The long-term nature of clinical trials means that engaging a contract research organisation (CRO) is the start of a close relationship that must weather any difficulties that arise. Throw in the critical importance and high value of any clinical trial for the sponsor and this puts a great deal of pressure on the process of selecting the right partner.

As with any important business decision, there are many different parameters to consider when choosing a CRO, the blend of which will vary according to the specifics of an individual study.

"With CRO selection, there are many things to look for and evaluate, but it always depends on the nature of the trial you are conducting," says Dr Estrella Garcia, head of global clinical operations at international pharmaceutical company Almirall. "We have a fully outsourced model, so it is essential that we choose the right CRO. We look for expertise in a particular area that is relevant to each study, and we look for how much access the CRO has to investigators in that area. If we are looking at a multinational phase III trial, then we also need the CRO to have a global presence.

"Of course, we also care a lot about the CRO having very good processes and technology, and we look carefully at all of their technologies and quality control systems. Their track record is also important," she adds.

Headquartered in Barcelona, Spain, Almirall is firmly founded on the concept of constant innovation. Its core activities are the research, development, production and marketing of medicines based on proprietary R&D. The key therapeutic areas on which it focuses are asthma, chronic obstructive pulmonary disease (COPD), gastrointestinal disorders, psoriasis and other dermatological conditions.

"Although no one can be certain what the outcome of a clinical trial will be, there is a need to factor in as much predictability as possible. This applies to the issue of cost just as much as it applies to matters of quality."

So far, Almirall has marketed medicines in over 70 countries, and it has bases of operation across Europe and Latin America. Its fully outsourced model for clinical trials goes hand in hand with its sizable internal investment in R&D, and it has numerous products in clinical trials phase (see ‘Almirall’s product development pipeline’).

"With our model, the risk if we don’t choose the right partner would be complete disruption of the trial," says Garcia. "So, we look at what a CRO has done in the past. We also have to look closely at the current compromises, ensuring that a CRO is not handling competing trials for other sponsors and it has enough capacity available to handle the needs of our trial.

"Another key factor is financial stability. Trials last for a number of years, so we need to make sure we choose a partner that will be around for the duration. Our purchasing department goes through all the public records and databases to make an assessment of financial stability, and we do audits before we start the process of contracting."

Keep a close eye on your partner

For Garcia, a successful CRO relationship is based on setting clear parameters for performance at the very start. After that, it is a matter of constant assessment to ensure the CRO is sticking to those parameters and consistently moving towards the deliverables that have been agreed by both parties.

"If we got the wrong CRO, then it would be a nightmare, but usually any challenges that arise are small ones," she says. "Sometimes, there is an issue with recruiting the right people or the right investigators, for instance, but those challenges can usually be overcome without too much difficulty.

"Once a contract is under way, we monitor the CRO very closely. We always set very clear contract milestones that the CRO must reach if it wants to get paid, so it is also very important for the CRO to have contingency plans in place to deliver on the quality that we expect if any problems arise. It is essential to clarify right from the beginning of a relationship what you expect from the CRO."

"You have to understand how the CRO works. You don’t have to be in a hurry. You cannot afford to be too impatient."

In defining the CRO relationship, too much haste can be the biggest problem. Garcia firmly believes that both parties should take the time to get the basics right. After all, something worth doing is worth doing well.

"At the RFP stage, everyone is in a hurry, but after signing an agreement you must be very thorough and do an in-depth analysis of all of the processes used in the trials," she explains. "You have to clarify the quality of the deliverables because that is what counts. The CRO can use its own standard operating procedures, but the sponsor has to lead the way in setting the parameters for the trial."

Although no one can be certain what the outcome of a clinical trial will be, there is a need to factor in as much predictability as possible. This applies to the issue of cost just as much as it applies to matters of quality.

"It is very important to know the exact cost forecast for the study, which could last up to three years," stresses Garcia. "Almirall is listed on the stock market in Spain, which means we have to report figures regularly. We have to be very specific, therefore, about factors such as professional fees and investigator fees. CROs must deliver on time because we agree payments on the basis of deliverables.

"What we have done is make a contract model that fixes professional fees and investigator fees. It is also important to understand at the very start what the geographical distribution of investigators is, as that helps us to get an understanding of what the costs will be."

