Clinical trials in drug development - procedures and safety
The acute adverse reactions experienced by volunteers during the Phase 1 drug trial at Northwick Park, London, England, in 2006 attracted international media attention. How much do we know about the procedures involved in clinical trials and drug development and how safe are they? Professor Walter Nimmo provides an overview of this important area.
- A substantial public health benefit follows from the introduction and development of new therapies.
- New medicines are regulated in the UK by the Medicines and Healthcare Products Regulatory Agency (MHRA).
- Animal studies may predict human toxicity in up to 70% of cases for conventional small molecules.
- Unpredictable drug reactions are usually allergic reactions or affect the immune system.
- Following the adverse outcome of the Tegenero TGN1412 trial, specific ‘first in man’ clinical trial recommendations were developed to reduce future risks to volunteers.
Declaration of interests: WS Nimmo was formerly the CEO of Inveresk Research Group.
Drug development is a process in which new potential therapies are studied and brought to market to treat diseases. New drugs are developed almost exclusively by for-profit companies. Only companies have access to the capital required and investors with an appetite for the risks involved. The average cost of developing a drug in 2004 was more than $800 million (£410 million) and for every drug licensed successfully there are many that fail during the development process. In the long term this cost is unlikely to be sustainable because investors are no longer receiving an acceptable return on their investment. This is likely to reduce the number of new medicines becoming available. Already there is evidence that this is so.1
In spite of the criticism often directed towards drugs and drug companies there has been a substantial public health benefit from the introduction of new therapies. The rates of death from heart disease and stroke have been cut in half in the last 30 years, largely by the use of drugs that decrease arterial pressure and lipid concentrations. The development of effective drugs to treat HIV infection has transformed the disease.
In the United Kingdom the Medicines and Healthcare Products Regulatory Agency (MHRA) http://www.mhra.gov.uk is the government agency which is responsible for ensuring that medicines are effective and are acceptably safe. No product is risk free but the MHRA reviews evidence and opinions to ensure that the benefits to patients and the public justify the risks. After licensing, the MHRA keeps watch over the safety of medicines.
UK Medicines Regulation
Safety, quality and efficacy are the only criteria on which legislation to control human medicines is based. It is the responsibility of the MHRA and the expert advisory bodies set up by the Medicines Act to ensure that quality, safety and effectiveness are achieved. MHRA experts assess all applications for new medicines to ensure they meet the required standards. This is followed by a system of inspection and testing which continues throughout the lifetime of the medicine.
Clinical trials form a major part of the assessment of safety and efficacy in drug development and are subject to the approval of the MHRA also.
A clinical trial is an investigation in humans intended to discover the clinical pharmacology of a potential medicine, to identify any adverse reactions or to study the pharmacokinetics with the object of identifying the safety and/or the efficacy of the product. A clinical trial authorisation (CTA) issued by the MHRA is required for substances or combinations of substances which prevent or treat disease in humans or are administered to humans with a view to making a medical diagnosis. Clinical trials may be classified as follows:
- Phase 1 Studies often but not always in healthy volunteers to identify the tolerability of the drug for the first time in humans.
- Phase 2 Studies in patients to identify the dose response/efficacy.
- Phase 3 Larger studies in patients to confirm efficacy and safety.
- Phase 4 Post marketing authorisation studies in patients to identify extension to the product licence or to extend safety information.
The sponsor of the study (who is usually the drug company) in association with the principal investigator is responsible for obtaining the CTA and the positive opinion from a local ethics committee. He also is responsible for making arrangements for the conduct of the trial in accordance with the principles of good clinical practice as defined in the current standard.
In addition, the sponsor has the responsibility to report serious unexpected adverse reactions to the MHRA and relevant ethics committee within required time limits. Lastly, the sponsor is required to allow inspection of any trial premises by the MHRA inspectors.
Content of the CTA
The sponsor and the principal investigator should include the protocol in the application for the CTA. This protocol must define exactly the aim and conduct of the study. The investigational medicine or product dossier must give information on the quality of any product to be used in the clinical trial including reference products and placebos. This must include summaries of chemical, pharmaceutical and biological data with certificates of analysis.
