate patients will appear different depending on their rate of hair loss. Differences in degrees of shock loss or post-surgical telogen effluvium (especially in women) affect results in the same way adding to the difficulty of evaluating results.

Differences in Graft Size including Number of Hairs
With the new technology and terminology the most common graft used today is the follicular unit (1-4 hair). For hair growth and survival studies the 1 or 2-hair follicular unit are normally used. Sometimes a 3-hair graft is included or also 2 follicular unit grafts or MFU (multi-follicular unit)) are used. It is important to specify in the protocol which type of graft will be used to compare apples with apples. Those grafts for the study should also be prepared under the microscope.

There are clinical reasons where one type of graft may be preferred over the other. For example, when creating only a hairline or temporal points, it may be better to subdivide the follicular units in order to get 1-2 hair grafts. If the study area is the mid-scalp, it may be limit the number of single-hair grafts and used 3-4 follicular units, or even MFU. This information should be documented in the protocol in order to compare apples to apples.

Study Area
There are important issues that we want to discuss. Example, if we make a study to evaluate scar width in the donor area to compare two techniques for donor closure, the investigators should know in advance how wide the donor strip will be, one-layer or two layer closure, with or without undermining of the upper and/or lower flap, with or without trichophytic, suture material used, etc. It is also important to be patient to evaluate final results, generally speaking twelve or more months is the ideal time for scar evaluation. Any additional features for being evaluated should be described in advance such as: anagen/telogen effluvium, cyst formation, ingrown hairs, etc.
The study or target area in the recipient site should be in a baldness area for better appreciation of the hair growth and hair counts, the tiny tattoos in the study boxes are very important too. Fig 1

Evaluating the results

Comment [M5]What is your overall impression of our ability to accurately evaluate hair growth ? Do you think any of these techniques is truly excellent or reliable? Just personal curiosity. In medicine, there is a strong incentive to show positive results, and I feel that a large number of techniques for evaluating the effectiveness of HRS are subject to personal bias and interpretation.

Before starting the protocol we should know the best method to evaluate our results. There are several methods that include: visual evaluation, global pictures, macro pictures, thricograms, video-microscope, cross section trichometer, dry wet hair and scalp biopsies, etc. Macrophotography for hair growth, hair diameter, hair counts, anagen-telogen ratio. As we mentioned before, it is always recommended to mark the target zone with

Comment [M6]An alternative is to mark with a single tattoo point, and use this point to center a study area. For exmaple, if you wish to study a 1 cm square region of scalp, mark the center of the box with a tattoo. This avoids some tattooing.

with tinny tattoos in each corner’s box in the transition zone or bold area. This will validate that we always come back to the same study area. It is also recommended clipping the hair in the study area. The use of FotoFinder and TrichoScan software is an excellent and automatic tool to assist us to evaluate the results including the hair counts, hair diameter and the anagen-telogen ratio (when pictures are taken on day 0 and day 2). Also there a different manual techniques for hair counts of the study area. It is always recommended to get an independent evaluator of the results.
Global Photography- It is still an excellent tool for evaluating hair regrowth including side-by-side comparison. For the evaluation is required photos with excellent quality and resolution; the picture always must have the same view, same lighting, same background, and same hair direction. Fig 2-3, if this is not done properly we can’t compare the pictures and the results won’t be valued; this is one of the most common problems in HTS. The global assessment of the scalp should be done by independent investigator(s) following the 7-point scale,

Comment [M7]Is the 7 point scale validated?

the results ranging from greatly increased (+ 3) to greatly decrease (-3) with 0 as no change.

Comparing Grafts Counts and Degrees of Dense Packing
The grafts and hairs harvested, dissected and moved to the study area of each patient in the study should be always the same. When interpreting the “true” hair density of grafts placed in different recipient areas, again it is important to know the size of the grafts and hairs used in the study area. Dense packing has been a hot topic at the last hair restoration meetings but it doesn’t mean dense growing. It is very important to mention if 1, 2 or 3-hair follicular units were placed. Sometimes in hair studies, different size grafts are used and compared in the different study areas.

Wide Variety of Patient Expectations
Patient expectations and desires vary considerably. Some patients with hair loss truly only want a thin mature look to feel good and would actually feel self-conscious with too low or thick of a hairline after being bald for many years. It is important to discuss with the study patients what to expect at the end of the study including possible adverse events including the placebo effect. We need to remember that the same exact results and look produced in two different patients may lead to totally different levels of satisfaction especially those patients in hair regrowth and graft survival studies when different techniques, instruments or medications are used, this is critical when the study patients have to fill out questionnaires during the study period.

Unreliability of Studies on Survival and Density
For hair restoration surgeons it is very important to know the hair growth and survival of grafts when using different techniques or devices or storage solutions, however, this is very difficult to measure. Graft survival in small areas (1-4 cms) cannot automatically be extrapolated to the entire scalp. In addition, manually counting hairs in the target area before an after they have been planted is notoriously inaccurate and adds to the unreliability of the studies. Furthermore, general speaking 10-15% are in the invisible telogen hair but nobody is certain how many total hairs are, and therefore not visible to be counted at any point in time. For all these reasons, survival studies to date may be traditionally unreliable. This does not mean that studies are not of value but only that the information should be evaluated with this in mind. Now we have new devices (digital cameras and ThricoScan software) for hair counts that will hopefully lead to more reliable survival studies.

Differences in Methodology Used During Different Parts of a Procedure
There are many steps in a hair transplant surgery and therefore many places where the specific methodology can vary. In addition to the specific step being evaluated, often multiple differences exist between techniques. The variables make it difficult to evaluate the true effect of a single variable and include the following:

  • Differences in graft storage solutions
  • Differences in incision orientation (coronal vs. sagital)
  • Differences in degrees of graft trimming performed (chubby vs. medium vs. skinny)
  • Differences in method of graft distribution (random vs. selective distribution of different sized grafts to create density gradients)
  • Differences in the size of the recipient site incision (.6-1.2 mm)
  • Differences in the instrument for making the recipient sites (blades vs. needles)
  • Differences in method of placing (“stick and place” vs. “pre-made incisions”)
  • We point out that there are many factors that can vary within a technique. This introduces more variables into an already complex equation and further increases the difficulty of objectively comparing different techniques or devices.

    Understanding Importance of the Risk/Benefit Ratio When Evaluating a Technique
    Sometimes a new technique can be a double-edged sword by creating both the potential for better results on one hand yet increasing the degree of risk involved on the other. Some of the controversial questions in hair transplantation that need this type of evaluation include:

    1. What degree of dense packing is safe and optimal? If packing at very high densities (50 + grafts cm²) is associated with good survival and faster results most of the time but causes poor survival some of the time, is it worth the risk?

    2. What size sessions are optimal? If larger sessions requiring wide donor strips results in fine scars much of the time but lead to wide scars and poor survival some of the time, is it worth the risk?

    We have done progress but no one has the definitive answer to these and more questions. In general, we feel it is better to err on the side of limiting risk until we are sure that the benefits outweigh the risk. With this approach, we see a gradual but safe application of more aggressive techniques.

    Conclusion
    The above discussion elucidates some of the reasons it has been difficult for physicians to objectively compare the results of different surgical techniques or devices in the field of hair restoration surgery. In spite of these difficulties, we have made great progress in evaluating the relative advantages and disadvantages of using different techniques with respect to their effect on naturalness and density. Some of the progress is due to the knowledge gained from clinical studies with better research protocols. Some comes from clinical experience and empirical but valuable information. It is just important to be opened- minded and not dogmatic as we move ahead and improve in the field of hair restoration surgery.

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