Learning from experience

For a company like Almirall, the process of partnering with a CRO does not start from scratch with each new clinical study. Having taken the time to get to know a group of CROs and how they work, it would not make sense to ignore that knowledge and go back to square one every time. Instead, experience leads a sponsor to identify a group of reliable and capable partners.

"We have a list of preferred providers and it is rare that we go to a CRO we don’t know at all," Garcia notes. "We can, however, draw on the experience of other companies in particular therapeutic areas if we need to look beyond this list."

Almirall may not have always used the fully outsourced approach, but it was able to make the choice to move to such a model because it had built up its experience with CROs over many years. Through the lessons it learned, it gained the insight and confidence to adopt a new model
with clear parameters.

"We have not been using our current model for very long because full outsourcing is relatively new to us," says Garcia. "Previously, we did functional outsourcing for processes such as data management, but this was almost exclusively for early stage trials. Full outsourcing only came about in 2006.

"Now, we always use a maximum cost model, so there is a price that cannot be exceeded unless, of course, we change the parameters of the study."

Garcia is certainly well versed in the process of engaging a CRO, and her insight covers every aspect of the relationship and the factors that bring success to the outsourcing model. At the most basic level, however, her advice is simple.

"The most important thing is to clarify the scope of what you are outsourcing and spend time at the beginning of the contract process to build a strategy for the study with the CRO," she says. "You have to understand how the CRO works. You don’t have to be in a hurry. You cannot afford to be too impatient."

 

Almirall’s product development pipeline

Preclinical stage
LAS189913: sphingosine-1-phosphate receptor 1 (S1P1) agonist for the oral treatment of multiple sclerosis, which aims to reduce the undesirable side effects of other S1P1 agonists through an improved pharmacokinetic and safety profile. With the treatment currently in preclinical development, Almirall is exploring partnership options.

Phase I

  • LAS190792: dual long-acting muscarinic antagonist ß2 agonist (MABA), which combines two bronchodilator mechanisms in a single molecule for the treatment of COPD.
  • LAS186323: DHODH inhibitor for the oral treatment of rheumatoid arthritis that aims at reducing the undesirable side effects of the DHODH inhibitor commercially available at present. Almirall is exploring partnership options to develop the treatment.

Phase II

  • LAS100977: long-acting beta agonist inhaled bronchodilator for the treatment of asthma and COPD. Results obtained in asthmatic patients showed that LAS100977 is a potent bronchodilator, with a duration of action compatible with daily dosing.
  • LAS41004: the goal is to confirm its anti-inflammatory activity and its capacity to inhibit cellular proliferation through topical administration for the treatment of psoriasis and/or atopic dermatitis.

Phase III

  • Sativex: in essence a combination of two cannabinoids – tetrahydrocannabinol (THC) and cannabidiol (CBD) – this is formulated as an oromucosal spray, which is administered by spraying into the mouth. Each spray of Sativex delivers a fixed dose of 2.7mg THC and 2.5mg CBD.
  • LAS41008: a treatment for psoriasis.

Approved by the FDA and EMA

  • Aclidinium bromide monotherapy: anticholinergic bronchodilator, selective M3 muscarinic antagonist for the treatment of COPD currently in phase III clinical development. Aclidinium bromide is a long-acting drug with a very clean safety profile, and administered by inhalation through a user-friendly multidose inhaler device, which is also proprietary to Almirall.

Undergoing registration application for the EU

  • Combination of aclidinium bromide with the long-acting beta agonist formoterol (LAS40464): treatment with one or more long-acting bronchodilators is recommended by the international guidelines for treatment of COPD. This combination is aimed at providing higher efficacy than each component alone, as well as the improved convenience of having the two products in the same easy-to-use inhalation device.
  • LAS41002: topical anti-inflammatory agent for the treatment of eczema, which is in clinical phase III in comparison studies with Ecural. LAS41002 acts on a corticosteroid receptor and its different formulations will allow treatment of different skin conditions.
  • Linaclotide: this is a first-in-class medicine for the treatment of irritable bowel syndrome with constipation (IBS-C). It is a once daily, orally delivered peptide that acts locally in the gut with no detectable systemic exposure at therapeutic doses. Linaclotide is an agonist of guanylate cyclase type-C, a receptor found on the lining of the intestine.