Orthobiologics: Evidence and Regulation

Four groups cover most of what an athlete will be offered. Platelet-rich plasma is made by centrifuging the patient's own blood to concentrate platelets, and is by far the most commonly used. Bone marrow aspirate concentrate is produced by aspirating marrow, usually from the posterior iliac crest of the pelvis, and centrifuging it to concentrate the mononuclear cell fraction; it is often marketed as a stem cell treatment, but this is misleading, because cells with mesenchymal stromal or progenitor properties make up only a very small proportion of those present and the preparation is a heterogeneous mixture. Adipose-derived preparations use fat harvested by small-volume liposuction, and two distinct routes should not be conflated: mechanical processing produces preparations such as microfragmented adipose tissue, whereas enzymatic digestion can isolate a stromal vascular fraction, and the two differ in processing and may differ in regulatory status. Culture-expanded cell therapies, in which cells are grown in a laboratory before implantation, form a separate category and will generally meet the criteria for a medicinal product when intended for therapeutic use, although classification is product-specific.

The language used to market these treatments deserves scrutiny, because it is where patients are most often misled. The phrase stem cell treatment is applied loosely to preparations containing very few cells with mesenchymal stromal or progenitor properties, and words such as regenerative imply tissue regrowth that has not been demonstrated in these clinical settings. A useful discipline is to ask three questions of any offered product: what exactly is in it, how was it processed, and what human trial evidence exists for this specific preparation in this specific condition. In most cases the honest answers are that the content is heterogeneous and poorly characterised, that processing varies between providers, and that the trial evidence is limited, of low quality, or absent.

Taken as a whole, the evidence does not support routine use of orthobiologics as a treatment class across musculoskeletal conditions, and it must be assessed for the exact preparation, indication and protocol rather than by sweeping generalisation. PRP has the largest trial literature, and where it has been tested most rigorously, in knee osteoarthritis and mid-portion Achilles tendinopathy, placebo-controlled trials have not shown clinically important benefit. Bone marrow aspirate concentrate, adipose-derived preparations and culture-derived musculoskeletal products have a considerably thinner evidence base, dominated by small studies and case series, frequently without a credible placebo comparator and often with short follow-up. Systematic reviews repeatedly reach a similar conclusion: a plausible rationale, heterogeneous and poorly characterised preparations, low-quality evidence, and insufficient grounds for routine use.

Several recurring methodological problems explain the gap between claim and proof, and recognising them is a genuinely examinable skill. Preparations are heterogeneous and inconsistently characterised, so studies of the same nominal treatment are not comparable. Comparator choice is often weak: comparing an injection against no injection measures the effect of having a procedure rather than the effect of the biological agent, and without credible placebo control, treatment effects cannot be separated reliably from contextual and placebo effects. Blinding is difficult and frequently inadequate. Co-interventions such as rehabilitation are variably applied, and since loading programmes are effective in tendinopathy, an uncontrolled loading programme can generate an apparent treatment effect. Outcome measures and follow-up periods vary, allowing selective emphasis on whichever measure looks best. Conflicts of interest and selective publication may further increase the risk of bias. A clinician who can name these problems is far better placed than one who has memorised a list of study conclusions.

UK regulation turns on a conceptual distinction worth understanding properly, because it explains why PRP is widely available while cultured cell therapies are not. Cells that are substantially manipulated, for example by culture expansion or enzymatic digestion, or that are intended to perform a different essential function in the recipient than they performed in the donor, fall within the definition of an advanced therapy medicinal product (ATMP) and are regulated as medicines. Preparations involving only non-substantial processing, such as centrifugation, may fall outside that definition, depending on their composition and intended function. Importantly, autologous origin and same-procedure use do not by themselves determine status, classification is product-specific, and a classification opinion should be sought from the medicines regulator where there is uncertainty. The bodies involved have distinct roles: the Medicines and Healthcare products Regulatory Agency (MHRA) is the competent authority for medicinal products including advanced therapy medicinal products, for manufacture and for clinical trials; the Human Tissue Authority (HTA) regulates the donation, procurement, testing, processing, storage, distribution and import or export of tissues and cells for human application, with medicines regulation applying once the starting material enters medicinal-product manufacture; and the Health Research Authority (HRA) coordinates health service research approvals, with Research Ethics Committees providing ethical review. An advanced therapy medicinal product may reach patients through a marketing authorisation or an authorised clinical trial, or, if unlicensed, through the hospital exemption for non-routine preparation for a named patient for use in a hospital, or the specials route, both requiring an appropriate manufacturing licence. An experimental or unlicensed treatment without verifiable regulatory authorisation, trial registration or an appropriate exemption should prompt regulatory concern.

Counselling is where this knowledge becomes clinically useful, because athletes are frequently offered these treatments abroad, at considerable cost, on the basis of testimonials. The approach is to take the request seriously rather than dismiss it, establish what has actually been offered and what is in it, explain plainly what the evidence does and does not show for that specific preparation and condition, and set out the practical risks: financial cost, the procedural risks of injection or marrow aspiration, the risk of harm from a poorly characterised product, the absence of follow-up if a complication develops after returning home, and the opportunity cost of delaying treatment that works. Red flags worth naming explicitly include guaranteed cure claims, payment sought before a diagnosis is confirmed, no published protocol, no follow-up arrangements, and experimental treatment offered without verifiable regulatory approval or registered-trial oversight. On anti-doping, platelet-derived preparations are not prohibited, and non-transformed stem cells used alone for healing an injury are not prohibited where they return the functioning of the affected area to normal without enhancing it; however, cell and gene doping provisions prohibit the use of cells with the potential to enhance sport performance, and added growth factors, hormones or other prohibited substances may make a treatment prohibited, so the exact contents, processing and intended effect must be established and checked against the current World Anti-Doping Agency (WADA) Prohibited List. Where an athlete chooses to proceed despite advice, the professional response is to document the discussion, encourage participation in an authorised trial where one exists, and maintain the therapeutic relationship rather than withdraw from it.

• •Orthobiologics include platelet-rich plasma, bone marrow aspirate concentrate, adipose-derived preparations and culture-expanded cell therapies; marrow concentrate contains only a very small proportion of cells with mesenchymal stromal or progenitor properties, so calling it a stem cell treatment is misleading.
• •Distinguish mechanically processed adipose preparations, such as microfragmented adipose tissue, from enzymatically derived stromal vascular fraction; they are not interchangeable and may differ in regulatory status.
• •The evidence does not support routine use as a treatment class, and must be assessed for the exact preparation, indication and protocol.
• •Know the recurring methodological flaws: heterogeneous preparations, weak comparators without credible placebo control, inadequate blinding, uncontrolled rehabilitation co-interventions, variable outcomes, and conflicts of interest with selective publication.
• •Classification as an advanced therapy medicinal product turns on substantial manipulation or a different essential function, is product-specific, and should be confirmed with the medicines regulator when uncertain; autologous origin alone does not decide it.
• •Lawful routes are a marketing authorisation, an authorised clinical trial, or for unlicensed products the hospital exemption or specials route under an appropriate manufacturing licence.