The sponsor must provide summaries of non-clinical pharmacology and toxicology data, a reference list of studies conducted and a statement that copies of the references will be made available on request. The non-clinical information which should be available is shown in Table 1.
Within the CTA there must be a section devoted to the overall risk and benefit assessment. This must include the principal hazards of a new medicinal product based on available data and an indication of what might occur in humans. Where appropriate, safety margins and rationale for the dose selected must be defined.
The aim of pre-clinical safety evaluation is to identify potential toxic events as well as the organs or systems most sensitive to the effects of the drug. The relationship to dose and the potential reversibility of effects are also important. The information generated will normally give guidance on the selection of a safe starting dose for the first administration to man study and will highlight the safety monitoring which is required.
In general, pre-clinical animal studies predict human toxicity in approximately 70% of cases. The best predictability is for gastrointestinal, cardiovascular and haematological toxicity.2 Human toxicity with the poorest correlation with animal studies include hepatotoxicity and for drugs affecting the immune system.
Adverse Reactions during Phase I Clinical Trials3
Phase I trials in human volunteers have been very safe. Some 15 deaths have been reported during the last 30 years, although probably 100,000 healthy subjects are dosed each year. Of these 15 deaths, only 3 could not have been avoided if modern screening and rules had been used.
Adverse drug reactions seen in studies fall into two categories ie. predicted from animal studies and unpredictable. The predictable adverse events usually result from an extension of the normal pharmacological activity of the drug. The unpredictable reactions are much rarer and not related to the pharmacological effects of the drug. They often affect the immune system or result from drug allergy. In studies from Phase I clinics the instance of adverse event reporting in healthy volunteer studies is 34% to 39% with an almost identical incidence after placebo or active drug. Almost all adverse events are mild and self limiting. In particular, headache and somnolence are recorded commonly. These are probably not predictable from animal studies.
It is likely that screening of the volunteers to ensure that they are healthy, drug free and have no relevant medical history has made Phase I studies very safe. In particular, single dose studies have a very good safety record.
Lessons to be Learned from the TGN1412 Phase I Trial in March 20064
Eight young men participated in a study at a London hospital of Tegenero’s TGN1412 - a monoclonal antibody. The drug was given intravenously. Six received active drug and two received placebo. All six volunteers who received active drug developed a cytokine release syndrome. Within 12 to 16 hours all became critically ill and required intensive therapy. All six survived but some have sequelae which may be important in the future.
This trial caused the UK government to establish an independent expert scientific group to learn from this clinical trial and make recommendations. . The group made recommendations about ‘first-in-man’ clinical trials of biological molecules with a novel mechanism of action, new agents with a species specific action and new drugs directed towards immune system targets as well as providing general advice on future authorisation of such trials. The group made 22 recommendations including pre-clinical review, collection and sharing of data, selection of initial dose, trial design (including sequential dosing rather than dosing in parallel), the use of volunteers and the clinical environment for first-in-man studies. The recommendations were offered to the UK authorities and sponsors in November 2006. It is hoped they will be taken up internationally.
Phase I clinical trials are safe but the recent experience highlights that continued vigilance is necessary if the safety is to be maintained. For several reasons it is likely that drug development will change in the future. However, there will still be a time when a drug requires to be given for the first time to a human being. It is likely that the predictability of animal studies will not improve in the future.
More careful attention to the dosage selected, the rate of delivery and whether or not the drug should be given to several volunteers at the same time is likely to influence drug development in future.
- Wood AJJ. A proposal for radical changes in the drug-approval process. New Eng J Med 2006; 355:618-623.
- Olson H, Betton G, Robinson D et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regulatory Toxicology and Pharmacology 2000; 32:56-67.
- Sibille M, Donazzolo Y, Lecoz F, Krupka E. After the London tragedy, is it still possible to consider Phase I is safe. Br J Clin Pharmacol 2006; 62:502-503.
- Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a Phase I trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355:1018-1028.